Solid State Properties of Pharmaceutical Materials

Description

Presents a detailed discussion of important solid-state properties, methods, and applications of solid-state analysis

Key Features

• Illustrates the various phases or forms that solids can assume and discussesvarious issues related to the relative stability of solid forms and tendencies to undergo transformation
• Covers key methods of solid state analysis including X-ray powder diffraction, thermal analysis, microscopy, spectroscopy, and solid state NMR
• Reviews critical physical attributes of pharmaceutical materials, mainly related to drug substances, including particle size/surface area, hygroscopicity, mechanical properties, solubility, and physical and chemical stability
• Showcases the application of solid state material science in rational selection of drug solid forms, analysis of various solid forms within drug substance and the drug product, and pharmaceutical product development
• Introduces appropriate manufacturing and control procedures using Quality by Design, and other strategies that lead to safe and effective products with a minimum of resources and time

Table of Contents

1. Preface xi
2. Acknowledgments xiii
3. Solid-State Properties and Pharmaceutical Development 1
   1. Introduction, 1
   2. Solid-State Forms, 1
   3. ICH Q6A Decision Trees, 6
   4. “Big Questions” for Drug Development, 6
   5. Accelerating Drug Development, 9
   6. Solid-State Chemistry in Preformulation and Formulation, 11
   7. Learning Before Doing and Quality by Design, 14
   8. Performance and Stability in Pharmaceutical Development, 17
   9. Moisture Uptake, 18
   10. Solid-State Reactions, 19
   11. Noninteracting Formulations: Physical Characterizations, 19
   12. References, 20
4. Polymorphs 22
   1. Introduction, 22
   2. How are Polymorphs Formed?, 22
   3. Structural Aspect of Polymorphs, 23
   4. Physical, Chemical, and Mechanical Properties, 24
   5. Thermodynamic Stability of Polymorphs, 27
   6. Polymorph Conversion, 32
   7. Control of Polymorphs, 34
   8. Polymorph Screening, 35
   9. Polymorph Prediction, 36
   10. References, 36
5. Solvates and Hydrates 38
   1. Introduction, 38
   2. Pharmaceutical Importance of Hydrates, 38
   3. Classification of Pharmaceutical Hydrates, 40
   4. Water Activity, 42
   5. Stoichiometric Hydrates, 43
   6. Nonstoichiometric Hydrates, 44
   7. Hydration/Dehydration, 45
   8. Preparation and Characterization of Hydrates and Solvates, 45
   9. References, 46
6. Pharmaceutical Salts 48
   1. Introduction, 48
   2. Importance of Pharmaceutical Salts, 48
   3. Weak Acid, Weak Base, and Salt, 49
   4. pH-Solubility Profiles of Ionizable Compounds, 51
   5. Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts, 53
   6. Physical Stability of Pharmaceutical Salts, 56
   7. Strategies for Salt Selection, 57
   8. References, 59
7. Pharmaceutical Cocrystals 60
   1. Introduction, 60
   2. Cocrystals and Crystal Engineering, 60
   3. Solubility Phase Diagrams for Cocrystals, 62
   4. Preparation of Cocrystals, 63
   5. Dissolution and Bioavailability of Cocrystals, 64
   6. Comparison of Pharmaceutical Salts and Cocrystals, 66
   7. References, 68
8. Amorphous Solids 69
   1. Introduction, 69
   2. The Formation of Amorphous Solids, 70
   3. Methods of Preparing Amorphous Solids, 71
   4. The Glass Transition Temperature, 72
   5. Structural Features of Amorphous Solids, 75
   6. Molecular Mobility, 77
   7. Mixtures of Amorphous Solids, 84
   8. References, 87
9. Crystal Mesophases and Nanocrystals 89
   1. Introduction, 89
   2. Overview of Crystal Mesophases, 89
   3. Liquid Crystals, 90
   4. Conformationally Disordered (Condis) Crystals, 95
   5. Plastic Crystals, 95
   6. Nanocrystals, 96
   7. References, 97
10. X-Ray Crystallography and Crystal Packing Analysis 99
    1. Introduction, 99
    2. Crystals, 99
    3. Miller Indices and Crystal Faces, 99
    4. Determination of the Miller Indices of the Faces of a Crystal, 101
    5. Determination of Crystal Structure, 103
    6. References, 106
11. X-Ray Powder Diffraction 107
    1. Introduction, 107
    2. X-Ray Powder Diffraction of Crystalline Materials, 107
    3. Qualitative Analysis of Crystalline Materials, 109
    4. Phase Transformations, 110
    5. Quantitative Phase Analysis Using XRPD, 111
    6. Solving Crystal Structures Using Powder X-Ray Diffraction, 114
    7. X-Ray Diffraction of Amorphous and Crystal Mesophase Forms, 116
    8. Pair Distribution Function, 117
    9. X-Ray Diffractometers, 119
    10. Variable Temperature XRPD, 121
    11. References, 122
12. Differential Scanning Calorimetry and Thermogravimetric Analysis 124
    1. Introduction, 124
    2. The Basics of Differential Scanning Calorimetry, 124
    3. Thermal Transitions of Pharmaceutical Materials, 125
    4. DSC Instrumentation, 128
    5. Thermogravimetric Analysis, 132
    6. Operating a TGA Instrument, 133
    7. Evolved Gas Analysis, 133
    8. Applications of DSC and TGA, 134
    9. Summary of Using DSC and TGA, 139
    10. References, 140
13. Microscopy 142
    1. Introduction, 142
    2. Light Microscopy, 142
    3. Polarized Light Microscopy, 144
    4. Thermal Microscopy, 144
    5. Functionality of the Light Microscope, 145
    6. Digital Microscope, 146
    7. Application of Light Microscopy to Pharmaceutical Materials, 146
    8. Scanning Electron Microscope, 153
    9. Environmental Scanning Electron Microscopy, 155
    10. Atomic Force Microscopy, 155
    11. References, 157
14. Vibrational Spectroscopy 159
    1. Introduction, 159
    2. The Nature of Molecular Vibrations, 160
    3. Fourier Transformed Infrared Spectroscopy, 161
    4. Material Characterization by FT-IR Spectroscopy, 162
    5. FT-IR Instrumentation, 164
    6. Diffuse Reflectance FT-IR, 165
    7. Attenuated Total Reflectance FT-IR, 166
    8. FT-IR Microscopy, 167
    9. Near Infrared Spectroscopy, 168
    10. Raman Spectroscopy, 170
    11. Raman Instrumentation and Sampling, 171
    12. Raman Microscope, 173
    13. Terahertz Spectroscopy, 175
    14. Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy, 176
    15. References, 178
15. Solid-State NMR Spectroscopy 180
    1. Introduction, 180
    2. An Overview of Solid-State 13C CP/MAS NMR Spectroscopy, 180
    3. Solid-State NMR Studies of Pharmaceuticals, 185
    4. Phase Identification in Dosage Forms, 186
    5. Other Basic Solid-State NMR Experiments Useful for Pharmaceutical Analysis, 189
    6. Determination of the Domain Structure of Amorphous Dispersions Using
    7. Solid-State NMR, 192
    8. References, 196
16. Particle and Powder Analysis 197
    1. Introduction, 197
    2. Particles in Pharmaceutical Systems, 197
    3. Particle Size and Shape, 199
    4. Particle Size Distribution, 200
    5. Dynamic Light Scattering, 202
    6. Zeta Potential, 203
    7. Laser Diffraction, 205
    8. Dynamic Image Analysis, 206
    9. Sieve Analysis, 208
    10. Bulk Properties of Pharmaceutical Particulates and Powders, 208
    11. Surface Area Measurement, 209
    12. References, 211
17. Hygroscopic Properties of Solids 213
    1. Introduction, 213
    2. Water Vapor Sorption–Desorption, 214
    3. Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity, 214
    4. Measurement of Water Content and Water Vapor Sorption/Desorption Isotherms, 216
    5. Modes of Water Vapor Sorption, 218
    6. References, 229
18. Mechanical Properties of Pharmaceutical Materials 231
    1. Introduction, 231
    2. Stress and Strain, 231
    3. Elasticity, 232
    4. Plasticity, 233
    5. Viscoelasticity, 234
    6. Brittleness, 235
    7. Hardness, 236
    8. Powder Compression, 237
    9. Powder Compression Models and Compressibility, 238
    10. Compactibility and Tensile Strength, 239
    11. Effect of Solid Form on Mechanical Properties, 239
    12. Effect of Moisture on Mechanical Properties, 242
    13. Methods for Testing Mechanical Properties: Beam Bending, 243
    14. Nanoindentation, 246
    15. References, 247
19. Solubility and Dissolution 249
    1. Introduction, 249
    2. Principle Concepts Associated with Solubility, 249
    3. Prediction of Aqueous Drug Solubility, 250
    4. Solubility of Pharmaceutical Solid Forms, 252
    5. Solubility Determination Using the Shake Flask Method, 253
    6. High Throughput Screening of Solubility, 254
    7. Solubility Measurement of Metastable Forms, 255
    8. Kinetic Solubility Measurement, 256
    9. Solubility Determination of Drugs in Polymer Matrices, 256
    10. Dissolution Testing, 257
    11. Nonsink Dissolution Test, 260
    12. Intrinsic Dissolution Studies, 262
    13. References, 263
20. Physical Stability of Solids 265
    1. Introduction, 265
    2. Underlying Basis for Physical Instability in Pharmaceutical Systems, 266
    3. Disorder in Crystals, 267
    4. Examples of the Role of Process-Induced Disorder in Solid-State Physical Instability in Pharmaceutical Systems, 274
    5. Considerations in Evaluating Solid-State Physical Stability, 276
    6. References, 277
21. Chemical Stability of Solids 279
    1. Introduction, 279
    2. Examples of Chemical Reactivity in the Solid State, 279
    3. Some General Principles that Establish the Rate of Chemical Reactions in Solution, 282
    4. The Role of Crystal Defects in Solid-State Reactions, 286
    5. Chemical Reactivity in the Amorphous Solid State, 290
    6. Chemical Reactivity and Processed-Induced Disorder, 292
    7. The Effects of Residual Water on Solid-State Chemical Reactivity, 294
    8. Drug–Excipient Interactions, 298
    9. Summary, 300
    10. References, 300
22. Solid-State Properties of Proteins 302
    1. Introduction, 302
    2. Solution Properties of Proteins, 302
    3. Amorphous Properties of Proteins, 306
    4. Crystalline Properties of Proteins, 307
    5. Local Molecular Motions and the Dynamical Transitional Temperature, Td, 308
    6. Solid-State Physical and Chemical Stability of Proteins, 310
    7. Cryoprotection and Lyoprotection, 311
    8. References, 311
23. Form Selection of Active Pharmaceutical Ingredients 313
    1. Introduction, 313
    2. Form Selection, 313
    3. Amorphous form Screening, 315
    4. Salt Selection, 316
    5. Cocrystal Screening, 318
    6. Polymorph Screening, 320
    7. Slurrying, 321
    8. High Throughput Screening, 322
    9. Crystallization in Confined Space, 323
    10. Nonsolvent-Based Polymorph Screening, 325
    11. Polymer-Induced Heteronucleation, 325
    12. Physical Characterization, 326
    13. Thermodynamic Stability and form Selection, 327
    14. References, 328
24. Mixture Analysis 331
    1. Introduction, 331
    2. Limitations of Wet Chemistry, 331
    3. Pharmaceutical Analysis in the Solid State, 332
    4. Measurement of Amorphous Content, 335
    5. Detection of the Degree of Crystallinity, 337
    6. Quantification of Mixtures of Polymorphs, 339
    7. Salt and Free form Composition, 340
    8. Process Analytical Technology, 342
    9. References, 348
25. Product Development 351
    1. Chemistry, Manufacture, and Control, 351
    2. Preformulation, 353
    3. Drug Excipient Compatibility, 354
    4. Solid Dispersions, 355
    5. Abuse-Deterrent Dosage Forms, 361
    6. Drug-Eluting Stents, 363
    7. Dry Powder Inhalers (DPI), 365
    8. Lyophilization and Biopharmaceutical Products, 368
    9. References, 372
26. Quality by Design 375
    1. Introduction, 375
    2. Quality by Design Wheel, 375
    3. Learning Before Doing, 379
    4. Risk-Based Orientation, 380
    5. API Attributes and Process Design, 381
    6. Development and Design Space, 381
    7. Process Design: Crystallization, 385
    8. Phase Transformations During Wet Granulation, 386
    9. Dissolution Tests with an IVIVC for Quality by Design, 387
    10. Conclusion, 388
    11. References, 388
    12. Index 389

Authors Biography

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.