The Amorphous Form in Drug Development
Antonio Giordani, PhD Director, R&D Chemistry, Drug Development & OS. Rottapharm S.p.A. Monza, Italy.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012. [email protected]
Crystalline & Amorphous Solids
p. 2
Crystalline Amorphous
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012.
L. Yu. Amorphous Pharmaceutical Solids: preparation, characterization and stabilization. Adv. Drug Del. Rev., 2001, 27-42.
Higher Energy
Lower Energy
Amorphous solids are characterized by a short-range molecular order (local organization) but unlike crystalline solids they do not have a long-range order of
molecular packing.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Examples of Drugs Commercialized in the Amorphous Form
p. 3
Zafirlukast Accolate®
Astra-Zeneca
Quinapril.HCl Accupril®
Pfizer
Cefuroxime Axetil Ceftin®
GSK
Increased interest in the amorphous form due to favourable dissolution properties
Advantages in the use of the amorphous form Increased solubility enhanced
bioavailability
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
S
N O NH2
O
N
OO
O
N OO
O
O
O
N
O
OHO
NHO
O
N
NH
O
OO
O
NH
SO
O
The Solubility Issue
p. 4 G.L. Amidon et al.. Theoretical basis for a biopharmaceutical drug classification: correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 413-420
Biopharmaceutics Classification System (BCS)
Drug absorption in the GI is controlled by diffusion through membranes and solubility/dissolution rate.
Permeability is a function of Log P (Log D) and drugs with Log P >2 are considered
highly permeable.
Solubility is defined with reference to the dose number (Do), which is the ratio of the highest
drug dose strength to the administered volume (250mL).
Do >1 : low solubility compounds Do < 1 highly soluble compounds
Over 80% of drugs are commercialized as tablets,
the oral route being the preferred administration route.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Permeability & Dissolution
p. 5
BCS Distribution of Drugs
Most commercialized drugs are high permeability drugs,
dissolution is the rate limiting step for absorption of these drugs.
The solubility issue is nowadays a common problem in drug development,
the amorphous form could represent a solution.
Often drugs with high log P and hence high permeability
are characterized by low solubility.
Biopharmaceutics Classification System (BCS)
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous Atrovastatin-Ca, Solubility & Bioavailability
p. 6
Cystalline Atrovastatin Calcium
SAS precipitated amorphous
Spray dried amorphous
Dissolution Profiles of crystalline and amorphous Atrovastatin calcium
J.S. Kim et al.. Physicochemical properties and oral bioavailability of amorphous atrovastatin hemi-calcium using spraying drying and SAS processes. Int. J. Pharm., 2008, 211-219.
Plasma concentrations after amorphous and crystalline Atrovastatin calcium administration
The higher free energy of the amorphous form, the larger surface area, the lower organization of the solid state with a random orientation of the molecules which lead to the exposure of
both hydrophilic and hydrophobic groups improve wettability and solubility.
Equilibrium solubility of the crystalline compound is 0.14 mg/mL
and 0.64 mg/mL for the amorphous
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous Itraconazole
p. 7
Dissolution profile at pH 1.2 of spray-dried Itraconazole (F1) and crystalline (F3)
R.S.Prasad et al . Int.J. Chem.Tech. Res.2010,2(1), 133-142.
Itraconazole is a broad spectrum antifungal agent of the triazole group, it is commercialized in the amorphous form as Sporanox capsules.
It is an extremely water insoluble product, its higher solubility is at acidic pH
and corresponds to 4 !g/mL. The amorphous product was about eight times more soluble than the crystalline
counterpart.
Itraconazole belongs to BCS class II
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Itraconazole Co-crystals
p. 8 N. J. Babu, A. Nangia. Solubility advantages of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst. Growth & Des., 2011, 2662-2679.
Itraconazole forms co-crystals with organic acids, such as succinic, tartaric and L-malic acid.
All the co-crystals have dissolution properties better than those of the crystalline compound.
Amorphous
Succinic Tartaric
L-Mailc
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous Form: Thermodynamic Properties
p. 9 K.A. Graeser et al.. The Role of Configurational Entropy in Amorphous Systems. Pharmaceutics, 2010, 224-244.
Increased Solubility
Excess in: entropy
enthalpy
free energy
Lower Physical &
Chemical Stability
Decreasing temperature-molecular mobility R
educ
e fr
ee e
nerg
y Amorphous State
Crystallization Red
uce
mol
ecul
ar
mob
ility
Relaxation
Reduction in molecular mobility without crystalizzation
Molecular mobility is represented by the reciprocal of relaxation time Adams-Gibbs
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Below Tg
Amorphous Stability: Thermodynamic and Kinetic issues
p. 10
The relaxation time is a function of the configurational entropy
Configurational Entropy Heat Capacity
Melting Entropy
Crystallization is a multi-step process:
Pre-nucleation aggregates (molcular clusters)
Formation of crystal nuclei
Crystal growth
Nucleation
Growth
Though crystallization provides a means to reduce the excess in free energy, nucleation needs to overcome a barrier of potential
Reduction in free energy due to crystallization
Molecular Mobility Tg
Entropy & conformational effects
Is it easy to reach the right conformation to crystallize ?
ΔG*
D. Zhou et al.. Physical Stability of Amorphous Pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J. Pharm. Sci., 2002, 1803-1872.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
G
Adams-Gibbs equation
Amorphous Stability: Thermodynamic & Kinetic Properties
p. 11 K.A. Graeser et al.. Correlating Thermodynamic and Kinetic Parameters with amorphous stability.
Eu. J. Pharmaceutical science, 2009, 492-498.
Stability at 30 days of several drugs in the amorphous state
There is not a relationship between relaxation time
and stability
The reduced crystallization temperature is represented by:
Tc-Tg/Tm-Tg it allows the compounds to be represented
on a common normalized scale, expressing how far above the Tg the compound must be
heated before spontaneous crystallization occurs.
There is a relationship between the reduced temperature
and the configurational entropy
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
p. 12
R2
NH
O
O
OR1 R1
O
Nifedipine: R1= Me R2= NO2
Lacidipine R1=Et
R2=tButylacrylate K-channel blocker
hypertension
OH
NH
O
O
O
O
OO
O
Griseofulvin Antifungal
O
O
O
OOH
Simvastatin HMG-CoA reductasi inhib.
N
O
O
O
Cl
O
OO N
H
S
OH
O
O
Trogiltazone Type 2 diabetes
SNH
NH
O O O
Tolbutamide Type 2 diabetes
O
OH
OOH
O
Salsalate NSAID
S
N O NH2
O
N
OO
O
N OO
O
O
O
Cefuroxime axetil
Structure & Amorphous Stability
Indomethacin
Acetaminophen
Compounds with high configurational entropy barriers and low mobility are expected to give rise to more stable amorphous,
the flexibility of the molecule which may represent an entropic barrier to crystallization is an important factor for amorphous stability.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Conformational Effects & Crystallization
p. 13
L. Yu et al.. Crystallization and polymorphism of conformationally flexible molecules. Org. Proc. Res. & Dev., 2000, 4, 396.
The case of Taltirelin (Ceredist), a CNS drug
It crystallizes in two crystal forms " and #
Maruyama S., et al.. Crystallization behaviour of taltirelin polymorphs in a mixture of water and methanol. J. Crystal Growth, 2000, 239.
The conformation of each polymorph was determined by SC-XRD, the ! and " forms have quite different conformations:
Crystallization from water with methanol low concentrations leads to the !-form, at high methanol concentrations "-form is
preferred.
Thus the appropriate conformation should be present in solution to crystallize a form instead of the other If the rotational energy barrier to convert a wrong conformer into the right one is high, the crystallization is difficult.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
p. 14 A. Lerbert et al.. Molecular dynamics studies of the conformation of sorbitol. Carbohydrate Res., 2009,344(16): 229.
Conformational Effects & Amorphous Stability
OH OHOH
OH
OH
OH OHOH
OH
OH
OHOH
OH
OH
OH
OH
OHOH
OH
OH
OH
OH
Xylitol Arabitol
Mannitol Sorbitol
In the dynamic equilibrium among conformers in solution the process of crystallization must select “the right conformer”, which may not be the most abundant one in solution.
Alditols: polyols derived from carbohydrates, widely used in pharmaceutical formulations. Striking different tendency to crystallize even between isomers which differ
for the stereochemistry at one carbon.
Difficult to be crystallized Crystalline: bent-chain
conformation
Easy to be crystallized Crystalline: extended conformation
Easy to be crystallized Crystalline : extended conformation
Difficult to be crystallized Crystalline : bent-chain
conformation
Thus for alditols which easily crystallize, the conformation in the solid state corresponds to the lowest energy-conformer in solution, while for the slow crystallizing alditols (sorbitol and xylitol) the conformation in the solid state
is different from those more abundant in solution.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Glass Properties of Pentitols
p. 15 L. Carpentier et al.. Crystallization and glass properties of pentitols. J. of Thermal Analysis & Calorimetry, 2003, 577.
DSC cycle : the compound is melted (A), rapidly quenched to glass, then re-heated (B).
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous Form can be prepared by several methods
p. 16
Quenching of the melt
Fast precipitation from solution
Milling
Freeze Drying
Spray Drying
Wet granulation
Drying of solvated crystals
L. Yu, Amorphous Pharmaceutical Solids: preparation, characterization and stabilization, Adv. Drug Del. Rev., 2001, 27-42
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous Indomethacin
p. 17
γ-crystal form grows from the amorphous
α-crystal form grows from the amorphous
V. Andronis, G. Zografi. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Crystalline Solids, 2000, 236-248.
N
O
O
O
Cl
O
Amorphous indomethacin can be prepared by quenching of the melt and grinding the product to powder, by milling or by spray drying.
Amorphous Indomethacin Glass Transition Temperature is 42°C
More Stable γ-form α-form
Tm= 161°C, DHf = 110 J/g Tm =155°C, DHf = 91 J/g
Below Tg the γ-form is obtained
with a temperature dependent kinetic.
At 50°C both forms crystallize
while at 60°C the α-form is
favored
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
p. 18
Amorphous Threalose by Milling Milling is often used for formulation needs to reduce the particle size and
to enhance surface properties by co-milling APIs with excipients.
Milling can induce physical changes in the product, such as amorphization and mechanical induced
transition from one crystal form to another.
Piroxicam, budesonide, sucrose, lactose,
treahlose becomes partially or totally amorphous when
submitted to milling.
Trehalose ! (metastable) and " crystalline forms and a dihydrate
L. Yu. Amorphous Pharmaceutical Solids: preparation, characterization and stabilization. Adv. Drug Del. Rev., 2001, 27-42.
Amorphous treahlose Tg about 120°C
Amorphous trehalose can be obtained
by quenching of the melt or by milling of the #-form
but not by milling of the dihydrate
Amorphous treahlose dihydrate
Tg about 20°C
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous α-Lactose by Milling
p. 19
The amorphous form can be obtained by milling pure α-lactose
Tg = 110°C
After milling the amorphized
α-lactose is still in the α form ( >96%)
On heating the amorphous above Tg
the β fraction increases up to 50% at 132°C, this value remains unchanged by further heating
By milling it is possible to obtain the pure α-lactose amorphous form, which cannot be obtained by quenching of melt or spray-drying which gives rise to a 50% mixture.
Amorphization during the milling is not associated to a local heating/quenching process, since temperature higher than Tg
would have triggered the mutarotation effect.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
O
OH
OHOH
OHO
OH
H
OH
OHOHO
Galactose Glucose
J.F. Willart, M. Descamps. L. Yu. Solid state amoprphization of pharmaceuticals. Molecular Pharmaceutics, 2008, 905-9020.
Trehalose.2H2O: Amorphization by Desolvation
p. 20
Solvate Amorphous Desolvation
Desolvation often induces solid state transformations
Trehalose.2H2O Amorphous
Trehalose α-form
Slow Fast
L. Yu. Amorphous Pharmaceutical Solids: preparation, characterization and stabilization. Adv. Drug Del. Rev., 2001, 27-42.
α-Form
XRPD after slow and fast heating
Run 1: 1°C/min. dehydration, α-form Mp: 125°C Run 2: 10°C/min dehydration, α-form + amorphous
Run 2: 50°C/min dehydration, amorphous
DSC after slow and fast heating
In the case of mixtures annealing is a way to convert the metastable form-
alpha into the amorphous
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphization by Spray Drying
p. 21 M. Nystrom et al.. Fabrication of amorphous pharmaceutical material by spraying into reduced pressure. 2010, Proc Esa Ann. Meet.
M. G. Gohel et al.. Spray Drying: a Review, 2009, Pharmainfo.net
SEM of Spray-Dried Mannitol
SEM of Spray-Dried Trehalose
SEM images of the spray dried indomethacin (on the left), piroxicam (in the middle) and budesonide (on the right)
Spray Drying is one of the most used techniques for the industrial preparation of amorphous pharmaceutical solids, either as pure APIs or in a mixture with excipients or phase stabilizers.
Suitable to control properties
such as particle shape and size,
moisture content, flowability and dispersibility
Simple process which converts a fluid
(solution, a slurry, an emulsion, a gel)
into a dried particulate solid,
in one step, by spraying the fluid
into a hot drying medium
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Spray Drying
p. 22
2 Feedstock 3 Dried product, 4 Drying chamber, 5 Cyclone, 6 Sterile filter for feed, 7 Two-fluid / Pressure nozzle, 8 Prefilter for atomizing air, 9 Prefilter for drying air, 10 Indirect air heater,
K. Sollohub, K. Cal. Spry Drying Technique II. Current applications in pharmaceutical technology. J Pharm. Sci., 2010, 99(2), 587-597. M. G. Gohel et al., Spray Drying: a Review, 2009, Pharmainfo.net
Atomization of the liquid into small droplets
Mixing the droplets with a heated gas stream with consequent solvent evaporation
Separation and collection of dried powder from the gas stream
Pressure nuzzle
Rotary atomizer
The Process
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Amorphous Paclitaxel
p. 23 S.H. Pyo et al.. Preparation and dissolution profiles of the amorphous, dihydrated crystalline and anhydrous forms of Paclitaxel. Drying Technology, 2007, 1759-1767.
Paclitaxel is one of the most important anticancer agents.
Amorphous paclitaxel is used to increase solubility of the drug in
pharmaceutical solvents, since the drug is for parenteral formulations.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
p. 24
SNH
NH
O O O
Spray Drying: Tolbutamide Solid Dispersion in HPMC
R. Chen et al.. Improved dissolution of an insoluble drug using a 4-fluid nozzle spray-drying technique. Chem.Pharm.Bull.,2004, 1066-1070.
a) Crystalline tolbutamide (TLB) b) HPMC d) TLB:HPMC 1: 5 suspension e) TLB:HPMC 1: 5, 3 FN, 4 FN
a) Crystalline TLB XRPD b) HPMC XRPD c) TLB: HPMC 1:5 physical mixture d) TLB:HPMC 1:5 spray drying of the suspension e) TLB:HPMC 1:5 spry drying of the solution (3 FN) f) TLB:HPMC 1:5 spry drying of the solution (4 FN)
The solid dispersion of a drug in a water-soluble polymeric carrier such as PVP and HPMC can improve solubility and wettability and can contribute to stabilization of the amorphous state.
The spray drying techniques are widely used for the preparation of solid dispersions.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Assessment of the amorphous: XRPD
p. 25 P. Varlashkin. Approaches to quantification of amorphous content in crystalline drug substance by XRPD. Am. Pharm Review, 2011, 22-28.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
XRPD is considered the gold standard for identifying and quantifying crystalline phases in pharmaceutical products.
Crystalline compounds give rise to a powder diffraction spectrum, while pure amorphous substances give rise to a very broad peak referred to
as “halo”.
Amorphous or Nanocrystalline material?
DSC or other thermal techniques can be of help to distinguish
if amorphous or microcrystalline
Sample is constituted of a mixture of amorphous and crystalline
prepare standards of both pure amorphous and crystalline
calibration mixtures (100-10%) calibration curve
If the crystalline structure is known (SC-XRD) Rietveld Quantitative Analysis can be used.
XRPD & Stability of the Amorphous Phase: Troglitazone
p. 26
O
OH
O NH
SO
O**
N. Furuyama et al.. Do amorphous Troglitazone prepared from two diastereoisomer-pairs have the same molecular mobility and crystallization rate ? Chem. Pharm. Bull. 2011,1452-1457.
RR/SS SR/RS
Changes in XRPD pattern of amorphous Troglitazone diastereoisomers stored at 70°C, 100% RH
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
XRPD is a quite useful tool in the assessment of amorphous stability,
RR/SS
RS/SR
Crystalline: RR/SS couple (m.p.: 127°C) RS/SR couple (m.p.: 197°C) Amorphous: Tg about 70°C for both diastereoisomers.
The stability of each single amorphous diastereoisomer was comparatively assessed
using XRPD.
p. 27
XRPD & Stability of the Amorphous Phase : Irbesartan
G. Chawla, A.K. Bansal. Molecular Mobility and Physical Stability of Amorphous Irbesartan. Sci. Pharm. 2009, 695-709.
Amorphous Stability
at 40° C, 75% RH,
3 months
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Irbesartan is an AT1 antagonist approved for the treatment of hypertension. The product, commercialized as hydrochloride
sesquihydrate, has two crystalline forms (α and β) and a relatively stable amorphous form.
p. 28
XRPD & Amorphous Form : Quinapril hydrochloride
Y. Guo, S. R. Byrn, G. Zografi. Physical characteristics and chemical degradation of amorphous quinapril hydrochloride. J. Pharm. Sci., 2000, 128-143.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Quinapril hydrochloride (Accupril, Pfizer) is an angiotensin converting enzyme (ACE) inhibitor commercialized as amorphous drug.
The amorphous form of quinapril hydrochloride is obtained by desolvation on grinding of the
acetonitrile solvate.
Assessment of thermal stability for the amorphous (80°C, 5-10 hrs) highlighted the formation of a crystalline compound which is not quinapril.
N+
O
O N
OOHOHH
N
O
O
N
OO
-HCl
- H2O
Assessment of Low Amounts of Amorphous
p. 29
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
There are cases where formation of amorphous is undesired.
Unintentional amorphization during drug product manufacturing can occur in routine operations such as coating, granulation, drying, milling and compression.
The presence of amorphous even in small quantities can have an impact on the drug product performance.
Salbutamol was the first selective #2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and COPD.
Only small particles (2 – 5 !m) penetrate into the lower respiratory tract.
The product performance is critically dependent on the force of adhesion which is in turn dependent on
surface properties.
Presence of the amorphous can alter the surface properties of the particle thus reducing the
effectiveness of the administration.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
To detect small amounts of amorphous isothermal calorimetry is considered more appropriate
than XRPD.
Isothermal Microcalorimetry
p. 30
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012 T. Sebhatu et al.. Assessment of the degree of disorder in crystalline solids by isothermal microcalorimetry. Int. J. Pharmaceuticas, 1994, 135.
Microcalorimetric heat flow curve for 100% Amorphous SS monitored at 57% RH
Isothermal microcalorimetry can detect and quantify small amounts of amorphous material in a crystalline drug.
Isothermal calorimetry measures heat flow as a function of time.
I: absorption of water
II: exothermic recrystallization process that is proportional to the amount of amorphous present in the sample
III: desorption of water in excess
A calibration plot is obtained adding known amount of amorphous to crystalline salbutamol sulfate
The AUC varies linearly with the amorphous content
Assessment of Amorphous Salbutamol Sulfate
p. 31 S. Gaisford et al.. Following mechanical activation of salbutamol sulphate during ball-milling
with isothermal calorimetry. Int. J. Pharmaceutics, 2010, 393, 74-78. Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Salbutamol sulfate micronization
In order to assess amorphous formation during milling the samples milled up to 20 min. were
analyzed by isothermal calorimetry.
Over short milling times there was a sharp reduction in particle size with no
increase in the amorphous content, while between 5 and 20 min. milling
time the size of the particles remained relatively constant with an increase in
the amorphous content.
Assessment of Amorphous Content with DVS
p. 32 D. Burnett et al.. Characterizing amorphous materials with gravimetric vapour sorption techniques. PharmTech. April 2009.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
Gravimetric vapor sorption techniques are widely used to study amorphous materials and can be successfully used to detect small (<10%) amounts of amorphous
Using octane vapour is possible to assess low
concentration of amorphous in lactose.
DVS is useful also to study moisture-induced
phase changes
Vibrational Spectroscopy & Solid State
p. 33
B. Van Eedenburgh, L.S. Taylor. Application of mid-IR spectroscopy for the characterization of pharmaceutical systems. Int. J. Pharmaceutics, 2011, 3-16.
Raman
L.S. Taylor, G. Zografi. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersion. Pharmaceutical Research, 1997, 1691.
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
FT-IR
Indomethacin α-form structure
4000-400 cm-1 spectral region
FT-IR along with Raman spectroscopy belongs to the wider field of vibrational spectroscopy. These techniques are very
valuable tools to investigate the amorphous state.
FT-IR
13C ssNMR & Amorphous Fraction Assessment
p. 34
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012
13C solid state cross polarization magic angle spinning (CPMAS) NMR is becoming a widely used technique to provide information on solid state issue due to its remarkable sensitivity.
13CssCPMAS was used to assess the amorphous fraction in crystalline-amorphous mixtures of
trehalose
R. Lefort et al.. Solid state NMR and DSC methods for quantifying the amorphous content in solid dosage forms: an application to ball-milling trehalose. Int. J. Pharmaceutics, 2004, 209-219.
After recording the reference spectra of the pure crystalline and amorphous trehalose the
broadening of the NMR lines is evaluated by the software as a function of increasing amorphous
content.
p. 35
Thank You
Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012