Title Details

Rolf Hilfiker is vice president and head of the department Solid-State Development at Solvias AG in Kaiseraugst, Switzerland. He obtained his PhD in physical chemistry from Basel University (Switzerland) and then did postdoctoral work at Stony Brook University (New York). He returned to Basel University as a research fellow and then moved to Ciba-Geigy (now Novartis) in Basel. In 1997 he became head of the Stability & Kinetics group at Novartis. In 1999 he participated in a management buyout to form Solvias AG. He has taught physical chemistry in New York and Basel, as well as numerous courses in solid-state development in Europe, Asia, and the US.

Markus von Raumeris director and group leader of Preformulation and Preclinical Galenics at Idorsia Pharmaceuticals Ltd. in Allschwil, Switzerland. He obtained his PhD in physical chemistry from the University of Fribourg (Switzerland) and then did postdoctoral work in the field of mass spectrometry at the University of Warwick (UK). In 1997 he became head of laboratory of Physical Chemistry at Novartis in Basel, Switzerland. Two years later he moved to Solvias AG in Basel where he was project manager for Solid-State Development until 2008. He then joined Actelion Pharmaceuticals Ltd. in Allschwil where he built up and led the Material Science lab until 2017.

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