Preformulation

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Preformulation

  1. 1. TRD - Your Partner for Technical R&D Pharmaceutical Preformulation Wei-Qin (Tony) Tong, Ph.D. Novartis Pharmaceuticals Corporation Integrated Drug Product Development Process (3 day-course), University of Utah July 17-19, 2006
  2. 2. TRD - Your Partner for Technical R&D IntroductionIntroduction • Preformulation: l a stage of development during which the physicochemical properties of drug substance are characterized • Some commonly evaluated parameters: l Solubility l Dissolution behavior l Stability l Partition coefficient l Ionization constant (pKa) l Solid state properties such as crystal forms/polymorphs, water sorption behavior, surface properties, particle size and shape, and other mechanical properties, et. al.
  3. 3. TRD - Your Partner for Technical R&D Why is Preformulation Important?Why is Preformulation Important? “It is a capital mistake to theorize before one has data” - Scandal in Bohemia, Sir Arthur Conan Doyle l Thorough preformulation work is the foundation of developing robust formulations.
  4. 4. TRD - Your Partner for Technical R&D Learning before DoingLearning before Doing –– Develop a knowledge baseDevelop a knowledge base l There are critical differences between companies at the detailed level of knowledge and their ability to learn before doing – knowledge of the underlying variables and their relationship to performance – knowledge of the future manufacturing environment and the new variables introduced by that environment G. Pisano, “The Development Factory”, Harvard Business School Press, 1996
  5. 5. TRD - Your Partner for Technical R&D l Preformulation – A case of learning before doing
  6. 6. TRD - Your Partner for Technical R&D Preformulation in the Overall R&D ProcessPreformulation in the Overall R&D Process Preparation for and completion of PoC Study(ies) Hit validation and lead selection Lead optimization Candidate selection process 6 months to 24 months 3 months to 9 months 12 months to 24months3 months to 6 months Preformulation NDA
  7. 7. TRD - Your Partner for Technical R&D SolubilitySolubility l Importance of solubility l Theoretical and practical considerations in solubility determination
  8. 8. TRD - Your Partner for Technical R&D 0 10 20 30 40 50 60 70 80 90 <-2 -2 -1 0 1 2 3 4 >4 Lipophilicity (cLogP) NumberofDrugsineachCategory All Drugs CNS Drugs A SURVEY OF 257 MARKETED DRUGS AND THEIR LIPOPHILICITY BackgroundBackground 0 4 8 12 16 20 <-1 0 1 2 3 4 5 6 >7 Lipophilicity (cLogP) Percent RECENT TRENDS IN DISCOVERY PIPELINE • Drug candidates are becoming more lipophilic and poorly soluble
  9. 9. TRD - Your Partner for Technical R&D 0 10 20 30 40 50 Aqueous Solubility Percent <10µg/mL 10-100µg/mL >100µg/mL Practically Insoluble BackgroundBackground • Recent trends in aqueous solubility of discovery compounds
  10. 10. TRD - Your Partner for Technical R&D Formulation Challenges with Poorly Soluble CompoundsFormulation Challenges with Poorly Soluble Compounds l Poor dissolution rate l Low and variable bioavailability l More potential for food effect l Inability to deliver high doses for tox studies l Difficulty in developing parenteral formulations
  11. 11. TRD - Your Partner for Technical R&D Tablet or capsule Granules or aggregates Fine Particle Disintegration Deaggregation Dissolution Dissolu- tion Dissolution Precipitation Systemic circulation Drug in solution Fine fine particle Dissolution Absorption Drug has to be in solution to be absorbed!
  12. 12. TRD - Your Partner for Technical R&D Solubility Criteria: how soluble is soluble enough? lDependent on dose and permeability – Dissolution time – Maximum Absorbable Dose (MAD): S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min) lBiopharmaceutical Classification
  13. 13. TRD - Your Partner for Technical R&D Minimum Acceptable Solubility (mg/mL) 11 55 2121 1010 5252 207207 100100 520520 21002100 0.1 1 10 100 1000 10000 0.1 1 10 Projected Dose in mg/kg Solubility(µg/ml) High Pe Med Pe Low Pe 11 1010 100100 55 5252 520520 2121 207207 21002100
  14. 14. TRD - Your Partner for Technical R&D Biopharmaceutics Classification System (BCS) l Classification – Class I High Permeability, High Solubility – Class II High Permeability, Low Solubility – Class III Low Permeability, High Solubility – Class IV Low Permeability, Low Solubility l Class Boundaries l Highly soluble: the highest does is soluble in <250 ml water over a pH range of 1 to 7.5 l Highly permeable: >90% dose absorbed in humans l Rapidly dissolving: >85% of labeled amount of drug substance dissolves within 30 minutes
  15. 15. TRD - Your Partner for Technical R&D Solubility and BioavailabilitySolubility and Bioavailability l Dissolution rate limited absorption – The absolute amount of drug absorbed increases with the increasing of the dose – Reduce particle size and using solution formulation should enhance absorption l Solubility limited absorption – The absolute amount of drug absorbed does not increase with the increasing of the dose – Increasing dissolution rate does not increase absorption
  16. 16. TRD - Your Partner for Technical R&D Solvents for Solubility Studies l For developability assessment: – Simulated gastric fluid (SGF) – Simulated intestinal fluid (SIF) – pH 7.4 buffer – Intrinsic solubility to estimate pH-solubility profile l For Formulation Development: – pH solubility profile – Solubility in solubilization agents/systems • Co-solvents • Surfactants • Complexation agents • Combinations of techniques
  17. 17. TRD - Your Partner for Technical R&D l High crystallinity/high MP – Zwitterion formation – Insoluble salts – H-bonding networks l Hydrophobicity/High LogP – Lack of ionizable groups – High molecular weight Factors Causing Poor Solubility
  18. 18. TRD - Your Partner for Technical R&D l Amorphous vs. crystalline – Differences could be > 1000x l Polymorphs Effect of Solid State Form Equilibration Time (Days) Solubility(mcg/mL) 0 200 400 600 800 1000 1200 1 2 3 4 5 6 7 8 9
  19. 19. TRD - Your Partner for Technical R&D ExamplesExamples l Comparison of apparent solubility of amorphous material (A) and crystalline material (C): Solute Melting Point (°C) Solubility Ratio (A/C) Caffeine 238 5 Theophylline 272 50 Morphine 197 270 Hydrochlorthiazide 273 1.1 Sulfamethoxydiazine 215 1.5 •S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
  20. 20. TRD - Your Partner for Technical R&D ExamplesExamples l Comparison of apparent solubility of polymorphs: Solute ∆ Melting Point (°C) Solubility Ratio (L/H) Acemetacin 20 2.3 70 4.7 Cyclopenthiazide 41 2 57 3.6 Mebendazole 30 3.6 70 7.4 Spironolactone 05 1.2 10 1.9 •S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
  21. 21. TRD - Your Partner for Technical R&D l Definition of solubility – Molarity of the substance in a solution that is at chemical equilibrium with an excess of the undissolved substance l What is kinetic/non-equilibrium solubility? Equilibrium Solubility vs. Kinetic SolubilityEquilibrium Solubility vs. Kinetic Solubility
  22. 22. TRD - Your Partner for Technical R&D l Effect of intrinsic solubility on the shape of the pH-solubility profile: l Effect of temperature pH-Solubility Profile and Effect of Temperature 876543210.0 0.2 0.4 0.6 0.8 1.0 1.2 pKa' pH Solubility(mg/mL)
  23. 23. TRD - Your Partner for Technical R&D Solubility of SaltsSolubility of Salts l Challenges with weak acid or base – pH of the saturated solution vs. pHmax – It is only from a solubility experiment at a pH below pHmax that the solubility of the salt of a weak base can be estimated. l Different salts will have different solubility in non- aqueous systems.
  24. 24. TRD - Your Partner for Technical R&D DissolutionDissolution l Importance of Dissolution l Theoretical and practical considerations in dissolution rate determination
  25. 25. TRD - Your Partner for Technical R&D Importance of DissolutionImportance of Dissolution l Dissolution rate for poorly soluble compounds may often be the rate limiting step to absorption l Examples of drugs with dissolution rate limited absorption: – Digoxin – Penicillin V – Phenytoin – Quinidine – Tetracyclines
  26. 26. TRD - Your Partner for Technical R&D Factors Affecting Dissolution RateFactors Affecting Dissolution Rate l DC/Dt = kd (Cs – C) = KiA/V (Cs-C) – Kd dissolution rate constant – Ki intrinsic dissolution rate constant l Volume of the dissolution medium: dose:solubility ratio l Intrinsic dissolution rate constant: using rotating disk apparatus l Surface area of the solid – particle size effect – Effective surface area: the portion in actual contact with the dissolution medium
  27. 27. TRD - Your Partner for Technical R&D Choice of Dissolution MediumChoice of Dissolution Medium l Biorelevant dissolution media should be the most important consideration: – USP SGF (USP 2000) – USP SIF (USP 2000) – Simulated Gastric Fluid-fasted state – Simulated Intestinal Fluid-fasted state – Simulated intestinal Fluid-fed state (Dressman J et al. Pharm Res 15(1) 11-12 (1998)) – Surfactant such Sodium Lauryl Sulfate (SLS) – Milk l IVIVC: which comes first?
  28. 28. TRD - Your Partner for Technical R&D Dissolution Rate and Salt SelectionDissolution Rate and Salt Selection l What really happen in the gut? – Higher dissolution rate in the gut for soluble salts – Super-saturation possibility – Importance of knowing the solubility of the HCl salt – Potential negative impacts by salts: • Higher degradation • Conversion to free base on the surface – impact on the dissolution of the remaining salts • Potential toxicity l Effect of salts on solubility in solubilization systems
  29. 29. TRD - Your Partner for Technical R&D StabilityStability l Importance of stability l Theoretical and practical considerations in stability determination
  30. 30. TRD - Your Partner for Technical R&D Chemical StabilityChemical Stability l In SGF and SIF l pH-stability profile l Solid state stability – Effect of moisture – Effect of solid state form – amorphous vs. crystalline l Excipient compatibility – Effect of moisture – Effect of processing l Degradation mechanism – Hydrolysis – Oxidation potential – Effect of temperature
  31. 31. TRD - Your Partner for Technical R&D Physical StabilityPhysical Stability l Characterization of Amorphous Material – Tg and mobility – Effect of moisture on Tg – Solid solubility l Characterization of hydrates/solvates – Effect of processing – Impact on chemical stability and bioavailability
  32. 32. TRD - Your Partner for Technical R&D Solid State PropertiesSolid State Properties l Importance of Solid State Properties l Theoretical and practical considerations in solid state characterization
  33. 33. TRD - Your Partner for Technical R&D Impact on Pharmaceutical PropertiesImpact on Pharmaceutical Properties l Bioavailability (solubility/dissolution rate) l Stability (physical and chemical) l Processing Factors –Hygroscopicity –Bulk, mechanical, and rheological properties –Ease of isolation, filtration, and drying –Degree of purification
  34. 34. TRD - Your Partner for Technical R&D Risk Assessment Related to Crystal Form IssuesRisk Assessment Related to Crystal Form Issues l The Fundamental Question: What will be the consequence should a new thermodynamically more stable form is discovered? – High risk if this could lead to significant delay in the overall project timeline or product failure – Low risk if impact on timeline and resources are minimum
  35. 35. TRD - Your Partner for Technical R&D High Risk CompoundsHigh Risk Compounds l Poorly soluble compounds as defined by the FDA biopharmaceutical classification system: Solubility in pH 1-8 solutions x 250 mL < Dose l Compounds that would require one of the non- equilibrium methods or semi-solid/liquid formulations to enhance dissolution rate/ bioavailability – amorphous – meta-stable polymorphs – solid dispersion – lipid based formulations l Compounds with parenteral formulations formulated close to equilibrium solubilities at given temperature
  36. 36. TRD - Your Partner for Technical R&D Potential Risks Due to Salt or Form ChangesPotential Risks Due to Salt or Form Changes l Additional Studies Required Due to Salt and/or Form Changes – PK bridging studies – Repeated tox (1 month or 3 months) – Additional considerations due to potential impurity changes – Bio-equivalent studies l Risk Associated with Developability Assessment of Drug Candidate – Impact on tox formulation – Impact on bioavailability at clinically relevant doses
  37. 37. TRD - Your Partner for Technical R&D Patent Protection for Potential LCM OpportunitiesPatent Protection for Potential LCM Opportunities Compound Claimed 1990 Original API Product Lunch 2001 Polymorphs/Salts Claimed 1998 Patent expired 2010 Extension 2015 Generic Entry Generic Entry for All Other Forms not Covered Salts and Polymorphs PTR PTR: Patent Term Restoration = half of the investigational period + all of the FDA review period
  38. 38. TRD - Your Partner for Technical R&D Salt and Form Selection StrategySalt and Form Selection Strategy l Balancing Various Factors: – Physical stability: the thermodynamically most stable form is always the preferred choice – Bioavailability: clinically relevant doses vs. tox coverage – Process consideration – Other physicochemical properties such as hygroscopicity, morphology and chemical stability l Salt Selection vs. Form Selection – An integrated process
  39. 39. TRD - Your Partner for Technical R&D Some Practical Considerations in Salt Screening and SelectionSome Practical Considerations in Salt Screening and Selection l Dosage Form Considerations – IV vs. oral formulations – High dose vs. low dose – Excipient compatibility – Interaction with other actives in potential combination formulations l Salts and Other Solubilization Techniques – Effect of Salts on Complexation Binding Constants – Effect of Salts on Solublization by Surfactants – Solubility of Salts in Non-aqueous Solvents l Toxicological Considerations
  40. 40. TRD - Your Partner for Technical R&D Some Product Specific AspectsSome Product Specific Aspects l Solid dosage forms – Effect of micronization and processing such as granulation on solid state properties and chemical stability – Effect of excipients on crystallization/nucleation – Powder flow properties: bulk density, compression properties and particle size and shapes l Parenteral Dosage Forms – Injection site precipitation – Pain upon injection – Toxicity of new excipients – Effect of excipients on crystallization/nucleation l Suspensions – Effect of processing and formulation on the physical and chemical stability – Effect of excipients on crystallization/nucleation
  41. 41. TRD - Your Partner for Technical R&D Automation for Improving Efficiency and ProductivityAutomation for Improving Efficiency and Productivity l Automation of Common Preformulation Studies: – Solubility as a function of pH and composition – Solution stability as a function of pH and composition – Excipient compatibility studies – Others
  42. 42. TRD - Your Partner for Technical R&D Example: Platform for Excipient Compatibility StudiesExample: Platform for Excipient Compatibility Studies
  43. 43. TRD - Your Partner for Technical R&D Final ThoughtsFinal Thoughts l Thorough preformulation work is the foundation of developing robust formulations. l Pay now or pay later is a balancing act. l Organization structures vary, but the science doesn’t. l Good science is always the right thing to do!
  44. 44. TRD - Your Partner for Technical R&D Additional ReadingAdditional Reading l G. Banker and C.T. Rhodes, Modern Pharmaceutics, Marcel Dekker, Inc., 2000. l H. Brittain, Physical Characterization of Pharmaceutical Solids, Marcel Dekker, Inc., 1995. l H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999. l S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, Solid State Chemistry of Drugs, Second Edition, SSCI, Inc., 1999. l K.A. Connors, G.L. Amidon, and V.J. Stella. Chemical Stability of Pharmaceuticals (Second Edition), John Wiley & Sons, Inc., 1986. l E.F. Fiese and T.A. Hagen, “Preformulation”, Chapter 8 in the Theory and Practice of Industrial Pharmacy, Lea & Febiger, Philadelphia, 1986. l M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health Group, Englewood, CO, 2001. l D.J.W. Grant and T. Higuchi, Solubility Behavior of Organic Compounds, John Wiley & Sons, Inc., 1990. l L.F. Huang and W.Q. Tong, Impact of solid state properties on developability assessment of drug candidates, Advanced Drug Delivery Review, 56 (321-334), 2004. l L.J. Ravin and G.W. Radebaugh, “Preformulation”, Chapter 75 in Remington’s Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990. l W.Q. Tong, “Preformulation Aspects of Insoluble Compounds” in Water Insoluble Drug Formulation, Edited by R. Liu, Interpharm Press, 2000. l J. Wells, Pharmaceutical Preformulation, Ellis Horwood Limited, 1988. l S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. 1999.

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