nysas solid state spectroscopy of materials (polymorphism)
DESCRIPTION
SAS 2012 Tour Speaker PresentationTRANSCRIPT
1
Solid-state Spectroscopy of
Materials (Polymorphism)
Mark J. Sullivan, Ph.D.
2012 SAS Tour Speaker
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Outline
Solid Forms: Polymorphs, Pseudopolymorphs,
Salts, Hydrates and Co-crystals
Why polymorphism is important
Tools for characterizing polymorphs
Conventional
Spectroscopic
Applications of spectroscopy for polymorph
identification and quantitative analysis
3
Allotropes are the Elemental
Counterparts to Molecular Polymorphs
Diamond Graphite Fullerene, C60
4
Solid Forms of Drug Substances
Solvate
Salt
Hydrate
Co-crystal
Polymorph
Paracetamol: an Example of
Stacking Polymorphs
5 Boldyreva et al., Journal of Thermal Analysis and Calorimetry 2002,68,437-452
Polymorph I Polymorph II
Projection 1 Projection 2
Ritonavir: an Example of
Conformational Polymorphs
6 Bauer et al., Pharmaceutical Research 2001, 18(6), 859-866
Polymorph I Polymorph II
Why Polymorphism is Important
Physical properties
Bioavailability
Solubility
Processability
E.g., Compressability
Form stability
Most stable form
Metastable form
Intellectual property
Patent protection/ extension
•7 ICH Q6A, Federal Register, 2000, 65(251), 83041-83063
The Impact of Solid Form Issues
Can be Costly Ritonavir (Norvir)
Precipitate in semisolid capsules led to dissolution failure
Reformulated post marketing with polymorph II in place of polymorph I
Atorvastatin (Lipitor)
Amorphous salt crystallized during Phase III development
Bioequivalence study required to change from amorphous to crystalline
salt
Alendronate (Fosamax)
Generic version with a different crystalline form was launched before
patent expiration
Topiramate (Topamax)
Innovator licensed and paid royalties on the trihydrate patented by a
competitor
8
Solid Form Characterization is Important from
Discovery through Commercialization
Stage of Development Desired Outcome Possible Risk
Form screening/ selection Favorable solubility, dose and
formulation characteristics
Incomplete patent portfolio
coverage of solid forms
over product lifecycle
Preformulation Sufficient bioavailability Metastable form may yield
best exposure
Chemical Synthesis and
Scale-up
Form control, stability
New forms e.g., solvates
may appear
Pharmaceutical Process
Development
Favorable dissolution,
solubility, bioavailability,
stability
•Incompatibility with
excipients
•New forms e.g., hydrates
may appear
Commercialization Patents on all possible solid
forms with known
bioequivalence to extend
product lifecycle
•Generic competition for
innovator companies
•Licensing solid forms with
better characteristics 9
10
Pharmaceutical Processes That May Cause
Changes in Drug Substance Solid Form
Recrystallization
Filtration
Milling
Roller Compaction
Wet Granulation
Drying
Tablet Compression
Dissolution
Conventional Tools for
Characterizing Solid Forms Technique Property Measured Parameters Measured
X-ray diffraction
Single crystal &
powder
•Polymorphism
•Crystallinity
•Crystal structure
•Long range crystalline order
DSC Polymorphism
Glass transition
•Heat flow vs. temperature
•Tm, Tg, ΔH
TGA •Hydrate/ Solvate •Change in mass with temperature
Microscopy,
PLM
SEM
•Morphology
•Crystallinity
•Polymorphism
•Image
Dynamic Vapor
Sorption
•Hydrate/ Dehydration
•Amorph Crystallization
•Hygroscopicity
Solubility/
dissolution
•Solubility
•Dissolution rate
•Amount dissolved in different
solvents/ temperatures
Calorimetry •Quant of polymorph/
amorphous
•Heat flow vs. time
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Comparison of Calculated and
Experimental X-ray Powder Patterns
Operations: Y Scale Mul 0.208 | Import
VX-809 ref std lot A2792-037finely ground - File: A2658-225-4.raw - Type: 2Th/Th locked - Start: 2.700 ° - End: 39.978 ° - Step: 0.014 ° - Step time: 105. s - Temp.: 25 °C (Room) - Time Started: 16 s - 2-
Operations: Y Scale Mul 0.708 | Y Scale Mul 0.417 | Import
VX-809 ref std lot A2792-037 - File: A2658-225-1.raw - Type: 2Th/Th locked - Start: 2.700 ° - End: 39.978 ° - Step: 0.014 ° - Step time: 105. s - Temp.: 25 °C (Room) - Time Started: 19 s - 2-Theta: 2.700
Operations: Y Scale Add 42 | Y Scale Mul 0.125 | Import
vrt826809_form1 - File: VX-809.raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 42.000 ° - Step: 0.020 ° - Step time: 1. s - Temp.: 25 °C (Room) - Time Started: 0 s - 2-Theta: 2.000 ° - Theta: 1.000 ° - C
Lin
(C
ou
nts
)
0
100
200
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400
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600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
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2200
2300
2400
2500
2-Theta - Scale
2 10 20 30 40
Black – Calculated Powder Pattern
Green – Experimental as Received
Pink – Experimental Lightly Ground
Neat Drug Substance
Spectroscopic Tools for
Characterizing Solid Forms Technique Property Measured Molecular Parameters Solid Sampling Mode
FTIR •Chemical identity
•Polymorphism
•Crystallinity
•Fundamental molecular
vibrations
•Hydrogen bonding
•ATR at line
•ATR probe in situ
Raman •Chemical identity
•Polymorphism
•Fundamental molecular
vibrations
•96 well plate
•Probe through
vial/site glass
•Probe in situ
NIR •Assay/ Composition
•Moisture content/ Hydrates
•Polymorphism
•Crystallinity
•Combinations and overtones
of fundamental molecular
vibrations
•Diffuse reflectance
•Transmission
Terahertz
pulsed
spectroscopy
•Polymorphism
•Crystallinity
•Intermolecular bonding
Cooperative “Phonon modes”
•Intramolecular torsions
•Transmission
•Reflectance
•ATR
High
Resolution
SSNMR
•Chemical identity
•Polymorphism
•Crystallinity
•Phase Composition
•Conformation
•Molecular mobility
•Phase separation
•Off line
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Polymorph Identification by
Fourier Transform Infrared
(FTIR) Spectroscopy
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Attenuated Total Reflectance
FTIR Solid Sampling Mode
16
OH
N
OS
O
HO
1
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8'
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1415 17
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1911' 11
12'
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Multiple Solid Forms Can Be
Distinguished by FTIR
\\personalfiles\Personal-P-S\sullivam\Thermo Nicolet iS10 A3690-69 ref std form A
800100012001400160018002000220024002600280030003200340036003800
Wavenumber cm-1
60
65
70
75
80
85
90
95
Tra
nsm
itta
nce
[%
]
6/23/2010 12:59:58 PM
Form A
Form M
Tromethamine salt
Form H
Kinase
Inhibitor
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Si gnature: Mark Sul l ivan , 03 -26-2010 12:05:37 (GMT -04:00), A utho rsh ip - s igni fies ownersh ip
62
64
66
68
70
72
74
76
78
80
82
84
86
88
90
92
94
%T
600 800 1000 1200 1400 1600 1800 2000
W avenumbers (cm-1)
1725 743
719
727
1712
RED Form A
GREEN Form M
FTIR Spectra of Forms A and M
are distinct in the Fingerprint Region
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Proper Sample Preparation is Critical
for Polymorph Identification Si gnature: Mark Sul l ivan , 06 -14-2010 20:51:34 (GMT -04:00), A utho rsh ip - s igni fies ownersh ip
A3809 -74 V X-222 form M re f s td RE F-10 -012 'as is ' from Covance
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25
30
35
40
45
50
55
60
65
70
75
80
85
90
%T
500 1000 1500 2000 2500 3000 3500 4000
W avenumbers (cm-1)
a a a
a
a Gray – CRO spectrum
Red – Reference spectrum
a –additional peak
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Polymorph Characterization
with Terahertz Pulsed
Spectroscopy
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Terahertz Pulsed Spectroscopy
Instrumentation
Y.-C. Shen, International Journal of Pharmaceutics, 2011, 417, 48-60
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Vibrational Modes in the
Terahertz Region
Markus Walther et al., Anal Bioanal Chem, 2010, 397, 1009-1017
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5 Polymorphs of Sulfathiazole Can Readily Be
Distinguished with Terahertz Spectroscopy
Y.-C. Shen, International Journal of Pharmaceutics, 2011, 417, 48-60
sulfathiazole
Quantitative Measurement of
Crystallinity with Terahertz Spectroscopy
23
C.J. Strachan, et al. Chem. Phys. Lett., 2004, 390, 20-24
100
80
40
20
0
60
% crystallinity
indomethacin
24
Solid-state NMR
High-Speed
Magic-Angle Spinning
F-19 NMR
25
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High Speed Magic Angle Spinning Can Increase
Spectral Resolution by Reducing Dipolar Broadening
θ=54.7°
Iz Iz
rII
H0
HIIdipolar α (3 cos2θ – 1)
= 0 when θ = 54.7°
27
SSNMR has Inherent Advantages over XRPD
for Measuring Crystalline/Amorphous Phase
Composition
100% crystalline 100% amorphous
Phase composition
X-ray Powder Diffraction
Solid-state NMR
28
Quantitative Measurement of Amorphous
Content in DS by solid-state F-19 MAS NMR
Experiment Component T1,
sec
Recycle
delay, sec
= 5*T1
Scans
Total
time,
hours
A. Quantitative for crystalline
& amorphous
Low amorphous intensity
Crystalline 1000 5000 4 5.5
B. Non-quantitative for
crystalline (suppressed by
saturation)
Quantitative, high
amorphous intensity
for peak fitting
Amorphous 1 5 1000 1.4
C. Amorphous reference for
scaling and peak fitting
Amorphous 1 5 100 0.14
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F-19 MAS NMR
Amorphous Peak Fitting
SSB
SSB
SSB
SSB
30
-120-100-80-60-40-2040 20 0 ppm
-120-100-80-60-40-2040 20 0 ppm-120-100-80-60-40-2040 20 0 ppm
-120-100-80-60-40-2040 20 0 ppm
B – quantitative scan of
sample for amorphous content
only
C – quantitative scan of
amorphous VX-809 standard
scaled to fit peak shape
A - quantitative scan of
sample for crystalline +
amorphous content
Quantitative Measurement of Amorphous
Content in DS by solid-state F-19 MAS NMR
High-Resolution
C-13 CPMAS NMR
31
Form A
Form E
Form F
Polymorphs Can be Distinguished by
Chemical Shift or Relaxation Rate Differences
High-Resolution C-13 CPMAS NMR Spectra
A Solid Solution Can Be Distinguishfrom
a Solid Suspension by SSNMR
33 Pham et al., Molecular Pharmaceutics 2010, 7(5), 1667-1691
Amorphous Dispersion
Partially Crystalline
Suspension
34
Quantitative Polymorph
Determination Using
Vibrational Spectroscopy
Comparison of FTIR, NIR and Raman
Spectra of Sulfathiazole Polymorphs
35
FTIR-ATR Near IR Raman
Hu et al., Journal of Pharmaceutical and Biomedical Analysts 2010, 53, 412-420
Experimental Design for Ternary Polymorph
Mixtures for PLS Calibration and Validation
36 Hu et al., Journal of Pharmaceutical and Biomedical Analysts 2010, 53, 412-420
Form I Form III Form V
1 1 0 0
2 0 1 0
3 0 0 1
4 2/3 1/3 0
5 2/3 0 1/3
6 0 2/3 1/3
7 0 1/3 2/3
8 1/3 0 2/3
9 1/3 2/3 0
10 1/3 1/3 1/3
11 2/3 1/6 1/6
12 1/6 2/3 1/6
13 1/6 1/6 2/3
13 calibration x 3 replicates = 39
13 test x 3 replicates = 39
total spectra 78
Large NIR Sampling Area Yields
Best Accuracy and Precision
37
0.5mm
Raman
1 mm
FTIR-ATR
RMSEP Form I RMSEP Form III RMSEP Form V
FTIR 4.9 5.1 4.5
NIR 2.0 2.9 2.8
Raman 3.5 4.1 3.6
LOD Form I LOD Form III LOD Form V
NIR 3.6 5.8 6.3
LOQ Form I LOQ Form III LOQ Form V
NIR 10.9 17.6 19.0
15mm
NIR
38
Near Infrared Spectroscopy
NIR penetrates through glass
Weak absorption allows 1-2mm depth of penetration for diffuse reflectance
High S/N ~105:1
Overtones and combinations are heavily overlapped
Quantitative PLS
Model Comparisons
for Near IR and XRPD
39
40
Traces of Binary Mixtures of
Bicifadine· HCl Polymorphs
Patrick McArdle et al., Applied Spectroscopy, 2005, 59(11), 1365
XRPD Near Infrared (NIR)
41
NIR Yields a Lower SEP Than XRPD for
Quantitative Analysis Using PLS
RMSEP = 4.38% RMSEP = 1.42%
XRPD Near Infrared (NIR)
42
Solid-State Analysis
CRO’s and CMO’s
Aptuit (SSCI)
Triclinic Labs
Seventh Street Development
Solvias, AG
Solid Form Solutions, Ltd
Molecular Dimensions
Almac
43
Thank You
SAS Tour Speaker Program
NY Section SAS