in the Pharmaceutical Industry

Edited byRolf Hilfiker

Polymorphism

InnodataFile Attachment3527607722.jpg

Edited byRolf Hilfiker

Polymorphism

Related Titles

R. J. D. Tilley

Understanding SolidsThe Science of Materials

2005ISBN 0-470-85276-3

H.U. Blaser, E. Schmidt (Eds.)

Asymmetric Catalysis on Industrial ScaleChallenges, Approaches and Solutions

2004ISBN 3-527-30631-5

H. J. Scheel, T. Fukuda

Crystal Growth Technology2004ISBN 0-471-49524-7

P. Bamfield

Research and Development Managementin the Chemical and Pharmaceutical Industry2003ISBN 3-527-30667-6

F. Schüth, K.S.W. Sing, J. Weitkamp (Eds.)

Handbook of Porous Solids5 Volumes

2002ISBN 3-527-30246-8

in the Pharmaceutical Industry

Edited byRolf Hilfiker

Polymorphism

Editor

Dr. Rolf HilfikerSolvias AGKlybeckstrasse 1914002 BaselSwitzerland

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data:A catalogue record for this book is availablefrom the British Library

Bibliographic information published byDie Deutsche BibliothekDie Deutsche Bibliothek lists this publicationin the Deutsche Nationalbibliografie;detailed bibliographic data is available in theInternet at http://dnb.ddb.de

© 2006 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim, Germany

All rights reserved (including those of translationin other languages). No part of this book maybe reproduced in any form – by photoprinting,microfilm, or any other means – nor transmittedor translated into machine language withoutwritten permission from the publishers.Registered names, trademarks, etc. used in thisbook, even when not specifically marked as such,are not to be considered unprotected by law.

Cover illustration SCHULZ Grafik-Design,FußgönheimTypesetting K+V Fotosatz GmbH, BeerfeldenPrinting betz-druck GmbH, DarmstadtBinding J. Schäffer GmbH, Grünstadt

Printed on acid-free paperPrinted in the Federal Republic of Germany

ISBN-13: 978-3-527-31146-0ISBN-10: 3-527-31146-7

� All books published by Wiley-VCH arecarefully produced. Nevertheless, authors,editors, and publisher do not warrant theinformation contained in these books,including this book, to be free of errors.Readers are advised to keep in mind thatstatements, data, illustrations, proceduraldetails or other items may inadvertentlybe inaccurate.

Preface XV

List of Contributors XVII

1 Relevance of Solid-state Properties for Pharmaceutical Products 1Rolf Hilfiker, Fritz Blatter, and Markus von Raumer

1.1 Introduction 11.2 Drug Discovery and Development 41.3 Bioavailability of Solids 61.4 Phases of Development and Solid-state Research 71.4.1 Salt Selection 81.4.2 Polymorph Screening 91.4.3 Crystallization Process Development 121.4.4 Formulation 131.4.5 Method Development 141.5 Solid-state and Life Cycle Management 151.6 Conclusions 15

References 17

2 Thermodynamics of Polymorphs 21Sachin Lohani and David J. W. Grant

2.1 Introduction 212.2 Structural Origin of Polymorphism 222.3 Thermodynamic Theory of Polymorphism 222.4 Thermodynamic Relationship Between Polymorphs:

Enantiotropy and Monotropy 242.4.1 Energy–Temperature Diagrams 242.4.2 Pressure–Temperature Diagrams 282.4.3 Inversion of Polymorphic Behavior 30

V

Contents

2.5 Rules to Predict Thermodynamic Relationships BetweenPolymorphs 31

2.5.1 Heat of Transition Rule 312.5.2 Heat of Fusion Rule 312.5.3 Entropy of Fusion Rule 322.5.4 Heat Capacity Rule 322.5.5 Density Rule 332.5.6 Infrared Rule 332.6 Relative Thermodynamic Stabilities of Polymorphs 332.7 Crystallization of Polymorphs 342.7.1 Nucleation of Polymorphs 342.8 Introduction to Solvates and Hydrates 372.8.1 Thermodynamics of Hydrates 372.9 Summary 40

References 41

3 Characterization of Polymorphic SystemsUsing Thermal Analysis 43Duncan Q.M. Craig

3.1 Introduction – Scope of the Chapter 433.2 Use of Differential Scanning Calorimetry for the Characterization

of Polymorphs 443.2.1 Principles of DSC in the Context of Polymorphism 443.2.2 Examples of the Uses of DSC: Characterization of Drugs,

Excipients and Dosage Forms 493.2.3 Further Uses of DSC 543.3 Combined Approaches 583.3.1 Multi-instrument Approaches 583.3.2 Thermal and Crystallographic Studies 633.3.3 Interfaced Techniques 653.4 Additional Thermal Methods for the Study of Polymorphism 673.4.1 Thermogravimetric Analysis 673.4.2 Thermal Microscopy 683.4.3 Heat of Solution Studies 693.4.4 Modulated Temperature DSC 703.4.5 High-speed DSC 723.4.6 Microthermal Analysis 733.4.7 Thermally Stimulated Current 743.5 Conclusions 76

References 77

ContentsVI

4 Solid-state NMR Spectroscopy 81Joseph W. Lubach and Eric J. Munson

4.1 Introduction 814.1.1 Basics of Solid-state NMR 824.2 Applications 824.2.1 Identification 824.2.2 Selectivity 844.2.3 Mobility and Dynamics 854.2.4 Quantitation of Forms 864.3 Conclusions 92

References 92

5 Vibrational Spectroscopic Methods in PharmaceuticalSolid-state Characterization 95John M. Chalmers and Geoffrey Dent

5.1 Introduction 955.2 Mid-infrared, Raman and THz Spectroscopy:

Basic Comparison of Theory, Instrumentation and Sampling 975.2.1 Basic Theory 975.2.2 Instrumentation Brief 1005.2.3 Sampling 1045.2.3.1 Raman Sampling 1045.2.3.2 Mid-infrared Sampling 1055.2.3.3 THz Spectroscopy Sample Presentation 1095.3 Changes of State and Solid-state Effects on Infrared and

Raman Spectra 1105.3.1 Introduction 1105.3.2 Spectra of Gases, Liquids and Solutions 1105.3.3 Hydrogen Bonding 1115.3.4 Amine Salts (including Amino Acids) 1145.3.5 Solids 1155.3.6 Polymorphism 1175.3.7 Enantiomers and Racemates 1185.3.8 Tautomerism 1195.3.9 Summary 1195.4 Examples and Applications 1195.4.1 Polymorphism 1205.4.2 Hydration/Drying 1265.4.3 Quantitative Analysis and Process Monitoring 1285.4.4 Tablets 1305.5 Closing Remarks 135

References 136

Contents VII

6 Crystallography for Polymorphs 139Philippe Ochsenbein and Kurt J. Schenk

6.1 Introduction 1396.2 Solving Difficult Crystal Structures with Parallel Experiments 1406.3 Atropisomers and Desmotropes 1446.4 Salts 1486.5 Influence of Solvents 1496.6 Isolation of a Furtive Species 1536.7 Mizolastine Polymorphs 1546.8 Solid Solutions 1576.9 Structures from Powder Data 1606.10 “Behind Every Structure There is a Crystal” 164

References 165

7 Light Microscopy 167Gary Nichols

7.1 Introduction 1677.2 Why Use a Light Microscope to Study Solid-state Properties? 1687.3 Polarizing Light Microscope 1697.4 Photomicrography 1707.5 Specimen Preparation 1717.5.1 Permanent and Temporary Mounts 1727.5.1.1 Permanent Mounts 1727.5.1.2 Temporary Mounts 1737.5.2 Preparation of Temporary Mounts 1737.5.3 Examination of Tablets 1737.6 Observations Using Polarized Light Microscopy 1747.6.1 Polarized Light 1747.6.2 Crystal Studies with Plane Polarized Light 1757.6.3 Crystal Studies with Crossed Polarizers 1777.6.3.1 Interference Colors 1777.6.3.2 Extinction 1797.6.3.3 Interference Figures 1817.6.3.4 Compensator Plates 1837.6.3.5 Use of Circularly Polarized Light 1837.6.4 Crystallinity 1847.7 Refractive Index 1867.7.1 Measuring Refractive Indices 1877.7.2 The Becke Test 1887.7.3 Dispersion Staining 1887.8 Particle Size 1897.9 Particle Shape 1907.10 Comparing Powder Samples 1947.11 Thermomicroscopy 195

ContentsVIII

7.12 The Microscope as a Micro-scale Laboratory 1967.13 Twinning 1977.14 Color and Pleochroism 1997.15 Fluid Inclusions 2017.16 Mechanical Properties of Crystals 2037.17 Pseudomorphs 2047.18 Mesomorphism 2057.19 Identification of Contaminants and Foreign Matter 2067.20 Conclusion 207

References 207

8 The Importance of Solvates 211Ulrich J. Griesser

8.1 Introduction 2118.2 Terminology and Classification of Solvates 2138.2.1 General Terms and Definitions 2138.2.2 Types of Solvates 2158.2.2.1 Stoichiometric Solvates 2158.2.2.2 Non-stoichiometric Solvates 2168.2.3 Classification Models of Hydrates 2188.3 Statistical Aspects and Frequency of Solvates 2198.4 Generation and Characterization of Solvates 2228.5 Stability and Solubility of Solvates 2248.6 Processing of Solvates 2278.7 Relevance, Problems and Potential Benefits 2288.8 Patents 2298.9 Conclusions 230

References 230

9 Physical Characterization of Hygroscopicity in PharmaceuticalSolids 235Susan M. Reutzel-Edens and Ann W. Newman

9.1 Introduction 2359.1.1 Definition of Hygroscopicity 2359.1.2 Classification of Hygroscopic Behavior 2369.2 Water–Solid Interactions 2389.3 Characterizing Water–Solid Interactions 2399.3.1 Moisture Sorption Analysis 2399.3.2 Surface Energy Approaches 2439.3.3 Molecular Level Approaches 2449.3.3.1 Stoichiometric Hydrates 2449.3.3.2 Non-Stoichiometric/Channel Hydrates 2459.3.3.3 Isomorphic Desolvates 250

Contents IX

9.4 Significance of Water–Solid Interactions in PharmaceuticalSystems 251

9.4.1 Physicochemical Stability 2519.4.2 Dissolution 2529.4.3 Physical-mechanical Characteristics 2539.5 Strategies for Dealing with Hygroscopic Systems 2549.6 Conclusions 256

References 256

10 The Amorphous State 259Samuel Petit and Gérard Coquerel

10.1 Introduction 25910.2 Definition of the Amorphous State 26010.2.1 Order, Disorder and Structural Aspects 26010.2.2 Energetic Aspects: Thermodynamics and Kinetics 26210.3 Preparation of Amorphous Solids 26310.3.1 Preparation from a Liquid Phase: Quench-cooling 26410.3.2 From a Solution: Rapid Precipitation 26510.3.3 From a Frozen Solution: Freeze-drying (Lyophilization) 26510.3.4 From an Atomized Solution: Spray-drying 26610.3.5 From a Crystalline Phase: Grinding and Milling 26610.3.6 From a Crystalline Solvate: Desolvation/Dehydration 26810.3.7 Physical Mixture with Amorphous Excipients 26910.4 Properties and Reactivity 26910.4.1 The Glass Transition 27010.4.2 Molecular Mobility and Structural Relaxation 27110.4.3 Strong/Fragile Classification of Angell 27210.4.4 Mixing with Solvents/“Dissolution” Behavior 27310.4.5 Influence of Water Content: Plasticization and Chemical

Degradation 27410.4.6 Polyamorphism 27510.5 Characterization and Quantification 27610.5.1 Thermal Analysis and Spectroscopic Methods 27710.5.2 Detection and Quantification of Small Amorphous Contents 27710.6 Crystallization of Amorphous Solids 27810.6.1 “Difficult-to-crystallize” Compounds 27910.6.2 Inadvertent Crystallization 28010.6.3 Crystallization as a Tool for Insight into the Amorphous State 280

References 282

ContentsX

11 Approaches to Polymorphism Screening 287Rolf Hilfiker, Susan M. De Paul, and Martin Szelagiewicz

11.1 Introduction 28711.2 Crystallization Methods 28911.3 Solvent Parameters 29011.4 Systematic Polymorphism Screening 29111.5 High-throughput Methods 29411.6 An Example of a High-throughput Screening Approach 29611.6.1 Model Substance 29611.6.2 Solubility 29611.6.3 Crystallization Experiments 29711.6.4 Data Acquisition 29711.6.5 Data Analysis 29811.7 Theoretical Methods 30011.8 Characterization 30211.9 Conclusions 303

References 305

12 Salt Selection 309Peter Heinrich Stahl and Bertrand Sutter

12.1 Introduction 30912.2 Salt Formation and Polymorphism 30912.3 Target Properties of Active Substances for Drug Products 31112.3.1 Injectables 31112.3.2 Solid Dosage Forms 31212.3.3 Dosage Forms for Other Routes of Application 31212.3.3.1 Inhalation 31212.3.3.2 Topical Products and the Transdermal Route 31312.4 Basics of Salt Formation 31412.4.1 Ionization Constant 31412.4.2 Ionization and pH 31512.4.3 Solubility 31612.5 Approaches to Salt Screening 31912.5.1 Initial Data 31912.5.2 Selection of Salt Formers 31912.5.3 Automated Salt Screening 32012.6 Selection Procedures and Strategies 32212.6.1 Points to be Considered 32212.6.2 Final Decision 32312.6.3 Salt Form and Life Cycle Management of Drug Products 32512.7 Case Reports 32512.7.1 Overview of Salt Forms Selected 32512.7.2 Salt Selection Process 32512.7.3 Case 1: NVP-BS001 326

Contents XI

12.7.4 Case 2: NVP-BS002 32712.7.4.1 Discussion and Decision 32912.7.5 Case 3: NVP-BS003 329

References 332

13 Processing-induced Phase Transformations andTheir Implications on Pharmaceutical Product Quality 333Ramprakash Govindarajan and Raj Suryanarayanan

13.1 Introduction 33313.2 Processing-related Stress 33613.2.1 Mechanical Stress 33713.2.1.1 Milling 33713.2.1.2 Compression 33713.2.2 Thermal and Pressure Stresses 33813.2.2.1 Freezing 33813.2.2.2 Drying 33913.2.2.3 Melting 34013.2.3 Interaction with Other Components 34113.2.3.1 Hydrate Formation 34113.2.3.2 Complexation 34213.2.3.3 Salt–Free-acid/Base Conversions 34213.2.3.4 Metastable Phase Formation 34213.2.3.5 Multiple Interactions 34313.3 Detection and Quantification of Phase Transformations 34313.3.1 Generation (Creation) of Lattice Disorder 34313.3.2 Crystallization – Anhydrous Phase 34713.3.3 Hydrates – Formation and Dehydration 34913.3.4 Salt–Free-acid/Base Transformations 35113.4 Implications of Phase Changes 35213.4.1 Amorphization 35213.4.2 Crystallization 35613.4.3 Polymorphic Transitions 35713.4.4 Hydration/Dehydration 35813.4.5 Salt–Free-acid/Base Conversion 36013.5 Summary 360

References 361

ContentsXII

14 Polymorphism and Patents from a Chemist’s Point of View 365Joel Bernstein

14.1 Introduction 36514.2 Some Fundamentals of Patents Related to Polymorphism

and Some Historical Notes 36614.3 Ranitidine Hydrochloride (RHCl) 36914.4 Cefadroxil 37214.5 Paroxetine Hydrochloride 37514.6 The Importance of Seeding 37914.7 Concluding Remarks 381

References 382

15 Scientific Considerations of Pharmaceutical Solid Polymorphismin Regulatory Applications 385Stephen P.F. Miller, Andre S. Raw, and Lawrence X. Yu

15.1 Introduction 38515.2 General Principles of Pharmaceutical Solid Polymorphs 38515.3 Influence of Polymorphism on Product Quality

and Performance 38615.3.1 Effect on Bioavailability (BA)/Bioequivalence (BE) 38615.3.2 Effect on Stability 38715.3.3 Effect on Manufacturability 38815.4 Pharmaceutical Solid Polymorphism in Drug Substance 38915.4.1 Polymorph Screening 39015.4.2 Control of Polymorphism in Drug Substance 39115.4.3 Acceptance Criterion for Polymorph Content

in Drug Substance 39415.5 Pharmaceutical Solid Polymorphism in Drug Product 39515.5.1 Polymorphism Issues in Drug Product Manufacturing 39515.5.2 Control of Polymorphism in Drug Product 39615.6 Process Analytical Technology 39915.6.1 Process Analytical Technology and the Crystallization of

Polymorphic Forms 39915.6.2 Process Analytical Technology and Polymorphs

in Drug Products 40015.7 Summary 401

References 402

Subject Index 405

Contents XIII

Polymorphism, a term derived from the Greek words for “much/many” (poly,����� ) and “form” (morphē, ���� ), is used in disciplines as diverse as linguis-tics, computer science, biology, genetics, and crystallography. In the life sciencesindustry, two completely different types of polymorphism play a major role:polymorphisms in DNA sequence and polymorphs of crystalline substances. Inthe former, great strides are being made using polymorphisms in their DNA se-quence to predict an individual’s susceptibility to disease and response to drugs,making it possible to design and select appropriate drugs. In the latter, the poly-morphic form of a drug substance or excipient can have a profound impact ona spectrum of aspects, such as biological action, production, formulation and in-tellectual property protection. This book deals exclusively with the polymorphsof solids, covering not only polymorphs in the narrow sense, i.e., different crys-talline forms of the same molecular entity, but also other solid-state forms rele-vant to industry, such as solvates, salts, and the amorphous form.

Interest in the solid-state properties of drugs has grown tremendously in re-cent decades as can be seen, for example, by the numerous conferences andworkshops organized by various scientific and commercial institutions. This in-terest is well deserved. Anyone who has worked in the field for some time canpoint to examples where insufficient understanding of solid-state properties hasled to serious setbacks. Problems encountered range from the sudden unex-pected inability to produce reliably a form that has been used for pivotal clinicalstudies and is the basis for registration documents to variations in the drugproduct properties due to seemingly random changes of the solid form duringprocessing or storage. Conversely, a thorough understanding of solid-state prop-erties can create opportunities, which are increasingly being exploited for thebenefit of both the company and the patient. Not only can patent protection bebroadened or prolonged, and production made more efficient and cheaper, butthe properties of the drug can also be improved to the advantage of the patient.

Increasing recognition of the importance of polymorphism to the life sciencesindustry has generated a great deal of interest and the field has been evolvingrapidly. Given the pace of recent developments, an update is both useful andtimely. This book discusses the whole breadth of the subject, covering all rele-vant aspects of solid-state issues for the pharmaceutical industry. It should actas a manual and a guideline for scientists dealing with solid-state issues, and

XV

Preface

serve both as an introduction to people new to the field and as a source for ex-perts to round off their knowledge. It also provides valuable information forscientists working in other areas where solid-state issues are important, such asanimal health, agrochemical, and specialty chemical industries.

Chapters are organized according to the following aspects of polymorphism:relevance, tools, properties, practical approaches, and legal issues. Chapter 1 dis-cusses the relevance of solid-state forms in the pharmaceutical industry andmakes recommendations on how best to approach solid-state issues. Chapter 2,on the thermodynamics of polymorphs, provides the theoretical tools needed tounderstand solid-state behavior. Chapters 3 to 7 give detailed descriptions, in-structions, and hints on how to characterize solids, since solid-state behaviorcan only be understood after thorough characterization. Such an understandingis crucial to making the right decisions at key stages of drug development andproduction. Chapters 8 to 10 highlight the properties and importance of solid-state forms that are not included in the narrow definition of polymorphism,namely, solvates, hydrates and the amorphous form. Essential practical aspectsfor development scientists are described in Chapters 11 to 13, which deal withidentifying relevant polymorphs, finding optimal salts and controlling solid-statebehavior during processing. The last two chapters discuss legislative aspects ofsolid-state properties. Often, solid-state forms can be protected by patents, whichmay create significant financial benefits. Chapter 14 outlines the principles ofintellectual property protection and provides relevant examples. Finally, sincethe solid form can have an impact on the safety and efficacy of drugs, Chapter15 explains regulatory issues in connection with solid-state behavior. Rules,based on scientific considerations, are elucidated.

The broad range of topics discussed in this text, from thermodynamics to le-gal issues, emphasizes the complexity of the subject. It also demonstrates thatthe challenges and opportunities connected with solid-state properties can onlybe addressed successfully through an integral approach that considers all theseaspects.

The strength of this volume lies in the quality of its contributions. My sincerethanks go to every author for the excellent standard of their submissions andtheir engaged cooperation. The balance of contributions from industry, acade-mia and government highlights the far-reaching importance of the subject.From a personal perspective, I very much appreciated the fact that after develop-ing the concept for this book and inviting authors to submit chapters on specif-ic themes, colleagues willingly agreed to do so despite their very busy schedules.Finally, I thank Wiley-VCH for recognizing the timeliness of such a volume andDr. Elke Maase and Dr. Bettina Bems for an enjoyable collaboration in the prep-aration of this book.

Basel, January 2006 Rolf Hilfiker

PrefaceXVI

XVII

List of Contributors

Joel BernsteinDepartment of ChemistryBen-Gurion University of the NegevBeer Sheva 84105Israel

Fritz BlatterSolvias AGKlybeckstrasse 1914002 BaselSwitzerland

John M. ChalmersVS Consulting14 Croft HillsTame Bridge, Stokesley TS9 5NWUnited Kingdom

Gérard CoquerelSciences et Méthodes Séparatives,EA 3233Université de RouenIRCOF, Rue Tesnière76821 Mont Saint Aignan CedexFrance

Duncan Q. M. CraigSchool of Chemical Sciences andPharmacyUniversity of East AngliaNorwich, Norfolk NR4 7 TJUnited Kingdom

Susan M. De PaulSolvias AGKlybeckstrasse 1914002 BaselSwitzerland

Geoffrey DentGD Analytical Consulting53 Nudger GreenDobcross, Oldham OL3 5AWUnited Kingdom

Ramprakash GovindarajanDepartment of PharmaceuticsUniversity of Minnesota308 Harvard Street SEMinneapolis, MN 55455USA

David J. W. GrantDepartment of PharmaceuticsCollege of PharmacyUniversity of Minnesota308 Harvard Street SEMinneapolis, MN 55455USA

Ulrich J. GriesserInstitute of PharmacyUniversity of InnsbruckInnrain 526020 InnsbruckAustria

List of ContributorsXVIII

Rolf HilfikerSolvias AGKlybeckstrasse 1914002 BaselSwitzerland

Sachin LohaniDepartment of PharmaceuticsCollege of PharmacyUniversity of Minnesota308 Harvard Street SEMinneapolis, MN 55455-0343USA

Joseph W. LubachDepartment of PharmaceuticalChemistryUniversity of Kansas2095 Constant Ave.Lawrence, KS 66047USA

Stephen P.F. MillerOffice of New Drug QualityAssessmentFood and Drug Administration –Center for Drug Evaluationand ResearchBld. 22, Mail Stop 241110903 New Hampshire Ave.Silver Spring, MD 20993USA

Eric J. MunsonDepartment of PharmaceuticalChemistryUniversity of Kansas2095 Constant Ave.Lawrence, KS 66047USA

Ann W. NewmanSSCI, Inc.3065 Kent AvenueWest Lafayette, IN 47906USA

Gary NicholsPharmaceutical SciencesPfizer Global R &DRamsgate RoadSandwich, Kent CT1 3NNUnited Kingdom

Philippe OchsenbeinSanofi-Aventis371, rue du Professeur J. Blayac34184 Montpellier Cedex 04France

Samuel PetitSciences et Méthodes Séparatives,EA 3233Université de RouenIRCOF, Rue Tesnière76821 Mont Saint Aignan CedexFrance

Markus von RaumerSolvias AGKlybeckstrasse 1914002 BaselSwitzerland

Andre S. RawOffice of Generics DrugsFood and Drug Administration –Center for Drug Evaluationand ResearchMetro Park North II, Room E2047500 Standish PlaceRockville, MD 20855USA

Susan M. Reutzel-EdensEli Lilly & CompanyPharmaceutical Research &DevelopmentLilly Corporate CenterIndianapolis, IN 46285USA

List of Contributors XIX

Kurt J. SchenkÉcole Polytechnique Fédéralede LausanneLCr1–IPMC–FSBBSP-521 Dorigny1015 LausanneSwitzerland

Peter Heinrich StahlPrivate ConsultantLerchenstrasse 2879104 FreiburgGermanyFormer business address:CIBA-GEIGY/Novartis PharmaBasel, Switzerland

Raj SuryanarayananDepartment of PharmaceuticsUniversity of Minnesota308 Harvard Street SEMinneapolis, MN 55455USA

Bertrand SutterNovartis Pharma AGPHAD Analytical R &DWSJ-360.508Lichtstrasse 354056 BaselSwitzerland

Martin SzelagiewiczSolvias AGKlybeckstrasse 1914002 BaselSwitzerland

Lawrence X. YuOffice of Generics DrugsFood and Drug Administration –Center for Drug Evaluationand ResearchMetro Park North II, Room 2857500 Standish PlaceRockville, MD 20855USA

Rolf Hilfiker, Fritz Blatter, and Markus von Raumer

1.1Introduction

Many organic and inorganic compounds can exist in different solid forms [1–6].They can be in the amorphous (Chapter 10), i.e., disordered, or in the crystal-line, i.e., ordered, state. According to McCrone’s definition [2], “The polymorph-ism of any element or compound is its ability to crystallize as more than onedistinct crystal species”, we will call different crystal arrangements of the samechemical composition polymorphs. Other authors use the term “polymorph”more broadly, including both the amorphous state and solvates (Chapter 15).Since different inter- and intramolecular interactions such as van der Waals in-teractions and hydrogen bonds will be present in different crystal structures, dif-ferent polymorphs will have different free energies and therefore different phys-ical properties such as solubility, chemical stability, melting point, density, etc.(Chapter 2). Also of practical importance are solvates (Chapter 8), sometimescalled pseudopolymorphs, where solvent molecules are incorporated in the crys-tal lattice in a stoichiometric or non-stoichiometric [6, 7] way. Hydrates (Chapter9), where the solvent is water, are of particular interest. If non-volatile moleculesplay the same role, the solids are called co-crystals. Solvates and co-crystals canalso exist as different polymorphs, of course.

In addition to the crystalline, amorphous and liquid states, condensed mattercan exist in various mesophases. These mesophases are characterized by exhibit-ing partial order between that of a crystalline and an amorphous state [8, 9].Several drug substances form liquid crystalline phases, which can be either ther-motropic, where liquid crystal formation is induced by temperature, or lyotropic,where the transition is solvent induced [10–12].

Polymorphism is very common in connection with drug substances, whichare mostly (about 90%) small organic molecules with molecular weights below600 g mol–1 [13, 14]. Literature values concerning the prevalence of true poly-morphs range from 32% [15] to 51% [16, 17] of small organic molecules. Ac-cording to the same references, 56 and 87%, respectively, have more than one

1

1Relevance of Solid-state Propertiesfor Pharmaceutical Products

solid form if solvates are included. When a compound is acidic or basic, it is of-ten possible to create a salt (Chapter 12) with a suitable base or acid, and sucha salt can in turn often be crystallized. Such crystalline salts may also exist asvarious polymorphs or solvates. Obviously, solvates, co-crystals and salts willhave different properties from the polymorphs of the active molecule. Sincesalts generally have higher water solubility and bioavailability than the corre-sponding uncharged molecule, they are popular choices for drug substances.About half of all active molecules are marketed as salts [14, 18]. Polymorphs,solvates, salts, and co-crystals are schematically depicted in Fig. 1.1. We will usethe term “drug substance” for the therapeutic moiety, which may be a solvate,salt or a co-crystal, while the single, uncharged molecule will be called the “ac-tive molecule”.

Most drug products (formulated drug substances) are administered as oraldosage forms, and by far the most popular oral dosage forms are tablets andother solid forms such as capsules. Drugs for parenteral application are also of-ten stored as solids (mainly as lyophilized products) and dissolved just prior touse since in general the chemical stability of a molecule in the solid form ismuch higher than in solution. Drugs administered by inhalation have becomeincreasingly popular, and dry powder inhalers are now commonly in use. Evi-dently, therefore, both the solid form of the drug substance and the selected ex-cipients have a strong impact on the properties of the formulated drug. Even ifthe envisaged market form of the drug is a solution, information about the sol-id-state properties of the drug substance may still be necessary [19]. If differentforms have significantly different solubilities, it may be possible to unintention-ally create a supersaturated solution with respect to the least soluble form bycreating a concentrated solution of a metastable form. Also, the drug substancewill in most cases be handled as a solid in some stages of the manufacturingprocess, and its handling and stability properties may depend critically on thesolid form.

1 Relevance of Solid-state Properties for Pharmaceutical Products2

Fig. 1.1 Schematic depiction of various types of solid forms.

In fact, the whole existence of a drug is affected by the properties of the solidform, and the final goal of solid form development is to find and select the sol-id with the optimal characteristics for the intended use.

Initially, when the drug substance is first produced, one has to be certain thatthe desired solid form is obtained in a consistent, pure and reproducible man-ner. Subsequently, when it is formulated to obtain the drug product, one has tomake sure that no undesired transitions occur (Chapter 13). For this phase, aprofound knowledge of potential solvate formation is especially useful. It ishighly advisable to avoid using solvents that can form solvates with the drugsubstance in the formulation process. Otherwise, such solvates might be gener-ated during formulation and subsequently desolvated in a final drying step. Insuch a situation the final polymorph would probably differ from the initial one– an undesirable effect in most cases. Similarly, the energy–temperature dia-gram (Chapter 2) of the polymorphs and the kinetics of the change from onepolymorph into another should be known so that one can be sure that tempera-ture variations during the formulation process will not lead to an unacceptabledegree of change in the solid form.

In the next step, when the drug substance or drug product is stored duringits shelf-life, it is imperative that the solid form does not transform over time.Otherwise, important properties of the drug might change drastically. Stabilityproperties have to be evaluated with respect to ambient conditions, storage, andpackaging. Thermodynamic stability depends on the environment. A solvate, forexample, represents a metastable form under ambient conditions but is likely tobe the most stable form in its solvent. Thermodynamically, any metastable formwill eventually transform into a more stable form. The kinetics under whichthis transformation occurs, however, are polymorph specific. Therefore, the exis-tence of a more stable polymorph does not necessarily imply that a metastablepolymorph cannot be developed.

In the final step, when the patient takes the drug, the solubility and dissolu-tion rate of the drug substance will be influenced by its solid form. This will af-fect the bioavailability if solubility is a rate-limiting step, i.e., if the drug belongsto class 2 or 4 of the biopharmaceutics classification system (BCS) [20]. Becausea change of solid form may render a drug ineffective or toxic, regulatory autho-rities demand elucidation and control of solid-state behavior (Chapter 15).

Finally, thorough, experimentally obtained knowledge of the solid-state behav-ior also has the advantages that a good patent situation for a drug substancecan be obtained and that valuable intellectual property can be generated (Chap-ter 14). Although in hindsight everything may appear to be easy and straightfor-ward, crystalline molecular solid-state forms are non-obvious, novel and requireinventiveness. For instance, typically, many attempts to crystallize an amor-phous drug substance fail until, suddenly, a stable crystalline form is obtained.Once seed crystals are available, the crystallization becomes the simple last stepof a production process.

1.1 Introduction 3

1.2Drug Discovery and Development

Typically, it takes eight to twelve years, or sometimes even longer, for a mole-cule with biological activity to progress from its first synthesis to market intro-duction as an efficacious, formulated drug [21]. This process is normally dividedinto two main phases: (a) research or discovery and (b) development [22]. In theresearch phase, the appropriate target for a particular disease model is identifiedand validated, and candidate molecules are synthesized or chosen from libraries.They are primarily tested with respect to binding affinity to the target or, if pos-sible, directly for their potential to alter a target’s activity. Sometimes other pa-rameters, such as selectivity, are also considered. Promising candidates areusually termed “hits”. As a rule at this stage, limited attention is paid to thepossibility to formulate a drug for a certain administration route. Often, from adrug delivery aspect, simple vehicles like DMSO solutions are used. As a result,the activity of especially poorly water-soluble drugs may not be identified at allbecause they precipitate under the used in vitro conditions [23]. In a medicinalchemistry program the “hits” are then modified to improve physicochemical pa-rameters such as solubility and partition coefficient. This is the first time thatsolid-state properties come into play. When solubility is evaluated, it is critical toknow whether the solubility of an amorphous or crystalline substance was mea-sured. Permeation measurements are performed using, e.g., Caco-2 [24], PAM-PA [25] or MDCK [26] assays, and dose–response studies are conducted in in vi-tro models. Selectivity is assessed in counter screens. At the same time, prelim-inary safety studies are carried out, and IP opportunities are assessed. Struc-ture–activity relationship (SAR) considerations play a large role at this stage.

Molecules that show promise in all important aspects are called “leads”. Oftenseveral series of leads are identified and are then further optimized and scruti-nized in more sophisticated models, including early metabolic and in vivo stud-ies. Both pharmacokinetics (PK, the quantitative relationship between the admi-nistered dose and the observed concentration of the drug and its metabolites inthe body, i.e., plasma and/or tissue) and pharmacodynamics (PD, the quantita-tive relationship between the drug concentration in plasma and/or tissue andthe magnitude of the observed pharmacological effect) are studied in animalmodels to predict bioavailability and dose in humans. Simultaneously with char-acterization of the drug substance, a proper dosage form needs to be designed,enabling the drug substance to exert its maximum effect. For freely water-solu-ble drugs this is less critical than for poorly water-soluble drugs, which withoutthe aid of an adequate dosage form cannot be properly investigated in the re-search stage. In the discovery phase, high-throughput methods play an increas-ingly important role in many aspects, such as target identification, synthesis ofpotential candidate molecules, and screening of candidate molecules. Consider-ing that only about 1 out of 10 000 synthesized molecules will reach the market[21], high-throughput approaches are a necessity. The optimal molecule arisingfrom these assessments is then promoted to the next stage, i.e., development.

1 Relevance of Solid-state Properties for Pharmaceutical Products4

The development process of a pharmaceutical product is depicted in Fig. 1.2. Itconsists of a non-clinical and a clinical phase. While drug companies’ approachesto the non-clinical phase can differ somewhat, the clinical phase is treated verysimilarly due to regulatory requirements. In the non-clinical phase enough datais gathered to compile an Investigational New Drug Application (IND) in theUS or a Clinical Trial Application (CTA) in the European Union, which is the pre-requisite for the first use of the substance in humans. For obvious reasons, partic-ular emphasis is placed on toxicology studies during this phase, including assess-ment of toxicity by single-dose and repeated-dose administration and evaluation ofcarcinogenicity, mutagenicity and reproductive toxicity. An absolute necessity atthis stage is that the drug is maximally bioavailable, resulting in sufficient expo-sure of the animals to the drug to obtain an adequate assessment of its toxicityprofile. Whenever possible, the need for animal studies is reduced by using,e.g., human cell in vitro tests. The non-clinical development phase lasts betweenone and two years, and the attrition rate is ca. 50% (Fig. 1.2). At the end of thenon-clinical phase, the decision has to be made whether the neutral molecule, asalt, or a co-crystal will be developed. If a salt form or co-crystal is chosen, ithas to be clear which salt (Section 1.4.1) or co-crystal is optimal. In the clinicalphases the product is first tested on healthy volunteers and then on small andlarge patient populations. For certain disease indications, like oncology, Phase Istudies are performed directly on patients. Approximate population sizes are givenin Fig. 1.2. One has to bear in mind, however, that these numbers depend signif-icantly on the indication the drug is intended to treat. Attrition rates during theclinical phases are between 80 and 90%. During the clinical phases, analytical,process and dosage-form development continues in parallel with long-term toxi-cology studies. Of course, solid-state properties continue to play a crucial role dur-

1.2 Drug Discovery and Development 5

Fig. 1.2 Drug development process with a description of respective phases,approximate number of test persons, timelines and attrition rates. Thesenumbers are a rough guideline only and can differ significantly accordingto the specific indication, the characteristics of the drug substance, etc.

ing both chemical development of the drug substance and pharmaceutical devel-opment of the dosage form.

1.3Bioavailability of Solids

An issue that has to be addressed for every drug product, and which is closelyrelated to its solid-state properties, is whether its solubility and dissolution rateare sufficiently high. This leads to the question of what the minimal acceptablesolubility and dissolution rates are.

Bioavailability essentially depends on three factors: solubility, permeabilityand dose [27], and the question of minimal acceptable solubility can only be an-swered if the other two factors are known. According to the BCS a drug sub-stance is considered highly soluble when the highest strength dosage is solublein 250 mL of aqueous media over the pH range 1.0–7.5 [28].

A valuable concept for estimating what the minimum solubility of a drug sub-stance for development purposes should be uses the maximum absorbable dose(MAD) [29, 30]. MAD corresponds to the maximum dose that could be absorbedif there were a saturated solution of the drug in the small intestine during thesmall intestinal transit time (SITT �270 min). The bioavailable dose is smallerthan MAD due to metabolism of components in the portal blood in the liver(first pass effect) and in the intestinal mucosal tissue [20]. MAD can be calcu-lated from the solubility, S, at pH 6.5 (corresponding to typical conditions inthe small intestine), the transintestinal absorption rate (Ka), the small intestinalwater volume (SIWV �250 mL) and the SITT.

MAD (mg) = S (mg mL–1)�Ka (min–1)�SIWV (mL)�SITT (min) (1)

Human Ka can be estimated from measured rat intestinal perfusion experi-ments [30, 31]. It is related to the permeability (P) through SIWV and the effec-tive surface of absorption (Sabs) [20].

Ka (min–1) = P (cm min–1)�Sabs (cm2)/SIWV (mL) (2)

In the absence of active diffusion, permeability is related to the diffusion coeffi-cient (D), the partition coefficient K (= cin membrane/cin solution) and the mem-brane thickness (�).

P (cm min–1) = D (cm2 min–1)�K/� (cm) (3)

In reality, proportionality between the partition coefficient and the permeabilityis only found for a rather small range of partition coefficients [24, 32]. This isbecause the model of a single homogeneous membrane is an oversimplification.The intestinal wall is better represented by a bilayer membrane consisting of an

1 Relevance of Solid-state Properties for Pharmaceutical Products6

aqueous and an adjoining lipid region. Therefore, for highly lipophilic sub-stances, the water layer becomes the limiting factor and leads to a decrease inpermeability as K is increased [33].

Implicit in Eq. (1) is that the solution stays saturated during the SITT andtherefore that there is a large excess of solid drug in the small intestine. In de-riving this equation as a limiting case, the authors [29] took into account thedissolution kinetics of a polydisperse powder and showed how the percentage ofthe dose that is absorbed is influenced by solubility, particle size and permeabil-ity. They showed that for highly soluble drugs, as defined above, the percentageof dose absorbed is only limited by permeability. For smaller solubilities, thedissolution rate and hence the particle size become important factors as well.The influence of particle size is greatest for low-solubility and low-dose drugs.

MAD readily translates into minimal acceptable solubility [30].

Minimal acceptable solubility= S� {target dose (mg)/MAD}= target dose/{Ka�SIWV�SITT} (4)

Realistic values for Ka lie between 0.001 and 0.05 min–1 and vary over a much nar-rower range than typical solubilities (0.1 �g mL–1 to 100 mg mL–1) [30]. Consider-ing these facts and assuming a typical dose of 70 mg, i.e., 1 mg kg–1, minimal ac-ceptable solubilities between 20 �g mL–1 and 1 mg mL–1 are obtained. When mak-ing these estimates, one has to keep in mind that the assumptions of the modelbreak down if there is possible absorption in other parts of the gastrointestinaltract or if the diffusivity of the drug is changed due to the meal effect, etc. [34].Furthermore, it is important to realize that S represents a “kinetic” solubility. Aweakly basic drug might be freely soluble in the stomach while its equilibrium sol-ubility in the small intestine might be very low. Nevertheless, it may remain in thesupersaturated state in the small intestine, in which case that “kinetic” solubilitywould be the relevant one for calculating the MAD.

1.4Phases of Development and Solid-state Research

Normally, solid-state research and development involves the following stages,which may also overlap:

� deciding whether the uncharged molecule or a salt should be developed;� identifying the optimal salt;� identifying and characterizing all relevant solid forms of the chosen drug

substance;� patenting new forms;� choosing a form for chemical and pharmaceutical development;� developing a scalable crystallization process to obtain the desired form of the

drug substance;

1.4 Phases of Development and Solid-state Research 7

� developing a method to determine the polymorphic purity of the drug sub-stance;

� formulating the drug substance to obtain the drug product;� developing a method to determine the polymorphic purity of the drug sub-

stance in the drug product.

Not all of these stages may be necessary for every drug substance, and the order ofthe stages may be varied according to the specific properties and behavior of thedrug. Particularly for drugs that are poorly water soluble, polymorphism in formu-lations can play a crucial role since it could significantly influence the dissolutionrate and degree of dissolution required to achieve adequate bioavailability.

1.4.1Salt Selection

Clearly, the first decision is whether it is more desirable to develop the un-charged molecule or, if possible, a salt thereof (Chapter 12). In general, salt for-mation will be possible if the molecule contains acidic or basic groups, which isthe case for most active molecules. Since making a salt will normally involve anadditional step in the synthesis and since the molecular weight of a salt will al-ways be higher than that of the neutral molecule, salts will only be chosen ifthey promise to have clear advantages compared with the free acid/base. As arule, a salt is chosen if the free acid/base has at least one of the following unde-sirable properties:

� very low solubility in water;� apparently not crystallizable;� low melting point (typical cutoff 80 �C [35]);� high hygroscopicity;� low chemical stability, etc.;� IP issues.

Low water solubility is relative and always has to be assessed in the context ofdose and permeability (Section 1.3). A very low water solubility may mean ahigh lipophilicity, enabling efficient passage through membranes, or a verylarge binding constant with the receptor, allowing a low dose. Also, the amor-phous state of a neutral molecule may be the best option to get high oral bio-availability, provided the amorphous form can be kinetically stabilized over areasonable time scale. Therefore, the decision to develop a salt should be basedon a head-to-head broad comparison, taking into consideration both in vivo per-formance and physicochemical properties. If the decision has been made to de-velop a salt, it is obviously important to carry out a broad salt screening and saltselection process to identify the optimal salt. Potential counterions are chosenbased on pKa differences, counterion toxicity (preferably GRAS status [18, 36]),etc. (Chapter 12). Desirable properties of the salts include crystallinity, highwater solubility, low hygroscopicity, good chemical stability, and high melting

1 Relevance of Solid-state Properties for Pharmaceutical Products8