Solid-Form Screening and Selection: Challenges and Strategies of Difficult Molecules

P.Y. Chen,* J. Bis, S. Carino, R. Couch, D. Igo, L. Katrincic, D. Kinder, B. Norton, S. Sukumar

Catalent Pharma Solutions

©2011 Catalent Pharma Solutions. All rights reserved.

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PPXRD-11 May 17 2011 1

Objectives

• Pharmaceutical impact

• HT solid-state form screening and selection processes

• Can Raman spectroscopy differentiate ALL solid-forms of an API?

• Salt screening strategies to crystallize highly soluble and difficult to crystallize compound

• Polymorph screening and selection of highly polymorphic compounds/salts

PPXRD-11 May 17 2011 2

Pharmaceutical Impact of Solid-State Forms

• Manufacturing Processes

— API purification and isolation

— Drug product (dosage form)

• Material Properties

— Solubility (bioavailability)

— Stability (chemical and physical)

— Physical properties

• Product Performance

— Efficacy

— Safety

— Shelf life

• Regulatory & IP

— CMC

— Patents

StructureStructure

PropertiesProperties

PerformancePerformance

Processing

• C. Sun, J. Pharm. Sci. 2008, 97, 2855.• G. Zografi, AAPS/FDA Workshop on Evolving Science and

Technology in Physical Pharmacy and Biopharmaceutics,Baltimore, May 2009.

PPXRD-11 May 17 2011 3

Fit-for-Purpose

• Risks related to target and mechanism viability, toxicolology(tolerance, safety), efficacy, etc.

• Portfolio considerations

• Financial considerations

• Timeline considerations

SpeedSpeedCostCost

Quality or RiskQuality or Risk

CommercialNDAClinical StudiesPreclinicalToxicology

Lead Nomination

Preclinical Efficacy

Lead Optimization

Development Timeline

proof-of-conceptP.Y. Chen, D. Igo, Drug Dev. & Delivery. 2011, 11(1), pp.38-40.

PPXRD-11 May 17 2011 4

Salt & Polymorph Screening: Timing and Scope

Solid-Form Screening• 50-1000 crystallization experiments• Yields uncertain (a few crystals to ~mg)• Diverse range of solvent properties (e.g., viscosity, boiling point)• Salts and crystal-form differentiation

• Material limitations (1~5 g)

• Fast-to-decision (~1 month)

CommercialNDAClinical StudiesPreclinicalToxicology

Lead Nomination

Preclinical Efficacy

Lead Optimization

Development Timeline

Salt selectionSalt selection Polymorph selectionPolymorph selection

PPXRD-11 May 17 2011 5

Optiform™ Technologies

• High-throughput platform for salt, crystal-form, and cocrystalscreening

• Developed and refined over the past ten years

• Applied to more than 500 compounds, spanning from early stage lead compounds through launched products

Filtration and Analysis Plate

PPXRD-11 May 17 2011 6

Tiered Analytical Strategy

Crystal

Scale-upRaman•PLM, PXRD•DSC/TGA-IR•NMR, IC, HPLC•GVS

XRPD, DSC, TGA-IR

PPXRD-11 May 17 2011 7

PXRD vs. Raman

• PXRD— Gold standard

— Sensitivity & sample size

— Sample presentation

— Data quality and interpretation (resolution, preferred orientation)

• Raman — Sample presentation

— High sensitivity with small samples (single crystal)

— Chemical information

— Can Raman differentiate different crystals forms reliably?

PPXRD-11 May 17 2011 8

Dispersive vs. FT-Raman

• Dispersive Raman Microscope— Better sensitivity (single crystal)— Microscope (µm laser spot) → Orientation effect

— System stability and calibration introduce larger spectral variation

— Local heating and fluorescence

• FT-Raman — Lower sensitivity with small samples (<50 µg)

— Great spectral reproducibility (HeNe laser reference, < 0.1 cm-1)

— Larger laser spot (50 µm ~ 1 mm)

— Less fluorescent interference (1064 nm)

• Igo, D.; Chen, P. in Application of Vibrational Spectroscopy in the Pharmaceutical Research and Development, Ed. Pivonka, D.; Chalmers, J. and Griffiths, P., John Wiley & Sons, 2007, pp. 293-308.

• B.T. Bowie, D.B. Chase, P. R. Griffiths, Appl. Spectrosc. 54, 164A & 200A (2000).

PPXRD-11 May 17 2011 9

FT-Raman Spectroscopy

Camera

XYZ stage

PPXRD-11 May 17 2011 10

FT-Raman Spectra of Compound A

216.

60787.

29

1273

.10

1608

.72 16

22.2

6

1642

.95

1657

.18

2958

.86

3095

.49

300-600um - Sample A300-600um - Sample B300-600um - Sample C300-600um - Sample D300-600um - Sample E

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1608

.7216

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6

1642

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.18

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Particle sizes: <20 ~ >600 µmPeak positions

SD: < 0.16 cm-1

Range: < 0.51 cm-1

• S.M. Mehrens, U.J. Kale, X. Qu, J. Pharm. Sci. 94, 1354 (2005).

PPXRD-11 May 17 2011 11

Compound B: Samples from Screening

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PPXRD-11 May 17 2011 12

Compound C: Two Different Polymorphs

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PPXRD-11 May 17 2011 13

Succinylsulfathiazole (SST)

SO O

NOH

H

O

O

N

SNH

Six anhydrous polymorphs

Three polymorphic monohydrates

Solvates (acetone, 1-butanol)

A. Burger and U. J. Grieβer, Sci. Pharm. 57, 293-305 (1989)

PPXRD-11 May 17 2011 14

Inter-conversion Chart of SST

100 oC

100 oC

ACNSlurry in H 2O

H 2O

SST (anhydrous)

HI

Crystallization

HII III SAH2O

III

Acetone

IV

130 oC

160 oC

Ethanol

100%RH

100% RHslurry slurry

org. solv.

Ethyl acetateslurry

VI V

H 2O sl

urry

20 m

in

HIII

H2O

slu

rry

A. Burger, U.L. Grieβer, Eur. J. Pharm. Biopharm. 37, 118-124 (1991)

S.R. Burns; R.R.Pfeiffer; J.G. Stowell, Solid-State Chemistry of Drugs, 2nd Ed. p.171

PPXRD-11 May 17 2011 15

Overlaid Spectra of All SST Samples

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163 samples

Temp. Cycling - 88Fast Evaporation - 30Slow Evaporation - 39Cooling - 6

PPXRD-11 May 17 2011 16

SST - Raman Spectra of Unique Groups

SST HI monohydrateSST HIISST-2 Form ISST-2m Form IVSST 1-butanol solvateSST acetone solvateSST dioxane solvateSST-2 THF solvateSST 1-pentanol solvateSST-2 (formamide) solvateSST (ethanol) solvateSST-2 (ACN) solvateSST-2 (methylacetate) solvate

-35

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PPXRD-11 May 17 2011 17

SST - XRD Patterns of Unique Groups

PPXRD-11 May 17 2011 18

SST - IR Spectra of Unique Groups

SST HI aldrichSST HIISST1 form ISST2 Form IVSST 1-butanol solvateSST acetone solvate*SST2 1,4-dioxane solvate*SST2 THF solvate*SST2 (1-pentanol) solvate*SST1 (formamide) solvateSST (ethanol) solvate*SST2 (ACN) solvate

-0.6

-0.4

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1.6

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orba

nce

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PPXRD-11 May 17 2011 19

SST - DSC of Unique Groups

hydrate I

hydrate II

form I

form IV

1-butanol solvate

dioxane solvate

tetrahydrofuran solvate

ethanol solvate

new polymorph or solvate from formamide

-8

-6

-4

-2

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t Flo

w (W

/g)

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Temperature (°C)Exo Up Universal V3.5B TA Instruments

PPXRD-11 May 17 2011 20

Case Study #1: Improve Solubility and Polymorphism

Project Background

• MW: ~ 600

• high dose (100-400 mg IR tablet/capsule)

• pKa = 5.2 (acyl sulfonamide)

Free-acid (FA)

• Two polymorphs

• Practically insoluble

• Poor exposure (<1%F in dog)

Na Salt

• Good aqueous solubility and exposure (30%F in dog)

• 19 crystal forms (anhydrate, hydrate, many solvates)

• Preparation of the “anhydrous” form in large scale was not feasible due to channel solvate formation (Form 9).

• Residual solvent in the channel solvate was extremely difficult to remove.

PPXRD-11 May 17 2011 21

Case Study#1:Single Crystal Structure of Na Salt

Channel solvate•residual solvents

•hygroscopic

First campaign batch was dried at 65 oC for 3 days!

PPXRD-11 May 17 2011 22

Case Study#1: Salt & Polymorph Screening

Salt Screening & Evaluation

• Crystalline K+, Mg++, Ca++, choline, ethanolamine salts

• K+, Mg++, Ca++, and ethanolamine salts have complicated polymorphism and/or poor aqueous solubilities/PK

Choline Salt is the Optimal Salt

• Aqueous solubility (60 mg/mL)

• Bioavailability (60% in dog)

• Polymorph – 1 (mp ~180C)

• Non-hygroscopic

• Good stability

PPXRD-11 May 17 2011 23

Case Study#2 – Improve Crystallinity and Chemical Stability

Project background• Aggressive timeline (FTIH start in <9 months)

• Highly soluble

• No crystalline form

• Improve chemical stability w/strong acid salts

Ar

N

O

NH2

Ar'

Ar

NH

ONH2

Ar'

8.41

MW=427

PPXRD-11 May 17 2011 24

Case Study#2 – Improve Crystallinity and Chemical Stability

HT salt screen identified two crystalline salts:

• Acetate salt is unstable & eliminated quickly

— mp ~ 136 C

— Loss of acetic acid starts ~ 80oC on TGA-IR

— Loss of acetic acid when dried at 50oC overnight.

• Fumarate salt (mp ~ 180oC) was supplied to support DRF studies

— Good phys. prop. & solubility

— Risks associated with the fumarate salt

• Acyl migration

• Poor solubility of fumaric acid (CD)

• Potential API and DP stability (Michael addition)

PPXRD-11 May 17 2011 25

Case Study#2 – Crystallinity and Chemical Stability

Carefully designed manual expts crystallized HCl salt

• Good phys. prop. (mp ~ 211oC)

• A single anhydrous form

• Good solubility in bio-relevant media (~80 mg/mL)

• No acyl migration and Micheal addition risks

Solution Stability of GSK2110183 in MeOH

0.00

2.00

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8.00

10.00

12.00

0 1 2 3 4 5 6 7 8 9

Time (hrs)A

rea

%of

Tran

sam

idat

ion

Imp HCl Salt at 60C

HCl Salt at 20CFumarate at 60CFumarate at 20C

PPXRD-11 May 17 2011 26

Case Study#3: Co-crystal to Improve Crystallinity

• Sodium-dependent glucose cotransporter (SGLT) inhibitor

• Highly soluble

• Difficult to crystallize

• Cocrystals to confer crystallinity and improve mp.

Patent: US2010/0222599A1

PPXRD-11 May 17 2011 27

Case Study#4: Polymorphism of Opt0802

Objective: Examine form space of an API with moderate flexibility and MW

• API has several heteroatoms that can act as H-bond donors and acceptors thus propensity for polymorphism is expected to be high

• Screen was performed using 48 solvent systems and three crystallization modes (thermal treatments/temperature-cycling, evaporation, rapid cooling)

PPXRD-11 May 17 2011 28

Case Study#4: Polymorphism of Opt0802

Anhydrate 3(Group G)

Anhydrate 2(Group D)

Anhydrate 1(Group A)

DMSO Solvate(Group F)

THF Solvate(Group E)

Iso-structural Solvates(Group B)

•Acetonitrile•Acetone•1-Butanol•Chloroform•Dichloromethane•Diethyl Ether•Ethanol •Ethyl Acetate •2-Methoxyethanol•1-Methoxy-2-Propanol•Methyl Acetate•Nitromethane•2-Propanol•Trifluoroethanol

Iso-structural Solvates(Group B)

•Acetonitrile•Acetone•1-Butanol•Chloroform•Dichloromethane•Diethyl Ether•Ethanol •Ethyl Acetate •2-Methoxyethanol•1-Methoxy-2-Propanol•Methyl Acetate•Nitromethane•2-Propanol•Trifluoroethanol

Methanol Solvate(Group C)

Evaporation THF/H2O

Anhydrate 1 and 3Slurry at 25C

Evaporation fromAcetone/H2O

Anhydrate 1 and 2Slurry at 25C

Methanol Slurry

Evaporation from THF

Room Temperature Drying

∆105C

Evaporation from DMSO

PPXRD-11 May 17 2011 29

Case Study#4: FT-Raman Spectra of Opt0802

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PPXRD-11 May 17 2011 30

Case Study#4: Iso-structural Solvates of Opt0802

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5 0 0

1 0 0 0

1 5 0 0

C o u n t s

P o s i t i o n [ ° 2 T h e t a ]

1 0 2 0 3 0

0 1 p - s p i n 2 - T C 2 4 - 1 _ 5 1 6 x _ 1 0 1 p - s p i n 2 - T C 1 8 - 1 _ 5 1 6 x _ 1 0 1 p - s p i n 2 - T C 1 3 - 1 _ 5 1 6 x _ 1 0 1 p - s p i n 2 - T C 1 1 - 1 _ 5 1 6 x _ 1 0 1 p - s p i n 2 - T C 1 0 - 1 _ 5 1 6 x _ 1 d - 0 1 p s p i n 2 _ t c 2 8 - 1 _ 1

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• L.Yu, S.M. Reutzel, G.A. Stephenson, PSTT, 1, 118-127 (1998)

PPXRD-11 May 17 2011 31

Case Study#5: Complicated Polymorphism of GW786034B (Pazopanib)

H2NO2S NH

N

N NN

N

HCl

Class Description CommentsAnhydrate 1 MP= 290°C w/decompositionAnhydrate 2 MP= 216°C, then recrys. to Anhydrate 1Monohydrate 3.8% water content (monohydrate)

Dihydrate 8.2% water content (dihydrate)Acetone, MeOH (1) , EtOH, 2-

butanone1:1 stoichiometry; Desolvates to Anhydrate 2 (heat

to ~150°C)1-Propanol, cyclohexanone, DMSO, Chloroform, DMF, 1-

Methyl 2-pyrrolindone1:1 stoichiometry; Desolvates to Anhydrate 1 (heat

to ~150°C)ethylene glycol, chlorobenzene,

MeOH (2), MIBK, THFnon-stoichiometric; Desolvates to Anhydrate 1

(heat to ~150°C)

1,4 dioxane 0.5:1 (solvent:API) stoichiometry; Desolvates to Anhydrate 1 (heat to ~150°C)

Acetonitrile Solvatenonstoichiometric; forms desolvated solvate heated to 150°C, then conversion to Anhydrate 1 heated to

200°CDesolvated ACN solvate structurally similar to ACN solvate

Dehydrated Dihydrate structurally similar to dihydrate

Anhydrates

Hydrates

Solvates

Others

Votrient®, Pazopanib

•28 solid-state forms•Polymorph control•Data Analyses

“Utilization of FT-Raman Spectroscopy to Unravel the Complicated Polymorphism of GW786034B (Pazopanib)” P.Chen*, D. Igo, L. Katrincic, R. Couch; 2009 FACSS Meeting, Louisville, KY, Oct. 19-22, 2009.

31

PPXRD-11 May 17 2011 32

Case Study#5: Unsupervised Clustering Analyses

FTFT--Raman DataRaman Data

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Wavenumbers (cm-1)

“Utilization of FT-Raman Spectroscopy to Unravel the Complicated Polymorphism of GW786034B (Pazopanib)” P.Chen*, D. Igo, L. Katrincic, R. Couch; 2009 FACSS Meeting, Louisville, KY, Oct. 19-22, 2009.

-0.01-0.005

00.005

0.01

-0.015-0.01

-0.0050

0.0050.01

0.015

-0.01-0.005

00.0050.01

0.015

Sammon Comp. 2

Sammon Comp. 1

Sam

mon

Com

p. 3

0.846 1

1 77 4 10 19

Samples Cluster (Sammon) HCA Cluster HCA (order)F5.CSV 0 1 1F4.CSV 0 2 2F12.CSV 0 3 3F6.CSV 0 4 4F8.CSV 0 5 5F7.CSV 0 6 6F3.CSV 0 7 7F10.CSV 0 8 8F18.CSV 0 9 9F17.CSV 0 10 10ACN S20.CSV 3 11 24ACN S19.CSV 3 11 28ACN S18.CSV 3 11 13ACN S17.CSV 3 11 26ACN S16.CSV 3 11 19ACN S15.CSV 3 11 20ACN S14.CSV 3 11 11ACN S13.CSV 3 11 21ACN S12.CSV 3 11 17ACN S11.CSV 3 11 27ACN S10.CSV 3 11 16ACN S9.CSV 3 11 15ACN S8.CSV 3 11 12ACN S7.CSV 3 11 22ACN S6.CSV 3 11 18ACN S5.CSV 3 11 14ACN S4.CSV 3 11 29ACN S3.CSV 3 11 25ACN S2.CSV 3 11 30ACN S1.CSV 3 11 23F23.CSV 0 12 31F20.CSV 0 13 32F22.CSV 0 14 33F16.CSV 0 15 34F15.CSV 0 16 35F9.CSV 0 17 36F13.CSV 0 18 37F11.CSV 0 19 38F14.CSV 0 20 39F1 S19.CSV 2 21 48F1 S18.CSV 2 21 41F1 S17.CSV 2 21 49F1 S16.CSV 2 21 57F1 S15.CSV 2 21 52F1 S14.CSV 2 21 50F1 S13.CSV 2 21 44F1 S12.CSV 2 21 43F1 S11.CSV 2 21 56F1 S10.CSV 2 21 53F1 S9.CSV 2 21 55F1 S8.CSV 2 21 46F1 S7.CSV 2 21 47F1 S6.CSV 2 21 45F1 S5.CSV 2 21 54F1 S4.CSV 2 21 40F1 S3.CSV 2 21 42F1 S2.CSV 2 21 51F1 S1.CSV 2 21 58F19.CSV 0 22 59Hydrate1 S16.CSV 1 23 77Hydrate1 S15.CSV 1 23 69Hydrate1 S14.CSV 1 23 72Hydrate1 S13.CSV 1 23 68Hydrate1 S12.CSV 1 23 74Hydrate1 S11.CSV 1 23 75Hydrate1 S10.CSV 1 23 71Hydrate1 S9.CSV 1 23 70Hydrate1 S8.CSV 1 23 67Hydrate1 S7.CSV 1 23 66Hydrate1 S6.CSV 1 23 63Hydrate1 S5.CSV 1 23 60Hydrate1 S4.CSV 1 23 62Hydrate1 S3.CSV 1 23 61Hydrate1 S2.CSV 1 23 64

Hierarchical Cluster Analysis

PPXRD-11 May 17 2011 33

Case Study#5: Final API Crystallization Process

Risk assessment: • Process-Relevant Forms:

• Form 1 • Monohydrate • ACN Solvate

• ACN/water mixtures • T = 0-80°C

Situation: • Stable ACN solvate discovered• Current process: 5%aq. ACN (water addition)

T (C

elsi

us)

Form 1

Monohydrate

AC

N s

olva

te

% Vol H2O in ACN

Heated Transformation

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10 200 15 255

Risk Mitigation: •Heated transformation of monohydrate in 10% aq. ACN

PPXRD-11 May 17 2011 34

Concluding Remarks

• Solid-form selection is a critical development activity for small-molecule drug candidates.

• HT screening is valuable & effective in most cases, but some difficult molecules will require careful design and control of crystallization, and nucleation aid such as seeding with crystals of a structurally similar compound.

• Raman spectral differences between different solid-forms of an API are relatively small, and appears throughout the entire spectral range.

• All solid-state forms of an API can be differentiated with the appropriate Raman spectrometers and sampling parameters.

— Spectral quality (S/N, resolution, minimal background)

— Spectral reproducibility (better than 1 cm-1)

• FT-Raman is nearly ideal for solid-form screening & routine characterization.

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