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

Introduction
Preformulation:
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a stage of development during which the physicochemical properties of drug substance are characterized Solubility Dissolution behavior Stability Partition coefficient Ionization constant (pKa) Solid state properties such as crystal forms/polymorphs, water sorption behavior, surface properties, particle size and shape, and other mechanical properties, et. al.

Some commonly evaluated parameters:
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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
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Thorough preformulation work is the foundation of developing robust formulations.

TRD - Your Partner for Technical R&D

Learning before Doing – Develop a knowledge base 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

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G. Pisano, “The Development Factory”, Harvard Business School Press, 1996

Your Partner for Technical R&D l Preformulation – A case of learning before doing .TRD .

Your Partner for Technical R&D Preformulation in the Overall R&D Process Hit validation and lead selection Lead optimization Candidate selection process Preparation for and completion of PoC Study(ies) NDA 3 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 Solubility l Importance of solubility Theoretical and practical considerations in solubility determination l .TRD .

TRD .Your Partner for Technical R&D Background Drug candidates are becoming more lipophilic and poorly soluble A SURVEY OF 257 MARKETED DRUGS AND THEIR LIPOPHILICITY RECENT TRENDS IN DISCOVERY PIPELINE 90 80 70 60 50 40 30 20 10 0 <-2 -2 -1 0 1 2 3 4 Lipophilicity (cLogP) >4 All Drugs 20 Percent 16 12 8 4 0 <-1 0 1 2 3 4 5 6 >7 Lipophilicity (cLogP) CNS Drugs .

Your Partner for Technical R&D Background • Recent trends in aqueous solubility of discovery compounds 50 40 Practically Insoluble Percent 30 20 10 0 <10µg/mL 10-100µg/mL >100µg/mL Aqueous Solubility .TRD .

TRD .Your Partner for Technical R&D ormulation Challenges with Poorly Soluble Compounds l l l l l Poor dissolution rate Low and variable bioavailability More potential for food effect Inability to deliver high doses for tox studies Difficulty in developing parenteral formulations .

TRD .Your Partner for Technical R&D Drug has to be in solution to be absorbed! Disintegration Tablet or capsule Dissolution Deaggregation Granules or aggregates Dissolution Fine Particle Dissolution Precipitation Drug in solution Dissolution Absorption Fine fine particle Systemic circulation .

TRD .Your Partner for Technical R&D Solubility 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 .

Your Partner for Technical R&D Minimum Acceptable Solubility (mg/mL) 10000 Solubility ( g/ml) µ 1000 100 10 1 0.TRD .1 1 1 21 21 55 10 10 207 52 52 207 2100 2100 520 520 100 100 High Pe Med Pe Low Pe 1 10 Projected Dose in mg/kg .1 0.

TRD . Low Solubility l Class l l l Boundaries Highly soluble: the highest does is soluble in <250 ml water over a pH range of 1 to 7.5 Highly permeable: >90% dose absorbed in humans Rapidly dissolving: >85% of labeled amount of drug substance dissolves within 30 minutes . High Solubility Low Permeability.Your Partner for Technical R&D Biopharmaceutics Classification System (BCS) l Classification – Class I – Class II – Class III – Class IV High Permeability. Low Solubility Low Permeability. High Solubility High Permeability.

Your Partner for Technical R&D Solubility and Bioavailability rate limited absorption l Dissolution – 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 .TRD .

4 buffer – Intrinsic solubility to estimate pH-solubility profile l l 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 Solvents for Solubility Studies For developability assessment: – Simulated gastric fluid (SGF) – Simulated intestinal fluid (SIF) – pH 7.

Your Partner for Technical R&D Factors Causing Poor Solubility l High crystallinity/high MP – Zwitterion formation – Insoluble salts – H-bonding networks l Hydrophobicity/High LogP – Lack of ionizable groups – High molecular weight .TRD .

TRD . crystalline – Differences could be > 1000x l Polymorphs Solubility (mcg/mL) 1200 1000 800 600 400 200 0 1 2 3 4 5 6 7 8 9 Equilibration Time (Days) .Your Partner for Technical R&D Effect of Solid State Form l Amorphous vs.

Yalkowsky.C. American Chemical Society.Your Partner for Technical R&D Examples l Comparison of apparent solubility of amorphous material (A) and crystalline material (C): Solute Caffeine Theophylline Morphine Hydrochlorthiazide Sulfamethoxydiazine Melting Point (°C) 238 272 197 273 215 Solubility Ratio (A/C) 5 50 270 1. Solubility and Solubilization in Aqueous Media.1 1. Washington D. .5 •S. (1999).TRD .

TRD . (1999).3 4. Yalkowsky.6 7.2 1. American Chemical Society. .4 1.Your Partner for Technical R&D Examples of apparent solubility of polymorphs: Solute Acemetacin Cyclopenthiazide Mebendazole Spironolactone ∆ Melting Point (°C) 20 70 41 57 30 70 05 10 Solubility Ratio (L/H) 2.C. Solubility and Solubilization in Aqueous Media.7 2 3.9 l Comparison •S.6 3. Washington D.

TRD . Kinetic Solubility of solubility l Definition – 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? .Your Partner for Technical R&D Equilibrium Solubility vs.

2 1.6 0.8 0.0 1 2 3 4 5 6 7 8 pH l Effect of temperature .Your Partner for Technical R&D pH-Solubility Profile and Effect of Temperature l Effect of intrinsic solubility on the shape of the pH-solubility profile: Solubility (mg/mL) 1.4 pKa' 0.0 0.TRD .2 0.

l Different salts will have different solubility in nonaqueous systems. 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.TRD . .Your Partner for Technical R&D Solubility of Salts l Challenges with weak acid or base – pH of the saturated solution vs.

TRD .Your Partner for Technical R&D Dissolution l Importance of Dissolution Theoretical and practical considerations in dissolution rate determination l .

Your Partner for Technical R&D Importance of Dissolution l l Dissolution rate for poorly soluble compounds may often be the rate limiting step to absorption Examples of drugs with dissolution rate limited absorption: – Digoxin – Penicillin V – Phenytoin – Quinidine – Tetracyclines .TRD .

TRD .Your Partner for Technical R&D Factors Affecting Dissolution Rate l DC/Dt = kd (Cs – C) = KiA/V (Cs-C) – Kd dissolution rate constant – Ki intrinsic dissolution rate constant l l l Volume of the dissolution medium: dose:solubility ratio Intrinsic dissolution rate constant: using rotating disk apparatus Surface area of the solid – particle size effect – Effective surface area: the portion in actual contact with the dissolution medium .

Your Partner for Technical R&D Choice 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? .TRD .

TRD .Your Partner for Technical R&D Dissolution 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 .

Your Partner for Technical R&D Stability l Importance of stability l Theoretical and practical considerations in stability determination .TRD .

Your Partner for Technical R&D Chemical Stability l l l In SGF and SIF pH-stability profile 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 .TRD .

TRD .Your Partner for Technical R&D Physical 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 .

TRD .Your Partner for Technical R&D Solid State Properties l Importance of Solid State Properties l Theoretical and practical considerations in solid state characterization .

and rheological properties – Ease of isolation. filtration.Your Partner for Technical R&D Impact on Pharmaceutical Properties l Bioavailability l Stability (solubility/dissolution rate) (physical and chemical) Factors l Processing – Hygroscopicity – Bulk.TRD . and drying – Degree of purification . mechanical.

Your Partner for Technical R&D Risk 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 .TRD .

TRD .Your Partner for Technical R&D High Risk Compounds l l Poorly soluble compounds as defined by the FDA biopharmaceutical classification system: Solubility in pH 1-8 solutions x 250 mL < Dose Compounds that would require one of the nonequilibrium 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 .

Your Partner for Technical R&D Potential 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 .TRD .

Your Partner for Technical R&D Patent Protection for Potential LCM Opportunities Compound Claimed 1990 Product Lunch 2001 Patent expired 2010 Extension 2015 Original API PTR Salts and Polymorphs Generic Entry Polymorphs/Salts Claimed 1998 Generic Entry for All Other Forms not Covered PTR: Patent Term Restoration = half of the investigational period + all of the FDA review period .TRD .

morphology and chemical stability l Salt Selection vs. Form Selection – An integrated process .TRD .Your Partner for Technical R&D Salt 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.

oral formulations – High dose vs.Your Partner for Technical R&D Some Practical Considerations in Salt Screening and Selection l Dosage Form Considerations – IV vs.TRD . 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 .

compression properties and particle size and shapes Injection site precipitation Pain upon injection Toxicity of new excipients Effect of excipients on crystallization/nucleation Effect of processing and formulation on the physical and chemical stability Effect of excipients on crystallization/nucleation l Parenteral Dosage Forms – – – – l Suspensions – – .TRD .Your Partner for Technical R&D Some 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.

TRD .Your Partner for Technical R&D Automation 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 .

Your Partner for Technical R&D Example: Platform for Excipient Compatibility Studies .TRD .

Your Partner for Technical R&D Final Thoughts l Thorough preformulation work is the foundation of developing robust formulations. but the science doesn’t. Good science is always the right thing to do! l l l . Pay now or pay later is a balancing act. Organization structures vary.TRD .

SSCI. Pennsylvania. Solubility and Solubilization in Aqueous Media. Lea & Febiger. J. Stella. Inc. Hagen. 1995. E.J. and V. 18th edition. Brittain. Yalkowsky.L. Impact of solid state properties on developability assessment of drug candidates. 1990. Englewood. 1986. Advanced Drug Delivery Review. W. CO.. Liu. Radebaugh. John Wiley & Sons.. G. “Preformulation”. Brittain. .. Byrn. Pharmaceutical Preformulation. Rhodes. Physical Characterization of Pharmaceutical Solids. S. Pharmaceutical Preformulation and Formulation.A. Modern Pharmaceutics. Polymorphism in Pharmaceutical Solids. HIS Health Group. Wells.. Chapter 75 in Remington’s Pharmaceutical Sciences. Interpharm Press.J.Q. Inc. Gibson. 1990. Higuchi. Solubility Behavior of Organic Compounds.T. Marcel Dekker. K. Stowell. Inc. 1999. H. Edited by R. Amidon. 1988. Ellis Horwood Limited. Inc.. “Preformulation”. 2000. H.Your Partner for Technical R&D Additional Reading l l l l l l l l l l l l l G. Inc. L. Tong. R. Connors. 2000. “Preformulation Aspects of Insoluble Compounds” in Water Insoluble Drug Formulation. 2004. 2001. Chemical Stability of Pharmaceuticals (Second Edition). Washington D. Inc. Mack Publishing Company. American Chemical Society. Marcel Dekker. Easton.F. Philadelphia..R. Chapter 8 in the Theory and Practice of Industrial Pharmacy. Pfeiffer and J.TRD . Grant and T. 1986.F.Q. John Wiley & Sons. Fiese and T. Huang and W.C. Marcel Dekker. Tong.W.W.J. Second Edition.R. Banker and C. S.G.A. D. Ravin and G. L. 1999. Solid State Chemistry of Drugs. 56 (321-334). M. 1999.