Polymorphism and Pharmaceuticals Steve Byrn

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• Polymorphism and PharmaceuticalsSteve Byrn
• stephen.byrn_at_gte.net

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Dimensions

• Solid State Chemical Science
• Regulatory
• Patents
• Speed to market
• Public health
• Costs

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Solid State Technology
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Cardinal Rules
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Eliminate The Pipeline Problem
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Polymorph Discovery
full
Focused
Early
Comprehensive (lifecycle)
may include salt, cocrystal, amorphous forms
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Frequency of Multiple Forms
Based on about 150 studies 87 gt than 1
form 51 multiple polymorphs 37 hydrates 39
amorphous 31 solvatesSSCI Data
(Pat Stahly)
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Prediction from Energy-Temperature Diagrams
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ICH Decision Tree - Polymorphs Question 1
Note broad definition of polymorphs
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ICH Decision Tree - Polymorph Question 2
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ICH Decision Tree - Question 3
For solid dosage form or liquid containing
undissolved drug substanceN.B. Undertake the
following process only if technically possible
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(No Transcript)
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Law,et al., J. Pharm. Sci. 93 (2004) 563
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Law,et al., J.Pharm.Sci. 93 (2004) 563
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(Ralph Pfeiffer)
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Four Simple ROY Derivatives
4-Me-ROY
The Original ROY
C. A. Bunnell (Eli Lilly, 1995)
X. He, U. Griesser (2001)
4-Me-5-norMe-ROY
5-norMe-ROY
H. Li (2003)
J. Hatakama (2005)
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The Original ROY
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4-Me-ROY

• Four Polymorphs

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5-norMe-ROY

• Two Polymorphs

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Four Simple ROY Derivatives
C. A. Bunnell (Eli Lilly, 1995)
X. He, U. Griesser (2001)
6 Polymorphs
4 Polymorphs
This Work
H. Li (2003)
2 Polymorphs
? Polymorphs
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Synthesis of 4-Me-5-norMe-ROY
46.8g (18)
98.4g (53)
ca 36g (14)a
a Needs further purification
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Polymorph Discovery

• 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 gt
  700,000 experiments
• Need rational approach

Vapor diffusion
Vapor depostion
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Red Form R4M5N

• Initial crystallization studies gave only a red
  form (R4M5N).
• Is this the first ROY derivative with only one
  form?

R4M5N
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Seeding with other ROY Derivatives

• Using yellow needles of 5-Et-ROY as seed crystals
• Slow evaporation method in EtOH at room
  temperature afforded orange form (O4M5N).
• Not cocrystal
• Pure orange form

Y5ET
O4M5N
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XRPD O4M5N and R4M5N
R4M5N
O4M5N
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New Form of 4-Me-5-norMe-ROY O4M5N
R4M5N O4M5N Y5ET
Color Red Orange Yellow
XRPD A B -
mp (C) (Capillary) 142-143 139-140 104-105
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X-Ray Crystallography

• Crystal structures of each form were solved.

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The Unit Cells
O4M5N
R4M5N
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Equilibrium Solubility in EtOH Results

• vant Hoff Plot

ln C a bT-1
r2 gt 0.99
Regression Coefficients
a b r2
R4M5N 15.002 -4222.8 0.994
O4M5N 16.684 -4788.7 0.996
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Equilibrium Solubility in EtOH Results

• Relative Energy-Temperature Diagram

a
b
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.
Free Energy-Difference ?GR,O RTln(CR /CO)
63.5C
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Relative Energy-Temperature Diagram

• Dcalc (calcd. density)
• mp
• Solubility

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Conclusion

• Fourth derivative of simple ROY has been newly
  synthesized.
• In initial polymorph study, various
  crystallization conditions gave only a red form
  (R4M5N).
• Seeding with another ROY (Y5ET) afforded new form
  (orange form, O4M5N).
• Solubility studies showed that the new form
  (O4M5N) 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 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?

supersaturation ratios as high as 60 have
been achieved
(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 ROY
Morris, K. Hilden, J. Kelm, M. Reyes, C.
Purdue University, to be published
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SSCI Case Study Nabumetone

• The anti-inflammatory Relafen
• One solid form reported in the literature

• 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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Nabumetone Form II
1000 mm
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Confidential
X-ray Powder Diffraction Software and Analysis of
Crystal Structures using XRPD
(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 Density
map for Rietveld
Form A 67.4 Form C1 32.6
Rietveld analysis (MAUD) using electron density
for Quantitative analysis
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XRPD Pattern Analysis Indexing
Monoclinic P21/n a14.724 b7.0953 c21.5057
beta103.77
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XRD Pattern Analysis Physical Properties
Prediction
Form A Morphology
Form C1 Morphology
Density Stability Rule Form A density 1.19
g/cm3 Form C1 density 1.18 g/cm3 Experimental
Occurrence Form A 123 Form C1
32 Inter-conversion lt 95 C Form C1 gtgt Form A
Inter-conversion gt 95 C Form A gtgt Form C1 Form
C1 proved difficult to manufacture!
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XRPD Pattern Analysis The Next Step - 2.)
Pair-Wise Distribution Functions

• Fourier Sine Transform of Reduced Structure
  Factors -gt 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 - Disorder
relationships
Significant Peak broadening!
Measured XRPD patterns - are materials related?
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XRPD Pattern Analysis - PDF Order - Disorder
relationships
Local Order matches
Loss of long range order in disordered form
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XRPD Pattern Analysis - The PDF Transform for
Indomethacin (Gamma)
17.1Å
10.3Å
Characteristic Length Scales
5.33Å
Distance in Å
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10.3Å Cl-Cl distances
Gamma Form
17.1Å Cl-Cl distances
View 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.
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XRPD Pattern Analysis - The PDF Transform
Cryo-grinding of IMC gamma
0 minutes
12 minutes
30 minutes
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XRPD Pattern Analysis - The PDF Transform
0 minutes
12 minutes
Loss of long range order
Residual memory
30 minutes
40.0Å
Distance in Å
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Utilization 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 Initiatives
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FDA Critical Path
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PAT Process Understanding
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PAT Integrated into Drug Substance Manufacturing
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Sensor Strategy
(Ken Morris)
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Raman Monitoring of Polymorph During
Crystallization
(Lynne Taylor)
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Desired 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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Conclusion

• 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

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Eliminate The Pipeline Problem
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XRPD Patterns

• Comparison between theoretical and observed
  pattern

R4M5N
O4M5N
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Number of Experiments

• 60 solvents 60x603600
• 10 concentrations 36000
• 10 temperature changes (or 10 evaporation rates)
  360,000
• With and without stirring 720,000