1

Polymorphism and Pharmaceuticals

Steve Byrn

stephen.byrn@gte.net

2

DimensionsDimensions

• Solid State Chemical Science

• Regulatory

• Patents

• Speed to market Public health Costs

3

Solid State TechnologySolid State Technology

Dosage Choice Manufacturing

Formulation & Drug Delivery

Marketing & Further Product ImprovementsPatents

Quality Control

RegulatoryStability

Research

Purification and Process

Development

Toxicology

no

d

4

Cardinal RulesCardinal Rules

HISTORICAL DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION

HEURISTIC RULES“Rules of Thumb”

EMPIRICAL

MODELS

MECHANISTICMODELS

Rules

Make the SameThing Every Time

Know What You Have

5

Eliminate The Pipeline ProblemEliminate The Pipeline Problem

6

Process Development

Clinical Trials

Drug ProductManufacture

Drug SubstanceManufacture

Formulation

Process Development

Preformulation

Synthesis

DISCOVERY LAUNCH1 - 6 Years

Polymorph DiscoveryPolymorph Discovery

Early full Comprehensive(lifecycle)

may include salt, cocrystal, &

amorphous forms

Focused

7

Frequency of Multiple FormsFrequency of Multiple Forms

Based on about 150 studies:

87% > than 1 form51% multiple polymorphs 37% hydrates39% amorphous 31% solvates

SSCI Data

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Num

ber o

f Com

poun

ds

Number of Solid Forms

(Pat Stahly)

8

Prediction from Energy-Temperature Prediction from Energy-Temperature DiagramsDiagrams

E nergy-Tem perature D iagram

SolubilityStability

Dissolution Dosage Form

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (min)

Flu

oxet

ine

HC

l Con

cent

ratio

n (m

M)

Fluoxetine HCl:Fumaric Acid

Fluoxetine HCl:Succinic Acid

Fluoxetine HCl

Fluoxetine HCl:Benzoic Acid

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ICH Decision Tree - Polymorphs: ICH Decision Tree - Polymorphs: Question 1Question 1

Note broad definition of polymorphs

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ICH Decision Tree - Polymorph Question 2ICH Decision Tree - Polymorph Question 2

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ICH Decision ICH Decision Tree - Question 3Tree - Question 3

For solid dosage form or liquid containing undissolved drug substanceN.B. Undertake the following process only if technically possible

12

13

Law,et al., J. Pharm. Sci. 93 (2004) 563

14

Law,et al., J.Pharm.Sci. 93 (2004) 563

15(Ralph Pfeiffer)

16

FFoouurr

SSii

mmppllee

RROOYY

DDeerriivvaattiivveess

S

NC

NH

NO2

4'

5Me

S

NC

NH

Me

NO2

4'

5Me

S

NC

NH

NO2

4'

5

S

NC

NH

Me

NO2

4'

5

C. A. Bunnell (Eli Lilly, 1995) X. He, U. Griesser (2001)

H. Li (2003) J. Hatakama (2005)

The Original ROY 4’-Me-ROY

5-norMe-ROY 4’-Me-5-norMe-ROY

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TThhee

OOrriiggiinnaall

RROOYY

S

NC

NH

NO2

4'

5Me

ROYC.A. Bunnell (Eli Lilly, 1995)

OPorange plates

ORPorange-red plates

Rred prisms

ONorange needles

YNyellow needles

Yyellow prisms

Yu, et. al. J. Am. Chem. Soc. 2000, 122, 585-591

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44’’--MMee--RROOYY

• Four Polymorphs

S

NC

NH

Me

NO2

4'

5Me

DRdark red

LRlight red

Rred

Oorange

He, et. al. J. Pharm. Sci. 2001, 90, 371-388.

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55--nnoorrMMee--RROOYY

• Two Polymorphs

S

NC

NH

NO2

4'

5

100 m

Oorange

100 m

Rred

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FFoouurr

SSii

mmppllee

RROOYY

DDeerriivvaattiivveess

S

NC

NH

NO2

4'

5Me

S

NC

NH

Me

NO2

4'

5Me

S

NC

NH

NO2

4'

5

S

NC

NH

Me

NO2

4'

5

C. A. Bunnell (Eli Lilly, 1995) X. He, U. Griesser (2001)

H. Li (2003)

6 Polymorphs 4 Polymorphs

2 PolymorphsThis Work

? Polymorphs

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SSyynntthheessiiss

ooff

44’’--MMee--55--nnoorrMMee--RROOYY

98.4g (53%) 46.8g (18%)

ca 36g (14%)a

a: Needs further purification

F

NO2

NaH / THFS

NC

NH

NO2

S

NC

H2NS

S OH

HO

CN

CN

( 2 eq)

NaOH

1 2

3

4

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PPoollyymmoorrpphh

DDiissccoovveerryy

• Simple heat-cool method

• Evaporation method

• Vapor diffusion method

• Hotstage/melt methods

• Vapor deposition method

• Rapidly changing the

solvent by pouring the

solution into anti-solvent

• Even for solvent based

methods there are

> 700,000 experiments

• Need rational approach

Vapor diffusion

Vapor depostion

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• Initial crystallization studies gave only a red form (R4’M5N).

• Is this the first ROY derivative with only one form?

RReedd

FFoorrmm

RR44’’

MM55NN

-1000

0

1000

2000

3000

4000

5000

6000

5 10 15 20 25 30 35 40

2 Theta

Toluene

CH3CNEtOH

IPA

R4’M5N

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SSeeeeddiinngg

wwiitthh

ootthheerr

RROOYY

DDeerriivvaattiivveess

• Using yellow needles of 5-Et-ROY as seed crystals

• Slow evaporation method in EtOH at room temperature afforded orange form (O4’M5N).

Not cocrystal

Pure orange form

S

NC

NH

NO2

5

Y5ETS

NC

NH

Me

NO2

4'

5

O4’M5N

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XXRRPPDD

OO44’’

MM55NN aanndd

RR44’’

MM55NN

-1000

0

1000

2000

3000

4000

5000

6000

7000

5 10 15 20 25 30 35 40

2 Theta

Jin-03047A

Jin-03041B

R4’M5N

O4’M5N

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NNeeww

FFoorrmm

ooff

44’’--MMee--55--nnoorrMMee--RROOYY

OO44’’

MM55NN

R4’M5N O4’M5N Y5ET

Color

Red Orange Yellow

XRPD A B -

mp (°C)(Capillary)

142-143 139-140 104-105

R4’M5N has higher mp.

R4’M5N is stable form ?

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XX--RRaayy

CCrryyssttaallllooggrraapphhyy

• Crystal structures of each form were solved.

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TThhee UUnniitt CCeellllss

O4’M5N R4’M5N

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EEqquuiilliibbrriiuumm SSoolluubbiilliittyy iinn EEttOOHH

RReessuullttss

• van’t Hoff Plot

y = -4788.7x + 16.684

R2 = 0.9955

y = -4222.8x + 15.002

R2 = 0.9939

-0.4

0.0

0.4

0.8

1.2

1.6

2.0

2.4

2.8

3.2

0.0028 0.0030 0.0032 0.0034 0.0036

1/T

Ln

C

ln C = a + b•T-1

r2 > 0.99

a b r2

R4’M5N

15.002

-4222.

80.994

O4’M5N

16.684

-4788.

70.996

Regression Coefficients

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EEqquuiilliibbrriiuumm SSoolluubbiilliittyy iinn EEttOOHH

RReessuullttss

• Relative Energy-Temperature Diagram

Free Energy-Difference

ΔGR,O

= RTln(CR /C

O)

y = -13.985x + 887.26

-200

0

200

400

600

800

1000

0 10 20 30 40 50 60 70

Temperature [C]

Fre

e E

nerg

y D

iffer

ence

[J/m

ol]

63.5°C

a. Calculated values from the regression line, y = 16.684 - 4788.7x.b. Calculated values from the regression line, y = 15.002 - 4222.8 x.

a b

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RReellaattiivvee

EEnneerrggyy--TTeemmppeerraattuurree

DDiiaaggrraamm

Dc

a

l

c

(calcd. density)mp

Solubility

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CCoonncclluussiioonn

• Fourth derivative of simple ROY has been newly synthesized.

• In initial polymorph study, various crystallization conditions gave only a red form (R4’M5N).

• Seeding with another ROY (Y5ET) afforded new form (orange form, O4’M5N).

• Solubility studies showed that the new form (O4’M5N) is the most stable form at room temperature

• The red and orange forms are enantiotropic

• Red form adopts the most planar conformation among ROY compounds.

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Strategies to Find New FormsStrategies to Find New Forms

• Guillory methods

• Seeding with related compounds

• Templated crystallization (Epitaxial growth)

• Ultrasound, Lasers

• Capillary crystallization Studied 18 top selling drugs The form on the market is most stable Found new forms in 13 cases

• Only 4 are solvates• In 9 of the 13 cases, the new forms could also be made by

other methods(Barbara Stahly)

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Why Capillaries?Why Capillaries?

supersaturation ratiosas high as 60 have beenachieved

(Ken Morris)

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Plots of Fraction of Most Stable Form vs Supersaturation for two conditions: (top) 50 mg/mL; and (bottom) 100 mg/mL.

As supersaturation increases fraction of most stable form decreases

Childs, Crystal Growth & Design, 4, 441 (2004)

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Fundamental Studies Using ROYFundamental Studies Using ROY

Morris, K.; Hilden, J.; Kelm, M.; Reyes, C. Purdue University, to be published

0

2

4

6

8

10

12

2 4 6 8 10 12 14 16

Saturation at Crystallization

Fre

quen

cy ONYPORPNew?

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OH3C

CH3

OThe anti-inflammatory Relafen®One solid form reported in the literature

SSCI Case Study: NabumetoneSSCI Case Study: Nabumetone

• About 250 traditional solvent experiments provided only the known Form I

• In capillaries new Form II was obtained in 18% of the experiments

• Appearance of Form II depended on supersaturation and quiescence, not solvent

Chyall, Crystal Growth & Design, 2, 505 (2002)

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1000 m

Nabumetone Form II

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X-ray Powder Diffraction X-ray Powder Diffraction Software and Analysis of Software and Analysis of Crystal Structures using Crystal Structures using

XRPDXRPD

Co

nfi

de

nti

al

(Simon Bates)

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Figure 1Example dendrogram from pattern matching program

based on modified HCA

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Figure 2

Pattern matching result

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Figure 3

Single cluster

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XRPD Pattern Analysis - Use of Electron XRPD Pattern Analysis - Use of Electron Density map for RietveldDensity map for Rietveld

Rietveld analysis (MAUD) using electron density for Quantitative analysis

Form A: 67.4%

Form C1: 32.6%

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XRPD Pattern Analysis: IndexingXRPD Pattern Analysis: Indexing

Monoclinic P21/n: a=14.724 b=7.0953 c=21.5057 beta=103.77

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XRD Pattern Analysis: Physical Properties XRD Pattern Analysis: Physical Properties PredictionPrediction

Form A Morphology

Form C1 Morphology

Density Stability Rule

Form A density = 1.19 g/cm^3

Form C1 density = 1.18 g/cm^3

Experimental Occurrence

Form A: 123 ; Form C1: 32

Inter-conversion: < 95° C: Form C1 >> Form A Inter-conversion: > 95° C: Form A >> Form C1

Form C1 proved difficult to manufacture!

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XRPD Pattern Analysis: The Next Step - 2.) XRPD Pattern Analysis: The Next Step - 2.) Pair-Wise Distribution FunctionsPair-Wise Distribution Functions

• Fourier Sine Transform of Reduced Structure Factors -> PDF. Can be used on 1D or 3D diffraction data. Used to isolate characteristic repeats and

packing of atoms within solid forms. Identify Order-Disorder relationships. Break Down Complex Molecular Structures

into Building Blocks.

• Improved Pattern Matching

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XRPD Pattern Analysis - PDF & Order - XRPD Pattern Analysis - PDF & Order - Disorder relationshipsDisorder relationships

Measured XRPD patterns - are materials related?

Significant Peak broadening!

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XRPD Pattern Analysis - PDF & Order - XRPD Pattern Analysis - PDF & Order - Disorder relationshipsDisorder relationships

Loss of long range order in disordered form

Local Order matches

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5.33Å

10.3Å17.1Å

Characteristic Length Scales

Distance in Å

XRPD Pattern Analysis - The PDF Transform XRPD Pattern Analysis - The PDF Transform for Indomethacin (Gamma)for Indomethacin (Gamma)

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10.3Å Cl-Cl distances

17.1Å Cl-Cl distancesView of crystal structure for Gamma form using Cl as a central atom.

Cl forms a very simple lattice acting as a frame for the organic components.

Gamma Form

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12 minutes

30 minutes

0 minutes

XRPD Pattern Analysis - The PDF TransformXRPD Pattern Analysis - The PDF Transform

Cryo-grinding of IMC gamma

52Distance in Å

Loss of long range order

12 minutes

30 minutes

0 minutes

40.0Å

XRPD Pattern Analysis - The PDF TransformXRPD Pattern Analysis - The PDF Transform

Residual memory

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Utilization of XRPD SoftwareUtilization of XRPD Software

• Predict Stability Density rule Tunnel area

• Select candidates for development Number of forms not as important as the fact

that several forms exist with about the same energy

• Analyze amorphous forms Determine residual order Predict ease of crystallization

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FDA InitiativesFDA Initiatives

Critical Path

Industrialization - GMP 21st Century Safety Medical Utility

PATQUALITYSYSTEMS

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FDA Critical PathFDA Critical Path

Safety

Medical

Industrial-ization

Critical Path

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PAT = Process UnderstandingPAT = Process Understanding

HISTORICAL DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION

HEURISTIC RULES“Rules of Thumb”

EMPIRICAL MODELS

MECHANISTICMODELS

Rules

Current Level of Knowledge

Desired Level of Knowledge

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PAT Integrated into Drug Substance PAT Integrated into Drug Substance ManufacturingManufacturing

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Sensor StrategySensor Strategy

PCCP variables –Model dev/refine

What variables should be important?

Sensor development and refinement

What variables are measurable?

Production - Scale up/down/same

Product performance

PCCP variables –Model dev/refine

What variables should be important?

Sensor development and refinement

What variables are measurable?

Production - Scale up/down/same

Product performance

(Ken Morris)

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Raman Monitoring of Polymorph During Raman Monitoring of Polymorph During CrystallizationCrystallization

0 100 200 300 1200 1300 1400 1500

0

50

100

150

200

250

Co

nce

ntr

atio

n (

mg

/mL

)

Time (minutes)

Solute FormIII FormI

(Lynne Taylor)

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Desired Future StateDesired Future State

• Quality by Design Know what you have – form discovery

• Specifications based on mechanistic understanding

• Continuous quality assurance Make the same thing every time

• Risk based regulatory scrutiny

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ConclusionConclusion

• Know what you have – polymorph discovery

• Make the same thing every time – characterization/analytical aspects

• Speed is paramount• Major advances in application of

XRPD • Quality by design – Risk based

regulations

62

Eliminate The Pipeline ProblemEliminate The Pipeline Problem

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XXRRPPDD

PPaatttteerrnnss

• Comparison between theoretical and observed pattern

O4’M5N R4’M5N

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Number of ExperimentsNumber of Experiments

• 60 solvents – 60x60=3600

• 10 concentrations – 36000

• 10 temperature changes (or 10 evaporation rates) – 360,000

• With and without stirring – 720,000