DRUG DISCOVERY
`AND DEVELOPMENT
`
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`.
`.
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`BICENTENNIAL
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`THE WILEY BICENTENNIAL-KNOWLEDGE FOR GENERATIONS
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`

`DRUG DISCOVERY
`AND DEVELOPMENT
`
`Volume 2: Drug Development
`
`Edited by
`
`MUKUND S. CHORGHADE
`
`l!ICENTENNIAL
`
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`~ @WILEY ~ WILEY-
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`BICENTENNIAL
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`A JOHN WILEY & SONS, INC., PUBLICATION
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`Copyright © 2007 by John Wiley & Sons, Inc. All rights reserved.
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`Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
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`
`Library of Congress Cataloging-in-Publication Data:
`
`Drug discovery and development / edited by Mukund S. Chorghade.
`
` p. cm.
`
`Includes bibliographical references and index.
`
`ISBN 978-0471-39847-9 (cloth : v. 2)
`
`ISBN 978-0471-39846-2 (2-vol set)
` 1. Drug development.
`I. Chorghade, Mukund S. (Mukund Shankar)
`
`[DNLM: 1. Drug Design. 2. Chemistry, Pharmaceutical–methods.
` 3. Drug Evaluation, Preclinical–methods. QV 744 D79334 2006]
` RM301.25C488 2006
` 615⬘.19–dc22
`
`2005021297
`
`Printed in the United States of America
`
`10 9 8 7 6 5 4 3 2 1
`
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`CONTENTS
`
`Contributors
`Preface
`
`17
`
` Bioactive Molecules in Medicinal Plants: A Perspective on Their
`Therapeutic Action
`S. C. Taneja and G. N. Qazi
`
`17.1 Introduction, 1
`17.2 Evolutionary Relationships Among Plants and Humans, 2
`17.3 Traditional Wisdom, 3
`17.4 Unique Libraries for Plants, 4
`17.5 Drugs and Bioactive Molecules from Plants, 6
`17.6 Synergism in Herbal Formulations, 36
`17.7 Interactions Between Modern Drugs and Natural Products, 37
`17.8 Bioavailability and Bioeffi cacy Enhancers, 38
`17.9 Combination Therapies in Modern Drugs, 39
`17.10 Role of Developments in Technologies and Analytical Tools, 40
`17.10.1 Developments in Separation Technologies, 40
`17.10.2 Developments in Combined Techniques
`and Advanced Technologies, 41
`17.10.3 Molecular Farming and Bioengineering of Medicinal Plants, 42
`17.10.4 High-Throughput Screening of Natural Products, 42
`17.11 Herbal Medicine: The Best Possible Route to Health Care, 43
`References, 44
`
`xi
`xiii
`
`1
`
`
`
`v
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`
` CONTENTS
`
`18
`
` Natural Products as an Inspiration for the Discovery
`of New High-Throughput Chemical Synthesis Tools
`Steven V. Ley, Ian R. Baxendale, Deborah A. Longbottom, and Rebecca M. Myers
`
`18.1 Introduction, 51
`18.2 Solid-Supported Reagents as Tools in Natural Product Synthesis, 52
`18.3 Multistep Use of Supported Reagents in Natural Product Synthesis, 57
`18.4 Conclusions, 85
`References, 86
`
`19 Insulin Sensitizers: Emerging Therapeutics
`Braj B. Lohray and Vidya B. Lohray
`
`19.1 Introduction, 91
`19.2 Therapeutic Interventions, 92
`19.3 Discovery of Insulin Sensitizers, 92
`19.4 Journey Toward New Drugs, 94
`19.5 Conclusions, 116
`References, 117
`
`51
`
`91
`
`20
`
` Criteria for Industrial Readiness of Chiral Catalysis Technology
`for the Synthesis of Pharmaceuticals
`Raymond McCague and Ian C. Lennon
`
`121
`
`20.1 Introduction, 121
`20.2 Criteria for Technology Readiness, 122
`20.3 Examples of Industrially Ready Chiral Catalytic Technologies
`and Their Application, 124
`20.3.1 Lipase Bioresolution: Ethyl 3-Amino-3-Phenylpropionate, 124
`20.3.2 Aminoacylase Bioresolution of N-Acylamino Acids, 126
`20.3.3 Asymmetric Hydrogenation of Prochiral Olefi ns
`by Rhodium–DuPhos Catalysts, 127
`20.3.4 Asymmetric Hydrogenation of Prochiral Ketones
`by Ruthenium–Biphosphine–Diamine Catalysts, 129
`20.3.5 Asymmetric Hydroformylation with Rhodium–
`Phosphite Catalysts, 132
`20.3.6 Asymmetric Allylic Substitution with Palladium-Based
`Catalysts, 133
`20.4 How Industrially Ready Technology Can Deliver Commercial
`Advantages, 136
`20.5 Conclusions, 138
`References, 138
`
`21
`
` Enantioselective Synthesis of Propargyl Alcohols
`as Multifunctional Synthons
`J. S. Yadav and S. Chandrasekhar
`
`141
`
`21.1 Introduction, 141
`21.2 Asymmetric Reduction of Prochiral α, β-Alkynyl Ketones, 142
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` vii
`
`21.3 Addition of Acetylenic Anion to Carbonyl Carbon, 148
`21.4 Desymmetrization and Enzymatic Strategies for Chiral Propargyl
`Alcohol Synthesis, 155
`21.5 β-Elimination Strategy and Miscellaneous Approaches, 157
`21.6 Conclusions, 159
`References, 159
`
`22 Carbohydrates: From Chirons to Mimics
`G. V. M. Sharma and Palakodety Radha Krishna
`
`161
`
`22.1 Introduction, 161
`22.2 Synthetic Strategies for C-Glycosides, 162
`22.3 Synthetic Strategies for Carbon-Linked Disaccharides
`and Pseudosaccharides, 168
`References, 178
`
`23
`
` Meeting the Challenges of Process Development and Scale-up of Active
`Pharmaceutical Ingredients
`Yatendra Kumar and B. Vijayaraghavan
`
`181
`
`23.1 Introduction, 181
`23.1.1 Drug Development in the Pharmaceutical Industry, 181
`23.1.2 Challenges in Developing and Scaling Up Chemical
`Processes, 182
`23.2 Process Development Cycle, 183
`23.2.1 Stage I. Literature Survey and Analysis: Preparing the
`Blueprint, 184
`23.2.2 Stage II. Process Development: Laying the Foundation, 189
`23.2.3 Stage III. Process Optimization: Constructing the Building
`Brick by Brick, 192
`23.2.4 Stage IV. Process Validation: Finishing Touches—Grinding
`and Polishing, 195
`23.2.5 Stage V. Process Scale-up: The Moment of Truth, 196
`23.3 Conclusions, 198
`References, 198
`
`24 Importance of Polymorphs and Salts in the Pharmaceutical Industry
`Bipin Pandey, Vidya B. Lohray, and Braj B. Lohray
`
`201
`
`24.1 Introduction, 201
`24.2 Drug Discovery and Development, 202
`24.3 Salt Selection, 204
`24.4 Pseudopolymorphs, 206
`24.4.1 Hydrates, 206
`24.4.2 Solvates, 207
`24.4.3 Amorphous Solids, 208
`24.5 Analytical Tools, 208
`24.6 Process Development, 210
`24.7 Formulation Development, 212
`24.8 Regulatory Concerns, 213
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` CONTENTS
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`24.9 Patent Implications, 213
`24.10 Predictions and Uncertainties, 214
`24.11 Conclusions, 215
`References, 216
`
`25 Role of Outsourcing in Drug Manufacture
`Peter Pollak
`
`25.1 Introduction, 219
`25.2 Outsourcing in the Pharmaceutical Industry, 220
`25.2.1 Outsourcing of Chemical Manufacturing, 222
`25.2.2 Outsourcing of Research and Development, 231
`References, 232
`
`26 Regulation-Driven Process Chemistry
`Shrikant V. Kulkarni
`
`26.1 Introduction, 233
`26.2 Chemical Industry Regulatory Guidelines, 233
`26.3 Manufacturing Techniques in Process Chemistry, 237
`26.4 Effects of Pesticide Industry Regulation, 239
`26.5 Efforts at Denitrifi cation, 241
`26.6 Evolution to Green Chemistry, 247
`References, 248
`
`27
`
` Chemical Process Scale-up Tools: Mixing Calculations, Statistical
`Design of Experiments, and Automated Laboratory Reactors
`Andrei A. Zlota
`
`27.1 Chemical Process Scale-up Challenges, 251
`27.2 Case Study: Development of an Active Pharmaceutical Ingredient
`Crystallization Process, 253
`27.3 Case Study: Determination of a Scale-up Factor for the Bourne III
`Reactive System, 256
`27.4 Conclusions, 261
`References and Notes, 262
`
`28
`
` Library Quality Metrics
`Richard L. Wife and Johan Tijhuis
`
`28.1 Drug Discovery and Development, 265
`28.2 Compound Libraries, 267
`28.3 Library Metrics, 268
`28.3.1 Chemical Structure, 268
`28.3.2 Druglikeness, 269
`28.3.3 Novelty, 270
`28.3.4 Diversity, 272
`28.3.5 Numbers and Costs, 273
`28.3.6 Analogs, 274
`
`219
`
`233
`
`251
`
`265
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`
`
`ix
`
`28.3.7 Resupply, 275
`28.3.8 Compound Purity, 275
`28.3.9 Compound Stability, 276
`28.3.10 Compound Solubility, 276
`28.3.11 Serendipity, 276
`28.4 Conclusions, 277
`
`29
`
` Tying a GABA from Copenhagen to Chicago: The Chemistry
`of Tiagabine
`Mukund S. Chorghade, Mahendra N. Deshpande, and Richard J. Pariza
`
`279
`
`29.1 Introduction, 279
`29.2 Synthesis of Symmetrical Analogs: Tiagabine, 285
`29.3 Synthesis of Unsymmetrical Analogs: Desmethyltiagabine, 288
`29.3.1 Syntheses of Regioisomers of Tiagabine, 291
`29.3.2 Human Metabolite of Tiagabine: 5-Hydroxytiagabine, 292
`29.4 Attempted Biomimetic Synthesis of 5-Hydroxytiagabine, 296
`29.5 Oxidative Degradation Products of Tiagabine, 298
`29.5.1 Dihydroxytiagabine, 298
`29.5.2 Ketotiagabine, 299
`29.6 Metalloporphyrins as Chemical Mimics of Cytochrome P450
`Systems, 301
`29.6.1 Oxometalloporphyrins, 302
`29.6.2 Synthesis of the Sterically Protected and Electronically
`Activated Metalloporphyrins, 303
`29.6.3 Application of the Methodology to Selected Drugs, 303
`References, 306
`
`30
`
` Building Contract Research Businesses Based on Integration of Basic
`and Applied Research
`Mukund S. Chorghade, Mukund K. Gurjar, C. V. Ramana, and Sreenivas Punna
`
`309
`
`30.1 Introduction, 309
`30.2 Solving Real-World Problems, 312
`30.2.1 Synthesis of β-Blockers, 315
`30.2.2 Ring-Closing Metatheses as a Pathway to Chiral
`Compounds, 319
`30.3 Synthesis of Pharmaceutically Relevant Chiral
`Tetrahydrofurans, 323
`30.3.1 Discovery Route, 325
`30.3.2 Alternative Strategies for Synthesis of Compounds
`130 to 133 Based on C-Alkynyl Furan Derivatives, 334
`30.4 Drugs for the Treatment of Skin Disorders, 339
`30.4.1 Discovery Synthesis of Compound 229, 340
`30.4.2 Process Innovation for Compound 229: Systematic
`Investigation, 341
`30.4.3 Alternative Routes for Compound 229, 346
`30.5 Conclusions, 350
`References, 350
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` CONTENTS
`
`31 Principles and Practice of Clinical Drug Development
`Colin Scott
`
`31.1 Introduction, 355
`31.2 History of Ethical Medical Research, 356
`31.3 History of the Regulation of Medical Research, 360
`31.4 Preclinical Development, 364
`31.5 Clinical Development, 369
`31.6 Conclusions, 374
`
`Index
`
`355
`
`375
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`24
`
`IMPORTANCE OF POLYMORPHS
`AND SALTS IN THE PHARMACEUTICAL
`INDUSTRY
`
`BIPIN PANDEY
`Zydus Research Centre
`Ahmedabad, Gujarat, India
`
`VIDYA B. LOHRAY AND BRAJ B. LOHRAY
`BHUVID Research Laboratory
`Ahmedabad, Gujarat, India
`
`24.1 INTRODUCTION
`
`Polymorphism is the ability of a solid compound to exist in more than one crystalline form.
`These crystalline forms, although chemically identical, result from a different ordered
`arrangement of molecules in a unit cell within the crystal lattice. Polymorphism affects vari-
`ous kinds of physical properties depending on the nature and stability of crystal lattice. Some
`of these properties are heat capacity, conductivity, viscosity, surface tension, diffusivity, crys-
`tal hardness, crystal shape and color, refractive index, electrolytic conductivity, sublimation
`properties, latent heat of fusion, enthalpy of transition, phase diagram, and rate of reaction.
`Some of the other and more pertinent physical properties of polymorphs relevant to the phar-
`maceutical industry are solubility, dissolution rate and consequent bioavailability, chemical
`and physical stability, melting point, bulk density, electrostatic properties, and fl ow proper-
`ties, including processability. Changes in the aforementioned properties of a solid substance
`are of considerable importance to pharmaceutical companies. A number of drugs have shown
`considerable differences in their physical properties due to change in their crystalline struc-
`ture or polymorphic properties.1 Naturally, the differences in solubility can affect drug ef-
`fi cacy, bioavailability, and safety.2 It is reported that because of alterations in process or stor-
`
`Drug Discovery and Development, Volume 2: Drug Development, Edited by Mukund S. Chorghade
`Copyright © 2007 John Wiley & Sons, Inc.
`
`
`
`201
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`202
`
`
`
`IMPORTANCE OF POLYMORPHS AND SALTS IN THE PHARMACEUTICAL INDUSTRY
`
`age conditions, one polymorph of chloramphenicol-3-palmitate can have an eightfold-higher
`bioactivity3 than another, creating a danger of fatal doses when the unwanted polymorph is
`administered unwittingly. Changes in polymorphic behavior may pose considerable chal-
`lenges not only to scientists involved in new drug discovery but also to people involved
`in processing, formulation, and manufacturing research. Since different polymorphs are
`considered as new and patentable, they add tremendous commercial implications in terms
`of prolonging the patent life of a drug for the originator company, simultaneously offering
`opportunities to generic manufacturers for the discovery of new polymorph(s) and salts as a
`noninfringement strategy with a view to getting market exclusivity or market share.
`Polymorph research encompasses a variety of activities and technologies. From the very
`outset, one should be clear about the nature of a solid drug substance either in acidic or basic
`salt form, or as a neutral compound, and its polymorphic nature. Suitable analytical tech-
`niques should be developed for qualitative and quantitative identifi cation and characterization
`of different polymorphs. Simultaneously, process chemists should develop reproducible pro-
`cesses to ensure production of the same polymorphs all the time. Similarly, formulation ex-
`perts should ensure the stability of polymorphs during selection of excipients and should
`devise appropriate technologies during granulation, compacting, wetting, and tableting.
`Therefore, pharmaceutical industry scientists and technologists have to make serious
`chemical and engineering decisions that take into account not only safety, effi cacy, and
`processability of the drug substance or product in a reproducible manner, but also defi ne
`strategies to defend the intellectual property.
`Approximately half of all the drug molecules used in medicine are administered as salts,
`whereas polymorphism is encountered in most of the drug substances known in solid form.4
`The issues of salts and polymorphs are at the center of new drug discovery, chemical process
`development, analytical chemistry, pharmaceutical sciences, pharmacokinetics, toxicity, and
`clinical studies, and these issues are encountered repeatedly by pharmaceutical companies.
`Selection of an appropriate salt form for a new chemical entity provides the pharmaceuti-
`cal chemist and formulation scientist with an opportunity to modify the characteristics of
`the potential drug substance and develop dosage forms with good bioavailability, stability,
`manufacturing, and patient compliance. Salts are most commonly employed for modifying
`aqueous solubility, but the selection of a salt also infl uences a range of other properties, such
`as physical form, melting point, hygroscopicity, chemical stability, dissolution rate, pH of
`aqueous solution, crystal form, and mechanical and electrostatic properties.
`
`24.2 DRUG DISCOVERY AND DEVELOPMENT
`
`A modern drug discovery program is a multidisciplinary team effort involving medicinal
`chemistry, pharmacology, process development, cell biology, molecular biology, and drug
`metabolism pharmacokinetics/absorption, distribution, metabolism, excretion (DMPK/
`ADMET) science, along with intellectual property management under strict regulatory
`conditions. Usually, the initial stages of research are focused on drug target (enzyme or
`receptor) identifi cation and validation. Subsequently, a hit is found through an appropri-
`ate screening procedure, which is further optimized to get a lead. After lead optimization,
`a candidate is selected. The issue of a suitable salt and polymorph has to be addressed at
`the preclinical stage (Fig. 24.1). During these studies, variations in the crystalline form of
`new chemical entities (NCEs) might be observed which includes variation in the melting
`point, bulk density, and solubility profi les. Diffraction studies, solid-state infrared (IR) and
`
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`DRUG DISCOVERY AND DEVELOPMENT
`
` 203
`
`~-1+~1 --~l+~I __ _
`
`Discovery
`
`Development
`
`Product/Commercialization
`
`Target
`Identification
`
`Selection of
`appropriate
`salt/Polymorph
`of NCE
`
`New Polymorphs for
`ANDA filing by Generic
`Companies
`
`IND
`
`NDA
`
`Target
`Validation
`
`Lead
`Generation
`
`Lead
`Optimization
`
`Candidate
`Selection
`
`Pre-clinical
`Development
`
`Phase I
`
`Phase II
`
`Phase III
`
`Submit
`
`Global
`Launch
`
`Global
`Optimization
`
`Polymorphs & Kinetic
`behavior
`
`New Polymorph
`for lifecycle
`management of drug
`
`Polymorph as a
`tool for legal
`battles
`
`Figure 24.1
`
`Importance of polymorphs and salts in different stages of drug development.
`
`differential scanning calorimetry (DSC) may reasonably be considered supportive for the
`solid-state characterization of drug candidates at this stage.5
`When studies of a drug candidate in humans (phase I) are planned, the U.S. Food and
`Drug Administration (FDA) requires that an investigational new drug application (IND)
`be submitted. Prudence suggests that this may be the best time to begin a search for novel
`polymorphs. As we know that different solvents and impurities/degradation products can
`trigger formation of different polymorphs, it is important at this stage to study the nature of
`the polymorph. Since different polymorphs may have different pharmacokinetic profi les,
`it is essential that various polymorphs of the drug candidate be studied before selecting
`a particular polymorph for the dose escalation studies in phase I and subsequently for
`phase II studies. At the later stage of drug development, a change of polymorph will be
`economically untenable. Apart from appropriate process development of NCE, one needs
`to reproduce in pilot-plant scale the formation of the polymorph selected, which usually
`comprises a batch of drug produced for phase II and III studies.
`To derive maximum reliable information from phase II and III clinical trials, it be-
`comes imperative to control the physical and chemical characteristics of the drug sub-
`stance and the drug product and to ensure that the quality remains consistent throughout.
`Unanticipated variations in quality, such as discovering a new polymorph or a solvate,
`can have a major fi nancial impact and disturb the overall development time line. During
`these studies one must ensure that during scale-up, parameters such as choice of sol-
`vent of crystallization, recrystallizing conditions, volatile impurities, drying conditions
`(temperature and vacuum), milling, grinding, storage, and transportation conditions be
`rigorously fi xed.
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`204
`
`
`
`IMPORTANCE OF POLYMORPHS AND SALTS IN THE PHARMACEUTICAL INDUSTRY
`
`At the stage of process optimization, it is best to “fi x the last step fi rst.” In a multistep
`synthetic operation, it is advisable to fi x the key reaction critical parameters of the last step
`very rigorously at the very beginning so that the same solid form is obtained reproducibly.
`Later, one may optimize the process of prior stages.
`During manufacture of the drug product, the drug substance is exposed to a variety of
`physical and mechanical stresses. In addition to pressure, the environment needs to be con-
`trolled. Hygroscopic substances require special control to ensure same degree of solvation.
`A granulation step before a tablet is compacted may include a liquid, which is subsequently
`removed in drying, which may alter the crystalline form of the active ingredient. Awareness
`of the physical conditions at each step of manufacturing provides a rationale for the support
`of in-process or release controls (e.g., hardness dissolution). For further details, see Section
`24.6. In case of interconversion of polymorphs at this stage, the kinetics of phase change
`should be studied to ensure that the interconversion does not change the quality of product
`adversely. If a phase change takes place over a period of days to months, appropriate con-
`trols during formulation manufacturing and packaging should be incorporated. Adequate
`statements for storage conditions should be printed on labels to assure consistency of qual-
`ity. Extremely slow phase change may not have any major impact on the product, but
`extremely rapid changes in phase may require appropriate guidelines for release of drug
`substance and storage conditions.
`If a new polymorph is discovered at a later stage, one needs to establish the bioequiva-
`lence of the formulation containing the new polymorph, which may require a different
`composition or amount of active ingredient. As the drug candidate moves to phase III
`clinical trials, the bulk manufacturing process should be fi xed as per current good manu-
`facturing practice, including all in-process controls and impurity profi ling. All detailed
`studies related to polymorphic state, including issues of solvates, hydrates, and amor-
`phousness or crystallinity, must be carried out, and any problem must be assessed to
`the smallest detail. Acceptance criteria should be clearly established. The manufacturing
`process must be validated rigorously before the drug enters phase III clinical evalua-
`tion, and enough evidence should be collected to ensure the biological profi le of various
`polymorphs.
`
`24.3 SALT SELECTION
`
`Modern drug discovery technologies propelled by combichem, computer-aided drug
`design (CADD), and high-throughput screening (HTS) of biological targets (enzymes,
`receptors) generate a large number of hits, which are usually refi ned by further screen-
`ing and selection, based on druglike properties, to a manageable number of leads. Many
`leads will show only weak or moderate activity, because biological assays (in vitro) are
`usually done in dimethyl sulfoxide (DMSO) solution, which requires further refi nement
`and optimization of properties. These optimization protocols usually involve numer-
`ous structural modifi cations and reexamination through in vivo and in vitro biological
`assays until a small number (usually two to fi ve) of the most highly active candidates
`are advanced for further study. At this stage, most candidates are usually free bases,
`free acids, or neutral molecules rather than salts. Due to the increasing use of DMSO
`solutions and solubility considerations, more lipophilic candidates are preferred. Quite
`frequently, several of the lead candidates are either amorphous or partially crystalline.
`Usually at this stage of development, little effort has been made to investigate formal
`
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`IPR2020-00040
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`SALT SELECTION
`
` 205
`
`crystallization procedures. However, it is widely accepted that water-soluble candidates
`will have better biological profi les as drugs. Therefore, salt formation of lead candidates
`becomes an important objective.6 Salts offer not only improvement in purity, crystal-
`linity (e.g., melting point), stability, and hygroscopicity, thereby enhancing operational
`simplicity during bulk manufacturing and pharmaceutical formulation processing, but
`also improve the biological profi le by enhancing the solubility and dissolution rates as
`well. Added to this comes the opportunity of patenting new salts, along with various
`polymorphs of the salt, thereby prolonging the patent term of commercially useful com-
`pounds.6 Alternatively, as a result of recent regulatory guidelines, discovery of new salts
`and polymorphs offers opportunities for market exclusivity for generic manufacturers.
`However, complete characterization of salt form and solid state is an important criteria
`for drug development.
`Systematic screening for salts is advantageous at an early stage of candidate selec-
`tion with a view to optimize solubility, dissolution rate, solid-state stability, hygroscop-
`icity, toxicity, and drug delivery (formulation) properties. In particular, toxicological
`consequences of counterions during salt formation are very important, especially dur-
`ing early stages of drug safety evaluation. When high-dose screening is required for
`toxicity studies, the concentration of counterion is much more than that actually pres-
`ent in the marketed drug (acute toxicity studies), and at this stage, concerns are high.
`Table 24.1 shows the classifi cation of various common pharmaceutical salts as anions
`and cations.
`Measurement of the key physiochemical properties of solid forms of lead candidates
`is essential during the early discovery process, not only from manufacturing and regula-
`tory perspectives, but from a formulation viewpoint as well, where dosage form, pro-
`cessability, and compatibility with other excipients are the key issues. Some of the key
`physical, chemical, and biologically relevant properties that should be evaluated com-
`prehensively prior to making a fi nal decision on salts for further development are listed
`in Table 24.2.
`
`TABLE 24.1 Classifi cation of Commonly Accepted Pharmaceutical Salts
`
`Salt Class
`
`Anions
`Inorganic acids
`
`Sulfonic acids
`Carboxylic acids
`Anionic amino acids
`Hydroxy acids
`Fatty acids
`Insoluble salts
`Cations
`Organic amines
`
`Insoluble salts
`Metals
`Cationic amino acids
`
`Examples
`
`Hydrochloride, hydrobromide, sulfate, hydrogen sulfate,
`nitrate, phosphate
`Mesylate, esylate, tosylate, napsylate, besylate
`Acetate, propionate, maleate, benzoate, salicylate, fumarate
`Glutamate, aspartate
`Citrate, lactate, succinate, tartarate, glycollate
`Hexanoate, octanoate, decanoate, oleate, stearate
`Palmoate, polystyrene sulfonate (resinate)
`
`Triethylamine, ethanolamine, triethanolamine,
`ethylenediamine, choline
`Procaine, benzathine
`Sodium, potassium, calcium, magnesium, zinc
`Arginine, lysine, histidine
`
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`IPR2020-00040
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`
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`IMPORTANCE OF POLYMORPHS AND SALTS IN THE PHARMACEUTICAL INDUSTRY
`
`TABLE 24.2 Physiochemical Property Evaluation for Salt Selection
`
`Property
`
`Melting point
`
`Crystallinity (crystal shape and appearance)
`Particle size and bulk density, surface area
`
`Polymorphism
`Powder properties
`
`Stability
`Solution stability (to acid, base, oxidation, heat)
`Solid-state stability according to ICH guidelines
`Electrostatic behavior
`Hygroscopicity
`Processability
`Impurity profi ling; usually, salt formation
`enhances purity of drug substance
`Partition coeffi cient: c log P
`Aqueous solubility as a function of pH
`
`Solubility at various pH values (pH 2, stomach;
`pH 6.8–8, mouth, esophagus, colon, intestine;
`and pH 9, duodenum)
`Dissociation constants: (pKa/pKb)/ionization
`constant
`Intrinsic dissolution rate
`Permeability
`Solubility in organic solvents [e.g., ethanol,
`polyethylene glycol, propylene glycol,
`glycerol, etc. (formulation requirement)]
`
`24.4 PSEUDOPOLYMORPHS
`
`Criteria
`
`Generally, higher-melting-point products are
`preferred
`Crystalline nonhygroscopic material
`Smaller particle size, bulk density, and large
`surface area
`Stable polymorph
`Nonhygroscopic powder with a high melting
`point
`Stable in accelerated stability condition (e.g.,
`40⬚C/75% RH 25⬚C/60% RH)
`
`Nonelectrostatic nature
`Nonhygroscopic
`Easy processability
`Need to be fi xed before phase III clinical
`development
`Generally, lipophilic for better bioavailability
`Aqueous solubility at neutral pH (7.2) is
`preferred
`Depending on the target organ, stability and
`solubility of the drug at various pH values
`need to be determined
`
`High permeability is preferred
`Nonreactivity, easy processability, and stability
`with formulation is desired
`
`Pseudopolymorphs are not strictly polymorphs because they differ from each other in
`the solid crystalline phase, through incorporation of either solvents (solvates) or water
`(hydrates). The principle of hydrogen bonding and packing arrangements of the same
`drug substance in the crystal lattice is the guiding principle for pseudopolymorphs as
`well. Like polymorphs, pseudopolymorphs, exhibit different physicochemical properties
`and are suitable as drug substances for development and should be evaluated while se-
`lecting the fi nal solid drug substance. There can be stoichiometric or nonstoichiometric
`pseudopolymorphs.
`
`24.4.1 Hydrates
`
`Generally, hydrates are considered appropriate psuedopolymorphs for development.7 Many
`drugs are marketed as hydrates, presumably because they are either the most stable form
`
`Merck Exhibit 2045, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`PSEUDOPOLYMORPHS
`
` 207
`
`as hydrates during stability studies or because they offer improved physicochemical prop-
`erties. The potential impact of changes in hydration state of a crystalline drug substance
`and excipients exists throughout the bulk drug manufacturing and development