Polymorphism and Pharmaceuticals Steve Byrn stephen.byrn@gte.net

1. Polymorphism and PharmaceuticalsSteve Byrn stephen.byrn@gte.net

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

3. Solid State Technology

4. Know What You Have Make the SameThing Every Time Rules MECHANISTIC MODELS EMPIRICAL MODELS HEURISTIC RULES “Rules of Thumb” HISTORICAL DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION Cardinal Rules

5. Eliminate The Pipeline Problem

6. Polymorph Discovery Drug Substance Synthesis Process Development Manufacture Drug Product Preformulation Formulation Process Development Manufacture Clinical Trials 1 - 6 Years DISCOVERY LAUNCH full Focused Early Comprehensive (lifecycle) may include salt, cocrystal, &amorphous forms

7. Frequency of Multiple Forms Based on about 150 studies: 87% > than 1 form 51% multiple polymorphs 37% hydrates 39% amorphous 31% solvatesSSCI Data (Pat Stahly)

8. Solubility Stability Dosage Form Dissolution Prediction from Energy-Temperature Diagrams

9. ICH Decision Tree - Polymorphs: Question 1 Note broad definition of polymorphs

10. ICH Decision Tree - Polymorph Question 2

11. ICH Decision Tree - Question 3 For solid dosage form or liquid containing undissolved drug substanceN.B. Undertake the following process only if technically possible

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

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

15. (Ralph Pfeiffer)

16. 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)

17. The Original ROY

18. 4’-Me-ROY • Four Polymorphs

19. 5-norMe-ROY • Two Polymorphs

20. Four Simple ROY Derivatives C. A. Bunnell (Eli Lilly, 1995) X. He, U. Griesser (2001) 4 Polymorphs 6 Polymorphs This Work H. Li (2003) 2 Polymorphs ? Polymorphs

21. Synthesis of 4’-Me-5-norMe-ROY 46.8g (18%) 98.4g (53%) ca 36g (14%)a a: Needs further purification

22. 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 > 700,000 experiments • Need rational approach Vapor diffusion Vapor depostion

23. Red Form R4’M5N • Initial crystallization studies gave only a red form (R4’M5N). • Is this the first ROY derivative with only one form? R4’M5N

24. 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 (O4’M5N). • Not cocrystal • Pure orange form Y5ET O4’M5N

25. XRPD O4’M5N and R4’M5N R4’M5N O4’M5N

26. R4’M5N has higher mp. R4’M5N is stable form ? New Form of 4’-Me-5-norMe-ROY O4’M5N

27. X-Ray Crystallography • Crystal structures of each form were solved.

28. The Unit Cells O4’M5N R4’M5N

29. Equilibrium Solubility in EtOH Results • van’t Hoff Plot ln C = a + b•T-1 r2 > 0.99 Regression Coefficients

30. 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 ΔGR,O = RTln(CR /CO) 63.5°C

31. Relative Energy-Temperature Diagram • Dcalc (calcd. density) • mp • Solubility

32. Conclusion • 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.

33. 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)

34. Why Capillaries? supersaturation ratios as high as 60 have been achieved (Ken Morris)

35. 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)

36. Fundamental Studies Using ROY Morris, K.; Hilden, J.; Kelm, M.; Reyes, C. Purdue University, to be published

37. 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)

38. Nabumetone Form II 1000 mm

39. Confidential X-ray Powder Diffraction Software and Analysis of Crystal Structures using XRPD (Simon Bates)

40. Figure 1Example dendrogram from pattern matching program based on modified HCA

41. Figure 2 Pattern matching result

42. Figure 3 Single cluster

43. 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

44. XRPD Pattern Analysis: Indexing Monoclinic P21/n: a=14.724 b=7.0953 c=21.5057 beta=103.77

45. XRD Pattern Analysis: Physical Properties Prediction 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!

46. XRPD Pattern Analysis: The Next Step - 2.) Pair-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

47. XRPD Pattern Analysis - PDF & Order - Disorder relationships Significant Peak broadening! Measured XRPD patterns - are materials related?

48. XRPD Pattern Analysis - PDF & Order - Disorder relationships Local Order matches Loss of long range order in disordered form

49. XRPD Pattern Analysis - The PDF Transform for Indomethacin (Gamma) 17.1Å 10.3Å Characteristic Length Scales 5.33Å Distance in Å

50. 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.