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1 Polymorphism and Pharmaceuticals Steve Byrn stephen.byrn@gte.net
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2 Dimensions Solid State Chemical Science Regulatory Patents Speed to market Public health Costs
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3 Solid State Technology
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4 Cardinal Rules HISTORICAL DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION HEURISTIC RULES “Rules of Thumb” EMPIRICAL MODELS MECHANISTIC MODELS Rules Make the Same Thing Every Time Know What You Have
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5 Eliminate The Pipeline Problem
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6 Process Development Clinical Trials Drug Product Manufacture Drug Substance Manufacture Formulation Process Development Preformulation Synthesis DISCOVERYLAUNCH 1 - 6 Years Polymorph Discovery Early full Comprehensive (lifecycle) may include salt, cocrystal, & amorphous forms Focused
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7 Frequency of Multiple Forms Based on about 150 studies: 87% > than 1 form 51% multiple polymorphs 37% hydrates 39% amorphous 31% solvates SSCI Data (Pat Stahly)
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8 Prediction from Energy-Temperature Diagrams Solubility Stability Dissolution Dosage Form
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9 ICH Decision Tree - Polymorphs: Question 1 Note broad definition of polymorphs
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10 ICH Decision Tree - Polymorph Question 2
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11 ICH Decision Tree - Question 3 For solid dosage form or liquid containing undissolved drug substance N.B. Undertake the following process only if technically possible
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13 Law,et al., J. Pharm. Sci. 93 (2004) 563
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14 Law,et al., J.Pharm.Sci. 93 (2004) 563
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15 (Ralph Pfeiffer)
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16 Four Simple ROY Derivatives 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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17 The Original ROY
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18 4’-Me-ROY Four Polymorphs
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19 5-norMe-ROY Two Polymorphs
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20 Four Simple ROY Derivatives C. A. Bunnell (Eli Lilly, 1995)X. He, U. Griesser (2001) H. Li (2003) 6 Polymorphs 4 Polymorphs 2 Polymorphs This Work ? Polymorphs
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21 Synthesis of 4’-Me-5-norMe-ROY 98.4g (53%) 46.8g (18%) ca 36g (14%) a a: Needs further purification
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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
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23 Initial crystallization studies gave only a red form (R4’M5N). Is this the first ROY derivative with only one form? Red Form R4’M5N R4’M5N
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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
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25 XRPD O4’M5N and R4’M5N R4’M5N O4’M5N
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26 New Form of 4’-Me-5-norMe-ROY O4’M5N R4’M5N has higher mp. R4’M5N is stable form ? R4’M5NO4’M5NY5ET Color RedOrangeYellow XRPDAB- mp (°C) (Capillary) 142-143139-140104-105
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27 X-Ray Crystallography Crystal structures of each form were solved.
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28 The Unit Cells The Unit Cells O4’M5NR4’M5N
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29 Equilibrium Solubility in EtOH Results van’t Hoff Plot ln C = a + bT -1 r 2 > 0.99 abr2r2 R4’M5N15.002-4222.80.994 O4’M5N16.684-4788.70.996 Regression Coefficients
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30 Equilibrium Solubility in EtOH Results Relative Energy-Temperature Diagram Free Energy-Difference Δ G R,O = RTln(C R /C O ) 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. ab
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31 Relative Energy-Temperature Diagram D calc (calcd. density) mp Solubility
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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.
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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)
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34 Why Capillaries? supersaturation ratios as high as 60 have been achieved (Ken Morris)
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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)
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36 Fundamental Studies Using ROY Morris, K.; Hilden, J.; Kelm, M.; Reyes, C. Purdue University, to be published
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37 The anti-inflammatory Relafen® One solid form reported in the literature SSCI 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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38 1000 m Nabumetone Form II
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39 X-ray Powder Diffraction Software and Analysis of Crystal Structures using XRPD Confidential (Simon Bates)
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40 Figure 1 Example dendrogram from pattern matching program based on modified HCA
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41 Figure 2 Pattern matching result
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42 Figure 3 Single cluster
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43 XRPD Pattern Analysis - Use of Electron Density map for Rietveld Rietveld analysis (MAUD) using electron density for Quantitative analysis Form A: 67.4% Form C1: 32.6%
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44 XRPD Pattern Analysis: Indexing Monoclinic P21/n: a=14.724 b=7.0953 c=21.5057 beta=103.77
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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: > Form A Inter-conversion: > 95° C: Form A >> Form C1 Form C1 proved difficult to manufacture!
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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
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47 XRPD Pattern Analysis - PDF & Order - Disorder relationships Measured XRPD patterns - are materials related? Significant Peak broadening!
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48 XRPD Pattern Analysis - PDF & Order - Disorder relationships Loss of long range order in disordered form Local Order matches
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49 5.33Å 10.3Å 17.1Å Characteristic Length Scales Distance in Å XRPD Pattern Analysis - The PDF Transform for Indomethacin (Gamma)
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50 10.3Å Cl-Cl distances 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. Gamma Form
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51 12 minutes 30 minutes 0 minutes XRPD Pattern Analysis - The PDF Transform Cryo-grinding of IMC gamma
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52 Distance in Å Loss of long range order 12 minutes 30 minutes 0 minutes 40.0Å XRPD Pattern Analysis - The PDF Transform Residual memory
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53 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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54 FDA Initiatives Critical Path Industrialization - GMP 21 st Century PAT QUALITY SYSTEMS SafetyMedical Utility
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55 FDA Critical Path Safety Medical Industrial- ization Critical Path
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56 PAT = Process Understanding HISTORICAL DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION HEURISTIC RULES “Rules of Thumb” EMPIRICAL MODELS MECHANISTIC MODELS Rules Current Level of Knowledge Desired Level of Knowledge
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57 PAT Integrated into Drug Substance Manufacturing
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58 Sensor Strategy (Ken Morris)
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59 Raman Monitoring of Polymorph During Crystallization (Lynne Taylor)
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60 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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61 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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62 Eliminate The Pipeline Problem
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63 XRPD Patterns Comparison between theoretical and observed pattern O4’M5N R4’M5N
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64 Number of Experiments 60 solvents – 60x60=3600 10 concentrations – 36000 10 temperature changes (or 10 evaporation rates) – 360,000 With and without stirring – 720,000
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