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Contents  
 
Preface XV
List of Contributors XVII
1 Relevance of Solid-state Properties for Pharmaceutical Products
Rolf Hilfiker, Fritz Blatter, and Markus von Raumer 		1
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
Sachin Lohani and David J.W. Grant 		21
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
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
Duncan Q.M. Craig 		43
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
4 Solid-state NMR Spectroscopy
Joseph W. Lubach and Eric J. Munson 		81
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
John M. Chalmers and Geoffrey Dent 		95
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
6 Crystallography for Polymorphs
Philippe Ochsenbein and Kurt J. Schenk 		139
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
Gary Nichols 		167
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
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
Ulrich J. Griesser 		211
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
Susan M. Reutzel-Edens and Ann W. Newman 		235
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
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
Samuel Petit and Grard Coquerel 		259
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
11 Approaches to Polymorphism Screening
Rolf Hilfiker, Susan M. De Paul, and Martin Szelagiewicz 		287
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
Peter Heinrich Stahl and Bertrand Sutter 		309
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
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
Ramprakash Govindarajan and Raj Suryanarayanan 		333
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 SaltFree-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 SaltFree-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 SaltFree-acid/Base Conversion 360
13.5 Summary 360
References 361
14 Polymorphism and Patents from a Chemist's Point of View
Joel Bernstein 		365
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
Stephen P.F. Miller, Andre S. Raw, and Lawrence X. Yu 		385
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

 
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