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
