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
TRD - Your Partner for Technical R&D IntroductionPreformulation:l a stage of development during which the physicochemical properties of drug substance are characterizedSome commonly evaluated parameters:l Solubilityl Dissolution behaviorl Stabilityl Partition coefficientl 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.
TRD - Your Partner for Technical R&D 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.
TRD - Your Partner for Technical R&D Learning before Doing – Develop a knowledge basel 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
TRD - Your Partner for Technical R&Dl Preformulation – A case of learning before doing
TRD - Your Partner for Technical R&D Preformulation in the Overall R&D Process Candidate Preparation for andHit validation and Lead optimization selection completion of PoC lead selection process Study(ies) NDA3 months to 6 months 6 months to 24 months 3 months to 9 months 12 months to 24months Preformulation
TRD - Your Partner for Technical R&D Solubilityl Importance of solubilityl Theoretical and practical considerations in solubility determination
TRD - Your Partner for Technical R&D Background Drug candidates are becoming more lipophilic and poorly soluble A SURVEY OF 257 MARKETED DRUGS RECENT TRENDS IN DISCOVERY PIPELINE AND THEIR LIPOPHILICITY9080 All Drugs 2070 CNS Drugs 16 Percent6050 1240 83020 410 0 0 <-2 -2 -1 0 1 2 3 4 >4 <-1 0 1 2 3 4 5 6 >7 Lipophilicity (cLogP) Lipophilicity (cLogP)
TRD - Your Partner for Technical R&D Background• Recent trends in aqueous solubility of discovery compounds 50 Practically Insoluble 40 Percent 30 20 10 0 <10µg/mL 10-100µg/mL >100µg/mL Aqueous Solubility
TRD - Your Partner for Technical R&Dormulation 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
TRD - Your Partner for Technical R&D Drug has to be in solution to be absorbed! Disintegration Deaggregation Tablet Granules Fine or capsule or aggregates Particle Dissolu- Dissolution tion Dissolution Precipitation Fine fine Drug particle in solution Dissolution Absorption Systemic circulation
TRD - Your Partner for Technical R&DSolubility Criteria: how soluble is soluble enough? l Dependent on dose and permeability – Dissolution time – Maximum Absorbable Dose (MAD): S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min) l Biopharmaceutical Classification
TRD - Your Partner for Technical R&D Minimum Acceptable Solubility (mg/mL) 10000Solubility ( g/ml) 2100 1000 2100 520 207 520 207 µ 100 100 100 High Pe 52 52 21 21 Med Pe 10 10 10 Low Pe 55 1 1 1 0.1 0.1 1 10 Projected Dose in mg/kg
TRD - Your Partner for Technical R&DBiopharmaceutics 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 Solubilityl Class Boundariesl Highly soluble: the highest does is soluble in <250 ml water over a pH range of 1 to 7.5l Highly permeable: >90% dose absorbed in humansl Rapidly dissolving: >85% of labeled amount of drug substance dissolves within 30 minutes
TRD - Your Partner for Technical R&D Solubility and Bioavailabilityl 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 absorptionl 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
TRD - Your Partner for Technical R&D Solvents for Solubility Studiesl For developability assessment: – Simulated gastric fluid (SGF) – Simulated intestinal fluid (SIF) – pH 7.4 buffer – Intrinsic solubility to estimate pH-solubility profilel For Formulation Development: – pH solubility profile – Solubility in solubilization agents/systems • Co-solvents • Surfactants • Complexation agents • Combinations of techniques
TRD - Your Partner for Technical R&D Factors Causing Poor Solubilityl High crystallinity/high MP – Zwitterion formation – Insoluble salts – H-bonding networksl Hydrophobicity/High LogP – Lack of ionizable groups – High molecular weight
TRD - Your Partner for Technical R&D Effect of Solid State Forml Amorphous vs. crystalline – Differences could be > 1000xl Polymorphs 1200 Solubility (mcg/mL) 1000 800 600 400 200 0 1 2 3 4 5 6 7 8 9 Equilibration Time (Days)
TRD - Your Partner for Technical R&D Examplesl 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).
TRD - Your Partner for Technical R&D Examplesl Comparison of apparent solubility of polymorphs: Solute ∆ Melting Point Solubility Ratio (°C) (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).
TRD - Your Partner for Technical R&D Equilibrium Solubility vs. Kinetic Solubilityl Definition of solubility – Molarity of the substance in a solution that is at chemical equilibrium with an excess of the undissolved substancel What is kinetic/non-equilibrium solubility?
TRD - Your Partner for Technical R&D pH-Solubility Profile and Effect of Temperaturel Effect of intrinsic solubility on the shape of the pH-solubility profile: 1.2 Solubility (mg/mL) 1.0 0.8 0.6 0.4 pKa 0.2 0.0 1 2 3 4 5 6 7 8 pHl Effect of temperature
TRD - Your Partner for Technical R&D Solubility of Saltsl 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.
TRD - Your Partner for Technical R&D Dissolutionl Importance of Dissolutionl Theoretical and practical considerations in dissolution rate determination
TRD - Your Partner for Technical R&D Importance of Dissolutionl Dissolution rate for poorly soluble compounds may often be the rate limiting step to absorptionl Examples of drugs with dissolution rate limited absorption: – Digoxin – Penicillin V – Phenytoin – Quinidine – Tetracyclines
TRD - Your Partner for Technical R&D Factors Affecting Dissolution Ratel DC/Dt = kd (Cs – C) = KiA/V (Cs-C) – Kd dissolution rate constant – Ki intrinsic dissolution rate constantl Volume of the dissolution medium: dose:solubility ratiol Intrinsic dissolution rate constant: using rotating disk apparatusl Surface area of the solid – particle size effect – Effective surface area: the portion in actual contact with the dissolution medium
TRD - Your Partner for Technical R&D Choice of Dissolution Mediuml 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) – Milkl IVIVC: which comes first?
TRD - Your Partner for Technical R&D Dissolution Rate and Salt Selectionl 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 toxicityl Effect of salts on solubility in solubilization systems
TRD - Your Partner for Technical R&D Stabilityl Importance of stabilityl Theoretical and practical considerations in stability determination
TRD - Your Partner for Technical R&D Chemical Stabilityl In SGF and SIFl pH-stability profilel Solid state stability – Effect of moisture – Effect of solid state form – amorphous vs. crystallinel Excipient compatibility – Effect of moisture – Effect of processingl Degradation mechanism – Hydrolysis – Oxidation potential – Effect of temperature
TRD - Your Partner for Technical R&D Physical Stabilityl Characterization of Amorphous Material – Tg and mobility – Effect of moisture on Tg – Solid solubilityl Characterization of hydrates/solvates – Effect of processing – Impact on chemical stability and bioavailability
TRD - Your Partner for Technical R&D Solid State Propertiesl Importance of Solid State Propertiesl Theoretical and practical considerations in solid state characterization
TRD - Your Partner for Technical R&D Impact on Pharmaceutical Propertiesl 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
TRD - Your Partner for Technical R&DRisk Assessment Related to Crystal Form Issuesl 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
TRD - Your Partner for Technical R&D High Risk Compoundsl Poorly soluble compounds as defined by the FDA biopharmaceutical classification system: Solubility in pH 1-8 solutions x 250 mL < Dosel 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 formulationsl Compounds with parenteral formulations formulated close to equilibrium solubilities at given temperature
TRD - Your Partner for Technical R&D Potential Risks Due to Salt or Form Changesl 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 studiesl Risk Associated with Developability Assessment of Drug Candidate – Impact on tox formulation – Impact on bioavailability at clinically relevant doses
TRD - Your Partner for Technical R&D Patent Protection for Potential LCM Opportunities Compound Claimed Product Lunch Patent expired Extension 1990 2001 2010 2015 Original API PTR Salts and Polymorphs Generic Entry Polymorphs/Salts Claimed Generic Entry for All Other Forms 1998 not CoveredPTR: Patent Term Restoration = half of the investigational period + all of the FDA review period
TRD - Your Partner for Technical R&D Salt and Form Selection Strategyl 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 stabilityl Salt Selection vs. Form Selection – An integrated process
TRD - Your Partner for Technical R&DSome 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
TRD - Your Partner for Technical R&D Some Product Specific Aspectsl 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 shapesl Parenteral Dosage Forms – Injection site precipitation – Pain upon injection – Toxicity of new excipients – Effect of excipients on crystallization/nucleationl Suspensions – Effect of processing and formulation on the physical and chemical stability – Effect of excipients on crystallization/nucleation
TRD - Your Partner for Technical R&DAutomation 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
TRD - Your Partner for Technical R&DExample: Platform for Excipient Compatibility Studies
TRD - Your Partner for Technical R&D Final Thoughtsl 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!
TRD - Your Partner for Technical R&D Additional Readingl 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.