NYSAS Solid State Spectroscopy Of Materials (Polymorphism)

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NYSAS Solid State Spectroscopy Of Materials (Polymorphism)

  1. 1. Solid-state Spectroscopy ofMaterials (Polymorphism) Mark J. Sullivan, Ph.D. 2012 SAS Tour Speaker 1
  2. 2. Outline Solid Forms: Polymorphs, Pseudopolymorphs, Salts, Hydrates and Co-crystals Why polymorphism is important Tools for characterizing polymorphs  Conventional  Spectroscopic Applications of spectroscopy for polymorph identification and quantitative analysis 2
  3. 3. Allotropes are the ElementalCounterparts to Molecular Polymorphs Diamond Graphite Fullerene, C60 3
  4. 4. Solid Forms of Drug Substances Polymorph Salt HydrateCo-crystal Solvate 4
  5. 5. Paracetamol: an Example of Stacking Polymorphs Projection 2 1 Projection Polymorph I Polymorph IIBoldyreva et al., Journal of Thermal Analysis and Calorimetry 2002,68,437-452 5
  6. 6. Ritonavir: an Example ofConformational Polymorphs Polymorph I Polymorph II Bauer et al., Pharmaceutical Research 2001, 18(6), 859-866 6
  7. 7. Why Polymorphism is Important Physical properties  Bioavailability  Solubility  Processability  E.g., Compressability Form stability  Most stable form  Metastable form Intellectual property  Patent protection/ extension ICH Q6A, Federal Register, 2000, 65(251), 83041-83063 •7
  8. 8. The Impact of Solid Form Issues Can be Costly Ritonavir (Norvir)  Precipitate in semisolid capsules led to dissolution failure  Reformulated post marketing with polymorph II in place of polymorph I Atorvastatin (Lipitor)  Amorphous salt crystallized during Phase III development  Bioequivalence study required to change from amorphous to crystalline salt Alendronate (Fosamax)  Generic version with a different crystalline form was launched before patent expiration Topiramate (Topamax)  Innovator licensed and paid royalties on the trihydrate patented by a competitor 8
  9. 9. Solid Form Characterization is Important from Discovery through CommercializationStage of Development Desired Outcome Possible RiskForm screening/ selection Favorable solubility, dose and Incomplete patent portfolio formulation characteristics coverage of solid forms over product lifecyclePreformulation Sufficient bioavailability Metastable form may yield best exposureChemical Synthesis and Form control, stability New forms e.g., solvatesScale-up may appearPharmaceutical Process Favorable dissolution, •Incompatibility withDevelopment solubility, bioavailability, excipients stability •New forms e.g., hydrates may appearCommercialization Patents on all possible solid •Generic competition for forms with known innovator companies bioequivalence to extend •Licensing solid forms with product lifecycle better characteristics 9
  10. 10. Pharmaceutical Processes That May Cause Changes in Drug Substance Solid Form Recrystallization Filtration Milling Roller Compaction Wet Granulation Drying Tablet Compression Dissolution 10
  11. 11. Conventional Tools for Characterizing Solid FormsTechnique Property Measured Parameters MeasuredX-ray diffraction •Polymorphism •Long range crystalline orderSingle crystal & •Crystallinitypowder •Crystal structureDSC Polymorphism •Heat flow vs. temperature Glass transition •Tm, Tg, ΔHTGA •Hydrate/ Solvate •Change in mass with temperatureMicroscopy, •Morphology •ImagePLM •CrystallinitySEM •PolymorphismDynamic Vapor •Hydrate/ Dehydration •HygroscopicitySorption •Amorph CrystallizationSolubility/ •Solubility •Amount dissolved in differentdissolution •Dissolution rate solvents/ temperaturesCalorimetry •Quant of polymorph/ •Heat flow vs. time amorphous 11
  12. 12. Comparison of Calculated and Experimental X-ray Powder Patterns 2500 Neat Drug Substance 2400 2300 Black – Calculated Powder Pattern 2200 2100 Green – Experimental as Received 2000 Pink – Experimental Lightly Ground 1900 1800 1700 1600Lin (Counts) 1500 1400 1300 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 2 10 20 30 40 2-Theta - Scale vrt826809_form1 - File: VX-809.raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 42.000 ° - Step: 0.020 ° - Step time: 1. s - Temp.: 25 °C (Room) - Time Started: 0 s - 2-Theta: 2.000 ° - Theta: 1.000 ° - C 12 Operations: Y Scale Add 42 | Y Scale Mul 0.125 | Import
  13. 13. Spectroscopic Tools for Characterizing Solid FormsTechnique Property Measured Molecular Parameters Solid Sampling ModeFTIR •Chemical identity •Fundamental molecular •ATR at line •Polymorphism vibrations •ATR probe in situ •Crystallinity •Hydrogen bondingRaman •Chemical identity •Fundamental molecular •96 well plate •Polymorphism vibrations •Probe through vial/site glass •Probe in situNIR •Assay/ Composition •Combinations and overtones •Diffuse reflectance •Moisture content/ Hydrates of fundamental molecular •Transmission •Polymorphism vibrations •CrystallinityTerahertz •Polymorphism •Intermolecular bonding •Transmissionpulsed •Crystallinity Cooperative “Phonon modes” •Reflectancespectroscopy •Intramolecular torsions •ATRHigh •Chemical identity •Conformation •Off lineResolution •Polymorphism •Molecular mobilitySSNMR •Crystallinity •Phase separation •Phase Composition 13
  14. 14. Polymorph Identification byFourier Transform Infrared (FTIR) Spectroscopy 14
  15. 15. Attenuated Total ReflectanceFTIR Solid Sampling Mode 15
  16. 16. Multiple Solid Forms Can Be Distinguished by FTIRKinase OHInhibitor 6/23/2010 12:59:58 PM 13 personalfilesPersonal-P-SsullivamThermo Nicolet iS10 A3690-69 ref std form A 12 12 11 11 19 10 17 18 95 16 N 15 17 14 16 5 3 90 1 O8 7 S 9 O Form A 8 HO 85 8" Transmittance [%] 80 Form M 75 70 Tromethamine salt 65 Form H 60 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 Wavenumber cm-1 16
  17. 17. FTIR Spectra of Forms A and M are distinct in the Fingerprint Region Si gnature: Mark Sul livan , 03 -26-2010 12:05:3 7 (GMT -04:0 0), A utho rs h ip - s igni fies own ers h ip 94 RED Form A 92 GREEN Form M 90 88 86 84 82 80%T 78 76 74 72 70 719 68 66 1725 743 727 64 62 1712 20 00 18 00 16 00 14 00 12 00 10 00 80 0 60 0 W aven umb ers (c m-1) 17
  18. 18. Proper Sample Preparation is Critical for Polymorph Identificationp - s i g n i fi e s o w n e rs h i p a Gray – CRO spectrum a Red – Reference spectrume rs 20 00 (c m - 1 ) 15 00 10 00 a –additional peak 50 0 aa a 18
  19. 19. Polymorph Characterization with Terahertz Pulsed Spectroscopy 19
  20. 20. Terahertz Pulsed Spectroscopy Instrumentation Y.-C. Shen, International Journal of Pharmaceutics, 2011, 417, 48-60 20
  21. 21. Vibrational Modes in the Terahertz RegionMarkus Walther et al., Anal Bioanal Chem, 2010, 397, 1009-1017 21
  22. 22. 5 Polymorphs of Sulfathiazole Can Readily Be Distinguished with Terahertz Spectroscopy sulfathiazole Y.-C. Shen, International Journal of Pharmaceutics, 2011, 417, 48-60 22
  23. 23. Quantitative Measurement ofCrystallinity with Terahertz Spectroscopy 0 20 40 60 80 100 % crystallinity indomethacin C.J. Strachan, et al. Chem. Phys. Lett., 2004, 390, 20-24 23
  24. 24. Solid-state NMR 24
  25. 25. High-SpeedMagic-Angle Spinning F-19 NMR 25
  26. 26. High Speed Magic Angle Spinning Can IncreaseSpectral Resolution by Reducing Dipolar Broadening H0 Iz Iz rII θ=54.7° HIIdipolar α (3 cos2θ – 1) = 0 when θ = 54.7° 26
  27. 27. SSNMR has Inherent Advantages over XRPD for Measuring Crystalline/Amorphous Phase Composition Phase composition100% crystalline 100% amorphous X-ray Powder Diffraction Solid-state NMR 27
  28. 28. Quantitative Measurement of Amorphous Content in DS by solid-state F-19 MAS NMRExperiment Component T1, Recycle Scans Total sec delay, sec time, = 5*T1 hoursA. Quantitative for crystalline Crystalline 1000 5000 4 5.5 & amorphousLow amorphous intensityB. Non-quantitative for Amorphous 1 5 1000 1.4crystalline (suppressed bysaturation)Quantitative, highamorphous intensityfor peak fittingC. Amorphous reference for Amorphous 1 5 100 0.14scaling and peak fitting 28
  29. 29. F-19 MAS NMRAmorphous Peak Fitting SSB SSB SSBSSB 29
  30. 30. Quantitative Measurement of AmorphousContent in DS by solid-state F-19 MAS NMR A - quantitative scan of sample for crystalline + amorphous content B – quantitative scan of sample for amorphous content only C – quantitative scan of 40 20 0 -20 -40 -60 -80 -100 -120 ppm amorphous VX-809 standard scaled to fit peak shape 40 20 0 -20 -40 -60 -80 -100 -120 ppm 40 20 0 -20 -40 -60 -80 -100 -120 ppm 40 20 0 -20 -40 -60 -80 -100 -120 ppm 30
  31. 31. High-ResolutionC-13 CPMAS NMR 31
  32. 32. Polymorphs Can be Distinguished by Chemical Shift or Relaxation Rate DifferencesHigh-Resolution C-13 CPMAS NMR Spectra Form A Form E Form F
  33. 33. A Solid Solution Can Be Distinguishfrom a Solid Suspension by SSNMR Partially Crystalline Suspension Amorphous Dispersion Pham et al., Molecular Pharmaceutics 2010, 7(5), 1667-1691 33
  34. 34. Quantitative Polymorph Determination UsingVibrational Spectroscopy 34
  35. 35. Comparison of FTIR, NIR and Raman Spectra of Sulfathiazole Polymorphs FTIR-ATR Near IR Raman Hu et al., Journal of Pharmaceutical and Biomedical Analysts 2010, 53, 412-420 35
  36. 36. Experimental Design for Ternary Polymorph Mixtures for PLS Calibration and Validation Form I Form III Form V1 1 0 02 0 1 03 0 0 14 2/3 1/3 05 2/3 0 1/36 0 2/3 1/37 0 1/3 2/38 1/3 0 2/39 1/3 2/3 010 1/3 1/3 1/311 2/3 1/6 1/6 13 calibration x 3 replicates = 3912 1/6 2/3 1/6 13 test x 3 replicates = 3913 1/6 1/6 2/3 total spectra 78 Hu et al., Journal of Pharmaceutical and Biomedical Analysts 2010, 53, 412-420 36
  37. 37. Large NIR Sampling Area Yields Best Accuracy and Precision RMSEP Form I RMSEP Form III RMSEP Form V FTIR 4.9 5.1 4.5 NIR 2.0 2.9 2.8 Raman 3.5 4.1 3.6 LOD Form I LOD Form III LOD Form V NIR 3.6 5.8 6.3 LOQ Form I LOQ Form III LOQ Form V NIR 10.9 17.6 19.0 0.5mm 1 mm 15mmRaman FTIR-ATR NIR 37
  38. 38. Near Infrared Spectroscopy  NIR penetrates through glass  Weak absorption allows 1-2mm depth of penetration for diffuse reflectance  High S/N ~105:1  Overtones and combinations are heavily overlapped 38
  39. 39. Quantitative PLS Model Comparisonsfor Near IR and XRPD 39
  40. 40. Traces of Binary Mixtures ofBicifadine· HCl PolymorphsXRPD Near Infrared (NIR)Patrick McArdle et al., Applied Spectroscopy, 2005, 59(11), 1365 40
  41. 41. NIR Yields a Lower SEP Than XRPD for Quantitative Analysis Using PLSRMSEP = 4.38% RMSEP = 1.42% XRPD Near Infrared (NIR) 41
  42. 42. Solid-State Analysis CRO’s and CMO’s Aptuit (SSCI) Triclinic Labs Seventh Street Development Solvias, AG Solid Form Solutions, Ltd Molecular Dimensions Almac 42
  43. 43. Thank YouSAS Tour Speaker Program NY Section SAS 43

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