Solid-State Properties of Pharmaceutical Materials

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

About the Author :
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.