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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

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Allotropes are the Elemental

Counterparts to Molecular Polymorphs

Diamond Graphite Fullerene, C60

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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

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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

)

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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

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OH

N

OS

O

HO

1

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78

8'

8"

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12

13

1415 17

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1911' 11

12'

16'

17'

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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

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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

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%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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%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

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C.J. Strachan, et al. Chem. Phys. Lett., 2004, 390, 20-24

100

80

40

20

0

60

% crystallinity

indomethacin

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Solid-state NMR

High-Speed

Magic-Angle Spinning

F-19 NMR

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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°

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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

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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

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-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

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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

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Quantitative Polymorph

Determination Using

Vibrational Spectroscopy

Comparison of FTIR, NIR and Raman

Spectra of Sulfathiazole Polymorphs

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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

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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

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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

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Traces of Binary Mixtures of

Bicifadine· HCl Polymorphs

Patrick McArdle et al., Applied Spectroscopy, 2005, 59(11), 1365

XRPD Near Infrared (NIR)

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NIR Yields a Lower SEP Than XRPD for

Quantitative Analysis Using PLS

RMSEP = 4.38% RMSEP = 1.42%

XRPD Near Infrared (NIR)

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Solid-State Analysis

CRO’s and CMO’s

Aptuit (SSCI)

Triclinic Labs

Seventh Street Development

Solvias, AG

Solid Form Solutions, Ltd

Molecular Dimensions

Almac

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Thank You

SAS Tour Speaker Program

NY Section SAS