basic principal of nir.pdf
TRANSCRIPT
wwwelseviercomlocateaddr
Advanced Drug Delivery Revi
Near-infrared spectroscopy and imaging Basic principles
and pharmaceutical applications
Gabriele ReichT
Institute for Pharmacy and Molecular Biotechnology Department of Pharmaceutical Technology and Pharmacology
University of Heidelberg Im Neuenheimer Feld 366 D-69120 Heidelberg Germany
Received 17 December 2003 accepted 19 January 2005
Abstract
Near-infrared (NIR) spectroscopy and imaging are fast and nondestructive analytical techniques that provide chemical and
physical information of virtually any matrix In combination with multivariate data analysis these two methods open many
interesting perspectives for both qualitative and quantitative analysis This review focuses on recent pharmaceutical NIR
applications and covers (1) basic principles of NIR techniques including chemometric data processing (2) regulatory issues (3)
raw material identification and qualification (4) direct analysis of intact solid dosage forms and (5) process monitoring and
process control
D 2005 Elsevier BV All rights reserved
Keywords Noninvasive qualitative and quantitative analysis Calibration and validation Chemometrics Raw material identification and
characterization Quality control of intact dosage forms Process analytical technologies (PAT) Process monitoring
Contents
1 Introduction 1110
2 Basic principles of near-infrared (NIR) spectroscopy 1111
21 Origin and characteristics of NIR absorption bands 1111
22 Instrumentation and sample presentation 1112
3 Theory and practice of chemometric data processing 1113
31 Data pretreatments 1113
32 Reduction of variables by principal component analysis (PCA) 1114
33 Multivariate calibration for quantitative analysis 1115
34 Multivariate classification for qualitative analysis 1115
0169-409X$ - s
doi101016jad
T Tel +49 62
E-mail addr
ews 57 (2005) 1109ndash1143
ee front matter D 2005 Elsevier BV All rights reserved
dr200501020
21 548335 fax +49 6221 545971
ess gabrielereichurzuni-heidelbergde
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431110
4 Regulatory aspects 1116
41 Actual status of pharmaceutical NIR analysis 1116
42 NIR spectroscopy in view of the USFDA initiative on PAT 1117
5 Pharmaceutical applications 1117
51 Identification and qualification of raw materials and intermediates 1118
511 Library approach 1118
512 Conformity approach 1119
513 Quantitative calibration models 1119
52 Analysis of intact dosage forms 1121
521 Tablets 1121
522 Capsules 1124
523 Lyophilized products 1126
524 Polymeric implants and microspheres 1126
53 Process monitoring and process control 1127
531 Powder blending 1128
532 Drying 1129
533 Granulation 1130
534 Pelletization 1131
535 Tabletting and capsule-filling 1131
536 Film coating 1132
537 Packaging 1133
6 NIR imaging 1133
61 Basic principles and instrumentation 1133
62 Analytical targets and strengths 1134
63 Pharmaceutical applications 1134
7 Concluding Remarks 1136
References 1137
1 Introduction
Near-infrared spectroscopy (NIRS) is a fast and
nondestructive technique that provides multi-constit-
uent analysis of virtually any matrix It covers the
wavelength range adjacent to the mid infrared and
extends up to the visible region Historically the
discovery of the NIR region in 1800 is ascribed to
Herschel who separated the electromagnetic spectrum
with a prism and found out that the temperature
increased markedly towards and beyond the red ie in
the region that is now called the near-infrared
Although a number of NIR experiments were carried
out in the early 1920s it was not before the mid to late
1960s that NIR spectroscopy was practically used It
was Karl Norris from the US Department of
Agriculture who recognized the potential of this
analytical technique and introduced bmodern NIRSQinto industrial practice [1] From then on the break-
through of the method as an industrial quality- and
process-control tool proceeded in jumps coinciding
with the introduction of efficient chemometric data
processing techniques and the development of novel
spectrometer configurations based on fiber optic
probes
In recent years NIR spectroscopy has gained wide
acceptance within the pharmaceutical industry for raw
material testing product quality control and process
monitoring The growing pharmaceutical interest in
NIR spectroscopy is probably a direct result of its
major advantages over other analytical techniques
namely an easy sample preparation without any
pretreatments the possibility of separating the sample
measurement position and spectrometer by use of
fiber optic probes and the prediction of chemical and
physical sample parameters from one single spectrum
This paper is dedicated to pharmaceutical applica-
tions of NIR spectroscopy To fully appreciate the
analytical versatility of this spectroscopic technique a
short introduction into the principles of the method is
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1111
helpful To this end the author provides the reader
with a short introduction into the theoretical funda-
mentals of the technique (Section 21) the equipment
it uses (Section 22) and the mathematical and
statistical tools that are needed to process recorded
signals and extract the relevant information for
qualitative or quantitative analysis (Section 3) Sec-
tion 4 focuses on regulatory aspects that are critical
for pharmaceutical NIR analyses Important current
and possible future pharmaceutical applications of
NIR spectroscopy including raw material identifica-
tion and characterization analysis of intact dosage
forms and process monitoring are discussed in
Section 5 Section 6 briefly emphasizes the pharma-
ceutical potential of NIR imaging techniques
2 Basic principles of near-infrared (NIR)
spectroscopy
21 Origin and characteristics of NIR absorption
bands
The American Society of Testing and Materials
(ASTM) defines the NIR region of the electro-
magnetic spectrum as the wavelength range of 780ndash
2526 nm corresponding to the wave number range
12820ndash3959 cm1 The most prominent absorption
bands occurring in the NIR region are related to
overtones and combinations of fundamental vibra-
tions of ndashCH ndashNH ndashOH (and ndashSH) functional
groups The key issues which determine the occur-
rence and spectral properties ie frequency and
intensity of NIR absorption bands are anharmonicity
and Fermi resonance the physical basis of which will
be briefly described in this section For a more
comprehensive treatise the reader is referred to some
excellent textbook chapters on the subject matter [23]
Since the energy curve of an oscillating molecule is
affected by intramolecular interactions vibrations
around the equilibrium position are non-symmetric
and the spacings between energy levels that the
molecule can attain are not identical but rather
decrease with increasing energy This situation
resembles the quantum mechanical model of an
anharmonic oscillator Since quantum mechanical
selection rules do not rigorously exclude transitions
with Dt N1 for anharmonic systems transitions
between vibrational states of Dt =2 or 3 are possible
although their probability decreases with an increase
in the vibrational quantum number t These multi-
level energy transitions are the origin of NIR overtone
bands that occur at multiples of the fundamental
vibrational frequency For most chemical bonds the
wave numbers of overtones can be estimated from
their fundamental vibrations with an anharmonicity
constant v of 001ndash005 by the following equation
mx frac14 Dy m0 1 Dyveth THORN eth1THORN
where mx =wave number of x overtone m0=wavenumber of fundamental vibration v =anharmonicity
constant
Combination bands appearing between 1900 nm
and 2500 nm are the result of vibrational interactions
ie their frequencies are the sums of multiples of each
interacting frequency A special type of configuration
interaction called Fermi resonance leads to the
feature that two NIR absorption bands of a polyatomic
molecule with the same frequency do not simply
overlay and sum up but split in two peaks of
somewhat higher and lower frequencies than the
expected unperturbed position Furthermore intermo-
lecular hydrogen bondings and dipole interactions
have to be considered since they alter vibrational
energy states thus shifting existing absorption bands
andor giving rise to new ones This effect allows
crystal forms for instance to be determined by NIR
spectroscopy
In conclusion NIR absorption bands are typically
broad overlapping and 10ndash100 times weaker than
their corresponding fundamental mid-IR absorption
bands These characteristics severely restrict sensitiv-
ity in the classical spectroscopic sense and call for
chemometric data processing to relate spectral infor-
mation to sample properties (see Section 3) The low
absorption coefficient however permits high pene-
tration depth and thus an adjustment of sample
thickness This aspect is actually an analytical
advantage since it allows direct analysis of strongly
absorbing and even highly scattering samples such as
turbid liquids or solids in either transmittance or
reflectance mode without further pretreatments
The dual dependence of the analytical signal on the
chemical and physical properties of the sample
resulting from absorption and scatter effects can be
favorably used to perform chemical and physical
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431112
analysis from one single measurement However if
not the analytical target scatter effects in NIR spectra
resulting from physical sample variations may also
pose more or less severe analytical problems In these
situations they have to be considered in the calibra-
tion process as dinterfering parametersT as will be
discussed in Section 3 More detailed information on
the theory of absorption and scatter effects in diffuse
reflectance and transmittance NIR spectroscopy can
be found elsewhere [45]
22 Instrumentation and sample presentation
A NIR spectrometer is generally composed of a
light source a monochromator a sample holder or a
sample presentation interface and a detector allowing
for transmittance or reflectance measurements (Fig 1)
The light source is usually a tungsten halogen
lamp since it is small and rugged [6] Detector types
include silicon lead sulfide (PbS) and indium gallium
arsenide (InGaAs) [6] Silicon detectors are fast low-
noise small and highly sensitive from the visible
region to 1100 nm PbS detectors are slower but very
popular since they are sensitive from 1100 to 2500 nm
and provide good signal-to-noise properties The most
expensive InGaAs detector combines the speed and
size characteristics of the silicon detector with the
wavelength range of the PbS detector
A number of optical configurations exist that can
be used to separate the polychromatic NIR spectral
region into dmonochromaticT frequencies A detailed
description of the different principles can be found in
various textbooks [7ndash9] Here the basic principles and
main differences will be shortly discussed from a
practical point of view Broadband discrete filter
Light Source Monochromator
DetDiffuse R
Fig 1 Basic NIR spectrom
photometers or light-emitting diode (LED)-based
instruments provide selected frequencies thus cover-
ing only a narrow spectral range of 50ndash100 nm
Diffraction grating interferometer diode-array or
acousto-optic tunable filter (AOTF)-based instruments
provide full spectral coverage Selection of the
appropriate technology is usually based upon the
required analyte sensitivity reliability ease of use
calibration transferability and implementation needs
The latter aspect requires laboratory and process
analyzers to be differentiated
Laboratory analyzers are intended for off-line or
at-line measurements in quality control research and
plant laboratories ie high analyte sensitivity and
reliability are required while speed is of lower
importance Optimum sample presentation to the
instrument high signal-to-noise ratio instrument
stability and sufficient resolution are the most
important aspects for analysis Presently grating and
interferometer-based instruments are mainly in use for
this purpose The appropriate NIR measuring mode
will be dictated by the optical properties of the
samples (Fig 2) Transparent materials are usually
measured in transmittance (Fig 2A) Turbid liquids or
semi-solids and solids may be measured in diffuse
transmittance (Fig 2B) diffuse reflectance (Fig 2C)
or transflectance (Figs 2DE) depending on their
absorption and scattering characteristics In any case
absorbance (A) values relative to a standard reference
material are measured with A corresponding to log 1
R and log 1T for reflectance and transmittance
spectra respectively
To measure good NIR spectra the proper sample
presentation is of utmost importance especially when
measuring solid samples since scatter effects and
ectoreflectance
DetectorTransmittance
Sample
eter configurations
Transmittance
DiffuseReflectance
Transflectance
(A)
(B)
(C)
(D)
(E)
Fig 2 NIR measuring modesmdash(AB) transmittance (C) diffuse
reflectance and (DE) transflectance
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1113
stray light induced by variations in packing density of
powders or sample positioning of tablets or capsules
may cause large sources of error in the spectra [10]
Therefore several types of sample cells such as
quartz cuvettes with defined optical path length for
liquids specifically designed sample cells with quartz
windows for semi-solids and powders and adjusted
sample holders for tablets and capsules have been
developed [11] Temperature control and sample
movement are other options that have been realized
Process analyzers are intended for in-line or on-
line measurements to provide real-time process
information while operating in harsh conditions This
requires fast and rugged instruments with no moving
parts such as AOTF-based instruments allowing for
numerous readings per second without being sensitive
to vibrations AOTF-based instruments choose wave-
lengths by using radio-frequency signals to alter the
refractive index of a birefringent crystal (usually
TeO2) Wavelength scans can thus be performed
much more rapidly than with other configurations
Since process analyzers are dedicated to performing a
particular analysis on a specific sample type the
process sample interface depends on the sample type
and the process conditions with NIR light being
transferred via fiber optics In-line analysis of clear to
opaque liquids and solids is typically carried out by
contact transmission and reflectance probes while
non-contact reflectance measurements are performed
on materials transported in hoppers or conveyor belts
3 Theory and practice of chemometric data
processing
Since NIR spectra are typically composed of broad
overlapping and thus ill-defined absorption bands
containing chemical and physical information of all
sample components the analytical information is
multivariate in nature and therefore hardly selective
To perform qualitative or quantitative NIR analysis
ie to relate spectral variables to properties of the
analyte mathematical and statistical methods (ie
chemometrics) are required that extract brelevantQinformation and reduce birrelevantQ information ie
interfering parameters
In the following sections the most frequently used
mathematical data pretreatments and their specific
purpose (Section 31) reduction of variables with
principal component analysis (Section 32) multi-
variate calibration methods for quantitative analysis
(Section 33) and multivariate classification techni-
ques for qualitative analysis (Section 34) will be
discussed Different methods for calibration transfer
between instruments an important economic and
regulatory issue for qualitative and quantitative
pharmaceutical NIR analysis have recently been
commented on by Blanco et al [12] and will thus
not be considered here in detail
31 Data pretreatments
Interfering spectral parameters such as light
scattering path length variations and random noise
resulting from variable physical sample properties or
instrumental effects call for mathematical corrections
so-called data pretreatments prior to multivariate
modeling in order to reduce eliminate or standardize
their impact on the spectra Since careful selection of
data pretreatments can significantly improve the
robustness of a calibration model the most commonly
used methods are briefly discussed with respect to the
effect they are able to correct A detailed description
of the techniques can be found elsewhere [13]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431114
Mathematical treatments used to compensate for
scatter-induced baseline offsets include multiplica-
tive scatter correction (MSC) and standard normal
variate (SNV) Both methods have originally been
developed to process reflectance spectra but they
are also applied to transmittance spectra Baseline
shifts and intensity differences resulting from vari-
able positioning or path length variations may be
reduced or eliminated by normalization algorithms
Derivatives can be applied to improve the resolution
of overlapping bands In addition they are able to
reduce baseline offsets Since spectral noise is also
amplified by derivation derivatives are usually
combined with Taylor or Savitzky Golay smoothing
algorithms
32 Reduction of variables by principal component
analysis (PCA)
Since multivariate NIR spectral data contain a huge
number of correlated variables (= collinearity) there is
a need for reduction of variables ie to describe data
variability by a few uncorrelated variables containing
the relevant information for calibration modeling The
best known and most widely used variable-reduction
Inte
nsity
λ1 λ2 λ3
λ1
λ2
λ3
λ2
λ3 F3
Fig 3 Transformation of a spectrum with three variables ie wavelength
thereby converting the spectrum to a single point in a three-dimensional s
and determination of principal components F1 F2 and F3 (e)
method is principal component analysis (PCA) PCA
is a mathematical procedure that resolves the spectral
data into orthogonal components whose linear combi-
nations approximate the original data The new
variables called principal components (PC) eigen-
vectors or factors correspond to the largest eigenval-
ues of the covariance matrix thus accounting for the
largest possible variance in the data set The first PC
represents maximum variance amongst all linear
combinations and each successive variable accounts
for as much of the remaining variability as possible
The transformation procedure is visualized schemati-
cally in Fig 3 on the basis of three original variables
ie three wavelengths per spectrum For real spectra
with p wavelengths the transformation leads to a p-
dimensional space
In pharmaceutical NIR analysis it is often possible
to compress most of the spectral variability to only a
few principal components ie factors with only a
rather small loss of information A number of multi-
variate calibration and classification methods there-
fore rely on PCA data (see Sections 33 and 34) For
further details on PCA interested readers are referred
to the excellent and comprehensive treatise of Howard
Mark [14]
λ1
λ2
λ3
λ1
F1F2
F2F3
F1
s (a) to a new coordinate system with one axis for each wavelength
pace (b) cloud formation of several spectra (c) mean centering (d)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431110
4 Regulatory aspects 1116
41 Actual status of pharmaceutical NIR analysis 1116
42 NIR spectroscopy in view of the USFDA initiative on PAT 1117
5 Pharmaceutical applications 1117
51 Identification and qualification of raw materials and intermediates 1118
511 Library approach 1118
512 Conformity approach 1119
513 Quantitative calibration models 1119
52 Analysis of intact dosage forms 1121
521 Tablets 1121
522 Capsules 1124
523 Lyophilized products 1126
524 Polymeric implants and microspheres 1126
53 Process monitoring and process control 1127
531 Powder blending 1128
532 Drying 1129
533 Granulation 1130
534 Pelletization 1131
535 Tabletting and capsule-filling 1131
536 Film coating 1132
537 Packaging 1133
6 NIR imaging 1133
61 Basic principles and instrumentation 1133
62 Analytical targets and strengths 1134
63 Pharmaceutical applications 1134
7 Concluding Remarks 1136
References 1137
1 Introduction
Near-infrared spectroscopy (NIRS) is a fast and
nondestructive technique that provides multi-constit-
uent analysis of virtually any matrix It covers the
wavelength range adjacent to the mid infrared and
extends up to the visible region Historically the
discovery of the NIR region in 1800 is ascribed to
Herschel who separated the electromagnetic spectrum
with a prism and found out that the temperature
increased markedly towards and beyond the red ie in
the region that is now called the near-infrared
Although a number of NIR experiments were carried
out in the early 1920s it was not before the mid to late
1960s that NIR spectroscopy was practically used It
was Karl Norris from the US Department of
Agriculture who recognized the potential of this
analytical technique and introduced bmodern NIRSQinto industrial practice [1] From then on the break-
through of the method as an industrial quality- and
process-control tool proceeded in jumps coinciding
with the introduction of efficient chemometric data
processing techniques and the development of novel
spectrometer configurations based on fiber optic
probes
In recent years NIR spectroscopy has gained wide
acceptance within the pharmaceutical industry for raw
material testing product quality control and process
monitoring The growing pharmaceutical interest in
NIR spectroscopy is probably a direct result of its
major advantages over other analytical techniques
namely an easy sample preparation without any
pretreatments the possibility of separating the sample
measurement position and spectrometer by use of
fiber optic probes and the prediction of chemical and
physical sample parameters from one single spectrum
This paper is dedicated to pharmaceutical applica-
tions of NIR spectroscopy To fully appreciate the
analytical versatility of this spectroscopic technique a
short introduction into the principles of the method is
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1111
helpful To this end the author provides the reader
with a short introduction into the theoretical funda-
mentals of the technique (Section 21) the equipment
it uses (Section 22) and the mathematical and
statistical tools that are needed to process recorded
signals and extract the relevant information for
qualitative or quantitative analysis (Section 3) Sec-
tion 4 focuses on regulatory aspects that are critical
for pharmaceutical NIR analyses Important current
and possible future pharmaceutical applications of
NIR spectroscopy including raw material identifica-
tion and characterization analysis of intact dosage
forms and process monitoring are discussed in
Section 5 Section 6 briefly emphasizes the pharma-
ceutical potential of NIR imaging techniques
2 Basic principles of near-infrared (NIR)
spectroscopy
21 Origin and characteristics of NIR absorption
bands
The American Society of Testing and Materials
(ASTM) defines the NIR region of the electro-
magnetic spectrum as the wavelength range of 780ndash
2526 nm corresponding to the wave number range
12820ndash3959 cm1 The most prominent absorption
bands occurring in the NIR region are related to
overtones and combinations of fundamental vibra-
tions of ndashCH ndashNH ndashOH (and ndashSH) functional
groups The key issues which determine the occur-
rence and spectral properties ie frequency and
intensity of NIR absorption bands are anharmonicity
and Fermi resonance the physical basis of which will
be briefly described in this section For a more
comprehensive treatise the reader is referred to some
excellent textbook chapters on the subject matter [23]
Since the energy curve of an oscillating molecule is
affected by intramolecular interactions vibrations
around the equilibrium position are non-symmetric
and the spacings between energy levels that the
molecule can attain are not identical but rather
decrease with increasing energy This situation
resembles the quantum mechanical model of an
anharmonic oscillator Since quantum mechanical
selection rules do not rigorously exclude transitions
with Dt N1 for anharmonic systems transitions
between vibrational states of Dt =2 or 3 are possible
although their probability decreases with an increase
in the vibrational quantum number t These multi-
level energy transitions are the origin of NIR overtone
bands that occur at multiples of the fundamental
vibrational frequency For most chemical bonds the
wave numbers of overtones can be estimated from
their fundamental vibrations with an anharmonicity
constant v of 001ndash005 by the following equation
mx frac14 Dy m0 1 Dyveth THORN eth1THORN
where mx =wave number of x overtone m0=wavenumber of fundamental vibration v =anharmonicity
constant
Combination bands appearing between 1900 nm
and 2500 nm are the result of vibrational interactions
ie their frequencies are the sums of multiples of each
interacting frequency A special type of configuration
interaction called Fermi resonance leads to the
feature that two NIR absorption bands of a polyatomic
molecule with the same frequency do not simply
overlay and sum up but split in two peaks of
somewhat higher and lower frequencies than the
expected unperturbed position Furthermore intermo-
lecular hydrogen bondings and dipole interactions
have to be considered since they alter vibrational
energy states thus shifting existing absorption bands
andor giving rise to new ones This effect allows
crystal forms for instance to be determined by NIR
spectroscopy
In conclusion NIR absorption bands are typically
broad overlapping and 10ndash100 times weaker than
their corresponding fundamental mid-IR absorption
bands These characteristics severely restrict sensitiv-
ity in the classical spectroscopic sense and call for
chemometric data processing to relate spectral infor-
mation to sample properties (see Section 3) The low
absorption coefficient however permits high pene-
tration depth and thus an adjustment of sample
thickness This aspect is actually an analytical
advantage since it allows direct analysis of strongly
absorbing and even highly scattering samples such as
turbid liquids or solids in either transmittance or
reflectance mode without further pretreatments
The dual dependence of the analytical signal on the
chemical and physical properties of the sample
resulting from absorption and scatter effects can be
favorably used to perform chemical and physical
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431112
analysis from one single measurement However if
not the analytical target scatter effects in NIR spectra
resulting from physical sample variations may also
pose more or less severe analytical problems In these
situations they have to be considered in the calibra-
tion process as dinterfering parametersT as will be
discussed in Section 3 More detailed information on
the theory of absorption and scatter effects in diffuse
reflectance and transmittance NIR spectroscopy can
be found elsewhere [45]
22 Instrumentation and sample presentation
A NIR spectrometer is generally composed of a
light source a monochromator a sample holder or a
sample presentation interface and a detector allowing
for transmittance or reflectance measurements (Fig 1)
The light source is usually a tungsten halogen
lamp since it is small and rugged [6] Detector types
include silicon lead sulfide (PbS) and indium gallium
arsenide (InGaAs) [6] Silicon detectors are fast low-
noise small and highly sensitive from the visible
region to 1100 nm PbS detectors are slower but very
popular since they are sensitive from 1100 to 2500 nm
and provide good signal-to-noise properties The most
expensive InGaAs detector combines the speed and
size characteristics of the silicon detector with the
wavelength range of the PbS detector
A number of optical configurations exist that can
be used to separate the polychromatic NIR spectral
region into dmonochromaticT frequencies A detailed
description of the different principles can be found in
various textbooks [7ndash9] Here the basic principles and
main differences will be shortly discussed from a
practical point of view Broadband discrete filter
Light Source Monochromator
DetDiffuse R
Fig 1 Basic NIR spectrom
photometers or light-emitting diode (LED)-based
instruments provide selected frequencies thus cover-
ing only a narrow spectral range of 50ndash100 nm
Diffraction grating interferometer diode-array or
acousto-optic tunable filter (AOTF)-based instruments
provide full spectral coverage Selection of the
appropriate technology is usually based upon the
required analyte sensitivity reliability ease of use
calibration transferability and implementation needs
The latter aspect requires laboratory and process
analyzers to be differentiated
Laboratory analyzers are intended for off-line or
at-line measurements in quality control research and
plant laboratories ie high analyte sensitivity and
reliability are required while speed is of lower
importance Optimum sample presentation to the
instrument high signal-to-noise ratio instrument
stability and sufficient resolution are the most
important aspects for analysis Presently grating and
interferometer-based instruments are mainly in use for
this purpose The appropriate NIR measuring mode
will be dictated by the optical properties of the
samples (Fig 2) Transparent materials are usually
measured in transmittance (Fig 2A) Turbid liquids or
semi-solids and solids may be measured in diffuse
transmittance (Fig 2B) diffuse reflectance (Fig 2C)
or transflectance (Figs 2DE) depending on their
absorption and scattering characteristics In any case
absorbance (A) values relative to a standard reference
material are measured with A corresponding to log 1
R and log 1T for reflectance and transmittance
spectra respectively
To measure good NIR spectra the proper sample
presentation is of utmost importance especially when
measuring solid samples since scatter effects and
ectoreflectance
DetectorTransmittance
Sample
eter configurations
Transmittance
DiffuseReflectance
Transflectance
(A)
(B)
(C)
(D)
(E)
Fig 2 NIR measuring modesmdash(AB) transmittance (C) diffuse
reflectance and (DE) transflectance
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1113
stray light induced by variations in packing density of
powders or sample positioning of tablets or capsules
may cause large sources of error in the spectra [10]
Therefore several types of sample cells such as
quartz cuvettes with defined optical path length for
liquids specifically designed sample cells with quartz
windows for semi-solids and powders and adjusted
sample holders for tablets and capsules have been
developed [11] Temperature control and sample
movement are other options that have been realized
Process analyzers are intended for in-line or on-
line measurements to provide real-time process
information while operating in harsh conditions This
requires fast and rugged instruments with no moving
parts such as AOTF-based instruments allowing for
numerous readings per second without being sensitive
to vibrations AOTF-based instruments choose wave-
lengths by using radio-frequency signals to alter the
refractive index of a birefringent crystal (usually
TeO2) Wavelength scans can thus be performed
much more rapidly than with other configurations
Since process analyzers are dedicated to performing a
particular analysis on a specific sample type the
process sample interface depends on the sample type
and the process conditions with NIR light being
transferred via fiber optics In-line analysis of clear to
opaque liquids and solids is typically carried out by
contact transmission and reflectance probes while
non-contact reflectance measurements are performed
on materials transported in hoppers or conveyor belts
3 Theory and practice of chemometric data
processing
Since NIR spectra are typically composed of broad
overlapping and thus ill-defined absorption bands
containing chemical and physical information of all
sample components the analytical information is
multivariate in nature and therefore hardly selective
To perform qualitative or quantitative NIR analysis
ie to relate spectral variables to properties of the
analyte mathematical and statistical methods (ie
chemometrics) are required that extract brelevantQinformation and reduce birrelevantQ information ie
interfering parameters
In the following sections the most frequently used
mathematical data pretreatments and their specific
purpose (Section 31) reduction of variables with
principal component analysis (Section 32) multi-
variate calibration methods for quantitative analysis
(Section 33) and multivariate classification techni-
ques for qualitative analysis (Section 34) will be
discussed Different methods for calibration transfer
between instruments an important economic and
regulatory issue for qualitative and quantitative
pharmaceutical NIR analysis have recently been
commented on by Blanco et al [12] and will thus
not be considered here in detail
31 Data pretreatments
Interfering spectral parameters such as light
scattering path length variations and random noise
resulting from variable physical sample properties or
instrumental effects call for mathematical corrections
so-called data pretreatments prior to multivariate
modeling in order to reduce eliminate or standardize
their impact on the spectra Since careful selection of
data pretreatments can significantly improve the
robustness of a calibration model the most commonly
used methods are briefly discussed with respect to the
effect they are able to correct A detailed description
of the techniques can be found elsewhere [13]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431114
Mathematical treatments used to compensate for
scatter-induced baseline offsets include multiplica-
tive scatter correction (MSC) and standard normal
variate (SNV) Both methods have originally been
developed to process reflectance spectra but they
are also applied to transmittance spectra Baseline
shifts and intensity differences resulting from vari-
able positioning or path length variations may be
reduced or eliminated by normalization algorithms
Derivatives can be applied to improve the resolution
of overlapping bands In addition they are able to
reduce baseline offsets Since spectral noise is also
amplified by derivation derivatives are usually
combined with Taylor or Savitzky Golay smoothing
algorithms
32 Reduction of variables by principal component
analysis (PCA)
Since multivariate NIR spectral data contain a huge
number of correlated variables (= collinearity) there is
a need for reduction of variables ie to describe data
variability by a few uncorrelated variables containing
the relevant information for calibration modeling The
best known and most widely used variable-reduction
Inte
nsity
λ1 λ2 λ3
λ1
λ2
λ3
λ2
λ3 F3
Fig 3 Transformation of a spectrum with three variables ie wavelength
thereby converting the spectrum to a single point in a three-dimensional s
and determination of principal components F1 F2 and F3 (e)
method is principal component analysis (PCA) PCA
is a mathematical procedure that resolves the spectral
data into orthogonal components whose linear combi-
nations approximate the original data The new
variables called principal components (PC) eigen-
vectors or factors correspond to the largest eigenval-
ues of the covariance matrix thus accounting for the
largest possible variance in the data set The first PC
represents maximum variance amongst all linear
combinations and each successive variable accounts
for as much of the remaining variability as possible
The transformation procedure is visualized schemati-
cally in Fig 3 on the basis of three original variables
ie three wavelengths per spectrum For real spectra
with p wavelengths the transformation leads to a p-
dimensional space
In pharmaceutical NIR analysis it is often possible
to compress most of the spectral variability to only a
few principal components ie factors with only a
rather small loss of information A number of multi-
variate calibration and classification methods there-
fore rely on PCA data (see Sections 33 and 34) For
further details on PCA interested readers are referred
to the excellent and comprehensive treatise of Howard
Mark [14]
λ1
λ2
λ3
λ1
F1F2
F2F3
F1
s (a) to a new coordinate system with one axis for each wavelength
pace (b) cloud formation of several spectra (c) mean centering (d)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1111
helpful To this end the author provides the reader
with a short introduction into the theoretical funda-
mentals of the technique (Section 21) the equipment
it uses (Section 22) and the mathematical and
statistical tools that are needed to process recorded
signals and extract the relevant information for
qualitative or quantitative analysis (Section 3) Sec-
tion 4 focuses on regulatory aspects that are critical
for pharmaceutical NIR analyses Important current
and possible future pharmaceutical applications of
NIR spectroscopy including raw material identifica-
tion and characterization analysis of intact dosage
forms and process monitoring are discussed in
Section 5 Section 6 briefly emphasizes the pharma-
ceutical potential of NIR imaging techniques
2 Basic principles of near-infrared (NIR)
spectroscopy
21 Origin and characteristics of NIR absorption
bands
The American Society of Testing and Materials
(ASTM) defines the NIR region of the electro-
magnetic spectrum as the wavelength range of 780ndash
2526 nm corresponding to the wave number range
12820ndash3959 cm1 The most prominent absorption
bands occurring in the NIR region are related to
overtones and combinations of fundamental vibra-
tions of ndashCH ndashNH ndashOH (and ndashSH) functional
groups The key issues which determine the occur-
rence and spectral properties ie frequency and
intensity of NIR absorption bands are anharmonicity
and Fermi resonance the physical basis of which will
be briefly described in this section For a more
comprehensive treatise the reader is referred to some
excellent textbook chapters on the subject matter [23]
Since the energy curve of an oscillating molecule is
affected by intramolecular interactions vibrations
around the equilibrium position are non-symmetric
and the spacings between energy levels that the
molecule can attain are not identical but rather
decrease with increasing energy This situation
resembles the quantum mechanical model of an
anharmonic oscillator Since quantum mechanical
selection rules do not rigorously exclude transitions
with Dt N1 for anharmonic systems transitions
between vibrational states of Dt =2 or 3 are possible
although their probability decreases with an increase
in the vibrational quantum number t These multi-
level energy transitions are the origin of NIR overtone
bands that occur at multiples of the fundamental
vibrational frequency For most chemical bonds the
wave numbers of overtones can be estimated from
their fundamental vibrations with an anharmonicity
constant v of 001ndash005 by the following equation
mx frac14 Dy m0 1 Dyveth THORN eth1THORN
where mx =wave number of x overtone m0=wavenumber of fundamental vibration v =anharmonicity
constant
Combination bands appearing between 1900 nm
and 2500 nm are the result of vibrational interactions
ie their frequencies are the sums of multiples of each
interacting frequency A special type of configuration
interaction called Fermi resonance leads to the
feature that two NIR absorption bands of a polyatomic
molecule with the same frequency do not simply
overlay and sum up but split in two peaks of
somewhat higher and lower frequencies than the
expected unperturbed position Furthermore intermo-
lecular hydrogen bondings and dipole interactions
have to be considered since they alter vibrational
energy states thus shifting existing absorption bands
andor giving rise to new ones This effect allows
crystal forms for instance to be determined by NIR
spectroscopy
In conclusion NIR absorption bands are typically
broad overlapping and 10ndash100 times weaker than
their corresponding fundamental mid-IR absorption
bands These characteristics severely restrict sensitiv-
ity in the classical spectroscopic sense and call for
chemometric data processing to relate spectral infor-
mation to sample properties (see Section 3) The low
absorption coefficient however permits high pene-
tration depth and thus an adjustment of sample
thickness This aspect is actually an analytical
advantage since it allows direct analysis of strongly
absorbing and even highly scattering samples such as
turbid liquids or solids in either transmittance or
reflectance mode without further pretreatments
The dual dependence of the analytical signal on the
chemical and physical properties of the sample
resulting from absorption and scatter effects can be
favorably used to perform chemical and physical
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431112
analysis from one single measurement However if
not the analytical target scatter effects in NIR spectra
resulting from physical sample variations may also
pose more or less severe analytical problems In these
situations they have to be considered in the calibra-
tion process as dinterfering parametersT as will be
discussed in Section 3 More detailed information on
the theory of absorption and scatter effects in diffuse
reflectance and transmittance NIR spectroscopy can
be found elsewhere [45]
22 Instrumentation and sample presentation
A NIR spectrometer is generally composed of a
light source a monochromator a sample holder or a
sample presentation interface and a detector allowing
for transmittance or reflectance measurements (Fig 1)
The light source is usually a tungsten halogen
lamp since it is small and rugged [6] Detector types
include silicon lead sulfide (PbS) and indium gallium
arsenide (InGaAs) [6] Silicon detectors are fast low-
noise small and highly sensitive from the visible
region to 1100 nm PbS detectors are slower but very
popular since they are sensitive from 1100 to 2500 nm
and provide good signal-to-noise properties The most
expensive InGaAs detector combines the speed and
size characteristics of the silicon detector with the
wavelength range of the PbS detector
A number of optical configurations exist that can
be used to separate the polychromatic NIR spectral
region into dmonochromaticT frequencies A detailed
description of the different principles can be found in
various textbooks [7ndash9] Here the basic principles and
main differences will be shortly discussed from a
practical point of view Broadband discrete filter
Light Source Monochromator
DetDiffuse R
Fig 1 Basic NIR spectrom
photometers or light-emitting diode (LED)-based
instruments provide selected frequencies thus cover-
ing only a narrow spectral range of 50ndash100 nm
Diffraction grating interferometer diode-array or
acousto-optic tunable filter (AOTF)-based instruments
provide full spectral coverage Selection of the
appropriate technology is usually based upon the
required analyte sensitivity reliability ease of use
calibration transferability and implementation needs
The latter aspect requires laboratory and process
analyzers to be differentiated
Laboratory analyzers are intended for off-line or
at-line measurements in quality control research and
plant laboratories ie high analyte sensitivity and
reliability are required while speed is of lower
importance Optimum sample presentation to the
instrument high signal-to-noise ratio instrument
stability and sufficient resolution are the most
important aspects for analysis Presently grating and
interferometer-based instruments are mainly in use for
this purpose The appropriate NIR measuring mode
will be dictated by the optical properties of the
samples (Fig 2) Transparent materials are usually
measured in transmittance (Fig 2A) Turbid liquids or
semi-solids and solids may be measured in diffuse
transmittance (Fig 2B) diffuse reflectance (Fig 2C)
or transflectance (Figs 2DE) depending on their
absorption and scattering characteristics In any case
absorbance (A) values relative to a standard reference
material are measured with A corresponding to log 1
R and log 1T for reflectance and transmittance
spectra respectively
To measure good NIR spectra the proper sample
presentation is of utmost importance especially when
measuring solid samples since scatter effects and
ectoreflectance
DetectorTransmittance
Sample
eter configurations
Transmittance
DiffuseReflectance
Transflectance
(A)
(B)
(C)
(D)
(E)
Fig 2 NIR measuring modesmdash(AB) transmittance (C) diffuse
reflectance and (DE) transflectance
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1113
stray light induced by variations in packing density of
powders or sample positioning of tablets or capsules
may cause large sources of error in the spectra [10]
Therefore several types of sample cells such as
quartz cuvettes with defined optical path length for
liquids specifically designed sample cells with quartz
windows for semi-solids and powders and adjusted
sample holders for tablets and capsules have been
developed [11] Temperature control and sample
movement are other options that have been realized
Process analyzers are intended for in-line or on-
line measurements to provide real-time process
information while operating in harsh conditions This
requires fast and rugged instruments with no moving
parts such as AOTF-based instruments allowing for
numerous readings per second without being sensitive
to vibrations AOTF-based instruments choose wave-
lengths by using radio-frequency signals to alter the
refractive index of a birefringent crystal (usually
TeO2) Wavelength scans can thus be performed
much more rapidly than with other configurations
Since process analyzers are dedicated to performing a
particular analysis on a specific sample type the
process sample interface depends on the sample type
and the process conditions with NIR light being
transferred via fiber optics In-line analysis of clear to
opaque liquids and solids is typically carried out by
contact transmission and reflectance probes while
non-contact reflectance measurements are performed
on materials transported in hoppers or conveyor belts
3 Theory and practice of chemometric data
processing
Since NIR spectra are typically composed of broad
overlapping and thus ill-defined absorption bands
containing chemical and physical information of all
sample components the analytical information is
multivariate in nature and therefore hardly selective
To perform qualitative or quantitative NIR analysis
ie to relate spectral variables to properties of the
analyte mathematical and statistical methods (ie
chemometrics) are required that extract brelevantQinformation and reduce birrelevantQ information ie
interfering parameters
In the following sections the most frequently used
mathematical data pretreatments and their specific
purpose (Section 31) reduction of variables with
principal component analysis (Section 32) multi-
variate calibration methods for quantitative analysis
(Section 33) and multivariate classification techni-
ques for qualitative analysis (Section 34) will be
discussed Different methods for calibration transfer
between instruments an important economic and
regulatory issue for qualitative and quantitative
pharmaceutical NIR analysis have recently been
commented on by Blanco et al [12] and will thus
not be considered here in detail
31 Data pretreatments
Interfering spectral parameters such as light
scattering path length variations and random noise
resulting from variable physical sample properties or
instrumental effects call for mathematical corrections
so-called data pretreatments prior to multivariate
modeling in order to reduce eliminate or standardize
their impact on the spectra Since careful selection of
data pretreatments can significantly improve the
robustness of a calibration model the most commonly
used methods are briefly discussed with respect to the
effect they are able to correct A detailed description
of the techniques can be found elsewhere [13]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431114
Mathematical treatments used to compensate for
scatter-induced baseline offsets include multiplica-
tive scatter correction (MSC) and standard normal
variate (SNV) Both methods have originally been
developed to process reflectance spectra but they
are also applied to transmittance spectra Baseline
shifts and intensity differences resulting from vari-
able positioning or path length variations may be
reduced or eliminated by normalization algorithms
Derivatives can be applied to improve the resolution
of overlapping bands In addition they are able to
reduce baseline offsets Since spectral noise is also
amplified by derivation derivatives are usually
combined with Taylor or Savitzky Golay smoothing
algorithms
32 Reduction of variables by principal component
analysis (PCA)
Since multivariate NIR spectral data contain a huge
number of correlated variables (= collinearity) there is
a need for reduction of variables ie to describe data
variability by a few uncorrelated variables containing
the relevant information for calibration modeling The
best known and most widely used variable-reduction
Inte
nsity
λ1 λ2 λ3
λ1
λ2
λ3
λ2
λ3 F3
Fig 3 Transformation of a spectrum with three variables ie wavelength
thereby converting the spectrum to a single point in a three-dimensional s
and determination of principal components F1 F2 and F3 (e)
method is principal component analysis (PCA) PCA
is a mathematical procedure that resolves the spectral
data into orthogonal components whose linear combi-
nations approximate the original data The new
variables called principal components (PC) eigen-
vectors or factors correspond to the largest eigenval-
ues of the covariance matrix thus accounting for the
largest possible variance in the data set The first PC
represents maximum variance amongst all linear
combinations and each successive variable accounts
for as much of the remaining variability as possible
The transformation procedure is visualized schemati-
cally in Fig 3 on the basis of three original variables
ie three wavelengths per spectrum For real spectra
with p wavelengths the transformation leads to a p-
dimensional space
In pharmaceutical NIR analysis it is often possible
to compress most of the spectral variability to only a
few principal components ie factors with only a
rather small loss of information A number of multi-
variate calibration and classification methods there-
fore rely on PCA data (see Sections 33 and 34) For
further details on PCA interested readers are referred
to the excellent and comprehensive treatise of Howard
Mark [14]
λ1
λ2
λ3
λ1
F1F2
F2F3
F1
s (a) to a new coordinate system with one axis for each wavelength
pace (b) cloud formation of several spectra (c) mean centering (d)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431112
analysis from one single measurement However if
not the analytical target scatter effects in NIR spectra
resulting from physical sample variations may also
pose more or less severe analytical problems In these
situations they have to be considered in the calibra-
tion process as dinterfering parametersT as will be
discussed in Section 3 More detailed information on
the theory of absorption and scatter effects in diffuse
reflectance and transmittance NIR spectroscopy can
be found elsewhere [45]
22 Instrumentation and sample presentation
A NIR spectrometer is generally composed of a
light source a monochromator a sample holder or a
sample presentation interface and a detector allowing
for transmittance or reflectance measurements (Fig 1)
The light source is usually a tungsten halogen
lamp since it is small and rugged [6] Detector types
include silicon lead sulfide (PbS) and indium gallium
arsenide (InGaAs) [6] Silicon detectors are fast low-
noise small and highly sensitive from the visible
region to 1100 nm PbS detectors are slower but very
popular since they are sensitive from 1100 to 2500 nm
and provide good signal-to-noise properties The most
expensive InGaAs detector combines the speed and
size characteristics of the silicon detector with the
wavelength range of the PbS detector
A number of optical configurations exist that can
be used to separate the polychromatic NIR spectral
region into dmonochromaticT frequencies A detailed
description of the different principles can be found in
various textbooks [7ndash9] Here the basic principles and
main differences will be shortly discussed from a
practical point of view Broadband discrete filter
Light Source Monochromator
DetDiffuse R
Fig 1 Basic NIR spectrom
photometers or light-emitting diode (LED)-based
instruments provide selected frequencies thus cover-
ing only a narrow spectral range of 50ndash100 nm
Diffraction grating interferometer diode-array or
acousto-optic tunable filter (AOTF)-based instruments
provide full spectral coverage Selection of the
appropriate technology is usually based upon the
required analyte sensitivity reliability ease of use
calibration transferability and implementation needs
The latter aspect requires laboratory and process
analyzers to be differentiated
Laboratory analyzers are intended for off-line or
at-line measurements in quality control research and
plant laboratories ie high analyte sensitivity and
reliability are required while speed is of lower
importance Optimum sample presentation to the
instrument high signal-to-noise ratio instrument
stability and sufficient resolution are the most
important aspects for analysis Presently grating and
interferometer-based instruments are mainly in use for
this purpose The appropriate NIR measuring mode
will be dictated by the optical properties of the
samples (Fig 2) Transparent materials are usually
measured in transmittance (Fig 2A) Turbid liquids or
semi-solids and solids may be measured in diffuse
transmittance (Fig 2B) diffuse reflectance (Fig 2C)
or transflectance (Figs 2DE) depending on their
absorption and scattering characteristics In any case
absorbance (A) values relative to a standard reference
material are measured with A corresponding to log 1
R and log 1T for reflectance and transmittance
spectra respectively
To measure good NIR spectra the proper sample
presentation is of utmost importance especially when
measuring solid samples since scatter effects and
ectoreflectance
DetectorTransmittance
Sample
eter configurations
Transmittance
DiffuseReflectance
Transflectance
(A)
(B)
(C)
(D)
(E)
Fig 2 NIR measuring modesmdash(AB) transmittance (C) diffuse
reflectance and (DE) transflectance
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1113
stray light induced by variations in packing density of
powders or sample positioning of tablets or capsules
may cause large sources of error in the spectra [10]
Therefore several types of sample cells such as
quartz cuvettes with defined optical path length for
liquids specifically designed sample cells with quartz
windows for semi-solids and powders and adjusted
sample holders for tablets and capsules have been
developed [11] Temperature control and sample
movement are other options that have been realized
Process analyzers are intended for in-line or on-
line measurements to provide real-time process
information while operating in harsh conditions This
requires fast and rugged instruments with no moving
parts such as AOTF-based instruments allowing for
numerous readings per second without being sensitive
to vibrations AOTF-based instruments choose wave-
lengths by using radio-frequency signals to alter the
refractive index of a birefringent crystal (usually
TeO2) Wavelength scans can thus be performed
much more rapidly than with other configurations
Since process analyzers are dedicated to performing a
particular analysis on a specific sample type the
process sample interface depends on the sample type
and the process conditions with NIR light being
transferred via fiber optics In-line analysis of clear to
opaque liquids and solids is typically carried out by
contact transmission and reflectance probes while
non-contact reflectance measurements are performed
on materials transported in hoppers or conveyor belts
3 Theory and practice of chemometric data
processing
Since NIR spectra are typically composed of broad
overlapping and thus ill-defined absorption bands
containing chemical and physical information of all
sample components the analytical information is
multivariate in nature and therefore hardly selective
To perform qualitative or quantitative NIR analysis
ie to relate spectral variables to properties of the
analyte mathematical and statistical methods (ie
chemometrics) are required that extract brelevantQinformation and reduce birrelevantQ information ie
interfering parameters
In the following sections the most frequently used
mathematical data pretreatments and their specific
purpose (Section 31) reduction of variables with
principal component analysis (Section 32) multi-
variate calibration methods for quantitative analysis
(Section 33) and multivariate classification techni-
ques for qualitative analysis (Section 34) will be
discussed Different methods for calibration transfer
between instruments an important economic and
regulatory issue for qualitative and quantitative
pharmaceutical NIR analysis have recently been
commented on by Blanco et al [12] and will thus
not be considered here in detail
31 Data pretreatments
Interfering spectral parameters such as light
scattering path length variations and random noise
resulting from variable physical sample properties or
instrumental effects call for mathematical corrections
so-called data pretreatments prior to multivariate
modeling in order to reduce eliminate or standardize
their impact on the spectra Since careful selection of
data pretreatments can significantly improve the
robustness of a calibration model the most commonly
used methods are briefly discussed with respect to the
effect they are able to correct A detailed description
of the techniques can be found elsewhere [13]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431114
Mathematical treatments used to compensate for
scatter-induced baseline offsets include multiplica-
tive scatter correction (MSC) and standard normal
variate (SNV) Both methods have originally been
developed to process reflectance spectra but they
are also applied to transmittance spectra Baseline
shifts and intensity differences resulting from vari-
able positioning or path length variations may be
reduced or eliminated by normalization algorithms
Derivatives can be applied to improve the resolution
of overlapping bands In addition they are able to
reduce baseline offsets Since spectral noise is also
amplified by derivation derivatives are usually
combined with Taylor or Savitzky Golay smoothing
algorithms
32 Reduction of variables by principal component
analysis (PCA)
Since multivariate NIR spectral data contain a huge
number of correlated variables (= collinearity) there is
a need for reduction of variables ie to describe data
variability by a few uncorrelated variables containing
the relevant information for calibration modeling The
best known and most widely used variable-reduction
Inte
nsity
λ1 λ2 λ3
λ1
λ2
λ3
λ2
λ3 F3
Fig 3 Transformation of a spectrum with three variables ie wavelength
thereby converting the spectrum to a single point in a three-dimensional s
and determination of principal components F1 F2 and F3 (e)
method is principal component analysis (PCA) PCA
is a mathematical procedure that resolves the spectral
data into orthogonal components whose linear combi-
nations approximate the original data The new
variables called principal components (PC) eigen-
vectors or factors correspond to the largest eigenval-
ues of the covariance matrix thus accounting for the
largest possible variance in the data set The first PC
represents maximum variance amongst all linear
combinations and each successive variable accounts
for as much of the remaining variability as possible
The transformation procedure is visualized schemati-
cally in Fig 3 on the basis of three original variables
ie three wavelengths per spectrum For real spectra
with p wavelengths the transformation leads to a p-
dimensional space
In pharmaceutical NIR analysis it is often possible
to compress most of the spectral variability to only a
few principal components ie factors with only a
rather small loss of information A number of multi-
variate calibration and classification methods there-
fore rely on PCA data (see Sections 33 and 34) For
further details on PCA interested readers are referred
to the excellent and comprehensive treatise of Howard
Mark [14]
λ1
λ2
λ3
λ1
F1F2
F2F3
F1
s (a) to a new coordinate system with one axis for each wavelength
pace (b) cloud formation of several spectra (c) mean centering (d)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
Transmittance
DiffuseReflectance
Transflectance
(A)
(B)
(C)
(D)
(E)
Fig 2 NIR measuring modesmdash(AB) transmittance (C) diffuse
reflectance and (DE) transflectance
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1113
stray light induced by variations in packing density of
powders or sample positioning of tablets or capsules
may cause large sources of error in the spectra [10]
Therefore several types of sample cells such as
quartz cuvettes with defined optical path length for
liquids specifically designed sample cells with quartz
windows for semi-solids and powders and adjusted
sample holders for tablets and capsules have been
developed [11] Temperature control and sample
movement are other options that have been realized
Process analyzers are intended for in-line or on-
line measurements to provide real-time process
information while operating in harsh conditions This
requires fast and rugged instruments with no moving
parts such as AOTF-based instruments allowing for
numerous readings per second without being sensitive
to vibrations AOTF-based instruments choose wave-
lengths by using radio-frequency signals to alter the
refractive index of a birefringent crystal (usually
TeO2) Wavelength scans can thus be performed
much more rapidly than with other configurations
Since process analyzers are dedicated to performing a
particular analysis on a specific sample type the
process sample interface depends on the sample type
and the process conditions with NIR light being
transferred via fiber optics In-line analysis of clear to
opaque liquids and solids is typically carried out by
contact transmission and reflectance probes while
non-contact reflectance measurements are performed
on materials transported in hoppers or conveyor belts
3 Theory and practice of chemometric data
processing
Since NIR spectra are typically composed of broad
overlapping and thus ill-defined absorption bands
containing chemical and physical information of all
sample components the analytical information is
multivariate in nature and therefore hardly selective
To perform qualitative or quantitative NIR analysis
ie to relate spectral variables to properties of the
analyte mathematical and statistical methods (ie
chemometrics) are required that extract brelevantQinformation and reduce birrelevantQ information ie
interfering parameters
In the following sections the most frequently used
mathematical data pretreatments and their specific
purpose (Section 31) reduction of variables with
principal component analysis (Section 32) multi-
variate calibration methods for quantitative analysis
(Section 33) and multivariate classification techni-
ques for qualitative analysis (Section 34) will be
discussed Different methods for calibration transfer
between instruments an important economic and
regulatory issue for qualitative and quantitative
pharmaceutical NIR analysis have recently been
commented on by Blanco et al [12] and will thus
not be considered here in detail
31 Data pretreatments
Interfering spectral parameters such as light
scattering path length variations and random noise
resulting from variable physical sample properties or
instrumental effects call for mathematical corrections
so-called data pretreatments prior to multivariate
modeling in order to reduce eliminate or standardize
their impact on the spectra Since careful selection of
data pretreatments can significantly improve the
robustness of a calibration model the most commonly
used methods are briefly discussed with respect to the
effect they are able to correct A detailed description
of the techniques can be found elsewhere [13]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431114
Mathematical treatments used to compensate for
scatter-induced baseline offsets include multiplica-
tive scatter correction (MSC) and standard normal
variate (SNV) Both methods have originally been
developed to process reflectance spectra but they
are also applied to transmittance spectra Baseline
shifts and intensity differences resulting from vari-
able positioning or path length variations may be
reduced or eliminated by normalization algorithms
Derivatives can be applied to improve the resolution
of overlapping bands In addition they are able to
reduce baseline offsets Since spectral noise is also
amplified by derivation derivatives are usually
combined with Taylor or Savitzky Golay smoothing
algorithms
32 Reduction of variables by principal component
analysis (PCA)
Since multivariate NIR spectral data contain a huge
number of correlated variables (= collinearity) there is
a need for reduction of variables ie to describe data
variability by a few uncorrelated variables containing
the relevant information for calibration modeling The
best known and most widely used variable-reduction
Inte
nsity
λ1 λ2 λ3
λ1
λ2
λ3
λ2
λ3 F3
Fig 3 Transformation of a spectrum with three variables ie wavelength
thereby converting the spectrum to a single point in a three-dimensional s
and determination of principal components F1 F2 and F3 (e)
method is principal component analysis (PCA) PCA
is a mathematical procedure that resolves the spectral
data into orthogonal components whose linear combi-
nations approximate the original data The new
variables called principal components (PC) eigen-
vectors or factors correspond to the largest eigenval-
ues of the covariance matrix thus accounting for the
largest possible variance in the data set The first PC
represents maximum variance amongst all linear
combinations and each successive variable accounts
for as much of the remaining variability as possible
The transformation procedure is visualized schemati-
cally in Fig 3 on the basis of three original variables
ie three wavelengths per spectrum For real spectra
with p wavelengths the transformation leads to a p-
dimensional space
In pharmaceutical NIR analysis it is often possible
to compress most of the spectral variability to only a
few principal components ie factors with only a
rather small loss of information A number of multi-
variate calibration and classification methods there-
fore rely on PCA data (see Sections 33 and 34) For
further details on PCA interested readers are referred
to the excellent and comprehensive treatise of Howard
Mark [14]
λ1
λ2
λ3
λ1
F1F2
F2F3
F1
s (a) to a new coordinate system with one axis for each wavelength
pace (b) cloud formation of several spectra (c) mean centering (d)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431114
Mathematical treatments used to compensate for
scatter-induced baseline offsets include multiplica-
tive scatter correction (MSC) and standard normal
variate (SNV) Both methods have originally been
developed to process reflectance spectra but they
are also applied to transmittance spectra Baseline
shifts and intensity differences resulting from vari-
able positioning or path length variations may be
reduced or eliminated by normalization algorithms
Derivatives can be applied to improve the resolution
of overlapping bands In addition they are able to
reduce baseline offsets Since spectral noise is also
amplified by derivation derivatives are usually
combined with Taylor or Savitzky Golay smoothing
algorithms
32 Reduction of variables by principal component
analysis (PCA)
Since multivariate NIR spectral data contain a huge
number of correlated variables (= collinearity) there is
a need for reduction of variables ie to describe data
variability by a few uncorrelated variables containing
the relevant information for calibration modeling The
best known and most widely used variable-reduction
Inte
nsity
λ1 λ2 λ3
λ1
λ2
λ3
λ2
λ3 F3
Fig 3 Transformation of a spectrum with three variables ie wavelength
thereby converting the spectrum to a single point in a three-dimensional s
and determination of principal components F1 F2 and F3 (e)
method is principal component analysis (PCA) PCA
is a mathematical procedure that resolves the spectral
data into orthogonal components whose linear combi-
nations approximate the original data The new
variables called principal components (PC) eigen-
vectors or factors correspond to the largest eigenval-
ues of the covariance matrix thus accounting for the
largest possible variance in the data set The first PC
represents maximum variance amongst all linear
combinations and each successive variable accounts
for as much of the remaining variability as possible
The transformation procedure is visualized schemati-
cally in Fig 3 on the basis of three original variables
ie three wavelengths per spectrum For real spectra
with p wavelengths the transformation leads to a p-
dimensional space
In pharmaceutical NIR analysis it is often possible
to compress most of the spectral variability to only a
few principal components ie factors with only a
rather small loss of information A number of multi-
variate calibration and classification methods there-
fore rely on PCA data (see Sections 33 and 34) For
further details on PCA interested readers are referred
to the excellent and comprehensive treatise of Howard
Mark [14]
λ1
λ2
λ3
λ1
F1F2
F2F3
F1
s (a) to a new coordinate system with one axis for each wavelength
pace (b) cloud formation of several spectra (c) mean centering (d)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1115
33 Multivariate calibration for quantitative analysis
Before a NIR spectrometer can do any quantitative
analysis it has to be trained ie calibrated using
multivariate methods The calibration process basi-
cally involves the following steps
1 Selection of a representative calibration sample set
2 Spectra acquisition and determination of reference
values
3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical
target property
4 Validation of the model by cross validation set
validation or external validation
The multivariate regression methods most fre-
quently used in quantitative NIR analysis are principal
component regression (PCR) and partial least-squares
(PLS) regression [15] PCR uses the principal compo-
nents provided by PCA (see Section 32) to perform
regression on the sample property to be predicted
PLS finds the directions of greatest variability by
comparing both spectral and target property informa-
tion with the new axes called PLS components or
PLS factors Thus the main difference between the
two methods is that the first principal component or
factor in PCR represents the largest variations in the
spectrum whereas in PLS it represents the most
relevant variations showing the best correlation with
the target property values In both cases the optimum
number of factors used to build the calibration model
depends on the sample properties and the analytical
target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low
standard error of calibration (SEC) but a large
standard error of prediction (SEP) Such a model is
not very robust and may fail when tested with an
independent validation set
In some cases the spectral data and the target
property may not be linearly related as a result of
physical sample properties or instrumental effects
These cases can only be addressed by non-linear
calibration methods such as PLS-2 locally weighted
regression (LWR) or artificial neural networks
(ANNs) For details on these methods interested
readers are referred to the corresponding chapters in
a recent textbook on multivariate calibration [16]
34 Multivariate classification for qualitative analysis
In qualitative analysis sample properties that have
to be related to spectral variations have discrete values
that represent a product identity or a product quality
for example bgoodQ or bbadQ To solve the selectivity
and interference problems of NIR spectra multivariate
classification methods are used for grouping samples
with similar characteristics Multivariate classification
methods also known as pattern-recognition methods
are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the
class to which the samples belong is known
bNon-supervisedQ methods also known as cluster
analysis do not require any a priori knowledge
about the group structure in the data but instead
produces the grouping ie clustering itself This
type of analysis is often very useful at an early stage
of an investigation to explore subpopulations in a
data set for instance different physical grades of a
material Cluster analysis can be performed with
simple visual techniques such as PCA (see Section
32) or some hierarchical methods leading to so-called
dendrograms
bSupervised classificationQ methods also known as
discriminant analysis are used to build classification
rules for a number of pre-specified subgroups ie the
group structure of the training set is known The
classification rules are later used for allocating new or
unknown samples to the most probable subgroup
Identity or goodbad quality are thus defined as
belonging to a group with known properties Algo-
rithms of this type such as LDA (= linear discriminant
analysis) QDA (= quadratic discriminant analysis)
SIMCA (= Soft Independent Modelling of Class
Analogies) or KNN (= K nearest neighbours) are
typically used for constructing spectral libraries
Most of the classification methods can operate
either in wavelength space or in a dimension-reduced
factor space In any case their ultimate goal is to
establish mathematical criteria for parametrizing
spectral similarity thus allowing similarity between
samples or a sample and a class to be expressed
quantitatively For this purpose comprehensive libra-
ries of spectra that represent the natural variation of
each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a
correlation coefficient such as the spectral match
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431116
value (SMV) [17] or a distance measure such as
Euclidian or Mahalanobis distance
A detailed description of the different classification
procedures is certainly beyond the scope of this paper
Interested readers are therefore referred to a recent
textbook on the topic [18] Worth mentioning here are
the following practical aspects
The correlation coefficient being defined as the
cosine of the angle between vectors for the sample
spectrum and the average spectrum for each
product in the library is a rather robust parameter
that can be favorably used for chemical identity
testing (see Section 51) since it relies on second
derivative spectra and is thus not influenced by
spectral offsets and globalintensity variations
resulting from physical differences or concentra-
tion changes
Distance-based methods on the other hand also
allow for product qualification The conformity
index (CI) based on the wavelength distance
method is one such parameter that has been used
successfully to pinpoint quality differences in raw
materials and products by using a so-called C-plot
ie a plot of the absolute distance at each wave-
length as a function of the wavelength [19] (see
also Section 51)
4 Regulatory aspects
41 Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advan-
tages over other analytical techniques and thus
offers many interesting perspectives in pharmaceutical
analysis The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5) However in
the highly regulated pharmaceutical world an ana-
lytical method is only valuable for routine implemen-
tation if it is approved by regulatory authorities
Actually the major pharmacopoeias have generally
adopted NIR techniques The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry respectively These chapters ad-
dress the suitability of NIR instrumentation for use in
pharmaceutical analysis focussing mainly on opera-
tional qualification and performance verification com-
prising wavelength scale and repeatibility response
repeatibility photometric linearity and photometric
noise Only some limited guidance is provided in terms
of developing and validating an application
The general legal requirements for instrumentation
qualification procedures namely design qualification
(DQ) installation qualification (IQ) operational qual-
ification (OQ) and performance qualification (PQ)
are described in the cGMP guideline title 21 CFR part
211 For practical realization of these requirements
the American Society for Testing and Materials
(ASTM) has provided NIR specific directions regard-
ing appropriate methodology for establishing spec-
trophotometer performance tests including suitable
standards and multivariate calibration [22] Further
guidance for evaluation of a NIR spectrophotometer
has been provided in a special report of the Analytical
Methods Committee of the British Royal Society of
Chemistry [23]
Many pharmaceutical companies have success-
fully implemented NIR spectrometers in their
quality control laboratories for routine use in raw
material identification and qualification This is
based on the fact that major pharmacopoeias allow
manufacturers to use analytical methods other than
compendial ones for compliance testing provided
they are validated according to parameters such as
specificity linearity range accuracy precision
repeatibility reproducibility detection limit quanti-
fication limit and robustness as is detailed in the
USP Chapter 1225 on Validation of Compendial
Methods [24] and the general ICH Guidelines Q2A
and Q2B on Validation of Analytical Procedures
[25]
Interestingly only few quantitative NIR methods
have gained regulatory approval as yet The main
reason for this is that bnon-separativeQ multivariate
NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP
Chapter 1225 and the general ICH Guidelines Q2A
and Q2B were written Moffat et al [26] discussed
these aspects extensively in an excellent paper
published in 2000 Based on the example of a
quantitative NIR method for the analysis of para-
cetamol in tablets the authors made suggestions on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1117
how NIR assays can best meet the ICH Guidelines on
Validation The recently published Guidelines for the
Development and Validation of Near-Infrared Spectro-
scopic Methods in the Pharmaceutical Industry [27]
established by the NIR sub-group of the UK Pharma-
ceutical Analytical Sciences Group (PASG) cover the
unique and specific NIR requirements whilst remain-
ing complementary to ICH Q2A and Q2B which
address traditional method validation requirements It
might be expected that the PASG guidelines compris-
ing hardware as well as software aspects can help both
pharmaceutical industry and regulatory agencies in
evaluating future submissions of qualitative and
quantitative NIR methods For details of the PASG
guidelines see wwwpasgorgukNIRmay01pdf
42 NIR spectroscopy in view of the USFDA
initiative on PAT
The production of pharmaceutical dosage forms is
usually a multistage operation consisting of several
validated processes managed by standard operating
procedures (SOPs) Quality assurance including
decisions concerning the satisfactory completion of
each unit operation is actually based on off-line
testing to document quality of a small nominally
random product sample This approach is often very
time consuming and adds significantly to the manu-
facturing cycle time since it requires the process to be
stopped during sample removal data generation and
documentation In addition it does not assure zero
defect product quality since risk assessment and risk
management are not included eg critical process
parameters and material performance attributes may
not be identified
In view of this undesirable situation for industry
and public health it has been recognized that new
testing paradigms are required to succeed in both an
increase in manufacturing efficiency and product
safety The Process Analytical Technology (PAT)
initiative driven by the United States Food and
Drug Administration (USFDA) and major phar-
maceutical companies is a challenging approach
intended to assist the progression of real-time or
parametric release and quality-by-design concepts
by providing an opportunity to move from the
laboratory-based btesting to document quality para-
digmQ to a bcontinuous quality assurance paradigmQ
According to a recently published USFDA
Guidance for Industry [28] PATs are defined as
systems for real-time monitoring and control of
critical process parameters and material performance
attributes thus helping to improve process under-
standing manufacturing cycle time and final prod-
uct quality NIR spectroscopy and imaging may be
one of the major PAT tools since these techniques
are well-suited for at-line in-line and on-line
measurements They can provide a wealth of
chemical and physical information important for
measuring process performance and open up oppor-
tunities to move forward from traditional quality
control concepts to process qualification and product
conformity testing Although a number of challenges
concerning hardware design and regulatory approval
must be overcome to realize the full potential of NIR
spectroscopy and imaging as PAT tools it may be
expected that parametric or even real-time release
concepts may be well assisted by the use of NIR
techniques (see Sections 53 and 63)
5 Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis both qualitatively and
quantitatively Fast and nondestructive NIR measure-
ments without any sample pre-treatments may
increase the analytical throughput tremendously
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring The
special feature of combined chemical and physical
information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final
dosage forms which in turn offers the possibility of
a simultaneous determination of several sample
characteristics
Notwithstanding these advantages pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Sec-
tion 3) Although the earliest publications on phar-
maceutical NIR applications date back to the late
1960s it was not until the last 20 years that NIR
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431118
spectroscopy has gained increasing interest in the
pharmaceutical industry with the real breakthrough in
the 1990s as a result of hardware and software
improvements Within the last 10 years a growing
number of research and review articles have reported
on the great potential of NIR spectroscopy in
pharmaceutical research production and quality
control focussing on various banalytical targetsQ suchas identity content uniformity moisture content
particle size polymorphic and pseudopolymorphic
forms hardness thermal and biopharmaceutical prop-
erties These different aspects resulting from the dual
dependence of the NIR signal on chemical and
physical sample characteristics will be discussed in
the context of raw material and intermediate identi-
fication and qualification (Section 51) analysis of
intact dosage forms (Section 52) and process
monitoring (Section 53) with a main focus on solid
dosage forms
51 Identification and qualification of raw materials
and intermediates
Raw materials intended for use in pharmaceutical
products ie active ingredients and excipients are
subject to pharmaceutical quality requirements as
prescribed by Good Manufacturing Practice (GMP)
Guidelines for Medicinal Products and pharmaco-
poeial monographs To guarantee maximal product
safety the GMP guidelines require special testing
procedures within the material supply chain (Directive
91355EEC Chapter 530) In addition to the routine
release testing of the substance single container
identification has to be performed for any lot of raw
material at any time of dispensal
Since modern pharmaceutical processes rely heav-
ily on a reproducible source and grade of raw
materials to ensure consistent finished product quality
material qualification is another analytical require-
ment in the supply chain that has to be fulfilled
Qualification is supposed to confirm the grade andor
source of materials including physical properties such
as particle size density morphology etc which may
in turn indicate its suitability for the intended use
Traditionally pharmaceutical raw material identifica-
tion and qualification known as compliance testing
has been based on compendial methods andor
alternative validated in-house testing procedures
The methods are time-consuming as they are usually
performed in an off-line laboratory are often wet-
chemical in nature and are therefore not appropriate
to handle the enormous number of analyses of modern
industrial material identification and qualification
economically
With the pharmacopoeial-based authorization to
use methods other than the compendial ones for
compliance testing and the GMP-based opportunity
of using bany appropriate procedure or measure to
assure the identity of the contents of each container
of starting materialsQ it has been possible to take
advantage of multi-sensing NIR techniques based on
fiber optic probes for fast and nondestructive
pharmaceutical raw material identification and qual-
ification Many papers have reported on the feasi-
bility of NIR identification and qualification of both
active ingredients and excipients [29ndash38] and most
companies have adopted some form of NIR material
testing in their supply chain either in the warehouse
only andor elsewhere in a manufacturing operation
ie wherever rapid assessment of identity and quality
is needed In combination with bar-code readers
weighing stations and electronic batch documenta-
tion a bsmartQ system can be developed that
guarantees successful manufacturing operations by
ensuring that the correct materials of the appropriate
quality are used in the manufacturing process (see
also Sections 42 and 53)
Using NIR techniques the chemical identity of a
particular material is usually confirmed with a spectral
library approach If an appropriate library has been
constructed the combined chemical and physical
information in the spectra can also be used for material
qualification Moreover with an appropriate calibra-
tion setup simultaneous quantitative measurements
such as moisture content and particle size determi-
nations can be performed or bconformityQ approachescan be used to predict material performance in
manufacturing processes The different approaches
will be discussed in the following paragraphs
511 Library approach
Chemical identification usually does not involve
any conceptual problems with respect to spectral
library development [30313940] However exten-
sion of the identification concept to material qual-
ification is usually more complex The key parameters
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1119
for constructing a robust spectral library may there-
fore be defined as follows
1 Definition of library scope and purpose
2 Selection of authentic sample spectra for calibra-
tion internal and external validation
3 Rationale of data pretreatments
4 Selection of classification algorithm(s)
5 Determination of thresholds
6 Maintenance and updating
The library structure may depend on the software
limitations and the userrsquos requirements In the
simplest case all materials are incorporated into
one library [39] Alternatively they may be split into
sub-libraries to ensure the required level of specific-
ity as for discrimination of chemically similar
substances such as close members of a homologous
series or different grades of microcrystalline cellulose
or lactose
The selection of samples is critical to the success of
the application Two sets of samples are required one
for the construction of the library and an independent
one for external validation purposes to verify the
performance of the data base The number of batches
required to train the system depends on the intended
scope ie the required discriminatory power of the
method The training set must collectively describe
the typical variation of the substance being analyzed
As a rule of thumb identification normally requires a
much smaller number of different batches (usually 3)
than qualification (usually 20 or more)
Data pretreatments (see also Section 31) strongly
depend on the application For identification purposes
second derivative and scatter correction are often used
to reduce offsets due to variable physical material
characteristics The rationale of transforms in qual-
ification methods strongly depends on the parameter
of interest and is a case by case decision The effect of
NIR data pre-processing on the pattern recognition of
pharmaceutical excipients has been discussed by
Candolfi et al [41]
The classification model (see also Section 34) is
the heart of the library The proper choice of the
algorithm depends on the scope of the library For
identification purposes where physical parameters are
not determined it is usually sufficient to use a match
by wavelength correlation method based on second
derivative data For qualification of different grades of
excipients more sophisticated algorithms such as
SIMCA are recommended (see Section 34) Only
recently Kemper and Luchetta have published a
comprehensive paper giving practical guidelines for
construction validation and maintenance of spectral
libraries for raw material identification and qualifica-
tion [42]
512 Conformity approach
In the early 1990s van der Vlies and co-workers
[1719] developed a discriminating method which
they called the bconformityQ approach and introduced
a new quality parameter the Conformity Index (CI)
to replace compendial methods for identification
assay and moisture content determination of ampi-
cillin trihydrate It is worth mentioning that this was
the first NIR method for release testing of a bulk
pharmaceutical product for human consumption
approved by the USFDA
The CI is the largest value obtained by dividing the
absolute difference in absorption between sample and
reference spectrum (first or second derivative) for
each data point by the standard deviation of the
absorbance of the reference spectrum at that particular
data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or
lower and achieved a high sensitivity of CI for
chemical and physical deviations With the so-called
Conformity Plot (C-Plot CI versus wavelength plot) it
was possible to pinpoint the sources of even very
slight variations in chemical and physical properties
including crystallinity The conformity approach is
well suited for industrial raw material and intermedi-
ate qualification since it gives qualitative answers to
quantitative questions without the need of exhaustive
calibration work
513 Quantitative calibration models
Quantitative calibration models in raw material
qualification have been described for analytical
targets such as moisture content [43ndash46] particle
size [3746ndash51] specific surface area [52] polymor-
phic and pseudopolymorphic forms [53ndash56] amor-
phouscrystalline ratios [57ndash63] viscosity [34] and
gel strength [34] Moisture content particle size and
polymorphism also relevant to pharmaceutical inter-
mediates will be discussed in more detail
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431120
Since chemical physical technological and bio-
pharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification NIRS is an effective alternative
to traditional methods such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations This is due to the fact that
OndashH bands of water are very intensive in the NIR
region exhibiting five absorption maxima (at 760
970 1190 1450 1940 nm) the positioning of which
depends on the hydrogen bonding intensity The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level
NIR quantification of moisture content is usually an
easy task with respect to data processing ie MLR and
PLSR models have been reported Moreover reference
data provided by Karl Fischer titration are reliable It
is therefore not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature
Most of the early work has been summarized and
discussed by Blanco [12] Two papers are worth
mentioning here since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total
bound and surface bulk water in pharmaceutical raw
materials thus demonstrating the advantage of NIRS
over traditional methods such as KFT and LOD Dziki
et al [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products
since they have a profound effect on bulk physical
properties which in turn influence blending and flow
characteristics density compressibility and dissolu-
tion rate Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle size-
dependent scatter effect of powders resulting in non-
linearly sloping baselines [4749] Although the
potential of NIR spectroscopy for particle size
determination has been alluded to in many review
articles only a few research papers have been
dedicated to this subject Mean particle size [46ndash50]
or particle size distribution [3751] measurements
with NIR spectroscopy have been reported using
lactose monohydrate [374950] microcrystalline cel-
lulose [374951] NaCl and sorbitol [47] aspirin
caffeine and paracetamol [49] and piracetam [48] as
model excipients and active ingredients respectively
Various chemometric approaches have been sug-
gested for correlating particle size with NIR spectral
information and the literature data clearly reveal that
there is more than one way to model mean particle
size data with NIR spectra depending on the particle
size range shape of the particle size distribution
materials refractive index and absorption properties
Ciurczak et al [46] found an inverse relationship
between absorbance at each wavelength and mean
particle size with two distinct segments below and
above 85 Am indicating the complicating effect of
small particles for quantitative NIR mean particle size
measurements Burger and coworkers have investi-
gated this aspect in detail and the interested reader is
referred to some excellent papers of the group dealing
with radiative transfer investigations to quantify
absorption and scattering coefficients of pharmaceut-
ical powders [46465] From a more practical point of
view Blanco et al [48] revealed that spectral
reproducibility was affected by sample compactness
and varied in an exponential manner with particle size
(in the range 175ndash325 Am) thus pointing to the
importance of sample presentation for quantitative
particle size measurements
Pharmaceutical raw materials may exist in amor-
phous or crystalline form with polymorphism and
pseudopolymorphism being widely observed in crys-
talline compounds The impact of a certain poly-
morphic or pseudopolymorphic form or the degree of
crystallinity on the physicochemical and biopharma-
ceutical material characteristics is well known NIR
spectroscopy has been reported to be an alternative to
traditional techniques such as DSC and X-ray powder
diffraction for qualification and quantification of the
crystallinity [57ndash63] of miokamycin lactose mono-
hydrate mannitol sucrose and raffinose of polymor-
phic or pseudopolymorphic forms of sulfathiazol
caffeine and theophylline in bulk [5354] and of
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1121
crystallinity upon hydration during granulation pro-
cesses [5556] The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings The magnitude of spectral differences
between the different forms is therefore the key
issue for quantitative determinations Patel et al [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 03 ww For amorphous
crystalline mixtures of lactose monohydrate the
amorphous content was accurately determined to
within 1 ww The literature data clearly reveal that
NIR results are comparable with other techniques
thus reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates
52 Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharma-
ceutical analysis of intact dosage forms including
chemical physical and related biopharmaceutical
aspects This section will discuss NIR applications
for the characterization of solid dosage forms namely
tablets capsules lyophilized products and implants
521 Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets
ranging from identification and assay to physical and
biopharmaceutical parameters such as hardness coat-
ing thickness and dissolution rate It is certainly
beyond the scope of this paper to review all the
published data in these fields This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet Special attention will be paid to the
importance of sample selection sample presentation
and collection of reliable reference data for develop-
ing robust calibration models Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[1266] and a recent book chapter [67]
Fast and nondestructive identification of active
ingredients and exipients in whole tablets even
through the blister packaging is certainly a domain
of NIR spectroscopy [68ndash70] Generally the measur-
ing mode is not as critical as with quantitative
applications except for very thick highly absorbing
tablets and sugar-coated tablets for which the
reflectance mode is recommended to overcome
problems of low analyte signal intensity or even total
absorption in transmittance Challenges associated
with the identification of placebo and verum tablets
of different dosage levels (2 5 10 and 20 ww)
within the blister packaging have been reported by
Dempster et al [68] The results of this study clearly
revealed a higher discriminating ability of direct
measurements compared to measurements through
the blister packaging thus emphasizing that the effect
of the packaging material on the accuracy of NIR
identification approaches may not be neglected
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
literature However in the earliest NIR assays tablets
were not analysed intact The active was extracted
from the matrix or the tablets were at least pulverized
prior to NIR measurements The opportunity to
accurately measure active contents in whole tablets
started in the late 1980s with the development and
subsequent commercialization of appropriate sample
holders that allow for a proper fit of even curved
tablets thereby reducing variable positioning [10] and
stray light effects Within the last 10 years the number
of publications describing quantitative NIR measure-
ments of active ingredients in intact tablets has
increased tremendously [2671ndash84] Various aspects
have been addressed two of which will be discussed
in more detail namely the rationale for selecting the
appropriate measuring mode and the practical and
regulatory aspects to be considered in choosing the
appropriate chemometric approach including calibra-
tion sample selection and data pretreatments
Selecting the measuring mode for NIR tablet
analysis strongly depends on tablet thickness compo-
sition and target parameter Considering quantitative
analysis of active ingredients in tablets the reflectance
mode mainly used in early work may have some
limitations since it covers only a certain part of the
tablet [76] This in turn can cause false results if
homogeneity within the tablet cannot be assured or is
part of the delivery concept such as in multilayer
tablets Moreover the assay of coated tablets may be
complicated in cases where the majority of spectral
information is coming from the coating polymer In
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431122
view of this regulators have expressed their concerns
regarding reflectance measurements for content uni-
formity testing Transmittance spectra representing a
larger volume of the scanned tablet certainly provide
a better description of a tablet matrix in bulk
Improved accuracy precision and sensitivity of
transmittance measurements in various tablet assays
have been demonstrated in the literature [7172]
However it should not be neglected that a signifi-
cantly narrower wavelength range is available in
bdiffuseQ transmittance mode and limitations are
observed with very thick tablets [73] Recent papers
dealing with NIR tablet assays for content uniformity
testing therefore clearly reveal that selection of the
appropriate measuring mode is a case by case decision
[71ndash737578ndash84]
As a non-separative method quantitative NIR
measurements on tablets rely heavily on chemometric
procedures for data modelling with sample selection
and data pretreatments being the most critical issues
regarding calibration development Since process-
related natural variations in tablet mass and hardness
affect the optical properties and thus the baseline of
the recorded spectra derivative transformation andor
normalization are usually required for accurate NIR
content uniformity measurements Sample selection
for calibration modelling strongly depends on the
chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal
range of tablet variability including intra-batch and
batch-to-batch variability Out-of-specification sam-
ples should be considered in the validation step For
quantitative modelling additional requirements have
to be fulfilled namely the use of tablets with an
extended range of active concentrations in the
calibration step This is not an easy task in industrial
practice [77] since normal tablet production batches
are manufactured with tight tolerances In an excellent
and comprehensive paper Moffat and co-workers
have discussed this issue and given various options
for proper calibration sample selection [26] In the
same paper the authors provided suggestions on how
to meet the ICH Guidelines on Validation for NIR
quantitative analysis of active ingredients in tablets
(also see Section 41) Validation of quantitative NIR
methods has also been addressed by Blanco [7475]
Considering the huge amount of literature data on
NIR assays for active qualification and quantification
it is surprising that stability issues ie identification
and quantification of degradation products in tablets
have only rarely been addressed There is merely one
early paper by Drennen and Lodder [85] that reports
the use of NIR diffuse reflectance spectroscopy for
monitoring the hydrolysis of acetylsalicylic acid to
salicylic acid in tablets upon water absorption Due to
the combined spectral information on water and
salicylic acid the authors were able to predict both
parameters from one single measurement thus
emphasizing the great potential of NIRS for tablet
stability testing In addition to chemical stability
polymorphic transitions might be another target
parameter that could be addressed in tablets [86]
The mechanical performance of tablets is of
importance for bulk handling coating packaging
removal from blister and disintegration Current
methods of hardness testing are destructive in nature
and often subject to operator error NIR spectroscopy
on the other hand offers the opportunity for fast and
nondestructive hardness measurements and provides
additional information on structural features of the
tablet matrix Several groups have described the
application of NIRS as an alternative method for
tablet hardness testing [87ndash92] Since the approaches
are different with respect to the measuring mode the
range of hardness levels included in the model and
the chemometric data processing they will be
discussed in more detail
Drennen and co-workers [8789] were among the
first who applied NIR spectroscopy to tablet hardness
testing The authors used diffuse reflectance spectro-
scopy and realized that an increase in tablet hardness
causes a bprimaryQ effect of wavelength-dependent
nonlinear baseline shifting to higher absorbance
values which can be attributed to a decrease in
multiplicative light scattering Various tablet formula-
tions including coated tablets were investigated at
hardness levels ranging from 1 to 7 kp [89] and from 6
to 12 kp [87] respectively A pressure-dependent
bsecondaryQ spectral effect namely a peak shifting at
higher hardness levels arising from changes in
intermolecular bonding could be observed for some
materials In view of these observations the authors
used different approaches for different hardness
levels to correlate spectral data with hardness values
For hardness values in the range of 6 to 12 kp they
used PCAPCR based models considering mainly
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1123
bsecondaryQ spectral effects while removing baseline
shifts also resulting from tablet positioning variability
[87] The SEP values obtained were as precise as the
laboratory hardness test For hardness values in the
range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral
best-fit algorithm based on traditional statistical
methods [89] The proposed approach exploits the
baseline shift and involves the determination of a best-
fit line through each spectrum thereby reducing the
spectrum to slope and intercept values eg de-
weighting individual absorbance peaks and valleys
The method was found to be insensitive to slight
formulation changes (1ndash10 ww cimetidine) and
compared favorably to the multivariate PCAPCR
method with SEP values of around 05 kp
Morisseau and Rhodes [88] revealed SEP values in
the same range (03ndash06 kg) for different tablet
formulations namely hydrochlorothiazide (15 and
20 ww) and chlorpheniramine (2 and 6 ww) in
a matrix of microcrystalline cellulose and magnesium
stearate at six hardness levels ranging between 2 and
12 kg The authors used MLR and PLS to model the
diffuse reflectance spectra Obviously due to the wide
range of hardness levels included in the calibration
model it was not possible to develop acceptable
bmixedQ calibrations by combining data from two
concentrations of the same drug In a recent paper
Chen et al [92] described the favorable use of
artificial neural networks (ANN) to predict tablet
hardness from diffuse reflectance NIR spectral data
Interestingly there is only one paper that describes
the use of NIR transmittance measurements for tablet
hardness determinations [91] Based on the fact that
compaction of pharmaceutical powders results in
density variations in different directions and regions
of the tablet [93] the author suggests a better
predictability of whole tablet hardness values from
transmittance than from reflectance measurements
[91] Indeed the data revealed a strong correlation
between tablet hardness and transmission spectra over
a wide range of hardness levels (10ndash180 N) In
addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation
characteristics of different pharmaceutical excipients
and active ingredients [94] indicating the potential of
NIR transmittance applications in tablet formulation
development
Prediction of drug dissolution rates from whole
tablet NIR spectra is another application that has been
alluded to in many review articles However only a
few research papers are really concerned with this
topic probably due to the challenge of providing
tablet samples that cover the appropriate range of
variability required to develop robust calibration
models The first papers dating back to the early
1990s [9596] deal with the prediction of the
dissolution rate of carbamazepine tablets following
exposure to high humidity NIR diffuse reflectance
spectra were collected periodically from whole tablets
stored in a hydrator Dissolution rates were correlated
with the spectral data using PCR and the bootstrap
(BEST) algorithm for modelling Although this
example clearly indicates the potential of NIRS for
nondestructive dissolution testing its citation in
review articles is somewhat misleading since in this
special example the most prominent parameter affect-
ing dissolution rate was the moisture content Quanti-
tative modelling of drug dissolution rates of
commercialized tablets stored under normal condi-
tions is certainly a greater challenge and requires
exhaustive calibration work based on a priori knowl-
edge of the formulation- and process-dependent tablet
variables as well as their effect on both the drug
dissolution profile and the spectra A qualitative
bconformityQ approach (see Section 34) might be a
more practical option for modelling drug dissolution
from fast dissolving tablets
Some authors [8797ndash101] have examined the
opportunity of predicting the drug dissolution profile
of tablets with a rate-controlling film coat from whole
tablet NIR spectra Kirsch and Drennen [87] used
theophylline tablets coated with various amounts of
ethylcellulose and collected the spectra in diffuse
reflectance mode Reich and co-workers [97ndash101]
used a transmittance configuration to collect spectra
from Eudragit RL-coated theophylline tablets In both
cases reliable quantitative calibration models could
be developed to predict the time required for 50 of
the theophylline to be released The rationale behind
these approaches is the effect of film coat thickness
and film coat uniformity on both drug dissolution rate
and NIR spectra It is therefore not surprising that the
same authors used NIR diffuse reflectance and trans-
mission spectroscopy to predict film coat thickness
[87102] and even film coat uniformity [97ndash99] on
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431124
tablets SEP values for the determination of film coat
thickness [102] were comparable for transmission and
diffuse reflectance mode However reliable reference
data were difficult to achieve and were thus the
major source of error in the quantitative models
Prediction of film coat uniformity and related gastro-
resistance with a conformity approach provided much
better results and required less calibration work [98]
This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with
NIRS are valuable tools to answer quantitative
questions
522 Capsules
Besides tablets capsules are among the most
prominent solid dosage forms Since hard and soft
capsules differ with respect to manufacturing technol-
ogy and formulation ie shell and fill composition
which in turn may affect analytical target parameters
and NIR measurements they will be discussed
separately
Hard capsules are a rather versatile dosage form
that can be filled with a variety of formulations such
as powders granules pellets microtablets and even
liquids or semi-solids The empty shell usually
composed of gelatin and 12ndash16 residual moisture
acting as a plasticizer is purchased from a contract
manufacturer and filled on automatic high speed
filling machines Identity assay moisture content
and drug dissolution are the key parameters in hard
capsule quality control At first glance NIR spectro-
scopy is actually an ideal method to simultaneously
determine these parameters from one single measure-
ment thus replacing time-consuming compendial
methods Moreover stability testing aiming at the
effect of storage conditions and shellfill interactions
might be facilitated The reality is however some-
what more difficult as will be discussed below
In 1987 Lodder and co-workers [103] published a
paper describing the use of NIR spectroscopy and a
quantile-BEAST bootstrap algorithm for discriminat-
ing adulterated and unadulterated capsules It is worth
mentioning that this was the first report of NIRS
applied to the analysis of intact dosage forms
following the deaths caused by cyanide-laced capsules
in the early and mid-1980s The authors reported the
significance of shell color which induced light
scattering and sample positioning which affected fill
monitoring for NIR measurements on intact hard
capsules The sources of variance in NIR measure-
ments on hard capsules being more pronounced than
with tablets has been stressed in detail by Candolfi et
al [10] Positioning and time of measurement were
found to be the most important sources of variance
Positioning effects were attributed to the loose and
movable filling and the round smooth and brilliant
shell which affected the reflection angles The time
factor expresses the effect of surrounding conditions
such as temperature and relative humidity on the
sample properties by inducing small changes in the
water content of the gelatin shell
Taking these aspects into consideration it is not
surprising that only a few papers mainly focussing on
empty capsule shell properties have been published
Buice et al [104] and Berntsson et al [105] described
NIR moisture determinations of empty capsule shells
using reflectance measurements with a filter and a
grating-based instrument respectively Buice et al
used the time-dependent weight gain upon water
uptake of the transparent capsule shells in a hydrator
at 100 relative humidity as reference data for the
PCR model and observed an inaccuracy of the NIR
method at high humidities Several possible explan-
ations were given However the most obvious one
namely structural changes of the gelatin shell induced
at high moisture levels [106] was not considered and
certainly omitted in the PCR model simply based on
the first PC Berntsson et al used loss on drying
reference data in the moisture range of 56ndash18 ww
and obtained best results using MLR based on three
wavelength regions for water and the gelatin back-
bone respectively
Since gelatin is susceptible to cross-linking when
traces of aldehydes are present in the fill non-
destructive monitoring of this reaction is highly
valuable since it affects the in vitro dissolution rate
of the capsules Gold et al [107] published a paper
on NIR reflectance monitoring of formaldehyde-
induced crosslinking of hard gelatin capsules
Although the measurements were performed with
empty capsules the target parameter for the calibra-
tion model was the dissolution rate of amoxicillin
used as a model drug in the fill The NIR spectra of
stressed versus unstressed capsule shells revealed
changes reflecting new chemical bonds and water
loss upon cross-linking
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1125
Within the last few years Reich and co-workers
[108ndash112] have presented a large body of data
demonstrating the potential of NIR transmittance
and reflectance spectroscopy in hard capsule shell
qualification focussing on identification of the gelatin
type manufacturing and storage-induced structural or
moisture changes and related performance problems
such as brittleness The studies revealed that the
spectral range between 1800 and 2500 nm is favorable
for hard gelatin capsule shell identification and
qualification purposes Different batches of chemi-
cally identical transparent and opaque capsules with
different mechanical performance upon filling result-
ing from manufacturing-induced structural changes
could be distinguished by characteristic band shifts in
this region (Fig 4) Moisture content evaluation was
found to depend strongly on the type of colorant
present in the shell Strong correlations of NIR
spectral data with DSC and DMTA test parameters
eg differences in gelatin physical state (Tg) struc-
tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data
clearly reveal that NIR spectroscopy is a powerful tool
for predicting hard capsule shell performance upon
filling thus allowing for at-line or even on-line
control of these parameters at capsule filling machines
(see Section 535)
Soft capsules consist of a lipophilic hydrophilic or
amphiphilic liquid or semi-solid fill enveloped by a
one-piece hermetically sealed outer shell Contrary to
hard capsules they are formed filled and sealed in
one continuous operation Their shell having a
thickness in the range of about 500 Am is usually
Empty Hard Gelatin Capsules -3D- Loading Plot
B1 elasticB1 brittle
Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule
shells
composed of gelatin water and one or two polyol
plasticizers [113114] Analysis of soft gelatin capsu-
les ie identity assay hardness moisture content
dissolution and stability testing is usually a very
time-consuming procedure due to the more or less
complex composition of shell and fill A non-
separative multi-sensing method such as NIR spec-
troscopy providing combined chemical and physical
information of shell and fill would certainly be
desirable However only a few papers have been
published dealing with the application of NIR to soft
gelatine capsule analysis [111115ndash119] Several
reasons might be responsible for this (1) The thick
often colored gelatin shell strongly absorbs in the NIR
region thus more or less complicating NIR measure-
ments of target parameters in the fill (2) Positioning
for spectra collection can be an important source of
variance due to shape effects eg variable shell
thickness within the capsule seam effects and bi-
coloring [10] (3) Room conditioning is required
during NIRS measurements to reduce undesired
effects of moisture changes in the shell [10]
Considering these challenges it is not surprising
that NIR feasibility studies focussing on shell cross-
linking [115] shell moisture content [116] plasticizer
content [116ndash119] and related physical shell perform-
ance [111] have been performed with transparent
emptied capsules andor film formulations Gold et al
[115] used NIR reflectance measurements to study the
migration of formaldehyde from a polyethylene glycol
(PEG) fill into the shell and its reaction with gelatin
The authors used clear capsules and extracted the fill
before data collection The spectral changes clearly
revealed the formation of new chemical bonds and a
depletion of water in the shell with increasing
concentration of formaldehyde in the PEG fill Only
recently Reich and co-workers presented a series of
conference proceedings demonstrating the potential of
NIRS for assessing the chemical and physical proper-
ties of soft gelatine capsule shells immediately after
processing and upon storage [111116ndash119] To
reduce the variance associated with positioning and
interferences with the fill the authors used transparent
film formulations instead of soft capsules in their
feasibility studies which were performed in trans-
flectance mode The spectral data revealed that the
complex dynamic gelatinwaterplasticizer system of a
soft capsule shell that has been reported in the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431126
literature [113114] requires careful selection of data
pretreatments and data processing for modelling
moisture and plasticizer content determinations
[116ndash119] Moreover the type of gelatin was found
to be an important issue that should not be neglected
However with the appropriate chemometric approach
robust calibration models were able to reliably
quantify moisture (range 6ndash12 ww SEP=03
Karl Fischer reference data) and plasticizer content
(range 0ndash50 ww relative to gelatin SEP=13) in
different formulations with respect to gelatin and
plasticizer type [116] These results clearly indicate
that understanding the NIR spectral changes of soft
gelatin capsule shells associated with water and
plasticizer changes is a prerequisite for future appli-
cations of NIR spectroscopy in soft capsule quality
control and stability testing
523 Lyophilized products
Lyophilization is usually performed to increase the
storage stability of hydrolytically unstable drugs that
are intended to be used as injectables or to achieve an
instantly soluble oral dosage form High cake poros-
ity low residual moisture and in the case of proteins
an amorphous glassy state are the most prominent
quality criteria of lyophilized products
Traditionally the moisture content of lyophilized
products is determined by time-consuming methods
such as Karl Fischer titration In addition the
procedure requires the vial to be opened for analysis
Moisture determination with NIR diffuse reflectance
techniques can be performed in a fast and non-
invasive manner through the glass vials Due to these
advantages the NIR technique has been well-
adopted in the pharmaceutical industry for efficient
moisture content determination of lyophilized prod-
ucts Early and recent scientific papers in this field
[120ndash128] have focussed on the investigation of
parameters affecting measurement accuracy such as
cake dimensions [120125] particle size [123]
porosity [123124] and formulation changes [124]
Derksen et al [123] used the NIR approach for
stability testing and correlated moisture content data
with the concentration of the active ingredient to
calculate product shelf-lives Only recently Sukow-
ski and Ulmschneider [125] described high speed
AOTF-based NIR measurements of lyophilized vials
for moisture compliance ie release testing
Interestingly very little data is available on the use
of NIRS for quality control of lyophilized proteins
[124126ndash128] Lin and Hsu [124] used five different
proteins to evaluate the accuracy of NIR moisture
content determinations using different chemometric
approaches The results revealed differences between
the proteins with respect to calibration modelling
Reich and co-workers [126127] reported the use of
NIR spectroscopy to evaluate stress-induced structural
changes of proteins and stabilization effects of sugars
upon lyophilization storage and rehydration Spectra
of stressed and unstressed proteins revealed changes
associated with the primary secondary and tertiary
structure of the proteins Sensitive amide I II and III
bands and the water absorption band could be used for
the assessment of protein structural changes and
aggregation moisture content changes and even the
physical state (Tg) of the lyophilized product Based
on MIR reference data reliable calibration models for
the determination of changes in the a-helical structure
were achieved [126] In addition feasibility of NIR
qualification and quantification of amorphous to
crystalline transitions as a function of storage con-
ditions were shown
Although there are still a number of challenges to
overcome it can be expected that in the near future
noninvasive NIR measurements will at least partly
replace mid-IR measurements for stability testing of
lyophilized proteins Moreover this approach is
interesting for on-line and in-line process monitoring
(see Section 532)
524 Polymeric implants and microspheres
Within the last 20 years polymeric implants and
microspheres have gained increasing interest as
parenteral drug delivery systems to provide sustained
release profiles The matrix of such systems usually
consists of a hydrophobic non-degradable polymer
and optionally a water-soluble pore-forming additive
or a biodegradable polymer such as polylactide-co-
glycolide (PLGA) Quantitative analysis of active
ingredients andor release-controlling excipients
within these dosage forms usually involves destruc-
tive extraction procedures Moreover release testing
is time-consuming and often requires huge amounts of
test samples since these dosage forms are sometimes
formulated to release the active component over
weeks or months
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1127
The application of NIRS as a fast and non-
destructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems such as implants films and microspheres has
been reported in the literature by two different groups
Brashear et al [129130] investigated the use of NIR
reflectance measurements for quantification of an
active compound namely lomefloxacin HCl and a
pore-forming excipient namely polyethylene glycol
(PEG) 600 in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG
respectively Reich and co-workers [131ndash135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection
second derivative transformation and PLS data
processing to determine theophylline and quinine
content (0ndash20 ww) within PLGA microparticles
and tablets [132] and lyophilized proteinsugar
mixtures (absolute protein content 0ndash25 ww) in
lipid matrices [134]
The same group described the application of NIR
transmittance and reflectance measurements for mon-
itoring matrix hydration matrix degradation and drug
release (theophylline and lysozyme) from biodegrad-
able PLGA tablets films and microspheres [131ndash
Lysozym rele
Lysozym in tablet after incubati2 4
2
4
6
8Validation Spectra f(x)=09601x+02566 r=
Calibration Spectra f(x)=09777x+00964 r
Lyso
zym
in t
able
t af
ter
incu
batio
n [m
g]-
NIR
mea
sure
men
t
Fig 5 Quantitative calibration model for NIR determination of in vitro lys
7437 8C)
133135] The studies revealed that release monitoring
of drugs from PLGA matrices is a great challenge
since upon incubation in buffer solution the polymer
hydrates and slowly hydrolyses and the matrix
erodes Spectral changes recorded from tablets films
or microspheres therefore comprise not only the
information of the decreasing drug content but also
the information of the changing structure of the
polymer matrix Anyhow reliable calibration models
could be obtained for both dried and hydrated
samples thus indicating the potential of NIRS even
for the analysis of complex matrix systems (Fig 5)
53 Process monitoring and process control
Noninvasive monitoring of all relevant process
steps leading to a pharmaceutical drug product is an
integral part of the PAT paradigm of real-time or
parametric release and quality by design (see Section
42) Ideally the pharmaceutical survey chain should
include raw material income (see Section 51) all unit
operations leading to intermediates and final products
and packaging
The noninvasive and multivariate character of NIR
techniques provides an interesting platform for
pharmaceutical process monitoring and control
Although most of the reported applications of NIR
spectroscopy in the pharmaceutical industry are off-
line or at-line there are also some on-line and in-line
ase from PLGA
on [mg] - Reference measurement6 8
0974755
=0988771
TransmittanceSEP = 042
ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431128
applications In this section the current state and
future potential of NIR techniques in pharmaceutical
at-line on-line and in-line process monitoring and
process control will be reviewed and discussed with
the main focus on technological unit operations that
are critical for the manufacture of solid dosage forms
A discussion on chemical reactions crystallization
and fermentation processes or extraction and purifi-
cation procedures all relevant operations in the
production of pharmaceutical raw materials is
beyond the scope of this paper and will not be
considered For these topics the interested reader is
referred to an excellent textbook chapter dealing with
chemical reaction monitoring [136] and some inter-
esting papers containing a comprehensive discussion
of chemical reaction [137138] polymorph conver-
sion [139140] and bioprocess [141ndash143] monitoring
with NIR spectroscopy
531 Powder blending
Mixing is a fundamental and critical process in the
manufacturing process of solid and semisolid phar-
maceutical dosage forms The ultimate goal of any
mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are
homogeneously distributed In practice this cannot be
achieved in many cases in particular when dealing
with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on
the material characteristics and the blender type [144]
Pharmaceutical powder blending processes are there-
fore optimized during development in such a way as
to stop the process when the mixture homogeneity is
within a pre-defined bspecificationQ regarding active
content uniformity
Current approaches to assess powder blend homo-
geneity are time consuming and hampered by
sampling errors [144] since they involve the removal
of unit-dose samples from defined mixer locations
using a sample thief the extraction of the active drug
from the sample matrix and the drug content analysis
by either HPLC or UV spectroscopy The distribution
of individual excipients is typically assumed to be
homogeneous if the active ingredient is uniformly
distributed In the traditional pharmaceutical sense
blend homogeneity obviously addresses only the
distribution ie the content uniformity of the active
drug substance while assuming that the excipients are
also evenly distributed The role of the excipients
which not only improves dosage form compliance but
also affects the technological and biopharmaceutical
performance of the formulation is simply neglected
Considering these disadvantages of traditional
powder blend monitoring procedures the potential
value of a noninvasive NIR on-line or in-line approach
is evident NIR monitoring of powder blending can be
performed with fiber-optic reflectance probes thus
minimizing assay time and sampling error Moreover
since most pharmaceutical active ingredients and
excipients absorb NIR radiation NIR measurements
can provide homogeneity information regarding all
mixture components The multi-sensing property of
NIR diffuse reflectance spectra resulting from absorp-
tion and scattering provides a bmultivariate finger-
printQ of both chemical and physical sample properties
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
by several authors using off-line analysis of samples
taken from different blender locations at various
blending times [145ndash147] and on-line or in-line
monitoring of powder mixing [148ndash153] For on-line
and in-line monitoring two different approaches of
spectral data acquisition have been used namely in a
bstop-startQ fashion where the blender is kept sta-
tionary during NIR measurements and in a bdynamicQfashion with moving samples
Sekulic and co-workers [148] were among the first
who reported the use of a NIR fiber-optic probe
inserted in the axis of rotation of a tumble blender for
real on-line stop-start measurements at different times
of the blending process Only recently El-Hagrasy
[154] pointed out that multiple spectral sampling
points in the blender are essential for accurate and
precise estimation of mixing end points when using
the stopndashstart fashion This result was further sub-
stantiated by the additional use of a NIR camera that
enabled large spectral images of the blend to be
obtained (see also Section 63)
To allow proper in situ analysis of moving powder
blends the effect of sample movement on the spectral
response was addressed in detail by Berntsson et al
[155156] The authors realized that sample move-
ment can cause unwanted spectral artefacts when
heterogeneous samples are analyzed with a dispersive
mechanically scanning grating spectrometer The
performance of an FT spectrometer was found to be
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1129
suitable for the analysis of powders moving at
moderate speeds (up to 1 m s1)
Several data processing strategies for the assess-
ment of blend homogeneity andor optimal blending
times from NIR measurements have been evaluated in
the literature Most of these reports were concerned
with qualitative assessments such as dissimilarity
between the spectra of a mixture and the ideal
spectrum of the mixture [146151] or a moving block
standard deviation of NIR spectra [146148150]
These approaches generally revealed acceptable
results although Wargo and Drennen [147] suggested
that bootstrap techniques provided a greater sensitiv-
ity for blend homogeneity assessment than chi-square
calculations Some recent papers [156157] are also
concerned with quantitative analysis pointing out that
quantitative analysis is a prerequisite for a complete
resolution of the chemical and physical properties of
the mixture Non-linearity which was found to be a
feature of powder blends containing coarse and fine
particles was not a problem when using a cubic PLS
calibration
To summarize it can be concluded that on- and in-
line powder blend monitoring with NIR spectroscopy
is not an easy task but feasible and in line with the
PAT paradigm of real-time release focussing on
continuous process understanding and quality control
of all production steps rather than a final product
control only
532 Drying
The manufacturing process of a solid pharmaceut-
ical dosage form usually involves several steps often
including at least one blengthyQ drying process
resulting from the time required to dry the material
plus the time to analytically verify the drying
endpoint Fluid-bed drying and tray drying in a large
oven are the most frequently used methods for wet
granules Microwave vacuum drying is another
option although less popular Freeze- and spray-
drying are the methods of choice for temperature- and
moisture-sensitive drug substances Current methods
to determine drying endpoints include indirect in-line
methods such as temperature measurements and
direct off-line moisture analysis of samples taken
from the dryer Since OndashH vibrations of water exhibit
a large absorption in the NIR region on-line
monitoring of moisture levels using NIR fiber-optic
probes is a feasible option to optimize drying times
Several approaches including microwave vacuum
fluid-bed and freeze drying processes have been
described in the literature
White [158] published a paper in 1994 reporting
the use of NIR for on-line moisture endpoint detection
in a microwave vacuum dryer The calibration
equation used NIR absorbances of water and the
matrix measured at 1410 1930 and 1630 nm
respectively For samples containing less than 6
moisture NIR values were within 1 of the Karl
Fischer reference data with a SEP of 06 At
moisture levels above 6 a bias was observed
which was attributed to sampling limitations and the
broad range of moisture contents (07ndash257) con-
sidered in the calibration Changes in drug content of
the granules did not affect the prediction of moisture
content thus demonstrating the robustness of the
calibration model
The work of Harris and Walker [159] involved
real-time quantification of organic solvents water and
mixtures thereof evaporating from a vacuum dryer A
fiber-optic coupled AOTF-NIR spectrometer was used
for data collection from the vapor stream and a
balance was placed in the dryer to record the reference
data PLS calibration models were built for on-line
prediction of optimal drying times Morris et al [160]
and Wildfong et al [161] used NIR in-line monitoring
to visualize the different stages during a fluid-bed
drying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes
Only recently Zhou et al [162] described the
advantage of NIRS for in-line monitoring of a drying
process with concomitant distinction between bound
and free water of a drug substance forming different
hydrates The study revealed that NIRS can serve as a
tool to ensure that the desired hydrate form is
achieved at the end of a drying process
An interesting paper on the in situ monitoring of a
freeze-drying process has recently been published by
Brqlls et al [163] A NIR fiber-optic probe fitted to a
FT spectrometer was placed in the center of a vial 1
mm above the bottom An aqueous PVP solution was
used as a model formulation NIR monitoring of the
different stages of the process namely freezing
primary and secondary drying was able to detect
the freezing point completion of ice formation and
transition from the frozen solution to an ice-free
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431130
material Moreover NIR spectra provided new infor-
mation about the drying process such as the
desorption rate and the steady-state value at which
drying was complete These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product character-
istics during freeze-drying thus increasing our
understanding of important parameters in the formu-
lation development of lyophilized products
533 Granulation
The production of tablets often requires a gran-
ulation step to improve powder flow and compaction
characteristics as well as to achieve content uniform-
ity Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps wetting granule formation
and drying At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content More-
over waterexcipient interactions hydrate formation
andor blend segregation may be assessed easily The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production
In 1996 List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15 ww was developed and validated using
Karl Fischer reference data Best results were obtained
with the following spectral pretreatments wavelength
selection (5000ndash5500 cm1) normalization and first
derivative The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation
Watano and co-workers [165166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
ments The authors observed a significant effect of the
liquid flow rate and the process air temperature [166]
Frake et al [167] reported the use of in-line NIR to
investigate granule water uptake and particle size
changes during aqueous top-spray fluid-bed granula-
tion During the process spectra were obtained every
25 min with a mounted fiber-optic probe fitted to a
grating-based spectrometer ranging from 1100 to
2500 nm To determine moisture content quantita-
tively and thus allowing for exact endpoint deter-
mination the second derivative absorbance changes at
1932 nm were calibrated against LOD and Karl
Fischer reference data A linear relationship was
obtained with SEC values in the order of 05 for
both models ranging from 15 to 11 ww of
moisture For particle growth monitoring the authors
tried to develop another calibration model again
based on one single wavelength only namely 2282
nm However considering the complex full range
spectral effects of particle size changes (see also
Section 51) it is not surprising that the authors failed
to develop an acceptable quantitative calibration
model for particle size determination
Goebel and Steffens [168] presented successful
data for a simultaneous on-line determination of
particle size and moisture content of samples in a
fluid-bed granulation process using a FT spectrometer
The robustness of the PLS calibration models based
on Karl Fischer and laser diffraction reference data
was evaluated by applying them to development and
pilot-scale plants The results clearly revealed that
particle size measurements are a greater challenge for
NIR on-line monitoring configurations than moisture
content determination a fact that was attributed to
sample presentation eg density effects and certain
variables of the fiber-optic probes
Rantanen and co-workers published a series of
papers [169ndash171] dealing with the evaluation of a
NIR sensor of only a few wavelengths for in-line
moisture monitoring of fluid-bed granulation In one
of the papers [171] the authors investigated the effect
of particle size particle composition and binder type
on NIR moisture monitoring using a full range off-line
FT spectrometer The study revealed that wetting and
particle growth changes the reflection and refraction
properties of the granules in a complex manner
depending not only on the wavelength but also on the
absorption properties of the powder matrix and the
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1131
binder type Calibration of in-line NIR moisture
measurements even with a fixed-wavelength setup
therefore requires understanding and consideration of
these factors affecting NIR signals
The use of spectral changes of solid powders and
granules associated with moisture uptake andor
moisture loss is not limited to moisture content
determinations They can help to understand the
chemical and physical performance of active com-
pounds and excipients in wet granulation processes
Buckton et al [172] used NIR to study the effect of
granulation on the structure of microcrystalline
(MCC) and silicified (SMCC) microcrystalline cellu-
lose and to explain the compressibility changes of
MCC after wet granulation It was found that MCC
SMCC and wet granulated SMCC had essentially
identical physical structures while wet granulated
MCC exhibited structural changes in the NIR spec-
trum related to CndashH bonding With the NIR assess-
ment of the altered physical structure it was possible
to explain the change in compressibility of MCC after
wet granulation
Derbyshire et al [173] used NIR together with
other analytical techniques namely DSC NMR and
TDS to study the molecular properties of water in
hydrated mannitol In accordance with the results
obtained from the other methods NIR spectral data at
5172 cm1 (OndashH bond of water) and 5930 cm1
(CndashH stretching peak) clearly indicated two transition
points for the coordination between water molecules
and mannitol molecules namely at 011 and 025 gg
respectively The authors speculate that the transitions
are associated with different stages of microdissolu-
tion of the solid thereby changing the hydrogen-
bonded network between water and mannitol eg the
molecular response of water and mannitol in the
spectra This result argues for the potential of NIR in-
line measurements in predicting the quantity of water
required for the successful formation of granules
[174]
With the opportunity to monitor solidwater inter-
actions ie to detect different states of water
molecules in a solid it is not surprising that NIR
spectra may also provide information on pseudopoly-
morphic transitions during wet granulation In two
subsequent papers R7sanen et al [55] and Jorgensen
et al [56] demonstrated the efficiency of NIR
spectroscopy to study the state of water and thus
the hydrate formation of anhydrous theophylline and
caffeine during wet granulation
534 Pelletization
Interestingly only little literature data is available
on NIR monitoring of pelletization In 1996 Wargo
and Drennen [175] developed an at-line NIR method
to monitor the layering of non-pareil seeds with an
aqueous suspension containing diltiazem HCl poly-
vinyl pyrrolidone and micronized talcum Three
independent calibration models were developed to
determine endpoint pellet potency of 15 30 and 55
ww diltiazem beads The models were successfully
transferred from a laboratory scale to pilot scale
Radtke et al [176] described in- and at-line NIR
configurations for moisture monitoring during matrix
pellet production in a rotary fluidized bed The authors
found out that sample presentation is as critical in this
case as in granulation process monitoring
535 Tabletting and capsule-filling
High speed automatic capsule filling and tabletting
machines require non-segregating powder blends or
granule mixtures with good flow characteristics to
work properly and ensure content uniformity and
consistent dissolution profiles of the final product In
practice segregation of free-flowing particulate mix-
tures with differences in particle size andor density is
likely to occur through inherent vibrations during
blender discharge batch transfer to the filling or
compression area and even within the equipment
Since NIR techniques are able to recognize
chemical and physical changes of particulate blends
[177] whole tablets and filled capsules noninvasive
NIR monitoring of tabletting and capsule filling from
the very beginning to the very end of the process
would be valuable to increase production speed and
improve product quality A NIR sensor on the feed
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
detect segregation problems of particulate matter upon
feeding the equipment The final product could be
further assessed for content uniformity dissolution
properties and in the case of tablets for hardness (see
also Section 52) Indeed there are some industrial
approaches leaning in this direction although they
have not yet been fully exploited due to limitations in
spectra collection of tablets or capsules produced at
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
Fig 6 NIR discrimination of Eudragit L film coats on tablets effect
of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431132
high speed However it might be expected that
progress in process instrumentation and chemometric
data processing will speed up the development of NIR
process monitoring in tabletting and capsule filling in
the near future
536 Film coating
Film coating is a process commonly employed in
the pharmaceutical industry to either improve the taste
or swallowing of tablets or to control drug dissolution
rate from the solid dosage forms Regardless of the
intended use the functionality of a film coat is closely
related to its thickness and uniformity around the solid
core In most production settings the endpoint of a
coating process is determined by in-process sample
acquisition the weighing of a known sample size and
the determination of the theoretical amount of applied
polymer Correct film coat thickness and uniformity
are evaluated indirectly by disintegration andor
dissolution testing In the PAT sense this analytical
procedure has two major disadvantages first deter-
mination of mass increase does not account for mass
loss of core material thus reducing the accuracy of
the method and secondly disintegration andor
dissolution testing are only indirect rather time-
consuming methods for the measurement of coating
levels and uniformity
NIR techniques on the other hand allow for a
rapid noninvasive at-line and in-line monitoring and
control of film coating processes prior to biopharma-
ceutical testing Kirsch and Drennen [178] and Wargo
and Drennen [175] were among the first to describe
the use of NIR for at-line monitoring of film coating
processes on tablets and pellets A Wurster column
was retrofitted with a sample thief allowing with-
drawal of 10-tablet samples during coating Samples
were collected after different time intervals and
measured on a grating-based NIR spectrometer in
reflectance mode In the case of pellets [175] coating
samples were classified by a bootstrap pattern
recognition technique The bootstrap standard devia-
tion plot made a qualitative identification of coating
endpoints possible In the case of tablets [178]
quantitative calibration models for the determination
of applied polymer solids namely ethylcellulose and
hydroxypropylmethyl cellulose formulations were
developed based on mass increase reference data (0ndash
30 ww) corrected for core attrition The NIR
method provided predictions of applied polymer films
with SEP values of 107 or less depending on the
coating formulation For pigment-free coating formu-
lations the calibration model was based mainly on
distinct absorption peaks of the coating polymer In
formulations containing high concentrations of water-
insoluble dyes and opacifying agents such as titanium
dioxide baseline shifts were the primary spectral
change caused by an increase in film thickness
Subsequent papers on this topic were published by
Andersson et al [179180] who described an indus-
trial in-line approach for film coat monitoring of
pharmaceutical pellets with fiber-optic probes Cali-
bration models for the determination of film coat
thickness were based on reference data obtained from
image analysis [181]
Despite these interesting and excellent papers
clearly reflecting the great value of NIR techniques
for at-line or in-line monitoring of a coating process
the multivariate potential of NIR spectroscopic meth-
ods has not been fully exploited in this field As
indicated by Reich and Frickel in a series of conference
proceedings [97ndash102] NIRS could be implemented as
a useful at-line or in-line tool to survey and determine
the effect of process conditions on film coat uniformity
(Fig 6) and related biopharmaceutical properties (see
also Section 521) As will be discussed in section
63 imaging techniques might be an additional tool to
improve product quality and the production speed of
film-coated dosage forms [182]
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1133
537 Packaging
Packaging is the last step in the production line of
a pharmaceutical product To ensure the product
safety of pharmaceuticals a last identity check of the
product on the packaging line would be highly
desirable Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently The system is supposed to
perform a 100 identity check at full line speed
(ie 12000 tablets per minute) before closing the
blister The potential of this type of equipment has
been evaluated in a feasibility study [183] Using
hard gelatin capsules of different shell and fill
compositions the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evalua-
tion of spectra collected on an off-line lab spectro-
meter to ensure the identification of flawed products
It may therefore be expected that other configu-
rations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines
ImagingOptic
Filter
FPASign
Proces
Sample
Fig 7 Basic configuration of a ne
6 NIR imaging
61 Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing A NIR imaging system
is basically composed of an illumination source an
imaging optic a spectral encoder selecting the wave-
lengths and a focal plane array (FPA) as indicated in
Fig 7 NIR light from an illumination system is
focussed upon the sample The diffuse reflectance
image of the sample is collected by an imaging optic
the configuration of which depends on the sample size
and type For macroscopic or microscopic images a
focusing lens or a microscope objective are used
respectively Data collection proceeds by recording a
series of images on the near-infrared (ie InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder such as a liquid crystal tunable
filter element (LCTF) or an interferometer The result
is a three-dimensional data set known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information
al
sing
False Colour Image
ar-infrared imaging system
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431134
Regarding instrumentation there are basically two
different approaches The first approach is the wave-
length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-
tionary and single images are recorded for each
wavelength The spectral information is provided
either by a number of discreet filters by tuneable
filters or by combination with an imaging Fourier-
transform spectrometer The images recorded for the
different wavelengths are combined by the software
and the spectra calculated The second approach also
known as bpush-broom scanningQ method requires a
relative movement between camera and sample to
scan over the surface The imaging system records the
spatial information linewise and provides the spectral
information for each pixel along the line by projection
along the second axis of the two-dimensional camera-
chip The spectral encoding is provided by either
linear variable filters a digital micro-mirror array in
combination with a grating or dispersive optics The
computer software combines the slices derives the
second axis and thus reconstructs the full image
Experimental setups based on the staring imager
method are mainly used in research and quality
control laboratories with data acquisition times of
typically 2 min or less The second approach is used
for conveyor belt survey with data acquisition times
depending on the spectral encoder A detailed
description of the different principles can be found
in some recent textbooks [184185]
62 Analytical targets and strengths
Conventional ie non-imaging NIR spectroscopy
analyzes the sample in bulk and determines an
average composition across the entire sample NIR
imaging on the other hand provides information
about the spatial distribution of the components
comprising the sample It is therefore a powerful
bline extensionb of conventional NIR analysis in a
number of different ways [186]
The opportunity to visualize the spatial distribution
of a chemical species throughout the sample enables
the degree of chemical andor physical heteroge-
neity within a given sample to be determined
The array-based spectral sensing of a NIR imaging
system also allows for trace sample measurements
because the spectral data are collected in parallel
and thus are not hampered by a dilution effect in
the same way as NIR bulk measurements are This
is a great advantage over conventional NIRS when
analyzing low dose actives or excipients in a
pharmaceutical formulation
Moreover NIR imaging enables quantitative infor-
mation to be obtained without running separate
calibration samples since pure component spectra
are directly available from the spectral imaging
data cube of heterogeneously mixed samples This
approach can help to save time and money when
building a quantitative calibration model for
pharmaceutical applications in particular for
expensive peptide or protein drug formulations
NIR spectroscopic imaging has only a short
history when compared with MIR and Raman
imaging techniques This is due to the fact that its
advantages over Raman and MIR imaging techni-
ques such as adaption to a wide variety of fields-
of-view (FOV) and extreme tolerance to variations
in sample geometry have only recently been fully
exploited [186] With the use of simple quartzndash
tungsten halogen sources and an image filtering
instead of a source filtering approach NIR imaging
techniques enable wide-field illumination for a
variety of magnifications and imaging modes
ranging from around 02 to 125 mm In addition
flatness of the sample is not a prerequisite as in
Raman and MIR imaging On the contrary NIR
imaging systems allow experiments to be performed
on very irregular samples since NIR imaging
systems perform well in the reflectance mode with
large depths-of-field and an excellent signal-to-noise
ratio of the arrays
63 Pharmaceutical applications
With the addition of spatial information and
parallel data collection NIR imaging certainly meets
the challenging analytical needs of pharmaceutical
quality and process control and may serve as a
versatile adjunct to conventional non-imaging NIR
spectroscopy in many fields Despite the obvious
strengths of NIR imaging techniques the number of
scientific papers and technical notes describing their
practical use is limited and mainly in other fields
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1135
eg plastic sorting [187] high-throughput screening
of biological material [186] on conveyor belts
remnant analysis of works of art [188] and
identification of atherosclerotique plaques by means
of an intra-arterial catheter imaging system recently
developed at the University of Kentucky Pharma-
ceutical papers as discussed in more detail in the
following paragraphs focus on three different
aspects namely blend uniformity analysis in pow-
ders and tablets composition and morphological
features of coated tablets and multi-layer granules
and spatial changes in biodegradable PLGA matrix
systems upon matrix hydration degradation and
active release
El-Hagrasy et al [154] used an InSb imaging
camera with discrete bandpass filters encompassing
absorption bands of the blend components in
addition to a conventional NIR fiber-optic probe in
six sapphire windows mounted at different locations
in a V-blender to monitor powder blend homoge-
neity of salicylic acidlactose mixtures and compare
the potential of the two techniques Data analysis
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
tional NIRS and clearly revealed that coupling both
techniques might provide a very robust tool for
monitoring powder blending since the volume of
powder captured by the imaging technique is much
larger
Koehler et al [186] demonstrated the use of NIR
imaging to visualize and quantify the spatial dis-
tribution of the active ingredient in a tablet The
authors used an unsupervised PCA score plot to
qualitatively visualise the degree of chemical hetero-
geneity of the formulation showing the active in
unevenly distributed clumps An alternate least
square regression method based on pure component
spectra isolated from the spectral data cube of the
tablet was used to build a quantitative concentration
distribution estimate of the active in the tablet
Although in this special case the active concen-
tration was 20 by weight the example clearly
demonstrates the strength of NIR imaging for the
analysis of low dose drugs
Correlation of physical properties and technolog-
ical functionality of powder blends with their chem-
ical heterogeneity is the approach described by
Hammond and Clarke [189] The group has used
NIR imaging to identify mixing problems as being
responsible for bad and good flow characteristics of
powder blends as well as tablet sticking and tablet
fracture The results clearly reveal that NIR imaging is
a powerful tool for matrix characterization not only in
final product control but also in research develop-
ment and scale-up of solid pharmaceutical dosage
forms ie for process and formulation optimization
purposes
The same group pointed out that matrix character-
ization of complex solid dosage forms requires an
understanding of the spatial relationship and inter-
action of drug formulation components NIR imaging
was therefore used to examine the internal structure
of time-release granules [190] The chemical image of
a bisected granule (09 mm2) was obtained at 10-nm
intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of
approximately 2 min In contrast to the visible image
the NIR chemical image clearly revealed that the
distinct layers and boundaries were consistent with the
expected physical structure and composition of this
particular formulation
Another interesting application of NIR imaging is
the chemical visualization of coating layers on
tablets In a technical note published at the AAPS
Annual Meeting in 2001 Lewis and co-workers
[190] showed the chemical image of a sectioned
multilayer-coated tablet The macroscopic chemical
image depicted the tablet core and two distinct
coating layers of different thickness Due to the large
field-of-view (FOV) a detailed examination of the
film coat uniformity on the tablet core was not
feasible Moreover sectioning of the tablet was
necessary to achieve the multilayer chemical image
of the tablet However considering that formulation-
andor process-induced microheterogeneities in film
coats on tablets or pellets might have rather
important implications on their biopharmaceutical
properties the necessity of spectroscopic imaging
techniques for film coat uniformity analysis is
obvious Interestingly the application of microscopic
ATR-FTIR imaging rather than NIR imaging has
been reported for this purpose [182] Nondestructive
chemical images (250 Am250 Am) of Eudragit FS
30 D film coats were obtained from different areas
(ie at the center part and at the edges) of the tablets
to visualize and relate different coating levels
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431136
process andor curing conditions to film coat
uniformity The study revealed that due to its low
penetration depth ATR-FTIR imaging may provide
interesting new insights in the processes involved in
film coating and thus a better understanding and
control of manufacturing defects resulting in func-
tionally important microheterogeneities Although
using the mid-IR this example again indicates the
overall great potential of spectroscopic imaging
techniques in research development scale-up and
production control of pharmaceutical dosage forms
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(dl-
lactide-co-glycolide) (PLGA) matrix systems for
parenteral use As discussed in Section 524
hydration degradation and drug release kinetics can
be successfully monitored by classical NIR spectro-
scopy however without any information on the
spatial changes In an attempt to fill this gap NIR
imaging was used (1) to investigate the time-depend-
ent spatial microenvironmental changes within bio-
degradable PLGA films upon in vitro hydration and
degradation in different media [191] and (2) to
chemically visualize the distribution and relative
abundance of a model protein namely lysozyme in
PLGA matrix tablets immediately after processing
and during the release phase [182] Within these
studies it could be demonstrated for the first time
without fluorescence-labeling that during the release
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600
15
10
5
-5
-10
0
Micron
Mic
ron
A
Fig 8 False-color near-infrared images of lysozyme distribution (10 ini
(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=
phase protein adsorption on the PLGA matrix
certainly occurs (Fig 8)
In conclusion the literature data discussed in this
section clearly reveal that spectroscopic imaging
approaches with NIR imaging in particular have a
huge potential for gaining rapid information about the
chemical structure and related physical or biopharma-
ceutical properties of all types of pharmaceutical
dosage forms thus improving product quality and
enhancing production speed
7 Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging As a fast and noninvasive
multivariate technique conventional NIR spectro-
scopy has already gained wide industrial acceptance
for raw material identification andor qualification
and nondestructive chemical analysis of intact dosage
forms Considering the continuing improvements in
hardware and software design and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release it is
anticipated that in the near future both NIR spectro-
scopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control
50
40
30
20
10
0
25750
25700
25650
25600
25550
53400 53450 53500 53550 53600Micron
Mic
ron
B
tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet
37 8C)
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1137
References
[1] PC Williams KH Norris WS Zarowski Influence of
temperature on estimation of protein and moisture in wheat by
near-infrared reflectance Cereal Chem 59 (1982) 473ndash480
[2] EW Ciurczak Principles of near-infrared spectroscopy in
DA Burns EW Ciurczak (Eds) Handbook of Near-
Infrared Analysis 2nd edition Marcel Dekker Inc New
YorkBasel 2001 pp 7ndash18
[3] L Bokobza Origin of near-infrared absorption bands in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41
[4] T Burger Radiative transfer in disperse mediamdashnew
procedures in spectroscopic infrared analysis PhD thesis
WqrzburgGermany 1998
[5] JM Olinger PR Griffiths T Burger Theory of diffuse
reflection in the NIR region in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51
[6] S Kawata New techniques in near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 75ndash84
[7] JJ Workman Jr DA Burns Commercial NIR instrumen-
tation in DA Burns EW Ciurczak (Eds) Handbook of
Near-Infrared Analysis 2nd edition Marcel Dekker Inc
New YorkBasel 2001 pp 53ndash70
[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak
(Eds) Handbook of Near-Infrared Analysis 2nd edition
Marcel Dekker Inc New YorkBasel 2001 pp 71ndash90
[9] S Kawata Instrumentation for near-infrared spectroscopy in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 43ndash74
[10] A Candolfi DL Massart S Heuerding Investigation of
sources of variance which contribute to NIR-spectroscopic
measurement of pharmaceutical formulations Anal Chim
Acta 345 (1997) 185ndash196
[11] S Kawano Sampling and sample presentation in HW
Siesler Y Ozaki S Kawata HM Heise (Eds) Near
Infrared Spectroscopy Principles Instruments Applications
Wiley-VCH Verlag GmbH Weinheim 2002 pp 115ndash124
[12] M Blanco J Coello H Itirriaga S Maspoch C de la
Pezuela Near-infrared spectroscopy in the pharmaceutical
industry Analyst 123 (1998) 135Rndash150R
[13] HM Heise R Winzen Fundamental chemometric meth-
ods in HW Siesler Y Ozaki S Kawata HM Heise
(Eds) Near Infrared Spectroscopy Principles Instruments
Applications Wiley-VCH Verlag GmbH Weinheim 2002
pp 125ndash162
[14] Mark Howard Data analysis multilinear regression and
principal component analysis in DA Burns EW
Ciurczak (Eds) Handbook of Near-Infrared Analysis
2nd edition Marcel Dekker Inc New YorkBasel 2001
pp 129ndash184
[15] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 27ndash54
[16] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 93ndash104
[17] W Plugge C van der Vlies The use of near infrared
spectroscopy in the quality control laboratory of the
pharmaceutical industry J Pharm Biomed Anal 10
(1992) 797ndash803
[18] T Naes T Isaksson T Fearn T Davies Multivariate
Calibration and Classification NIR Publications Chichester
2002 pp 221ndash260
[19] W Plugge C van der Vlies Near-infrared spectroscopy as
an alternative to assess compliance of ampicillin trihydrate
with compendial specifications J Pharm Biomed Anal 11
(1993) 435ndash442
[20] Near-infrared spectrometry Chapter 2240 European Phar-
macopoeia 4th edition 2001 pp 55ndash56
[21] Near-infrared spectrophotometry Chapter 1119 United
States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391
[22] American Society for Testing and Materials E1866-97
Standard Guide for Establishing Spectrophotometer Perform-
ance Tests and E1655 Standard practices for infrared
multivariate quantitative analysis Official ASTM Publica-
tions Philadelphia PA 2000
[23] Report by the analytical methods committee evaluation of
analytical instrumentation Part XIII Instrumentation for
UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374
[24] Validation of compendial methods Chapter 1225 United
States Pharmacopoeia USP26 2002 pp 2439ndash2442
[25] ICH Quality Guidelines for Method Validation Q2A Text on
Validation of Analytical Procedures and Q2B Validation of
Analytical Procedures Methodology November 1996 FDA
(httpwwwifpmaorgich5html)
[26] AC Moffat AD Trafford RD Jee P Graham Meeting
the International Conference on Harmonisationrsquos Guidelines
on Validation of Analytical Procedures quantification as
exemplified by a near-infrared reflectance assay of para-
cetamol in intact tablets Analyst 125 (2000) 1341ndash1351
[27] PASG Guidelines for the Development and Validation of Near
Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39
(httpwwwpasgorgukNIRmay01pdf)
[28] USFDA Draft Guidance for Industry PATmdasha framework for
innovative pharmaceutical manufacturing and quality assur-
ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft
doc)
[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S
Lonardi Application of NIRS to the control of pharmaceut-
icals identification and assay of several primary materials
Pharm Acta Helv 67 (1992) 57ndash61
[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active
substances using near-infrared spectroscopy Pharm Ind 62
(2000) 301ndash304
[31] M Ulmschneider G Barth E Trenke Building transferable
cluster calibrations for the identification of different solid
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431138
excipients with near-infrared spectroscopy Pharm Ind 62
(2000) 374ndash376
[32] K Kr7mer S Ebel Application of NIR reflectance spectro-
scopy for the identification of pharmaceutical excipients
Anal Chim Acta 420 (2000) 155ndash161
[33] K Beckenkamp M Ohm K Molt O Mandal The
challenge of identity testing Eur Pharm Rev (2001) 28ndash33
[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze
Dissertation Essen (1998)
[35] SS Thosar RA Forbess M Kemper AJ Shukla
Determination of copolymer ratios of poly(lactide-co-glyco-
lide) using near-infrared spectroscopy J Pharm Biomed
Anal 20 (1999) 107ndash114
[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni
CM Caramella Characteristics of hydroxypropyl methyl-
cellulose influencing compactibility and prediction of particle
and tablet properties by infrared spectroscopy J Pharm Sci
92 (2003) 494ndash504
[37] E Storz Untersuchung funktioneller Parameter pharmazeu-
tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-
tation Bonn (2003)
[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an
pharmazeutischen Hilfsstoffen und festen Arzneiformen
Dissertation Bonn (2003)
[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug
substances Appl Spectrosc 51 (1997) 1504ndash1510
[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung
DC Lee Construction and transferability of a spectral
library for the identification of common solvents by near-
infrared transflectance spectroscopy Analyst 124 (1999)
1197ndash1203
[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA
Hailey DL Massart The influence of data processing in the
pattern recognition of excipients near infrared spectra
J Pharm Biomed Anal 21 (1999) 115ndash132
[42] MS Kemper LM Luchetta A guide to raw material
analysis using near infrared spectroscopy J Near Infrared
Spectrosc 11 (2003) 155ndash174
[43] JE Sinsheimer NM Poswalk Pharmaceutical applications
of the near infrared determination of water J Pharm Sci 57
(1968) 2007ndash2010
[44] X Zhou P Hines ME Borer Moisture determination in
hygroscopic drug substances by near infrared spectroscopy
J Pharm Biomed Anal 17 (1998) 219ndash225
[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols
The use of near-infrared spectroscopy to monitor the mobility
of water within the sarafloxacin crystal lattice J Pharm
Biomed Anal 22 (2000) 829
[46] EW Ciurczak RP Torlini MP Demkowicz Determination
of particle size of pharmaceutical raw materials using near-
infrared reflectance spectroscopy Spectroscopy 1 (1986)
36ndash39
[47] IL Ikari H Martens T Isaksson Determination of particle
size in powders by scatter correction in diffuse near-infrared
reflectance Appl Spectrosc 42 (1988) 722ndash728
[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez
R Pous Chapter 64 in KI Hildrum T Isaksson T Naes
A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging
the Gap Between Data Analysis and NIR Applications) Ellis
Horwood Chichester 1992 pp 401ndash406
[49] AJ OrsquoNeil RD Jee AC Moffat The application of
multiple linear regression to the measurement of the
median particle size of drugs and pharmaceutical exci-
pients by near-infrared spectroscopy Analyst 123 (1998)
2297ndash2302
[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse
UA Jayasooriya Near-infrared mass median particle size
determination of lactose monohydrate evaluating several
chemometric approaches Analyst 123 (1998) 2043ndash2046
[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of
cumulative particle size distribution of microcrystalline
cellulose using near infrared reflectance spectroscopy
Analyst 124 (1999) 33ndash36
[52] E Storz K-J Steffens Bestimmung der spezifischen
Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-
frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402
[53] AD Patel PE Luner MS Kemper Quantitative analysis of
polymorphs in binary and multi-component powder mixtures
by near-infrared reflectance spectroscopy Int J Pharm 206
(2000) 63ndash74
[54] AD Patel PE Luner MS Kemper Low-level determi-
nation of polymorph composition in physical mixtures of
near-infrared reflectance spectroscopy J Pharm Sci 90
(2001) 360ndash370
[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T
Paakkari J Yliruusi Novel identification of pseudopoly-
morphic changes of theophylline during wet granulation
using near infrared spectroscopy J Pharm Sci 90 (2001)
389ndash396
[56] A Jaergensen J Rantanen M Karjaleinen L
Khriachtchev E R7sanen J Yliruusi Hydrate formation
during wet granulation studied by spectroscopic methods
Pharm Res 19 (2002) 1285ndash1291
[57] G Buckton E Yonemochi J Hammond A Moffat The use
of near infra-red spectroscopy to detect changes in the form
of amorphous and crystalline lactose Int J Pharm 168
(1998) 231ndash241
[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz
PC Schmidt Investigations on polymorphism of mannitol
sorbitol mixtures after spray-drying using differential scan-
ning calorimetry X-ray diffraction and near-infrared spectro-
scopy Pharm Ind 62 (2000) 231ndash235
[59] JJ Seyer PE Luner MS Kemper Application of diffuse
reflectance near-infrared spectroscopy for determination of
crystallinity J Pharm Sci 89 (2000) 1305ndash1316
[60] SE Hogan G Buckton The application of near-infrared
spectroscopy and dynamic vapor sorption to quantify low
amorphous contents of crystalline lactose Pharm Res 18
(2001) 112ndash116
[61] SE Hogan G Buckton Water sorptiondesorption-near IR
and calorimetric study of crystalline and amorphous raffi-
nose Int J Pharm 227 (2001) 57ndash69
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1139
[62] A Columbano G Buckton P Wikeley A study of the
crystallization of amorphous salbutamol sulphate using water
vapour sorption and near infrared spectroscopy Int J Pharm
237 (2002) 171ndash178
[63] M Blanco A Villar Development and validation of a method
for the polymorphic analysis of pharmaceutical preparations
using near infrared spectroscopy J Pharm Sci 92 (2003)
823ndash830
[64] T Burger J Kuhn R Caps J Fricke Quantitative
determination of the scattering and absorption coefficients
from diffuse reflectance and transmittance measurements
application to pharmaceutical powders Appl Spectrosc 51
(1997) 309ndash317
[65] T Burger J Fricke J Kuhn NIR radiative transfer
investigations to characterize pharmaceutical powders and
their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40
[66] JD Kirsch JK Drennen Near-infrared spectroscopy
applications in the analysis of tablets and solid pharma-
ceutical dosage forms Appl Spectrosc Rev 38 (1995)
139ndash174
[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK
Drennen III (Eds) Pharmaceutical and Medical Applications
of Near-Infrared Spectroscopy Marcel Dekker New York
Basel 2002 pp 73ndash105
[68] MA Dempster JA Jones IR Last BF McDonald KA
Prebbe Near-infrared methods for the identification of tablets
in clinical trial supplies J Pharm Biomed Anal 11 (1992)
1087ndash1092
[69] PK Aldridge RF Mushinsky MM Andino CL Evans
Identification of tablet formulations inside blister packages
by near-infrared spectroscopy Appl Spectrosc 48 (1994)
1272ndash1276
[70] N Sondermann K-A Kovar Screening experiments of
ecstasy street samples uring near infared spectroscopy
Forensic Sci Int 106 (1999) 147ndash156
[71] J Gottfries H Depui M Fransson M Jongeneelen M
Josefson FW Langkilde DT Witte Vibrational spectro-
scopy for the assessment of active substance in metoprolol
tablets a comparison between transmission and diffuse
reflectance near-infrared spectrometry J Pharm Biomed
Anal 14 (1996) 1495ndash1503
[72] SS Thosar RA Forbess NK Ebube Y Chen RL
Rubinovitz MS Kemper GE Reier TA Wheatley AJ
Shukla A comparison of reflectance and transmittance near-
infrared spectroscopic techniques in determinung drug
content in intact tablets Pharm Dev Technol 6 (2001)
19ndash29
[73] JL Ramirez MK Bellamy RJ Romanach A novel
method for analyzing thick tablets by near infrared spectro-
scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http
wwwpharmscitechcom))
[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch
Development and validation of a method for the analysis of a
pharmaceutical preparation by near-infrared diffuse reflec-
tance spectroscopy J Pharm Sci 88 (1999) 551ndash556
[75] M Blanco A Eustaquio JM Gonzalez D Serrano
Identification and quantification assays for intact tablets of
two related pharmaceutical preparations by reflectance near-
infrared spectroscopy validation of the procedure J Pharm
Biomed Anal 22 (2000) 139ndash148
[76] T Li AD Donner CY Choi GP Frunzi KR Morris A
statistical support for using spectroscopic methods to validate
the content uniformity of solid dosage forms J Pharm Sci
92 (2003) 1526ndash1530
[77] M Blanco J Coello H Iturriaga S Maspoch C de la
Pezuela Quantitation of the active compound and major
excipients in a pharmaceutical formulation by near infrared
diffuse reflectance spectroscopy with fibre optical probe
Anal Chim Acta 333 (1996) 147ndash156
[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative
near infrared spectrometry used for the determination of
the drug content of tolbutamide tablets Pharm Ind 58
(1996) 847ndash852
[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA
Robinson Use of near-infrared spectroscopy to evaluate an
active in a film coated tablet Pharm Res 13 (1996)
616ndash621
[80] P Merckle K-A Kovar Assay of effervescent tablets by
near-infrared spectroscopy in transmittance and reflectance
mode acetylsalicylic acid in mono and combination for-
mulations J Pharm Biomed Anal 17 (1998) 365ndash374
[81] A Eustaquio P Graham RD Jee AC Moffat AD
Trafford Quantification of paracetamol in intact tablets using
near-infrared transmittance spectroscopy Analyst 123 (1998)
2303ndash2306
[82] AD Trafford RD Jee AC Moffat P Graham A rapid
quantitative assay of intact paracetamol tablets by reflectance
near-infrared spectroscopy Analyst 124 (1999) 163ndash167
[83] P Corti G Ceramelli E Dreassi S Matti Near infrared
transmittance analysis for the assay of solid pharmaceutical
dosage forms Analyst 124 (1999) 755ndash758
[84] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[85] J-K Drennen RA Lodder Non-destructive near-infrared
analysis of intact tablets for determination of degradation
products J Pharm Sci 79 (1990) 622ndash627
[86] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 April
(2000) pp 279ndash280
[87] JD Kirsch JK Drennen Determination of film-coated
tablet parameters by near-infrared spectroscopy J Pharm
Biomed Anal 13 (1995) 1273ndash1281
[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as
a nondestructive alternative to conventional hardness testing
Pharm Res 14 (1997) 108ndash111
[89] JD Kirsch JK Drennen Nondestructive tablet hardness
testing by near-infrared spectroscopy a new and robust
spectral best-fit algorithm J Pharm Biomed Anal 19
(1999) 351ndash362
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431140
[90] NK Ebube SS Thosar RA Roberts MS Kemper
RL Rubinowitz DL Martin GE Reier TA Wheatley
AJ Shukla Application of near-infrared spectroscopy
(NIRS) for nondestructive analysis of powders and tablets
simultaneous determination of avicel type crushing
strength and lubricant concentration of intact tablets by
diffuse reflectance technique Pharm Dev Technol 4
(1999) 19ndash26
[91] G Reich Use of NIR transmission spectroscopy for non-
destructive determination of tablet hardness Proc 3rd World
Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106
[92] Y Chen SS Thosar RA Forbess MS Kemper RL
Rubinowitz AJ Shukla Prediction of drug content and
hardness of intact tablets using artificial neural network and
near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)
623ndash631
[93] C Nystrfm G Alderborn M Duberg P-G Karehill
Bonding surface area and bonding mechanism-two important
factors for the understanding of powder compactability Drug
Dev Ind Pharm 19 (1993) 2143ndash2196
[94] G Reich Nondestructive determination of tablet hardness
and consolidation characteristics using NIR transmission
spectroscopy AAPS Annual Meeting and Exposition Den-
ver 2001 p M 2283
[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-
scopic prediction of the dissolution rate of carbamazepine
tablets Pharm Res 8 (1991) 974ndash978
[96] JK Drennen RA Lodder Qualitative analysis using near-
infrared spectroscopy A comparison of discriminant methods
in dissolution testing Spectroscopy 8 (1991) 34ndash39
[97] G Reich H Frickel Use of transmission spectroscopy to
determine physical and functional film coat properties on
tablets Proc Int Symp Control Release Bioact Mater 26
(1999) 905ndash906
[98] G Reich H Frickel NIR spectroscopymdasha rapid method to
evaluate gastroresistance and drug release kinetics of film-
coated tablets Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 627ndash628
[99] H Frickel G Reich NIR spectroscopy of film-coated
tabletsmdashfast and nondestructive evaluation of film coat
uniformity and drug release kinetics Proc Int Symp
Control Release Bioact Mater 27 (2000) 740ndash741
[100] H Frickel G Reich Performance optimization of NIR
transmission spectroscopy of coated tabletsmdasha light-guided
journey Proc 3rd World Meeting APVAPGI Berlin 36
2000 (April) pp 625ndash626
[101] H Frickel G Reich Nondestructive monitoring of
physical and biopharmaceutical film coat properties on
tablets AAPS Annual Meeting and Exposition Denver
2001 p M 2309
[102] H Frickel P Aebi G Fricker G Reich Real thickness of
Eudragit-based film coats on tablet coresmdashnondestructive
analysis with near-infrared transmission spectroscopy
Pharm Sci Suppl 1 (1998) 22
[103] RA Lodder M Selby GM Hieftje Detection of capsule
tampering by near-infrared reflectance analysis Anal Chem
59 (1987) 1921ndash1930
[104] RG Buice Jr TB Gold RA Lodder GA Digenis
Determination of moisture in intact gelatin capsules by near-
infrared spectroscopy Pharm Res 12 (1995) 161ndash163
[105] O Berntsson G Zachrisson G Ostling Determination of
moisture in hard gelatin capsules using near-infrared spectro-
scopy applications to at-line process control of pharmaceu-
tics J Pharm Biomed Anal 15 (1997) 895ndash900
[106] G Reich Effect of drying on structure and properties of
gelatin capsule shells a study with model films Pharm Ind
57 (1995) 63ndash67
[107] TB Gold RG Buice Jr RA Lodder GA Digenis
Determination of extent of formaldehyde-induced crosslink-
ing in hard gelatin capsules by near infrared spectroscopy
Pharm Res 14 (1997) 1046ndash1050
[108] G Reich Use of DSC DMTA and NIRTS to determine hard
gelatin capsule characteristics associated with brittleness a
mechanistic study Pharm Sci Suppl 1 (1999)
[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared
transmission spectroscopy to detect batch-to-batch variability
of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)
[110] G Reich Fast and non-destructive quality control of gelatin
capsule shells Proc 3rd World Meeting APVAPGI Berlin
36 2000 (April) pp 493ndash494
[111] M Rama G Reich Monitoring structural changes in hard
and soft gelatin films and capsules using NIR transmission
and reflectance spectroscopy Proc 3rd World Meeting APV
APGI Berlin 36 2000 (April) pp 507ndash508
[112] G Reich NIR spectroscopymdashan alternative approach to
assess the mechanical performance of hard gelatin
capsules AAPS Annual Meeting and Exposition Denver
2001 p M 2233
[113] G Reich Mechanism and optimization of plasticizers in soft
gelatin capsules Pharm Ind 56 (1994) 915ndash920
[114] G Reich Effect of sorbitol specification on structure and
properties of soft gelatin capsule shells Pharm Ind 58
(1996) 941ndash946
[115] TB Gold RG Buice Jr RA Lodder GA Digenis
Detection of formaldehyde-induced crosslinking in soft
elastic gelatin capsules using near-infrared spectrophotom-
etry Pharm Dev Technol 3 (1998) 209ndash214
[116] J Mqller G Reich Importance of Wavelength Selection in
Quantitative Near-Infrared Spectroscopy of Polyols in Cap-
sule Formulations ICNIRS Cordoba 2003 p 67
[117] J Mqller G Reich A comparison of multivariate regression
models in quantitative near-infrared spectroscopy Poster at
DPhG Meeting of PhD students Frankfurt 2002
[118] J Mqller G Reich Influence of wavelength selection in
quantitative near-infrared spectroscopy Arch Pharm 335 (1)
(2002)
[119] J Mqller G Reich Determination of plasticizer content in
softgel capsule formulations using near-infrared spectroscopy
and multivariate regression methods AAPS Annual Meeting
and Exposition Toronto 2002 p W 5343
[120] MS Kamat RA Lodder PP DeLuca Near-infrared
spectroscopic determination of residual moisture in lyophi-
lised sucrose through intact glass vials Pharm Res 6 (1989)
961ndash965
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1141
[121] IR Last KA Prebbe Suitability of near-infrared methods
for the determination of moisture in a freeze-dried injection
product containing different amounts of active ingredient
J Pharm Biomed Anal 11 (1993) 1071ndash1076
[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-
ment and transferability of near-infrared methods for
determination of moisture in a freeze-dried injection product
J Pharm Biomed Anal 11 (1993) 1227ndash1231
[123] MWJ Derksen PJM van de Oetelaar FA Maris The
use of near-infrared spectroscopy in the efficient prediction
of a specification for the residual moisture content of a
freeze-dried product J Pharm Biomed Anal 17 (1998)
473ndash480
[124] TP Lin CC Hsu Determination of residual moisture in
lyophilized protein pharmaceuticals using a rapid and non-
invasive method near infrared spectroscopy J Pharm Sci
Technol 56 (2002) 196ndash205
[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy
High Speed Noninvasive Qualification of Lyophilized Vials
ICNIRS Cordoba 2003 p O61
[126] G Reich Noninvasive and simultaneous monitoring of
chemical and physical properties an analytical approach to
lyophilized proteins sugars and proteinsugar mixtures
Proc 3rd World Meeting APVAPGI Berlin 36 2000
(April) pp 279ndash280
[127] K K7lkert G Reich Near infrared spectroscopic evaluation
of stress-induced structural changes of proteins in solid and
solution state Proc 3rd World Meeting APVAPGI Berlin 3
6 2000 (April) pp 335ndash336
[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova
Y Ozaki Comparison between conventional spectral analysis
methods chemometrics and two-dimensional correlation
spectroscopy in the analysis of near-infrared spectra of
protein Appl Spectrosc 54 (2000) 978ndash985
[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for polymer implants and
microspheres PharmSci 1 (1998) 20
[130] RL Brashear DR Flanagan PE Luner JJ Seyer MS
Kemper Diffuse reflectance near-infrared spectroscopy as a
nondestructive analytical technique for implants J Pharm
Sci 88 (1999) 1348ndash1353
[131] G Reich Use of DSC and NIR spectroscopy to study the
hydration degradation and drug release behavior of PLA
PLGA microparticles and films with free and blocked
carboxylic end groups Proc Int Symp Control Release
Bioact Mater 27 (2000) 642ndash643
[132] G Reich T Schfnbrodt Fast and noninvasive near infrared
analysis of PLA and PLGA microparticles films and tablets
Proc Int Symp Control Release Bioact Mater 28 (2001)
387ndash388
[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel
approach to monitor drug release kinetics from biodegradable
PLGA tablets Proc 4th World Meeting ADRITELFAPGI
APV Florence 811 2002 (April) pp 303ndash304
[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-
tive quantification of lyophilised protein drugs in lipid
matrices AAPS Annual Meeting and Exposition Toronto
2002 p T 3355
[135] T Schfnbrodt G Reich Protein Release from Biodegradable
PLGA Tablets Monitored by Near Infrared Spectroscopy
ICNIRS Cordoba 2003 p P64
[136] HW Siesler Application to industrial process control in
HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-
Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-
heim Germany 2002 pp 247ndash268
[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ
Urbanski FF Sistare T Norris PK Aldridge On-line
determination of reaction completion in a closed-loop
hydrogenator using NIR spectroscopy Appl Spectrosc 52
(1998) 17ndash21
[138] C Coffey BE Cooley DS Walker Real time quantitaion
of a chemical reaction by fiber optic near-infrared spectro-
scopy Anal Chim Acta 395 (1999) 335ndash341
[139] T Norris PK Aldridge SS Sekulic Determination of end-
points for polymorph conversions of crystalline organic
compounds using on-line near-infrared spectroscopy Analyst
122 (1997) 549ndash552
[140] K De Braekeleer R De Maesschalk PA Hailey DCA
Sharp DL Massart On-line application of the orthogonal
projection approach (OPA) and the soft independent model-
ling of class analogy approach (SIMCA) for the detection of
the end point of a polymorph conversion reaction by near
infrared spectroscopy (NIR) Chemom Intell Lab Syst 46
(1999) 103ndash116
[141] H Chung MA Arnold M Rhiel DW Murhammer
Simultaneous measurements of glucose glutamine ammo-
nia lactate and glutamate in aqueous solution by near-
infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276
[142] KSY Yeung M Hoare NF Thornhill T Williams
JD Vaghjiani Near-infrared spectroscopy for bioprocess
monitoring and control Biotechnol Bioeng 63 (1999)
684ndash693
[143] MR Riley HM Crider The effect of analyte concentration
range on measurement errors obtained by NIR spectroscopy
Talanta 52 (2000) 473ndash484
[144] HJ Venables JI Wells Powder mixing Drug Dev Ind
Pharm 27 (2001) 599ndash612
[145] EW Ciurczak Pharmaceutical mixing studies using near-
infrared spectroscopy Pharm Technol 15 (1991) 140ndash145
[146] FC Sanchez J Toft B van den Bogaert DL Massart SS
Dive P Hailey Monitoring powder blending by NIR
spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778
[147] DJ Wargo JK Drennen Near-infrared spectroscopic
characterization of pharmaceutical powder blends J Pharm
Biomed Anal 14 (1996) 1415ndash1423
[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL
Evans ST Sciavolino PA Haily PK Aldridge Online
monitoring of powder homogeneity by near-infrared spectro-
scopy Anal Chem 68 (1996) 509ndash513
[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge
Automated system for the on-line monitoring of powder
blending processes using near-infrared spectroscopy
J Pharm Biomed Anal 14 (1996) 551ndash559
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431142
[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-
mated system for the on-line monitoring of powder blending
processes using near-infrared spectroscopy Part II Qualita-
tive approaches to blend evaluation J Pharm Biomed Anal
17 (1998) 1285ndash1309
[151] R De Maesschalck F Cuesta Sanchez DL Massart P
Doherty P Hailey On-line monitoring of powder blending
with near-infrared spectroscopy Appl Spectrosc 52 (1998)
731ndash752
[152] C Ufret K Morris Modeling of powder blending using on-
line near-infrared measurements Drug Dev Ind Pharm 27
(2001) 719ndash729
[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-
mans S Reynolds A homogeneity study using NIR
spectroscopy tracking magnesium stearate in Bohle bin-
blender Drug Dev Ind Pharm 29 (2003) 679ndash687
[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder
JK Drennen III Near-infrared spectroscopy and imaging for
the monitoring of powder blend homogeneity J Pharm Sci
90 (2001) 1298ndash1307
[155] O Berntsson L-G Danielsson S Folestad Characterization
of diffuse reflectance fiber probe sampling in moving solids
using a Fourier transform near-infrared spectrometer Anal
Chim Acta 431 (2001) 125ndash131
[156] O Berntsson Characterization and application of near infra-
red reflection spectroscopy for quantitative process analysis
of powder mixtures Doctoral Thesis Stockholm (2001)
[157] O Berntsson LG Danielsson B Lagerholm S Folestad
Quantitative in-line monitoring of powder blending by near
infrared reflection spectroscopy Powder Technol 123 (2002)
185ndash193
[158] JG White On-line moisture detection for a microwave
vacuum dryer Pharm Res 11 (1994) 728ndash732
[159] SC Harris DS Walker Quantitative real-time monitoring
of dryer effluent using fiber optic near infrared spectroscopy
J Pharm Sci 89 (2000) 1180ndash1186
[160] KR Morris JG Stowell SR Byrn AW Placette TD
Davis GE Peck Accelerated fluid-bed drying using NIR
monitoring and phenomenological modeling Drug Dev Ind
Pharm 26 (2000) 985ndash988
[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris
Accelerated fluid-bed drying using NIR monitoring and
phenomenological modeling method assessment and for-
mulation suitability J Pharm Sci 91 (2002) 631ndash639
[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker
J Wyvratt Determination and differentiation of surface and
bound water in drug substances by near infrared spectro-
scopy J Pharm Sci 92 (2003) 1058ndash1065
[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-
infrared spectroscopy monitoring of the lyophilization
process Pharm Res 20 (2003) 494ndash499
[164] K List K-J Steffens Supervising and controlling of
granulation processes by near-infrared spectroscopy Pharm
Ind 58 (1996) 347ndash353
[165] S Watano K Terashita K Miyanami Posture feed-back
control and process automation in fluidized bed granulation
Adv Powder Technol 3 (1992) 255ndash265
[166] S Watano H Takashima Y Sato T Yasutomo K
Miyanami Measurement of moisture content by IR sensor
in fluidized bed granulation effects of operating variables on
the relationship between granule moisture content and
absorbance IR spectra Chem Pharm Bull 44 (1996)
1267ndash1269
[167] P Frake D Greenhalgh SM Grierson JM Hempemstall
DR Rud Process control and endpoint determination of a
fluid bed granulation by application of near infra-red
spectroscopy Int J Pharm 151 (1997) 75ndash80
[168] SG Goebel K-J Steffens On-line measurement of mois-
ture and particle size in the fluidized-bed processing with
near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895
[169] J Rantanen S Lehtola P R7met J-P Mannerma J
Yliruusi On-line monitoring of moisture content in a
instrumented fluidized bed granulator with a multi-cannel
NIR moisture sensor Powder Technol 99 (1998) 163ndash170
[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use
of the near-infrared reflectance method for measurement of
moisture content during granulation Pharm Dev Technol 5
(2000) 209ndash217
[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during
granulation with a four-wavelength near infrared sensor an
evaluation of particle size and binder effects Eur J Pharm
Biopharm 50 (2000) 271ndash276
[172] G Buckton E Yonemochi WL Yoon AC Moffat Water
sorption and near IR spectroscopy to study the differences
between microcrystalline cellulose and silicified microcrys-
talline cellulose before and after wet granulation Int J
Pharm 181 (1999) 41ndash47
[173] HM Derbyshire Y Feldman CR Bland J Broadhead G
Smith A study of the molecular properties of water in
hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088
[174] A Mica T Yajima S Itai Prediction of suitable amount of
water addition for wet granulation Int J Pharm 195 (2000)
81ndash92
[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle
WA 1996 (paper PT6116)
[176] G Radtke K Knop C Lippold In-process control of direct
pelletisation in the rotary fluidized bed using NIR spectro-
scopy NIR News 10 (1999) 4ndash12
[177] C Roeseler K-A Kovar In-process control Eur Pharm
Rev 2 (2003) 63ndash67
[178] JD Kirsch JK Drennen Near-infrared spectroscopic
monitoring of the film coating process Pharm Res 13
(1996) 234ndash237
[179] M Andersson M Josefson F Langkilde K-G Wahlund
Monitoring of a film coating process for tablets using near
infrared reflectance spectroscopy J Pharm Biomed Anal
20 (1999) 27ndash37
[180] M Andersson S Folestad J Gottfries MO Johansson M
Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108
[181] M Andersson B Holmquist J Lindquist O Nilsson K-G
Wahlund Analysis of film coating thickness and surface area
of pharmaceutical pellets using fluorescence microscopy and
image analysis J Pharm Biomed Anal 22 (2000) 325ndash339
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-
G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1143
[182] G Reich Potential of attenuated total reflection infrared and
near-infrared imaging for quality assurancequality control of
solid pharmaceutical dosage forms Pharm Ind 64 (2002)
870ndash874
[183] T Herkert H Prinz K-A Kovar One hundred percent
online identity check of pharmaceutical products by near-
infrared spectroscopy on the packaging line Eur J Pharm
Biopharm 51 (2001) 9ndash16
[184] F van der Meer SM De John (Eds) Imaging Spectrometry
Basic Principles and Prospective Applications Kluwer
Academic Publishers 2000
[185] GH Bearman RM Levenson D Cabib (Eds) Spectral
Imaging Instrumentation Applications and Analysis SPIE
Publications 2000
[186] FW Koehler IV E Lee LH Kidder EN Lewis Near
infrared spectroscopy the practical chemical imaging sol-
ution Spectrosc Eur 143 (2002) 12ndash19
[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft
On-line classification of synthetic polymers using near
infrared spectral imaging Near Infrared Spectrosc 11
(2003) 71ndash81
[188] JR Mansfield MS Sowa C Majzels C Collins E
Clontis HH Mantsch Near infrared spectroscopic reflec-
tance imaging supervised vs unsupervised analysis using
an art conservation application Vibr Spectrosc 19 (1999)
33ndash45
[189] F Clarke NIR microscopy utilisation from research through
to full-scale manufacturing Presentation No 6 at the Euro-
pean Conference on Near Infrared Spectroscopy Heidelberg
2003
[190] EN Lewis JE Carroll F Clarke NIR imaging a near
infrared view of pharmaceutical formulation analysis NIR
News 12 (2001) 16ndash18
[191] G Reich Potential of ATR-IR and NIR spectroscopic
imaging for quality assurance of solid pharmaceutical dosage
forms Proc 4th World Meeting ADRITELFAPGIAPV
Florence April 8-11 2002 pp 291ndash292
- Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications
-
- Introduction
- Basic principles of near-infrared (NIR) spectroscopy
-
- Origin and characteristics of NIR absorption bands
- Instrumentation and sample presentation
-
- Theory and practice of chemometric data processing
-
- Data pretreatments
- Reduction of variables by principal component analysis (PCA)
- Multivariate calibration for quantitative analysis
- Multivariate classification for qualitative analysis
-
- Regulatory aspects
-
- Actual status of pharmaceutical NIR analysis
- NIR spectroscopy in view of the USFDA initiative on PAT
-
- Pharmaceutical applications
-
- Identification and qualification of raw materials and intermediates
-
- Library approach
- Conformity approach
- Quantitative calibration models
-
- Analysis of intact dosage forms
-
- Tablets
- Capsules
- Lyophilized products
- Polymeric implants and microspheres
-
- Process monitoring and process control
-
- Powder blending
- Drying
- Granulation
- Pelletization
- Tabletting and capsule-filling
- Film coating
- Packaging
-
- NIR imaging
-
- Basic principles and instrumentation
- Analytical targets and strengths
- Pharmaceutical applications
-
- Concluding Remarks
- References
-