SAS 2012 Tour Speaker Presentation

1. Solid-state Spectroscopy of
Materials (Polymorphism)
Mark J. Sullivan, Ph.D.
2012 SAS Tour Speaker
1

2. 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
2

3. Allotropes are the Elemental
Counterparts to Molecular Polymorphs
Diamond Graphite Fullerene, C60
3

4. Solid Forms of Drug Substances
Polymorph
Salt
Hydrate
Co-crystal Solvate
4

5. Paracetamol: an Example of
Stacking Polymorphs
Projection 2 1
Projection
Polymorph I Polymorph II
Boldyreva et al., Journal of Thermal Analysis and Calorimetry 2002,68,437-452 5

6. Ritonavir: an Example of
Conformational Polymorphs
Polymorph I Polymorph II
Bauer et al., Pharmaceutical Research 2001, 18(6), 859-866 6

7. Why Polymorphism is Important
 Physical properties
 Bioavailability
 Solubility
 Processability
 E.g., Compressability
 Form stability
 Most stable form
 Metastable form
 Intellectual property
 Patent protection/ extension
ICH Q6A, Federal Register, 2000, 65(251), 83041-83063
•7

8. 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

9. Solid Form Characterization is Important from
Discovery through Commercialization
Stage of Development Desired Outcome Possible Risk
Form screening/ selection Favorable solubility, dose and Incomplete patent portfolio
formulation characteristics coverage of solid forms
over product lifecycle
Preformulation Sufficient bioavailability Metastable form may yield
best exposure
Chemical Synthesis and Form control, stability New forms e.g., solvates
Scale-up may appear
Pharmaceutical Process Favorable dissolution, •Incompatibility with
Development solubility, bioavailability, excipients
stability •New forms e.g., hydrates
may appear
Commercialization Patents on all possible solid •Generic competition for
forms with known innovator companies
bioequivalence to extend •Licensing solid forms with
product lifecycle 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
10

11. Conventional Tools for
Characterizing Solid Forms
Technique Property Measured Parameters Measured
X-ray diffraction •Polymorphism •Long range crystalline order
Single crystal & •Crystallinity
powder •Crystal structure
DSC Polymorphism •Heat flow vs. temperature
Glass transition •Tm, Tg, ΔH
TGA •Hydrate/ Solvate •Change in mass with temperature
Microscopy, •Morphology •Image
PLM •Crystallinity
SEM •Polymorphism
Dynamic Vapor •Hydrate/ Dehydration •Hygroscopicity
Sorption •Amorph Crystallization
Solubility/ •Solubility •Amount dissolved in different
dissolution •Dissolution rate solvents/ temperatures
Calorimetry •Quant of polymorph/ •Heat flow vs. time
amorphous 11

12. Comparison of Calculated and
Experimental X-ray Powder Patterns
2500 Neat Drug Substance
2400
2300
Black – Calculated Powder Pattern
2200
2100
Green – Experimental as Received
2000 Pink – Experimental Lightly Ground
1900
1800
1700
1600
Lin (Counts)
1500
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
2 10 20 30 40
2-Theta - Scale
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
12
Operations: Y Scale Add 42 | Y Scale Mul 0.125 | Import

13. Spectroscopic Tools for
Characterizing Solid Forms
Technique Property Measured Molecular Parameters Solid Sampling Mode
FTIR •Chemical identity •Fundamental molecular •ATR at line
•Polymorphism vibrations •ATR probe in situ
•Crystallinity •Hydrogen bonding
Raman •Chemical identity •Fundamental molecular •96 well plate
•Polymorphism vibrations •Probe through
vial/site glass
•Probe in situ
NIR •Assay/ Composition •Combinations and overtones •Diffuse reflectance
•Moisture content/ Hydrates of fundamental molecular •Transmission
•Polymorphism vibrations
•Crystallinity
Terahertz •Polymorphism •Intermolecular bonding •Transmission
pulsed •Crystallinity Cooperative “Phonon modes” •Reflectance
spectroscopy •Intramolecular torsions •ATR
High •Chemical identity •Conformation •Off line
Resolution •Polymorphism •Molecular mobility
SSNMR •Crystallinity •Phase separation
•Phase Composition 13

14. Polymorph Identification by
Fourier Transform Infrared
(FTIR) Spectroscopy
14

15. Attenuated Total Reflectance
FTIR Solid Sampling Mode
15

16. Multiple Solid Forms Can Be
Distinguished by FTIR
Kinase OH
Inhibitor
6/23/2010 12:59:58 PM
13 personalfilesPersonal-P-SsullivamThermo Nicolet iS10 A3690-69 ref std form A
12' 12
11' 11 19
10 17'
18
95
16'
N 15 17
14 16
5 3
90
1 O
8
7
S
9
O
Form A
8' HO 85
8"
Transmittance [%]
80
Form M
75
70 Tromethamine salt
65
Form H
60
3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800
Wavenumber cm-1
16

17. FTIR Spectra of Forms A and M
are distinct in the Fingerprint Region
Si gnature: Mark Sul livan , 03 -26-2010 12:05:3 7 (GMT -04:0 0), A utho rs h ip - s igni fies own ers h ip
94
RED Form A
92
GREEN Form M
90
88
86
84
82
80
%T
78
76
74
72
70
719
68
66 1725 743 727
64
62 1712
20 00 18 00 16 00 14 00 12 00 10 00 80 0 60 0
W aven umb ers (c m-1)
17

18. Proper Sample Preparation is Critical
for Polymorph Identification
p - s i g n i fi e s o w n e rs h i p
a
Gray – CRO spectrum
a Red – Reference spectrum
e rs
20 00
(c m - 1 )
15 00 10 00
a –additional peak
50 0
aa
a
18

19. Polymorph Characterization
with Terahertz Pulsed
Spectroscopy
19

20. Terahertz Pulsed Spectroscopy
Instrumentation
Y.-C. Shen, International Journal of Pharmaceutics, 2011, 417, 48-60 20

21. Vibrational Modes in the
Terahertz Region
Markus Walther et al., Anal Bioanal Chem, 2010, 397, 1009-1017 21

22. 5 Polymorphs of Sulfathiazole Can Readily Be
Distinguished with Terahertz Spectroscopy
sulfathiazole
Y.-C. Shen, International Journal of Pharmaceutics, 2011, 417, 48-60 22

23. Quantitative Measurement of
Crystallinity with Terahertz Spectroscopy
0
20
40
60
80
100
% crystallinity
indomethacin
C.J. Strachan, et al. Chem. Phys. Lett., 2004, 390, 20-24
23

24. Solid-state NMR
24

25. High-Speed
Magic-Angle Spinning
F-19 NMR
25

26. High Speed Magic Angle Spinning Can Increase
Spectral Resolution by Reducing Dipolar Broadening
H0
Iz Iz
rII
θ=54.7°
HIIdipolar α (3 cos2θ – 1)
= 0 when θ = 54.7°
26

27. SSNMR has Inherent Advantages over XRPD
for Measuring Crystalline/Amorphous Phase
Composition
Phase composition
100% crystalline 100% amorphous
X-ray Powder Diffraction
Solid-state NMR
27

28. Quantitative Measurement of Amorphous
Content in DS by solid-state F-19 MAS NMR
Experiment Component T1, Recycle Scans Total
sec delay, sec time,
= 5*T1 hours
A. Quantitative for crystalline Crystalline 1000 5000 4 5.5
& amorphous
Low amorphous intensity
B. Non-quantitative for Amorphous 1 5 1000 1.4
crystalline (suppressed by
saturation)
Quantitative, high
amorphous intensity
for peak fitting
C. Amorphous reference for Amorphous 1 5 100 0.14
scaling and peak fitting
28

29. F-19 MAS NMR
Amorphous Peak Fitting
SSB
SSB
SSB
SSB
29

30. Quantitative Measurement of Amorphous
Content in DS by solid-state F-19 MAS NMR
A - quantitative scan of
sample for crystalline +
amorphous content
B – quantitative scan of
sample for amorphous content
only
C – quantitative scan of
40 20 0 -20 -40 -60 -80 -100 -120 ppm
amorphous VX-809 standard
scaled to fit peak shape
40 20 0 -20 -40 -60 -80 -100 -120 ppm
40 20 0 -20 -40 -60 -80 -100 -120 ppm
40 20 0 -20 -40 -60 -80 -100 -120 ppm 30

31. High-Resolution
C-13 CPMAS NMR
31

32. Polymorphs Can be Distinguished by
Chemical Shift or Relaxation Rate Differences
High-Resolution C-13 CPMAS NMR Spectra
Form A
Form E
Form F

33. A Solid Solution Can Be Distinguishfrom
a Solid Suspension by SSNMR
Partially Crystalline
Suspension
Amorphous Dispersion
Pham et al., Molecular Pharmaceutics 2010, 7(5), 1667-1691 33

34. Quantitative Polymorph
Determination Using
Vibrational Spectroscopy
34

35. Comparison of FTIR, NIR and Raman
Spectra of Sulfathiazole Polymorphs
FTIR-ATR Near IR Raman
Hu et al., Journal of Pharmaceutical and Biomedical Analysts 2010, 53, 412-420 35

36. Experimental Design for Ternary Polymorph
Mixtures for PLS Calibration and Validation
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
13 calibration x 3 replicates = 39
12 1/6 2/3 1/6 13 test x 3 replicates = 39
13 1/6 1/6 2/3 total spectra 78
Hu et al., Journal of Pharmaceutical and Biomedical Analysts 2010, 53, 412-420 36

37. Large NIR Sampling Area Yields
Best Accuracy and Precision
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
0.5mm 1 mm
15mm
Raman FTIR-ATR NIR
37

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
38

39. Quantitative PLS
Model Comparisons
for Near IR and XRPD
39

40. Traces of Binary Mixtures of
Bicifadine· HCl Polymorphs
XRPD Near Infrared (NIR)
Patrick McArdle et al., Applied Spectroscopy, 2005, 59(11), 1365 40

41. NIR Yields a Lower SEP Than XRPD for
Quantitative Analysis Using PLS
RMSEP = 4.38% RMSEP = 1.42%
XRPD Near Infrared (NIR)
41

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
42

43. Thank You
SAS Tour Speaker Program
NY Section SAS
43