Solid-State Properties of Pharmaceutical Materials

Stephen R. Byrn, PhD is Charles B. Jordan Professor of Medicinal Chemistry in the School of Pharmacy, Purdue University. Dr. Byrn has founded and directed several programs at Purdue University including CAMP, the Center for AIDS Research, the Molecules to Market program, and Purdue's graduate programs in regulatory and quality compliance. Dr. Byrn has served as chair of the Pharmaceutical Sciences Advisory Committee to the FDA and Chair of the Drug Substances Technical Committee, Product Quality Research Initiative. Dr. Byrn is co-founder of SSCI, Inc. a cGMP research and information Company. George Zografi, PhD is the Edward Kremers Professor Emeritus of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison. He was the recipient of the APhA Ebert Prize in 1984 and 2001, the AAPS Dale E. Wurster Award for Pharmaceutics in 1990 and its Distinguished Scientist Award in 1995, as well as the Volwiler Research Achievement Award of the American Association of Colleges of Pharmacy. Xiaoming (Sean) Chen, PhD is currently the Director of Formulation Development in Antares Pharma Inc. Prior to that, he held various positions in pharmaceutical product development at Schering-Plough, OSI Pharmaceuticals, Astellas Pharma, and Shionogi Inc. He has published over a dozen of papers in peer-reviewed journals and is a co-inventor of four US patents.

Preface xi

Acknowledgments xiii

1 Solid-State Properties and Pharmaceutical Development 1

1.1 Introduction, 1

1.2 Solid-State Forms, 1

1.3 ICH Q6A Decision Trees, 6

1.4 “Big Questions” for Drug Development, 6

1.5 Accelerating Drug Development, 9

1.6 Solid-State Chemistry in Preformulation and Formulation, 11

1.7 Learning Before Doing and Quality by Design, 14

1.8 Performance and Stability in Pharmaceutical Development, 17

1.9 Moisture Uptake, 18

1.10 Solid-State Reactions, 19

1.11 Noninteracting Formulations: Physical Characterizations, 19

References, 20

2 Polymorphs 22

2.1 Introduction, 22

2.2 How are Polymorphs Formed?, 22

2.3 Structural Aspect of Polymorphs, 23

2.4 Physical, Chemical, and Mechanical Properties, 24

2.5 Thermodynamic Stability of Polymorphs, 27

2.6 Polymorph Conversion, 32

2.7 Control of Polymorphs, 34

2.8 Polymorph Screening, 35

2.9 Polymorph Prediction, 36

References, 36

3 Solvates and Hydrates 38

3.1 Introduction, 38

3.2 Pharmaceutical Importance of Hydrates, 38

3.3 Classification of Pharmaceutical Hydrates, 40

3.4 Water Activity, 42

3.5 Stoichiometric Hydrates, 43

3.6 Nonstoichiometric Hydrates, 44

3.7 Hydration/Dehydration, 45

3.8 Preparation and Characterization of Hydrates and Solvates, 45

References, 46

4 Pharmaceutical Salts 48

4.1 Introduction, 48

4.2 Importance of Pharmaceutical Salts, 48

4.3 Weak Acid, Weak Base, and Salt, 49

4.4 pH-Solubility Profiles of Ionizable Compounds, 51

4.5 Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts, 53

4.6 Physical Stability of Pharmaceutical Salts, 56

4.7 Strategies for Salt Selection, 57

References, 59

5 Pharmaceutical Cocrystals 60

5.1 Introduction, 60

5.2 Cocrystals and Crystal Engineering, 60

5.3 Solubility Phase Diagrams for Cocrystals, 62

5.4 Preparation of Cocrystals, 63

5.5 Dissolution and Bioavailability of Cocrystals, 64

5.6 Comparison of Pharmaceutical Salts and Cocrystals, 66

References, 68

6 Amorphous Solids 69

6.1 Introduction, 69

6.2 The Formation of Amorphous Solids, 70

6.3 Methods of Preparing Amorphous Solids, 71

6.4 The Glass Transition Temperature, 72

6.5 Structural Features of Amorphous Solids, 75

6.6 Molecular Mobility, 77

6.7 Mixtures of Amorphous Solids, 84

References, 87

7 Crystal Mesophases and Nanocrystals 89

7.1 Introduction, 89

7.2 Overview of Crystal Mesophases, 89

7.3 Liquid Crystals, 90

7.4 Conformationally Disordered (Condis) Crystals, 95

7.5 Plastic Crystals, 95

7.6 Nanocrystals, 96

References, 97

8 X-Ray Crystallography and Crystal Packing Analysis 99

8.1 Introduction, 99

8.2 Crystals, 99

8.3 Miller Indices and Crystal Faces, 99

8.4 Determination of the Miller Indices of the Faces of a Crystal, 101

8.5 Determination of Crystal Structure, 103

References, 106

9 X-Ray Powder Diffraction 107

9.1 Introduction, 107

9.2 X-Ray Powder Diffraction of Crystalline Materials, 107

9.3 Qualitative Analysis of Crystalline Materials, 109

9.4 Phase Transformations, 110

9.5 Quantitative Phase Analysis Using XRPD, 111

9.6 Solving Crystal Structures Using Powder X-Ray Diffraction, 114

9.7 X-Ray Diffraction of Amorphous and Crystal Mesophase Forms, 116

9.8 Pair Distribution Function, 117

9.9 X-Ray Diffractometers, 119

9.10 Variable Temperature XRPD, 121

References, 122

10 Differential Scanning Calorimetry and Thermogravimetric Analysis 124

10.1 Introduction, 124

10.2 The Basics of Differential Scanning Calorimetry, 124

10.3 Thermal Transitions of Pharmaceutical Materials, 125

10.4 DSC Instrumentation, 128

10.5 Thermogravimetric Analysis, 132

10.6 Operating a TGA Instrument, 133

10.7 Evolved Gas Analysis, 133

10.8 Applications of DSC and TGA, 134

10.9 Summary of Using DSC and TGA, 139

References, 140

11 Microscopy 142

11.1 Introduction, 142

11.2 Light Microscopy, 142

11.3 Polarized Light Microscopy, 144

11.4 Thermal Microscopy, 144

11.5 Functionality of the Light Microscope, 145

11.6 Digital Microscope, 146

11.7 Application of Light Microscopy to Pharmaceutical Materials, 146

11.8 Scanning Electron Microscope, 153

11.9 Environmental Scanning Electron Microscopy, 155

11.10 Atomic Force Microscopy, 155

References, 157

12 Vibrational Spectroscopy 159

12.1 Introduction, 159

12.2 The Nature of Molecular Vibrations, 160

12.3 Fourier Transformed Infrared Spectroscopy, 161

12.4 Material Characterization by FT-IR Spectroscopy, 162

12.5 FT-IR Instrumentation, 164

12.6 Diffuse Reflectance FT-IR, 165

12.7 Attenuated Total Reflectance FT-IR, 166

12.8 FT-IR Microscopy, 167

12.9 Near Infrared Spectroscopy, 168

12.10 Raman Spectroscopy, 170

12.11 Raman Instrumentation and Sampling, 171

12.12 Raman Microscope, 173

12.13 Terahertz Spectroscopy, 175

12.14 Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy, 176

References, 178

13 Solid-State NMR Spectroscopy 180

13.1 Introduction, 180

13.2 An Overview of Solid-State 13C CP/MAS NMR Spectroscopy, 180

13.3 Solid-State NMR Studies of Pharmaceuticals, 185

13.4 Phase Identification in Dosage Forms, 186

13.5 Other Basic Solid-State NMR Experiments Useful for Pharmaceutical Analysis, 189

13.6 Determination of the Domain Structure of Amorphous Dispersions Using

Solid-State NMR, 192

References, 196

14 Particle and Powder Analysis 197

14.1 Introduction, 197

14.2 Particles in Pharmaceutical Systems, 197

14.3 Particle Size and Shape, 199

14.4 Particle Size Distribution, 200

14.5 Dynamic Light Scattering, 202

14.6 Zeta Potential, 203

14.7 Laser Diffraction, 205

14.8 Dynamic Image Analysis, 206

14.9 Sieve Analysis, 208

14.10 Bulk Properties of Pharmaceutical Particulates and Powders, 208

14.11 Surface Area Measurement, 209

References, 211

15 Hygroscopic Properties of Solids 213

15.1 Introduction, 213

15.2 Water Vapor Sorption–Desorption, 214

15.3 Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity, 214

15.4 Measurement of Water Content and Water Vapor Sorption/Desorption Isotherms, 216

15.5 Modes of Water Vapor Sorption, 218

References, 229

16 Mechanical Properties of Pharmaceutical Materials 231

16.1 Introduction, 231

16.2 Stress and Strain, 231

16.3 Elasticity, 232

16.4 Plasticity, 233

16.5 Viscoelasticity, 234

16.6 Brittleness, 235

16.7 Hardness, 236

16.8 Powder Compression, 237

16.9 Powder Compression Models and Compressibility, 238

16.10 Compactibility and Tensile Strength, 239

16.11 Effect of Solid Form on Mechanical Properties, 239

16.12 Effect of Moisture on Mechanical Properties, 242

16.13 Methods for Testing Mechanical Properties: Beam Bending, 243

16.14 Nanoindentation, 246

References, 247

17 Solubility and Dissolution 249

17.1 Introduction, 249

17.2 Principle Concepts Associated with Solubility, 249

17.3 Prediction of Aqueous Drug Solubility, 250

17.4 Solubility of Pharmaceutical Solid Forms, 252

17.5 Solubility Determination Using the Shake Flask Method, 253

17.6 High Throughput Screening of Solubility, 254

17.7 Solubility Measurement of Metastable Forms, 255

17.8 Kinetic Solubility Measurement, 256

17.9 Solubility Determination of Drugs in Polymer Matrices, 256

17.10 Dissolution Testing, 257

17.11 Nonsink Dissolution Test, 260

17.12 Intrinsic Dissolution Studies, 262

References, 263

18 Physical Stability of Solids 265

18.1 Introduction, 265

18.2 Underlying Basis for Physical Instability in Pharmaceutical Systems, 266

18.3 Disorder in Crystals, 267

18.4 Examples of the Role of Process-Induced Disorder in Solid-State Physical Instability in Pharmaceutical Systems, 274

18.5 Considerations in Evaluating Solid-State Physical Stability, 276

References, 277

19 Chemical Stability of Solids 279

19.1 Introduction, 279

19.2 Examples of Chemical Reactivity in the Solid State, 279

19.3 Some General Principles that Establish the Rate of Chemical Reactions in Solution, 282

19.4 The Role of Crystal Defects in Solid-State Reactions, 286

19.5 Chemical Reactivity in the Amorphous Solid State, 290

19.6 Chemical Reactivity and Processed-Induced Disorder, 292

19.7 The Effects of Residual Water on Solid-State Chemical Reactivity, 294

19.8 Drug–Excipient Interactions, 298

19.9 Summary, 300

References, 300

20 Solid-State Properties of Proteins 302

20.1 Introduction, 302

20.2 Solution Properties of Proteins, 302

20.3 Amorphous Properties of Proteins, 306

20.4 Crystalline Properties of Proteins, 307

20.5 Local Molecular Motions and the Dynamical Transitional Temperature, Td, 308

20.6 Solid-State Physical and Chemical Stability of Proteins, 310

20.7 Cryoprotection and Lyoprotection, 311

References, 311

21 Form Selection of Active Pharmaceutical Ingredients 313

21.1 Introduction, 313

21.2 Form Selection, 313

21.3 Amorphous form Screening, 315

21.4 Salt Selection, 316

21.5 Cocrystal Screening, 318

21.6 Polymorph Screening, 320

21.7 Slurrying, 321

21.8 High Throughput Screening, 322

21.9 Crystallization in Confined Space, 323

21.10 Nonsolvent-Based Polymorph Screening, 325

21.11 Polymer-Induced Heteronucleation, 325

21.12 Physical Characterization, 326

21.13 Thermodynamic Stability and form Selection, 327

References, 328

22 Mixture Analysis 331

22.1 Introduction, 331

22.2 Limitations of Wet Chemistry, 331

22.3 Pharmaceutical Analysis in the Solid State, 332

22.4 Measurement of Amorphous Content, 335

22.5 Detection of the Degree of Crystallinity, 337

22.6 Quantification of Mixtures of Polymorphs, 339

22.7 Salt and Free form Composition, 340

22.8 Process Analytical Technology, 342

References, 348

23 Product Development 351

23.1 Chemistry, Manufacture, and Control, 351

23.2 Preformulation, 353

23.3 Drug Excipient Compatibility, 354

23.4 Solid Dispersions, 355

23.5 Abuse-Deterrent Dosage Forms, 361

23.6 Drug-Eluting Stents, 363

23.7 Dry Powder Inhalers (DPI), 365

23.8 Lyophilization and Biopharmaceutical Products, 368

References, 372

24 Quality by Design 375

24.1 Introduction, 375

24.2 Quality by Design Wheel, 375

24.3 Learning Before Doing, 379

24.4 Risk-Based Orientation, 380

24.5 API Attributes and Process Design, 381

24.6 Development and Design Space, 381

24.7 Process Design: Crystallization, 385

24.8 Phase Transformations During Wet Granulation, 386

24.9 Dissolution Tests with an IVIVC for Quality by Design, 387

24.10 Conclusion, 388

References, 388

Index 389