Expediting Time-to-Market andReducing Time-to-Launch withPhysicochemical Optimization             Stephen R. ByrnPurdue Un...
Outline   Effectively selecting the correct form and correct salt of    your drug substance   Examining key strategies f...
Outline   Effectively selecting the correct form and correct salt of    your drug substance   Examining key strategies f...
Overall Considerations in Selecting theCorrect Form                     Bio-                          Mechanical   Solid S...
Workflow for Merck Strategy           Michael Palucki, John D. Higgins, Elizabeth Kwong, and           Allen C. Templeton,...
Only a Short Time to Select the Form inYear 1    Major Focus      Matest      of SSC
Form Selection
Form Selection   Polymorphs   Salts   Cocrystals   Amorphous forms   Nanoparticles (crystalline or amorphous)        ...
Screening Strategy - 1995                            9
Development Strategy with Polymorph Screening             – 8 Weeks        Week 1                                         ...
Development Strategy First 4 weeks        Week 1                                                   Week 4Solubility       ...
Strategy   Optimize form and formulation early       Merck Review in J. Med. Chem. Present similar strategy – see Higgin...
Acoustic Levitation – A Frist Step inFinding the Right Form   Finding best form   Very small amounts of material   One ...
Levitation Equipment                       14
Levitation Equipment on Beamline 11-ID-C          Each drop contains about 0.1 mg of drug           (assuming solubility =...
X-ray Patterns from Levitation Experiments                                                                                ...
Fast Crystallizers                     17
Slow Crystallizers                     18
Nanoparticles   Screen for nanoparticles in the case of fast    crystallization   Wet mill stable polymorph   Utilize L...
Salt Properties                                      CH3                  OH                                            CO...
Three Tier Salt Selection - MorrisTier 1          Hygroscopicity                 (7 Salts)Tier 2      Solubility Crystal C...
DSC Curves for theCalcium Salt of BMS 180431             5%RH     70%RH
Powder XRD Patterns of theMagnesium Salt of BMS 180431
Equilibrium Solubilities of BMS180431 Salts in Water and 0.01M HCl    Salts        Distilled Water                0.01M HC...
Solid State Accelerated Stability TestingResults of the Arginine and Lysine Salts
Outline   Effectively selecting the correct form and correct salt of    your drug substance   Examining key strategies f...
Dissolution Studies of Formulations (50 mgdrug formulation in capsule)- in situ probe                                     ...
Three Tier Salt SelectionTier 1          Hygroscopicity                 (7 Salts)Tier 2      Solubility Crystal Changes   ...
DSC Curves for theCalcium Salt of BMS 180431             5%RH     70%RH
Powder XRD Patterns of theMagnesium Salt of BMS 180431
Equilibrium Solubilities of BMS180431 Salts in Water and 0.01M HCl    Salts        Distilled Water                0.01M HC...
Outline   Effectively selecting the correct form and correct salt of    your drug substance   Examining key strategies f...
Solid Dispersion – Spring andParachute Concept                                J. Brouwers, Brewster et                    ...
Supersaturated Dissolution                                     Friesen, D.T. et al                                     Mol...
In vivo ExposureBeagle Dog, 5 x increase in exposure                                       Friesen, D.T. et al            ...
Outline   Effectively selecting the correct form and correct salt of    your drug substance   Examining key strategies f...
Itraconazole Blood Levels in Pigs                                     80Concentration itraconazole (ng/ml)                ...
Dissolution Rates – An IVIVC                                      ITR Dispersions with Controls                           ...
Improved Pharma Strategy for FastDevelopment – 1 Year to IND   Improved Pharma is a Virtual Company   CRO Strategy – IP ...
Improved Pharma Services   Chemical synthesis          Stability & Consistency   Solid state chemistry       Quality b...
Intellectual Property   Include best method of making cocrystals-    salts-polymorphs (amorphous forms)-    nanocrystals...
Four Examples of Claims
Conclusion   Effectively selecting the correct form and correct salt    of your drug substance   Examining key strategie...
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Expediting Time-to-Market and Reducing Time-to-Launch with Physicochemical Optimization

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Expediting Time-to-Market and Reducing Time-to-Launch with Physicochemical Optimization - Stephen R. Byrn - Purdue University

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Expediting Time-to-Market and Reducing Time-to-Launch with Physicochemical Optimization

  1. 1. Expediting Time-to-Market andReducing Time-to-Launch withPhysicochemical Optimization Stephen R. ByrnPurdue University and Improved Pharma, LLC West Lafayette, Indiana 1
  2. 2. Outline Effectively selecting the correct form and correct salt of your drug substance Examining key strategies for managing solubility in lead optimization Evaluating physicochemical properties, generating an understanding of the material’s stability under various conditions, leading to selecting the optimal drug delivery system Achieving the right balance between efficacy, patentability concerns, toxicity, and ADME properties for your compound 2
  3. 3. Outline Effectively selecting the correct form and correct salt of your drug substance Examining key strategies for managing solubility in lead optimization Evaluating physicochemical properties, generating an understanding of the material’s stability under various conditions, leading to selecting the optimal drug delivery system Achieving the right balance between efficacy, patentability concerns, toxicity, and ADME properties for your compound 3
  4. 4. Overall Considerations in Selecting theCorrect Form Bio- Mechanical Solid State Stability pharmaceutics Properties Formulation Design & Product Design (Dosage Form Design) Process Design 4
  5. 5. Workflow for Merck Strategy Michael Palucki, John D. Higgins, Elizabeth Kwong, and Allen C. Templeton, J. Med. Chem., 53, 5897 (2010) 5
  6. 6. Only a Short Time to Select the Form inYear 1 Major Focus Matest of SSC
  7. 7. Form Selection
  8. 8. Form Selection Polymorphs Salts Cocrystals Amorphous forms Nanoparticles (crystalline or amorphous) 8
  9. 9. Screening Strategy - 1995 9
  10. 10. Development Strategy with Polymorph Screening – 8 Weeks Week 1 Week 4 Week 5 Week 8Solubility Is drug Yes Select Formulation Solubility Study soluble? Polymorph Screen Form Screen Dissolution Rat PK No Stress Testing Can it Yes Select Salt Polymorph Select Formulation Solubility form salts? Salt Screen Form Screen Form Screen Dissolution Rat PK Optional Stress Testing No Milling Study Select Solubility Amorphous Dispersion Screen Form Dissolution Rat PK Optional Stress Testing Crystallization Inhibitor Screen Select Solubility Vehicle Screen Veh. Dissolution Rat PK Stress Testing 10
  11. 11. Development Strategy First 4 weeks Week 1 Week 4Solubility Is drug Yes Study soluble? Polymorph Screen No Can it Yes Select form salts? Salt Screen Form No Amorphous Dispersion Screen Vehicle Screen 11
  12. 12. Strategy Optimize form and formulation early  Merck Review in J. Med. Chem. Present similar strategy – see Higgins et al., Michael Palucki, John D. Higgins, Elizabeth Kwong, and Allen C. Templeton, J. Med. Chem., 53, 5897 (2010) Find best form within 12 weeks for toxicology and first in human clinical trials Utilize acoustic levitation method to facilitate early formulation development 12
  13. 13. Acoustic Levitation – A Frist Step inFinding the Right Form Finding best form Very small amounts of material One day study Can apply Taylor method to determine if the compound is a fast crystallizer Simulates spray drying 13
  14. 14. Levitation Equipment 14
  15. 15. Levitation Equipment on Beamline 11-ID-C Each drop contains about 0.1 mg of drug (assuming solubility = 10 mg/mL) 15
  16. 16. X-ray Patterns from Levitation Experiments 9000 14000 8000 12000x-ray intensity (abs. counts) 7000 Itraconazole x-ray intensity (abs. counts) 10000 6000 Ketoconazole 4-Bromoacetanilid Ritonavir 8000 5000 efavirenz 4000 6000 3000 4000 2000 2000 1000 0 0 0 2 4 6 8 0 2 4 6 8 -2000 -1000 Q (A-1) -2000 Q (A-1) 16
  17. 17. Fast Crystallizers 17
  18. 18. Slow Crystallizers 18
  19. 19. Nanoparticles Screen for nanoparticles in the case of fast crystallization Wet mill stable polymorph Utilize Liversidge screen for crystal growth inhibitors – US Patent 5,145,684 19
  20. 20. Salt Properties CH3 OH CO2 H3N OH H3CO HO NSAID compound melting percent weight aqueous solubility aqueous dissolution rate point (ºC) gain at 81% RH (mg/mL) at pH3 (mg/min/cm2) naproxen 160 0 0.016 ≤0.005 Na salt 267 21 178 21 THAM salt 191 0 11 1.0 Gu, L.; Strickley, R. G. Pharmaceutical Research 1987, 4, 255
  21. 21. Three Tier Salt Selection - MorrisTier 1 Hygroscopicity (7 Salts)Tier 2 Solubility Crystal Changes (4 salts)Tier 3 Stability and Compatibility
  22. 22. DSC Curves for theCalcium Salt of BMS 180431 5%RH 70%RH
  23. 23. Powder XRD Patterns of theMagnesium Salt of BMS 180431
  24. 24. Equilibrium Solubilities of BMS180431 Salts in Water and 0.01M HCl Salts Distilled Water 0.01M HCl Solubility** Solubility* (mg/mL) (mg/mL) Calcium 2.8 0.67 Magnesium 3.7 0.65 Lysine >100 0.64 Arginine >100 0.61 * 25°C; µ = 0.1 ** Solubilities are expressed in terms of free acid concentration
  25. 25. Solid State Accelerated Stability TestingResults of the Arginine and Lysine Salts
  26. 26. Outline Effectively selecting the correct form and correct salt of your drug substance Examining key strategies for managing solubility in lead optimization Evaluating physicochemical properties, generating an understanding of the material’s stability under various conditions, leading to selecting the optimal drug delivery system Achieving the right balance between efficacy, patentability concerns, toxicity, and ADME properties for your compound 26
  27. 27. Dissolution Studies of Formulations (50 mgdrug formulation in capsule)- in situ probe 27
  28. 28. Three Tier Salt SelectionTier 1 Hygroscopicity (7 Salts)Tier 2 Solubility Crystal Changes (4 salts)Tier 3 Stability and Compatibility
  29. 29. DSC Curves for theCalcium Salt of BMS 180431 5%RH 70%RH
  30. 30. Powder XRD Patterns of theMagnesium Salt of BMS 180431
  31. 31. Equilibrium Solubilities of BMS180431 Salts in Water and 0.01M HCl Salts Distilled Water 0.01M HCl Solubility** Solubility* (mg/mL) (mg/mL) Calcium 2.8 0.67 Magnesium 3.7 0.65 Lysine >100 0.64 Arginine >100 0.61 * 25°C; µ = 0.1 ** Solubilities are expressed in terms of free acid concentration
  32. 32. Outline Effectively selecting the correct form and correct salt of your drug substance Examining key strategies for managing solubility in lead optimization Evaluating physicochemical properties, generating an understanding of the material’s stability under various conditions, leading to selecting the optimal drug delivery system Achieving the right balance between efficacy, patentability concerns, toxicity, and ADME properties for your compound 32
  33. 33. Solid Dispersion – Spring andParachute Concept J. Brouwers, Brewster et al J Pharm Sci (2009) 98: 2549-2572 33 33
  34. 34. Supersaturated Dissolution Friesen, D.T. et al Mol Pharm 5 (2008) 1003-1019 cLogP Tg Tm 34 34
  35. 35. In vivo ExposureBeagle Dog, 5 x increase in exposure Friesen, D.T. et al Mol Pharm 35 5 (2008) 1003-1019
  36. 36. Outline Effectively selecting the correct form and correct salt of your drug substance Examining key strategies for managing solubility in lead optimization Evaluating physicochemical properties, generating an understanding of the material’s stability under various conditions, leading to selecting the optimal drug delivery system Achieving the right balance between efficacy, patentability concerns, toxicity, and ADME properties for your compound 36
  37. 37. Itraconazole Blood Levels in Pigs 80Concentration itraconazole (ng/ml) 70 60 average sporanox 50 40 average itra 100mg 30 20 average Itra HPMC 10 300mg 0 average itra HPMCP 12 16 24 36 42 48 31.3 0 1 2 4 8 0.5 Time (h)
  38. 38. Dissolution Rates – An IVIVC ITR Dispersions with Controls Dissolution - USP I (Basket) 100 Media (0.1N HCl, 0.5%CTAB), 50rpm(1hr), 250rpm 90 80 70 % Drug Release 60 50 40 30 Sporanox 100mg 20 ITR HPMCP55(1:2) 300mg 10 ITR HPMC(1:2) 300mg ITR Crystalline 100mg 0 0 500 1000 1500 2000 2500 3000 Time (min)
  39. 39. Improved Pharma Strategy for FastDevelopment – 1 Year to IND Improved Pharma is a Virtual Company CRO Strategy – IP Belongs to Contractor Merck approach  Michael Palucki, John D. Higgins, Elizabeth Kwong, and Allen C. Templeton, J. Med. Chem., 53, 5897 (2010) Best in Class, US Subcontractors/Performance Sites  Argonne National Labs  SSCI, an Aptuit Company  Purdue University A specific strategy, flow chart, timeline and plan developed for each compound 39
  40. 40. Improved Pharma Services Chemical synthesis  Stability & Consistency Solid state chemistry  Quality by design Preclinical/Toxicology  Validated methods IND  Regulatory issues Clinical Trials  Intellectual Property
  41. 41. Intellectual Property Include best method of making cocrystals- salts-polymorphs (amorphous forms)- nanocrystals Patent form and formulation Be sure to have claims that describe your invention is various ways and with various degrees of specificity. 41
  42. 42. Four Examples of Claims
  43. 43. Conclusion Effectively selecting the correct form and correct salt of your drug substance Examining key strategies for managing solubility in lead optimization Evaluating physicochemical properties, generating an understanding of the material’s stability under various conditions, leading to selecting the optimal drug delivery system Achieving the right balance between efficacy, patentability concerns, toxicity, and ADME properties for your compound 43
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