Polymorphism

Edited by
Rolf Hilfiker

Polymorphism: in the Pharmaceutical Industry. Edited by Rolf Hilfiker

Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-31146-7
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Polymorphism

in the Pharmaceutical Industry

Edited by
Rolf Hilfiker
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ISBN-13: 978-3-527-31146-0
ISBN-10: 3-527-31146-7
 V

Contents

Preface XV

List of Contributors XVII

1 Relevance of Solid-state Properties for Pharmaceutical Products 1

Rolf Hilfiker, Fritz Blatter, and Markus von Raumer
1.1 Introduction 1
1.2 Drug Discovery and Development 4
1.3 Bioavailability of Solids 6
1.4 Phases of Development and Solid-state Research 7
1.4.1 Salt Selection 8
1.4.2 Polymorph Screening 9
1.4.3 Crystallization Process Development 12
1.4.4 Formulation 13
1.4.5 Method Development 14
1.5 Solid-state and Life Cycle Management 15
1.6 Conclusions 15
References 17

2 Thermodynamics of Polymorphs 21
Sachin Lohani and David J. W. Grant
2.1 Introduction 21
2.2 Structural Origin of Polymorphism 22
2.3 Thermodynamic Theory of Polymorphism 22
2.4 Thermodynamic Relationship Between Polymorphs:
Enantiotropy and Monotropy 24
2.4.1 Energy–Temperature Diagrams 24
2.4.2 Pressure–Temperature Diagrams 28
2.4.3 Inversion of Polymorphic Behavior 30

Polymorphism: in the Pharmaceutical Industry. Edited by Rolf Hilfiker

Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-31146-7
VI Contents

2.5 Rules to Predict Thermodynamic Relationships Between

Polymorphs 31
2.5.1 Heat of Transition Rule 31
2.5.2 Heat of Fusion Rule 31
2.5.3 Entropy of Fusion Rule 32
2.5.4 Heat Capacity Rule 32
2.5.5 Density Rule 33
2.5.6 Infrared Rule 33
2.6 Relative Thermodynamic Stabilities of Polymorphs 33
2.7 Crystallization of Polymorphs 34
2.7.1 Nucleation of Polymorphs 34
2.8 Introduction to Solvates and Hydrates 37
2.8.1 Thermodynamics of Hydrates 37
2.9 Summary 40
References 41

3 Characterization of Polymorphic Systems

Using Thermal Analysis 43
Duncan Q. M. Craig
3.1 Introduction – Scope of the Chapter 43
3.2 Use of Differential Scanning Calorimetry for the Characterization
of Polymorphs 44
3.2.1 Principles of DSC in the Context of Polymorphism 44
3.2.2 Examples of the Uses of DSC: Characterization of Drugs,
Excipients and Dosage Forms 49
3.2.3 Further Uses of DSC 54
3.3 Combined Approaches 58
3.3.1 Multi-instrument Approaches 58
3.3.2 Thermal and Crystallographic Studies 63
3.3.3 Interfaced Techniques 65
3.4 Additional Thermal Methods for the Study of Polymorphism 67
3.4.1 Thermogravimetric Analysis 67
3.4.2 Thermal Microscopy 68
3.4.3 Heat of Solution Studies 69
3.4.4 Modulated Temperature DSC 70
3.4.5 High-speed DSC 72
3.4.6 Microthermal Analysis 73
3.4.7 Thermally Stimulated Current 74
3.5 Conclusions 76
References 77
 Contents VII

4 Solid-state NMR Spectroscopy 81

Joseph W. Lubach and Eric J. Munson
4.1 Introduction 81
4.1.1 Basics of Solid-state NMR 82
4.2 Applications 82
4.2.1 Identification 82
4.2.2 Selectivity 84
4.2.3 Mobility and Dynamics 85
4.2.4 Quantitation of Forms 86
4.3 Conclusions 92
References 92

5 Vibrational Spectroscopic Methods in Pharmaceutical

Solid-state Characterization 95
John M. Chalmers and Geoffrey Dent
5.1 Introduction 95
5.2 Mid-infrared, Raman and THz Spectroscopy:
Basic Comparison of Theory, Instrumentation and Sampling 97
5.2.1 Basic Theory 97
5.2.2 Instrumentation Brief 100
5.2.3 Sampling 104
5.2.3.1 Raman Sampling 104
5.2.3.2 Mid-infrared Sampling 105
5.2.3.3 THz Spectroscopy Sample Presentation 109
5.3 Changes of State and Solid-state Effects on Infrared and
Raman Spectra 110
5.3.1 Introduction 110
5.3.2 Spectra of Gases, Liquids and Solutions 110
5.3.3 Hydrogen Bonding 111
5.3.4 Amine Salts (including Amino Acids) 114
5.3.5 Solids 115
5.3.6 Polymorphism 117
5.3.7 Enantiomers and Racemates 118
5.3.8 Tautomerism 119
5.3.9 Summary 119
5.4 Examples and Applications 119
5.4.1 Polymorphism 120
5.4.2 Hydration/Drying 126
5.4.3 Quantitative Analysis and Process Monitoring 128
5.4.4 Tablets 130
5.5 Closing Remarks 135
References 136
VIII Contents

6 Crystallography for Polymorphs 139

Philippe Ochsenbein and Kurt J. Schenk
6.1 Introduction 139
6.2 Solving Difficult Crystal Structures with Parallel Experiments 140
6.3 Atropisomers and Desmotropes 144
6.4 Salts 148
6.5 Influence of Solvents 149
6.6 Isolation of a Furtive Species 153
6.7 Mizolastine Polymorphs 154
6.8 Solid Solutions 157
6.9 Structures from Powder Data 160
6.10 “Behind Every Structure There is a Crystal” 164
References 165

7 Light Microscopy 167

Gary Nichols
7.1 Introduction 167
7.2 Why Use a Light Microscope to Study Solid-state Properties? 168
7.3 Polarizing Light Microscope 169
7.4 Photomicrography 170
7.5 Specimen Preparation 171
7.5.1 Permanent and Temporary Mounts 172
7.5.1.1 Permanent Mounts 172
7.5.1.2 Temporary Mounts 173
7.5.2 Preparation of Temporary Mounts 173
7.5.3 Examination of Tablets 173
7.6 Observations Using Polarized Light Microscopy 174
7.6.1 Polarized Light 174
7.6.2 Crystal Studies with Plane Polarized Light 175
7.6.3 Crystal Studies with Crossed Polarizers 177
7.6.3.1 Interference Colors 177
7.6.3.2 Extinction 179
7.6.3.3 Interference Figures 181
7.6.3.4 Compensator Plates 183
7.6.3.5 Use of Circularly Polarized Light 183
7.6.4 Crystallinity 184
7.7 Refractive Index 186
7.7.1 Measuring Refractive Indices 187
7.7.2 The Becke Test 188
7.7.3 Dispersion Staining 188
7.8 Particle Size 189
7.9 Particle Shape 190
7.10 Comparing Powder Samples 194
7.11 Thermomicroscopy 195
 Contents IX

7.12 The Microscope as a Micro-scale Laboratory 196

7.13 Twinning 197
7.14 Color and Pleochroism 199
7.15 Fluid Inclusions 201
7.16 Mechanical Properties of Crystals 203
7.17 Pseudomorphs 204
7.18 Mesomorphism 205
7.19 Identification of Contaminants and Foreign Matter 206
7.20 Conclusion 207
References 207

8 The Importance of Solvates 211

Ulrich J. Griesser
8.1 Introduction 211
8.2 Terminology and Classification of Solvates 213
8.2.1 General Terms and Definitions 213
8.2.2 Types of Solvates 215
8.2.2.1 Stoichiometric Solvates 215
8.2.2.2 Non-stoichiometric Solvates 216
8.2.3 Classification Models of Hydrates 218
8.3 Statistical Aspects and Frequency of Solvates 219
8.4 Generation and Characterization of Solvates 222
8.5 Stability and Solubility of Solvates 224
8.6 Processing of Solvates 227
8.7 Relevance, Problems and Potential Benefits 228
8.8 Patents 229
8.9 Conclusions 230
References 230

9 Physical Characterization of Hygroscopicity in Pharmaceutical

Solids 235
Susan M. Reutzel-Edens and Ann W. Newman
9.1 Introduction 235
9.1.1 Definition of Hygroscopicity 235
9.1.2 Classification of Hygroscopic Behavior 236
9.2 Water–Solid Interactions 238
9.3 Characterizing Water–Solid Interactions 239
9.3.1 Moisture Sorption Analysis 239
9.3.2 Surface Energy Approaches 243
9.3.3 Molecular Level Approaches 244
9.3.3.1 Stoichiometric Hydrates 244
9.3.3.2 Non-Stoichiometric/Channel Hydrates 245
9.3.3.3 Isomorphic Desolvates 250
X Contents

9.4 Significance of Water–Solid Interactions in Pharmaceutical

Systems 251
9.4.1 Physicochemical Stability 251
9.4.2 Dissolution 252
9.4.3 Physical-mechanical Characteristics 253
9.5 Strategies for Dealing with Hygroscopic Systems 254
9.6 Conclusions 256
References 256

10 The Amorphous State 259

Samuel Petit and Gérard Coquerel
10.1 Introduction 259
10.2 Definition of the Amorphous State 260
10.2.1 Order, Disorder and Structural Aspects 260
10.2.2 Energetic Aspects: Thermodynamics and Kinetics 262
10.3 Preparation of Amorphous Solids 263
10.3.1 Preparation from a Liquid Phase: Quench-cooling 264
10.3.2 From a Solution: Rapid Precipitation 265
10.3.3 From a Frozen Solution: Freeze-drying (Lyophilization) 265
10.3.4 From an Atomized Solution: Spray-drying 266
10.3.5 From a Crystalline Phase: Grinding and Milling 266
10.3.6 From a Crystalline Solvate: Desolvation/Dehydration 268
10.3.7 Physical Mixture with Amorphous Excipients 269
10.4 Properties and Reactivity 269
10.4.1 The Glass Transition 270
10.4.2 Molecular Mobility and Structural Relaxation 271
10.4.3 Strong/Fragile Classification of Angell 272
10.4.4 Mixing with Solvents/“Dissolution” Behavior 273
10.4.5 Influence of Water Content: Plasticization and Chemical
Degradation 274
10.4.6 Polyamorphism 275
10.5 Characterization and Quantification 276
10.5.1 Thermal Analysis and Spectroscopic Methods 277
10.5.2 Detection and Quantification of Small Amorphous Contents 277
10.6 Crystallization of Amorphous Solids 278
10.6.1 “Difficult-to-crystallize” Compounds 279
10.6.2 Inadvertent Crystallization 280
10.6.3 Crystallization as a Tool for Insight into the Amorphous State 280
References 282
 Contents XI

11 Approaches to Polymorphism Screening 287

Rolf Hilfiker, Susan M. De Paul, and Martin Szelagiewicz
11.1 Introduction 287
11.2 Crystallization Methods 289
11.3 Solvent Parameters 290
11.4 Systematic Polymorphism Screening 291
11.5 High-throughput Methods 294
11.6 An Example of a High-throughput Screening Approach 296
11.6.1 Model Substance 296
11.6.2 Solubility 296
11.6.3 Crystallization Experiments 297
11.6.4 Data Acquisition 297
11.6.5 Data Analysis 298
11.7 Theoretical Methods 300
11.8 Characterization 302
11.9 Conclusions 303
References 305

12 Salt Selection 309

Peter Heinrich Stahl and Bertrand Sutter
12.1 Introduction 309
12.2 Salt Formation and Polymorphism 309
12.3 Target Properties of Active Substances for Drug Products 311
12.3.1 Injectables 311
12.3.2 Solid Dosage Forms 312
12.3.3 Dosage Forms for Other Routes of Application 312
12.3.3.1 Inhalation 312
12.3.3.2 Topical Products and the Transdermal Route 313
12.4 Basics of Salt Formation 314
12.4.1 Ionization Constant 314
12.4.2 Ionization and pH 315
12.4.3 Solubility 316
12.5 Approaches to Salt Screening 319
12.5.1 Initial Data 319
12.5.2 Selection of Salt Formers 319
12.5.3 Automated Salt Screening 320
12.6 Selection Procedures and Strategies 322
12.6.1 Points to be Considered 322
12.6.2 Final Decision 323
12.6.3 Salt Form and Life Cycle Management of Drug Products 325
12.7 Case Reports 325
12.7.1 Overview of Salt Forms Selected 325
12.7.2 Salt Selection Process 325
12.7.3 Case 1: NVP-BS001 326
XII Contents

12.7.4 Case 2: NVP-BS002 327

12.7.4.1 Discussion and Decision 329
12.7.5 Case 3: NVP-BS003 329
References 332

13 Processing-induced Phase Transformations and

Their Implications on Pharmaceutical Product Quality 333
Ramprakash Govindarajan and Raj Suryanarayanan
13.1 Introduction 333
13.2 Processing-related Stress 336
13.2.1 Mechanical Stress 337
13.2.1.1 Milling 337
13.2.1.2 Compression 337
13.2.2 Thermal and Pressure Stresses 338
13.2.2.1 Freezing 338
13.2.2.2 Drying 339
13.2.2.3 Melting 340
13.2.3 Interaction with Other Components 341
13.2.3.1 Hydrate Formation 341
13.2.3.2 Complexation 342
13.2.3.3 Salt–Free-acid/Base Conversions 342
13.2.3.4 Metastable Phase Formation 342
13.2.3.5 Multiple Interactions 343
13.3 Detection and Quantification of Phase Transformations 343
13.3.1 Generation (Creation) of Lattice Disorder 343
13.3.2 Crystallization – Anhydrous Phase 347
13.3.3 Hydrates – Formation and Dehydration 349
13.3.4 Salt–Free-acid/Base Transformations 351
13.4 Implications of Phase Changes 352
13.4.1 Amorphization 352
13.4.2 Crystallization 356
13.4.3 Polymorphic Transitions 357
13.4.4 Hydration/Dehydration 358
13.4.5 Salt–Free-acid/Base Conversion 360
13.5 Summary 360
References 361
 Contents XIII

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

Joel Bernstein
14.1 Introduction 365
14.2 Some Fundamentals of Patents Related to Polymorphism
and Some Historical Notes 366
14.3 Ranitidine Hydrochloride (RHCl) 369
14.4 Cefadroxil 372
14.5 Paroxetine Hydrochloride 375
14.6 The Importance of Seeding 379
14.7 Concluding Remarks 381
References 382

15 Scientific Considerations of Pharmaceutical Solid Polymorphism

in Regulatory Applications 385
Stephen P. F. Miller, Andre S. Raw, and Lawrence X. Yu
15.1 Introduction 385
15.2 General Principles of Pharmaceutical Solid Polymorphs 385
15.3 Influence of Polymorphism on Product Quality
and Performance 386
15.3.1 Effect on Bioavailability (BA)/Bioequivalence (BE) 386
15.3.2 Effect on Stability 387
15.3.3 Effect on Manufacturability 388
15.4 Pharmaceutical Solid Polymorphism in Drug Substance 389
15.4.1 Polymorph Screening 390
15.4.2 Control of Polymorphism in Drug Substance 391
15.4.3 Acceptance Criterion for Polymorph Content
in Drug Substance 394
15.5 Pharmaceutical Solid Polymorphism in Drug Product 395
15.5.1 Polymorphism Issues in Drug Product Manufacturing 395
15.5.2 Control of Polymorphism in Drug Product 396
15.6 Process Analytical Technology 399
15.6.1 Process Analytical Technology and the Crystallization of
Polymorphic Forms 399
15.6.2 Process Analytical Technology and Polymorphs
in Drug Products 400
15.7 Summary 401
References 402

Subject Index 405

 XV

Preface
Polymorphism, a term derived from the Greek words for “much/many” (poly,
poktè) and “form” (morphē, loqugè), is used in disciplines as diverse as linguis-
tics, computer science, biology, genetics, and crystallography. In the life sciences
industry, two completely different types of polymorphism play a major role:
polymorphisms in DNA sequence and polymorphs of crystalline substances. In
the 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 on
a spectrum of aspects, such as biological action, production, formulation and in-
tellectual property protection. This book deals exclusively with the polymorphs
of 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 and
workshops organized by various scientific and commercial institutions. This in-
terest is well deserved. Anyone who has worked in the field for some time can
point to examples where insufficient understanding of solid-state properties has
led to serious setbacks. Problems encountered range from the sudden unex-
pected inability to produce reliably a form that has been used for pivotal clinical
studies and is the basis for registration documents to variations in the drug
product properties due to seemingly random changes of the solid form during
processing or storage. Conversely, a thorough understanding of solid-state prop-
erties can create opportunities, which are increasingly being exploited for the
benefit of both the company and the patient. Not only can patent protection be
broadened or prolonged, and production made more efficient and cheaper, but
the properties of the drug can also be improved to the advantage of the patient.
Increasing recognition of the importance of polymorphism to the life sciences
industry has generated a great deal of interest and the field has been evolving
rapidly. Given the pace of recent developments, an update is both useful and
timely. This book discusses the whole breadth of the subject, covering all rele-
vant aspects of solid-state issues for the pharmaceutical industry. It should act
as a manual and a guideline for scientists dealing with solid-state issues, and

Polymorphism: in the Pharmaceutical Industry. Edited by Rolf Hilfiker

Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-31146-7
XVI 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 for
scientists working in other areas where solid-state issues are important, such as
animal 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 and
makes recommendations on how best to approach solid-state issues. Chapter 2,
on the thermodynamics of polymorphs, provides the theoretical tools needed to
understand solid-state behavior. Chapters 3 to 7 give detailed descriptions, in-
structions, and hints on how to characterize solids, since solid-state behavior
can only be understood after thorough characterization. Such an understanding
is crucial to making the right decisions at key stages of drug development and
production. 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 aspects
for development scientists are described in Chapters 11 to 13, which deal with
identifying relevant polymorphs, finding optimal salts and controlling solid-state
behavior during processing. The last two chapters discuss legislative aspects of
solid-state properties. Often, solid-state forms can be protected by patents, which
may create significant financial benefits. Chapter 14 outlines the principles of
intellectual property protection and provides relevant examples. Finally, since
the solid form can have an impact on the safety and efficacy of drugs, Chapter
15 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 that
the challenges and opportunities connected with solid-state properties can only
be addressed successfully through an integral approach that considers all these
aspects.
The strength of this volume lies in the quality of its contributions. My sincere
thanks go to every author for the excellent standard of their submissions and
their 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 and
Dr. Elke Maase and Dr. Bettina Bems for an enjoyable collaboration in the prep-
aration of this book.

Basel, January 2006 Rolf Hilfiker

 XVII

List of Contributors

Joel Bernstein Susan M. De Paul

Department of Chemistry Solvias AG
Ben-Gurion University of the Negev Klybeckstrasse 191
Beer Sheva 84105 4002 Basel
Israel Switzerland

Fritz Blatter Geoffrey Dent

Solvias AG GD Analytical Consulting
Klybeckstrasse 191 53 Nudger Green
4002 Basel Dobcross, Oldham OL3 5AW
Switzerland United Kingdom

John M. Chalmers Ramprakash Govindarajan

VS Consulting Department of Pharmaceutics
14 Croft Hills University of Minnesota
Tame Bridge, Stokesley TS9 5NW 308 Harvard Street SE
United Kingdom Minneapolis, MN 55455
USA
Gérard Coquerel
Sciences et Méthodes Séparatives, David J. W. Grant
EA 3233 Department of Pharmaceutics
Université de Rouen College of Pharmacy
IRCOF, Rue Tesnière University of Minnesota
76821 Mont Saint Aignan Cedex 308 Harvard Street SE
France Minneapolis, MN 55455
USA
Duncan Q. M. Craig
School of Chemical Sciences and Ulrich J. Griesser
Pharmacy Institute of Pharmacy
University of East Anglia University of Innsbruck
Norwich, Norfolk NR4 7 TJ Innrain 52
United Kingdom 6020 Innsbruck
Austria

Polymorphism: in the Pharmaceutical Industry. Edited by Rolf Hilfiker

Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-31146-7
XVIII List of Contributors
Rolf Hilfiker
Solvias AG
Klybeckstrasse 191
4002 Basel
Switzerland
Sachin Lohani
Department of Pharmaceutics
College of Pharmacy
University of Minnesota
308 Harvard Street SE
Minneapolis, MN 55455-0343
USA
Joseph W. Lubach
Department of Pharmaceutical
Chemistry
University of Kansas
2095 Constant Ave.
Lawrence, KS 66047
USA
Stephen P. F. Miller
Office of New Drug Quality
Assessment
Food and Drug Administration –
Center for Drug Evaluation
and Research
Bld. 22, Mail Stop 2411
10903 New Hampshire Ave.
Silver Spring, MD 20993
USA
Eric J. Munson
Department of Pharmaceutical
Chemistry
University of Kansas
2095 Constant Ave.
Lawrence, KS 66047
USA
Ann W. Newman
SSCI, Inc.
3065 Kent Avenue
West Lafayette, IN 47906
USA
Gary Nichols
Pharmaceutical Sciences
Pfizer Global R & D
Ramsgate Road
Sandwich, Kent CT1 3NN
United Kingdom
Philippe Ochsenbein
Sanofi-Aventis
371, rue du Professeur J. Blayac
34184 Montpellier Cedex 04
France
Samuel Petit
Sciences et Méthodes Séparatives,
EA 3233
Université de Rouen
IRCOF, Rue Tesnière
76821 Mont Saint Aignan Cedex
France
Markus von Raumer
Solvias AG
Klybeckstrasse 191
4002 Basel
Switzerland
Andre S. Raw
Office of Generics Drugs
Food and Drug Administration –
Center for Drug Evaluation
and Research
Metro Park North II, Room E204
7500 Standish Place
Rockville, MD 20855
USA
Susan M. Reutzel-Edens
Eli Lilly & Company
Pharmaceutical Research &
Development
Lilly Corporate Center
Indianapolis, IN 46285
USA
 List of Contributors XIX

Kurt J. Schenk Bertrand Sutter

École Polytechnique Fédérale Novartis Pharma AG
de Lausanne PHAD Analytical R & D
LCr1–IPMC–FSB WSJ-360.508
BSP-521 Dorigny Lichtstrasse 35
1015 Lausanne 4056 Basel
Switzerland Switzerland

Peter Heinrich Stahl Martin Szelagiewicz

Private Consultant
Lerchenstrasse 28
79104 Freiburg
Germany
Former business address:
CIBA-GEIGY/ Novartis Pharma
Basel, Switzerland
Raj Suryanarayanan
Department of Pharmaceutics
University of Minnesota
308 Harvard Street SE
Minneapolis, MN 55455
USA
Solvias AG
Klybeckstrasse 191
4002 Basel
Switzerland
Lawrence X. Yu
Office of Generics Drugs
Food and Drug Administration –
Center for Drug Evaluation
and Research
Metro Park North II, Room 285
7500 Standish Place
Rockville, MD 20855
USA