As such, the book underscores the importance of solid-state chemistry within chemical and pharmaceutical development. It emphasizes why solid-state issues are important, the approaches needed to avoid problems and the opportunities offered by solid-state properties. The authors include true polymorphs as well as solvates and hydrates, while providing information on physicochemical properties, crystallization thermodynamics, quantum-mechanical modelling, and up-scaling. Important analytical tools to characterize solid-state forms and to quantify mixtures are summarized, and case studies on solid-state development processes in industry are also provided.
Written by acknowledged experts in the field, this is a high-quality reference for researchers, project managers and quality assurance managers in pharmaceutical, agrochemical and fine chemical companies as well as for academics and newcomers to organic solid-state chemistry.
Table of Contents
Preface to the Second Edition xv
1 Solid State and Polymorphism of the Drug Substance in the Context of Quality by Design and ICH Guidelines Q8-Q12 1
Markus von Raumer and Rolf Hilfiker
1.1 Introduction 1
1.2 A Short Introduction to Polymorphism and Solid-State Development 1
1.3 A Short Introduction to Quality by Design (QbD) 3
1.4 The Solid State in the Context of Pharmaceutical Development 7
1.4.1 Typical Drug Discovery and Development 7
1.4.2 The Solid State at the Interface of Drug Substance and Drug Product 10
1.4.3 Biopharmaceutics and Bioavailability of Solids 11
1.4.4 Pharmaceutical Quality Assessment 14
1.5 Solid-State Development at Various Stages of the Pharmaceutical Development Process 15
1.5.1 The Solid State in the Discovery Phase 16
1.5.2 Salt and Co-crystal Screening and Selection 16
1.5.3 Polymorph Screening, Polymorph Landscape, and Polymorph Transformations 17
1.5.4 Crystallization and Downstream Processes 20
1.5.5 Formulation 21
1.5.6 AnalyticalMethods for Characterization and Physical Purity Determination 22
1.6 Conclusions 23
References 23
2 Alternative Solid Forms: Salts 31
P.H. Stahl, Bertrand Sutter, Arnaud Grandeury and Michael Mutz
2.1 Introduction 31
2.2 Salt Formation and Polymorphism in Pharmaceutical Development 31
2.3 Target Properties of Active Substances for Drug Products 33
2.3.1 Injectables 34
2.3.2 Solid Dosage Forms 35
2.3.3 Dosage Forms for Other Routes of Application 36
2.3.3.1 Inhalation 36
2.3.3.2 Topical Products and Transdermal Route 36
2.4 The Basics of Salt Formation 37
2.4.1 Dissociation Constant 37
2.4.2 Ionization and pH 39
2.4.3 Solubility 40
2.4.4 Disproportionation 43
2.5 Approaches to Salt Preparation and Characterization 45
2.5.1 Initial Data 45
2.5.2 Selection of Salt Formers 45
2.5.3 Salt Preparation Procedures 46
2.6 Selection Strategies 49
2.6.1 Points to be Considered 49
2.6.2 Final Decision 51
2.6.3 Salt Form and Life Cycle Management of Drug Products 52
2.7 Case Reports 53
2.7.1 Overview of Salt Forms Selected 53
2.7.2 The Salt Selection Process 53
2.7.3 Case 1: NVP-BS001 53
2.7.4 Case 2: NVP-BS002 54
2.8 Discussion and Decision 56
References 56
3 Alternative Solid Forms: Co-crystals 61
JohanWouters, Dario Braga, Fabrizia Grepioni, Luc Aerts and Luc Quéré
3.1 Introduction 61
3.2 Types of Pharmaceutical Co-crystals 62
3.2.1 Salts vs Co-crystals 62
3.2.2 Ionic Co-crystals of API 63
3.2.3 Polymorphism and Co-crystals 65
3.3 Relevant Pharmaceutical Co-crystal Properties 65
3.3.1 Solubility 66
3.3.2 Dissolution Rate 67
3.3.3 Bioavailability 69
3.3.4 Melting Point 69
3.3.5 Stability 70
3.3.6 Challenges and Undesired Effect of Co-crystallization 71
3.4 Analytical Tools to Characterize Co-crystals 73
3.4.1 Microscopy 74
3.4.2 X-Ray Diffraction 75
3.4.3 Thermal Analysis 77
3.4.4 Vibrational Spectroscopy 77
3.4.5 Solid-State NMR 78
3.5 Patent Literature Review 79
3.6 Current View on Regulatory Aspects of PCCs 83
3.6.1 Rules Governing Manufacturing (API GMP) 84
3.6.2 ICH Tripartite Guidelines on Specifications for New Drug Substances and New Drug Products 85
3.7 Conclusions 85
Acknowledgment 85
References 86
4 Thermodynamics of Polymorphs and Solvates 91
Gerard Coquerel
4.1 Basic Notions 91
4.1.1 Chemical Purity 92
4.1.2 Isotopic Purity 92
4.1.3 Structural Purity 92
4.1.4 Stability of the Component 93
4.1.5 Polymorphism, Desmotropy, Allotropism, and Chirality 93
4.1.6 Gibbs Phase Rule 93
4.1.7 Unary System or Unary SectionWithout Polymorphism 94
4.2 Unary System or Unary Section with Polymorphism 95
4.2.1 Access to Polymorphs 97
4.2.2 Mechanisms of Polymorphic Transition 98
4.3 Polymorphism in Binary Systems 98
4.3.1 No Mixed Crystals 98
4.3.1.1 Polymorphism of One Component Only 98
4.3.1.2 Three Enantiotropic Polymorphs 100
4.3.1.3 Two Enantiotropic Polymorphs and One Form with Monotropic Character 100
4.3.1.4 One Stable Polymorph and Two Forms with a Monotropic Character 100
4.3.1.5 Polymorphism of a Stoichiometric Compound 100
4.3.2 Polymorphism and Mixed Crystals 102
4.3.2.1 Polymorphism of One Component Only 102
4.3.2.2 Two Stable Polymorphic Forms for One Component with Full Miscibility in the Solid State (at a Certain Temperature) 105
4.3.2.3 Two Stable Polymorphic Forms for One Component with Limited Miscibility in the Solid State 108
4.3.2.4 One Stable Form and One Metastable Form (Monotropic Character) with Full Miscibility for the Metastable Form 109
4.3.2.5 One Stable Form and One Metastable Form (Monotropic Character) with Full Miscibility for the Metastable Form 111
4.3.2.6 Two Isostructural Monotropic Forms When Mixed Could Lead to an Enantiotropy 112
4.3.2.7 Limitations of the Concept of Polymorphism and Other Solid(s) to Solid(s) Transitions 112
4.3.3 Solvates 114
4.3.3.1 Differentiation between Stoichiometric and Nonstoichiometric Solvates 116
4.3.3.2 Hygroscopicity, Deliquescence, and Efflorescence 117
4.4 Ternary Systems 119
4.4.1 Chiral Discrimination via the Formation of Solvates 121
4.5 Temperature of Desolvation - Tg and New Polymorphs Only AccessibleThrough a Smooth Solvation - Desolvation Process 123
4.6 Concluding Remarks 126
Acknowledgments 127
References 127
5 Toward Computational Polymorph Prediction 133
Sarah L. Price and Louise S. Price
5.1 Could a Computer Predict Polymorphs for the Pharmaceutical Industry? 133
5.1.1 Predicting theThermodynamically Most Stable Structure from the Chemical Diagram 134
5.1.2 Using Crystal Structure Prediction Studies as a Complement to Solid-form Screening 134
5.2 Methods of Calculating the Relative Energies of Crystals 136
5.2.1 Lattice Energy 136
5.2.2 Free Energy 139
5.3 Searching for Possible Crystal Structures 140
5.4 Comparing Crystal Structures 141
5.5 Calculation of Properties from Crystal Structures 142
5.5.1 Spectroscopic - PXRD, IR, ss-NMR 142
5.5.2 Other Properties: Solubilities, Morphologies, and Mechanical Properties 143
5.6 Crystal Energy Landscapes 145
5.6.1 Interpretation of Crystal Energy Landscapes 145
5.6.2 Example of Tazofelone 146
5.7 Potential Uses of Crystal Energy Landscapes in the Pharmaceutical Industry 148
5.7.1 Confirming the Most Stable Structure is Known 148
5.7.2 Suggesting Experiments to Find New Polymorphs 148
5.7.3 Aiding Structural Characterization from Limited Experimental Data 149
5.7.4 Anticipating Disorder 149
5.7.5 Understanding Crystallization Behaviors 149
5.8 Outlook 150
References 151
6 Hygroscopicity and Hydrates in Pharmaceutical Solids 159
SusanM. Reutzel-Edens, Doris E. Braun, and AnnW. Newman
6.1 Introduction 159
6.2 Thermodynamics ofWater-Solid Interactions 160
6.3 Hygroscopicity 161
6.3.1 Moisture Sorption Analysis 162
6.3.2 Hygroscopic Behaviors in Pharmaceutical Solids 166
6.4 Hydrates 168
6.4.1 Statistics of Hydrate Appearance 168
6.4.2 Hydrate Crystallization 170
6.4.3 Structures and Properties 174
6.5 Significance and Strategies for Developing Hydrate-Forming Systems 180
6.6 Conclusions 184
References 184
7 The Amorphous State 189
Marc Descamps, Emeline Dudognon, and Jean-FrançoisWillart
7.1 Introduction 189
7.2 Amorphous/Crystalline Solids: Terminology and Brief Confrontation 190
7.2.1 Structural Aspects 190
7.2.2 The Concept(s) of Solid State: Rheological Aspect 191
7.2.3 Crystal Melting vs Glass Softening 192
7.3 Order and Disorder: Structural Identification of Amorphous and Crystal States 193
7.3.1 How Disordered can a Crystal Be? 193
7.3.1.1 Crystallinity: Definition, Experimental Identification 193
7.3.1.2 Small or Disordered “Perfect” Crystals 193
7.3.2 Structure of Glassy and Amorphous Compounds. How Ordered can they be? 194
7.4 Amorphous Stability, Crystallization Avoidance, and Glass Formation 198
7.4.1 Metastability, Driving Force for Crystallization 198
7.4.2 Kinetics of Crystallization via Nucleation and Growth 198
7.4.3 Conventional Glass Formation 201
7.4.4 Notes on the Assessment and Prediction of Amorphous Stability 202
7.4.4.1 Role of Molecular Mobility 202
7.4.4.2 Role of the Liquid/Crystal Interface Energy and Structural Similarity 202
7.4.4.3 Role of Polymorphism 203
7.4.4.4 Heterogeneous Nucleation 204
7.4.4.5 Confinement and Size Effect 204
7.4.4.6 To Summarize 205
7.5 The Glass Transition 205
7.5.1 Calorimetric Signature at Tg 205
7.5.2 Calorimetric Glass Transition: Signification 206
7.5.3 The Cp Jump at Tg: Fragile and Strong Glass Formers 207
7.5.4 Glass Transition and Entropy Crisis:The Kauzmann Paradox 207
7.5.5 Glassy Amorphous State: Instability and Energy Landscape 208
7.6 Molecular Mobility for T >Tg 210
7.6.1 Mobility of Fragile and Strong Glass Formers 210
7.6.2 Link between Mobility and Entropy 212
7.6.3 Cooperative Rearrangement Regions (CRR) 213
7.6.4 Dynamic Heterogeneity: Non-exponentiality of the Relaxation 213
7.7 Molecular Mobility and Instability for T
7.7.1 The Aging Phenomenon 214
7.7.2 Approximate Assessment of Stability 215
7.7.2.1 Fictive Temperature 216
7.7.3 Nonlinearity 217
7.7.4 Secondary Relaxations 218
7.8 Multicomponent Amorphous Systems: Solubility and Stability Issues 220
7.8.1 Solubility: Comparison of Crystalline and Amorphous States 220
7.8.2 Tg of Amorphous Multicomponent System 223
7.8.3 Improved Dissolution Properties 2 24
7.8.4 Mixing and Stabilization 224
7.9 Methods of Amorphization 226
7.10 Influence of Processing on Properties 230
7.11 Concluding Remarks 231
References 232
8 Approaches to Solid-Form Screening 241
Rolf Hilfiker, Fritz Blatter, Martin Szelagiewicz, and Markus von Raumer
8.1 Screening for Salts and Co-crystals 242
8.1.1 Example of a Co-crystal Screen 243
8.2 Polymorphs, Hydrates, and Solvates 245
8.3 Screening for Polymorphs, Hydrates, and Solvates 245
8.3.1 CrystallizationMethods 248
8.3.2 Choice of Solvent 250
8.3.3 Types of Polymorph Screens 251
8.3.4 Characterization and Selection 253
8.4 Conclusion 255
References 256
9 Nucleation 261
MarcoMazzotti, Thomas Vetter, David R. Ochsenbein, Giovanni M. Maggioni, and Christian Lindenberg
9.1 Introduction 261
9.2 Homogeneous Nucleation 262
9.2.1 Classical Nucleation Theory 264
9.2.2 Two-Step Nucleation Theory 266
9.3 Heterogeneous and Secondary Nucleation 268
9.3.1 Heterogeneous Nucleation 268
9.3.2 Secondary Nucleation 268
9.4 Characterization of Nucleation 270
9.4.1 Deterministic Nucleation Rates 270
9.4.2 Stochastic Nucleation Rates 272
9.5 Order of Polymorph Appearance - Ostwald’s Rule of Stages 275
9.6 To Seed or Not to Seed? 277
9.6.1 Process Control 277
9.6.2 Polymorphism Control 279
9.6.3 Impurity Control 279
References 280
10 Crystallization Process Modeling 285
MarcoMazzotti, Thomas Vetter, and David R. Ochsenbein
10.1 Introduction 285
10.1.1 Population Balance Equations 286
10.1.2 Notes Regarding Population Balance Models 288
10.1.2.1 Energy Balances and Fluid Dynamics 288
10.1.2.2 Solution of Population Balance Equations 288
10.1.2.3 Applications 289
10.2 System Characterization and Optimization 289
10.2.1 Crystal Growth 290
10.2.2 Polymorph Transformation 291
10.2.3 Agglomeration 292
10.2.4 Optimization 295
10.3 Multidimensional Population Balance Modeling 297
10.4 Conclusion 300
References 301
11 Crystallization Process Scale-Up, a Quality by Design (QbD) Perspective 305
Andrei A. Zlota
11.1 Introduction 305
11.2 API Critical Quality Attributes (CQAs) 306
11.3 Statistical Design of Experiments (DoE) for Crystallization Process Development 306
11.3.1 Example: DoE Methodology to Develop a Robust Crystallization Process, a Case of an API Developed as a Polymorphic Mixture 307
11.4 Process Analytical Technology (PAT) for Polymorph Control 314
11.5 Mixing and Scale-Up Investigations 316
11.5.1 Scale-Up Factors, Mass Transfer 316
11.5.2 Scale-Up Factors in Crystallization Processes 318
11.5.3 Mixing Impact on the Metastable ZoneWidth (MSZW) 324
11.5.4 Disappearing Polymorphs during Scale-Up 324
11.5.5 Polymorph Control Methods Based on Mixing 324
11.5.6 Heat Transfer 325
11.6 Conclusions and Outlook 326
References 326
12 Processing-Induced Phase Transformations and Their Implications on Pharmaceutical Product Quality 329
Seema Thakral, Ramprakash Govindarajan, and Raj Suryanarayanan
12.1 Introduction 329
12.2 Pharmaceutical Processes Causing Unintended Phase Transformations 333
12.2.1 Milling 333
12.2.2 Granulation and Drying - Hydration and Dehydration 336
12.2.2.1 Hydrate Formation 337
12.2.2.2 Dehydration 338
12.2.3 Compression 342
12.2.4 Freezing Aqueous Solutions 345
12.3 Pharmaceutical Processes Causing Intended Phase Transformations - Obtaining the Desired Physical Form 346
12.3.1 Spray-drying 346
12.3.2 Freeze-drying 347
12.3.3 Hot Melt Extrusion 349
12.3.4 Co-milling/Co-grinding 350
12.4 Phase Transformations during Pharmaceutical Processing - Implications 351
12.4.1 Creating Disorder - Amorphization 352
12.4.1.1 Altered Particulate and Bulk Properties 352
12.4.1.2 Implications on Chemical Stability 353
12.4.1.3 Solubility and Bioavailability Enhancement 356
12.4.2 Formation of Crystalline Mesophases 357
12.4.3 Restoring Order - Promoting In-process Recrystallization 358
12.4.3.1 In Frozen Solutions 358
12.4.3.2 Miscellaneous Processes 359
12.4.4 Amorphization and Crystallization during Freeze-drying 359
12.4.5 Changes in Chemical Composition 364
12.4.5.1 Hydrate Formation and Dehydration 364
12.4.5.2 “Co-amorphization” 365
12.4.5.3 Co-crystal Formation 366
12.4.5.4 Salt Formation and Disproportionation 366
12.5 Conclusion 368
References 369
13 Surface andMechanical Properties of Molecular Crystals 381
M. Teresa Carvajal and Xiang Kou
13.1 Introduction 381
13.2 Surface Properties 382
13.2.1 Structure-Property-Response/Performance 385
13.2.2 Case Study #1 - Milling-Induced Agglomeration 386
13.2.3 Case Study #2 - Batch-to-batch Variability 390
13.2.4 Case Study #3 - Hydration-Dehydration 393
13.2.5 Case Study #4 - Surface Interactions and Bulk Properties 395
13.3 Remarks 399
13.4 Impact of Polymorphism on Powder Flow 401
13.5 Impact of Polymorphism on Mechanical Properties of Molecular Crystals 402
13.6 Impact of Polymorphism on Size Reduction by Milling 405
13.7 Impact of Polymorphism on Powder Compaction Properties 406
References 409
14 Analytical Tools to Characterize Solid Forms 415
Rolf Hilfiker, SusanM. De Paul, and Timo Rager
14.1 Crystal Structure 415
14.1.1 X-ray Diffraction (XRD) 416
14.1.2 Vibrational Spectroscopy (Raman, mid-IR, NIR, and THz) 417
14.1.3 Solid-State NMR (ssNMR) Spectroscopy 424
14.2 Thermodynamic Properties 431
14.2.1 Differential Scanning Calorimetry (DSC) 431
14.2.2 Isothermal Microcalorimetry (IMC) 436
14.2.3 Solution Calorimetry (SolCal) 438
14.3 Composition Solvate/Hydrate Stoichiometry 439
14.3.1 Thermogravimetry (TGA, TG-FTIR, and TG-MS) 439
14.3.2 Dynamic Vapor Sorption (DVS) 440
14.4 Conclusion 443
References 443
15 Industry Case Studies 447
Ralph Diodone, Pirmin C. Hidber,Michael Kammerer, RolandMeier,Urs Schwitter, and Jürgen Thun
15.1 Introduction 447
15.1.1 Screening and Selection of Solid Forms 447
15.1.2 Control Strategy for the Solid Form 448
15.2 Case Study #1: Holistic Control Strategy for Solid Form 449
15.2.1 Solid-Form Control for Drug Substance 449
15.2.2 Solid-Form Control for Drug Product 450
15.3 Case Study #2: Solid-Form Control of API for Low-Dose Drug 451
15.4 Case Study #3: Development of Crystallization Process and Unexpected Influence of Impurity 453
15.5 Case Study #4: Hydrate/Anhydrate Dilemma 456
15.6 Case Study #5: Quality by Design by Selecting a Cocrystal 458
15.7 Case Study #6: Dealing with the Consecutive Appearance of New Polymorphs 460
15.8 Case Study #7: Amorphous API: Issues to be considered in Drug Development 464
15.9 Case Study #8: Computational Prediction of Unknown
Polymorphs and Experimental Confirmation 466
References 467
16 Pharmaceutical Crystal Forms and Crystal-Form Patents: Novelty and Obviousness 469
Joel Bernstein and Jill MacAlpine
16.1 Introduction 469
16.2 Novelty and Obviousness 470
16.3 The Scientific Perspective 471
16.3.1 Novelty from a Scientific Perspective 471
16.3.2 Obviousness from a Scientific Perspective 472
16.4 The Role of Serendipity in Crystal Forms 475
16.5 History of Crystal-Form Patents 477
16.6 Typical Ex Post Facto Arguments on Obviousness 478
16.7 Conclusion 482
Acknowledgment 482
References 482
Index 485
