Solid-State Materials in Pharmaceutical Chemistry

Updated and expanded information on the properties of pharmaceutical solids and their impact on drug product performance, quality, and stability Solid-State Materials in Pharmaceutical Chemistry provides readers with a comprehensive and up-to-date resource for understanding and controlling the solid-state properties of pharmaceutical materials, enabling the development of safe and effective medicines including small molecule compounds, peptides, proteins, and nucleotides. This new edition covers the significant transformations in the landscape of pharmaceutical research, development, and manufacturing since the previous edition was published, presenting both novel challenges and unprecedented opportunities. New chapters in this edition cover physical and chemical properties of RNA therapeutics, a frontier to many life-saving medicines and vaccines including Covid vaccines, and final stage drug substance manufacturing and control, addressing challenges in API process development including impurity purging, chiral separation, final form preparation, particle size reduction, and nitrosamine control. Readers will also find other updated topics including bulk and surface properties of solids, lipid nanoparticles, applications of pharmaceutical solvates in impurity purging and final form preparation, pharmaceutical cocrystal engineering to enable chiral separation, the emerging technique of microcrystal electron diffraction in solid form characterization, poor wettability of APIs, oral delivery of peptides such as semaglutide, injectable drug-device combination products, and N-nitrosamine control in drug product. This updated and revised Second Edition still features: Physical and chemical properties of solid-state pharmaceuticals such as amorphous forms, mesophases, polymorphs, hydrates/solvates, salts, co-crystals, nano-particles, and solid dispersions Characterization techniques for solid form identification and physical attribute analysis such as X-Ray powder diffraction, thermal analysis, microscopy, spectroscopy, solid state NMR, particle analysis, water sorption, mechanical property testing, solubility, and dissolution Applications of pharmaceutical chemistry and physical characterization techniques in developing and testing drug substances and drug products for small molecules and biopharmaceuticals This book is an essential resource on the subject for formulation scientists, process chemists, medicinal chemists, and analytical chemists. The book will also appeal to quality control, quality assurance, and regulatory affair specialists and advanced undergraduate and graduate students in pharmaceutical chemistry, drug delivery, material science, crystal engineering, pharmaceutics, and biopharmaceutics.

Biography of Authors xv Preface xvii Preface to the First Edition xvii Acknowledgment xix 1 Solid-State Properties and Pharmaceutical Development 1 1.1 Introduction 1 1.2 Solid-state Forms 1 1.3 Bulk and Surface Properties of Solids 6 1.4 ICH Q6A Decision Trees 7 1.5 “Big Questions” for Drug Development 8 1.6 Accelerating Drug Development 10 1.7 Solid-state Chemistry in Preformulation and Formulation 12 1.8 Solid–Lipid Nanoparticles 15 1.9 Learning Before Doing and Quality by Design 16 1.10 Performance and Stability in Pharmaceutical Development 19 1.11 Moisture Uptake 20 1.12 Solid-state Reactions 21 1.13 Noninteracting Formulations – Physical Characterizations 21 2 Polymorphs 27 2.1 Introduction 27 2.2 How Are Polymorphs Formed? 27 2.3 Structural Aspect of Polymorphs 29 2.3.1 Configurational Polymorphs 29 2.3.2 Conformational Polymorphs 30 2.4 Physical, Chemical, and Mechanical Properties 32 2.4.1 Solubility 33 2.4.2 Chemical Stability 34 2.4.3 Mechanical Properties 34 2.5 Thermodynamic Stability of Polymorphs 35 2.5.1 Monotropy and Enantiotropy 36 2.5.2 Burger and Ramberger’s Rules 37 2.5.3 van’t Hoff Plot 37 2.5.4 ​∆G​/temperature diagram 38 2.6 Polymorph Conversion 39 2.6.1 Solution-mediated Transformation 40 2.6.2 Solid-state Conversion 40 2.7 Control of Polymorphs 42 2.8 Polymorph Screening 43 2.9 Polymorph Prediction 44 3 Pseudopolymorphs: Hydrates and Solvates 49 3.1 Introduction 49 3.2 Pharmaceutical Importance of Hydrates 49 3.3 Classification of Pharmaceutical Hydrates 51 3.4 Water Activity 52 3.5 Stoichiometric Hydrates 53 3.6 Nonstoichiometric Hydrates 54 3.7 Emerging Interests in Organic Solvates 55 3.8 Isostructural Solvates 57 3.9 Dehydration and Desolvation 59 3.10 Preparation and Characterization of Hydrates and Solvates 61 4 Pharmaceutical Salts 65 4.1 Introduction 65 4.2 Importance of Pharmaceutical Salts 65 4.3 Weak Acid, Weak Base, and Salt 66 4.4 pH Solubility Profiles of Ionizable Compounds 69 4.5 Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts 71 4.6 Physical Stability of Pharmaceutical Salts 75 4.7 Strategies for Salt Selection 76 5 Pharmaceutical Cocrystals 81 5.1 Introduction 81 5.2 Cocrystals and Crystal Engineering 81 5.3 Solubility Phase Diagrams for Cocrystals 83 5.4 Preparation of Cocrystals 85 5.5 Dissolution and Bioavailability of Cocrystals 88 5.6 Pharmaceutical Applications of Cocrystals 90 5.7 Comparison of Pharmaceutical Salts and Cocrystals 92 5.7.1 Formation 93 5.7.2 Preparation 93 5.7.3 Polymorphism and Pseudopolymorphism 93 5.7.4 Characterization 93 5.7.5 Stability 93 5.7.6 Formulation 94 5.7.7 Regulatory 94 6 Amorphous Solids 97 6.1 Introduction 97 6.2 The Formation of Amorphous Solids 98 6.3 Methods of Preparing Amorphous Solids 99 6.4 The Glass Transition Temperature 100 6.5 Structural Features of Amorphous Solids 103 6.6 Molecular Mobility 105 6.6.1 Overview of Molecular Mobility 105 6.6.2 Viscosity and Molecular Mobility 106 6.6.3 Relaxation Time 107 6.6.4 Fragility in Supercooled Liquids 108 6.6.5 Diffusive Relaxation Time in the Glassy State 110 6.6.6 Secondary Relaxations in Amorphous Solids 112 6.7 Mixtures of Amorphous Solids 114 6.7.1 Overview 114 6.7.2 Thermodynamics of Molecular Mixing in Amorphous Solids 115 6.7.3 The Glass Transition Temperature and Molecular Mobility of Miscible Amorphous Mixtures 116 7 Crystal Mesophases and Nanocrystals 121 7.1 Introduction 121 7.2 Overview of Crystal Mesophases 121 7.3 Liquid Crystals 122 7.4 Conformationally Disordered (Condis) Crystals 127 7.5 Plastic Crystals 127 7.6 Nanocrystals 128 8 X-Ray Crystallography and Crystal-Packing Analysis 131 8.1 Introduction 131 8.2 Crystals 131 8.3 Miller Indices and Crystal Faces 131 8.4 Determination of the Miller Indices of the Faces of a Crystal 133 8.5 Determination of Crystal Structure 134 8.5.1 Diffraction of X-Rays 134 8.5.2 Experimental Measurements 135 8.5.3 Determination of Space Group Symmetry 136 8.5.4 Calculation of the Density of the Crystal 136 8.5.5 Structure Determination 136 8.5.6 Crystal-packing Drawings 137 8.5.7 Atomic Displacement Parameters and Molecular Mobility 137 8.6 Variable-Temperature X-ray Studies 138 9 X-Ray Powder Diffraction 139 9.1 Introduction 139 9.2 XRPD of Crystalline Materials 139 9.3 Qualitative Analysis of Crystalline Materials 141 9.4 Phase Transformations 143 9.5 Quantitative Phase Analysis Using XRPD 143 9.6 Solving Crystal Structures Using XRPD 147 9.7 X-ray Diffraction of Amorphous and Crystal Mesophase Forms 149 9.8 Pair Distribution Function 149 9.9 X-ray Diffractometers 152 9.10 Variable Temperature XRPD 156 10 Differential Scanning Calorimetry and Thermogravimetric Analysis 159 10.1 Introduction 159 10.2 The Basics of DSC 159 10.3 Thermal Transitions of Pharmaceutical Materials 160 10.3.1 Melting 160 10.3.2 Glass Transition in Amorphous Solids 161 10.3.3 Enthalpy Relaxation for Amorphous Solids 161 10.3.4 Crystallization 162 10.3.5 Crystal Form Transitions 162 10.3.6 Desolvation/Dehydration 163 10.3.7 Chemical Degradation 163 10.4 DSC Instrumentation 163 10.4.1 Heat-flux DSC 163 10.4.2 Power-compensated DSC 164 10.4.3 Modulated DSC 164 10.4.4 Fast-scan DSC 165 10.4.5 Operation of DSC Instrumentation 165 10.5 Thermogravimetric Analysis 168 10.6 Operating a TGA Instrument 169 10.7 Evolved Gas Analysis 169 10.8 Applications of DSC and TGA 169 10.8.1 The Study of Polymorphs, Solvates, and Hydrates 169 10.8.2 Polymer Characterization 171 10.8.3 Characterization of Amorphous Forms and Amorphous Solid Dispersions 172 10.8.4 Dehydration and Desolvation Kinetics 172 10.8.5 Optimization of the Freezing–Drying Cycle in Lyophilization 173 10.8.6 Melting-point Depression Method for Purity Analysis and Drug–Polymer Miscibility Assessment 174 10.8.7 Study of Solid-state Chemical Stability 176 10.8.8 Characterization of Macromolecules and Their Interactions 176 10.9 Summary of Using DSC and TGA 178 11 Microscopy 181 11.1 Introduction 181 11.2 Light Microscopy 181 11.3 Polarized Light Microscopy 183 11.4 Thermal Microscopy 183 11.5 Functionality of Light Microscopy 184 11.6 Digital Microscope 185 11.7 Application of Light Microscopy to Pharmaceutical Materials 186 11.7.1 Differentiation of Amorphous and Crystalline Materials 186 11.7.2 Characterization of Polymorphs, Hydrates, and Solvates 186 11.7.3 Polymorph Conversion 189 11.7.4 Control of Crystallization 190 11.7.5 Screening for Cocrystals 191 11.7.6 Analysis of Particle Size 192 11.7.7 Contaminant Analysis 192 11.8 Scanning Electron Microscope 193 11.9 Environmental SEM 195 11.10 TEM and ED 196 11.11 Atomic Force Microscopy 198 12 Vibrational Spectroscopy 203 12.1 Introduction 203 12.2 The Nature of Molecular Vibrations 204 12.3 FT-IR Spectroscopy 205 12.4 Material Characterization by FT-IR Spectroscopy 206 12.5 FT-IR Instrumentation 208 12.6 Diffuse Reflectance FT-IR 209 12.7 Atr Ft-ir 211 12.8 FT-IR Microscopy 212 12.9 NIR Spectroscopy 213 12.10 Raman Spectroscopy 215 12.11 Raman Instrumentation and Sampling 217 12.12 Raman Microscopy 219 12.13 Terahertz Spectroscopy 220 12.14 Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy 222 12.14.1 Spectral Information 222 12.14.2 Spectral Resolution 223 12.14.3 Sampling 223 12.14.4 Environmental Control 223 12.14.5 Microscopy 223 12.14.6 Fluorescence and Photodamage 224 13 Solid-State NMR Spectroscopy 227 13.1 Introduction 227 13.2 An Overview of Solid-state 13C CP/MAS NMR Spectroscopy 227 13.2.1 Dipolar Decoupling 228 13.2.2 Magic-Angle Spinning 231 13.2.3 Cross Polarization 232 13.3 Solid-state NMR Studies of Pharmaceuticals 232 13.4 Phase Identification in Dosage Forms 233 13.5 Other Basic Solid-state NMR Experiments Useful for Pharmaceutical Analysis 237 13.5.1 Interrupted Decoupling for Protonated Carbon Atoms 237 13.5.2 Block-Decay Experiments for Screening Submolecular Mobility 239 13.6 Determination of the Domain Structure of Amorphous Dispersions Using Solid-state NMR 241 13.7 Solid-state NMR of Amorphous Materials 242 13.8 Summary 244 14 Particle and Powder Analysis 247 14.1 Introduction 247 14.2 Particles in Pharmaceutical Systems 247 14.2.1 Micelles 247 14.2.2 Protein Aggregates 248 14.2.3 Liposomes 248 14.2.4 Microemulsions 248 14.2.5 Nanoemulsions 248 14.2.6 Nanosuspensions 249 14.2.7 Nanoparticles 249 14.2.8 Aerosols 249 14.2.9 Emulsions 249 14.2.10 Suspensions 249 14.2.11 Powders 249 14.2.12 Granules 250 14.2.13 Pellets 250 14.3 Particle Size and Shape 250 14.4 Particle Size Distribution 251 14.5 Dynamic Light Scattering 252 14.6 Zeta Potential 254 14.7 Laser Diffraction 256 14.8 Acoustic Spectroscopy 258 14.9 Dynamic Image Analysis 259 14.10 Sieve Analysis 260 14.11 Bulk Properties of Pharmaceutical Particulates and Powder 260 14.12 Surface Area Measurement 262 15 Hygroscopic Properties of Solids 267 15.1 Introduction 267 15.2 Water Vapor Sorption–Desorption 268 15.3 Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity 268 15.4 Measurement of Water Content and Water Vapor Sorption–Desorption Isotherms 270 15.4.1 Measurement of Water Content 270 15.4.2 Measurement of Water Vapor Sorption–Desorption Isotherms 271 15.5 Modes of Water Vapor Sorption 272 15.5.1 Introduction 272 15.5.2 Adsorption 273 15.5.3 Deliquescence 277 15.5.4 Capillary Condensation 278 15.5.5 Absorption by Amorphous Solids 280 16 Mechanical Properties of Pharmaceutical Materials 287 16.1 Introduction 287 16.2 Stress and Strain 287 16.3 Elasticity 288 16.4 Plasticity 289 16.5 Viscoelasticity 290 16.6 Brittleness 291 16.7 Hardness 293 16.8 Powder Compression 294 16.9 Powder Compression Models and Compressibility 295 16.10 Compactibility and Tensile Strength 296 16.11 Effect of Solid Form on Mechanical Properties 297 16.12 Effect of Moisture on Mechanical Properties 299 16.13 Methods for Testing Mechanical Properties 301 16.13.1 Beam Bending 301 16.13.2 Thermomechanical Analyzer 302 16.13.3 Dynamic Mechanical Analyzer 303 16.13.4 Nanoindentation 304 17 Solubility and Dissolution 307 17.1 Introduction 307 17.2 Principal Concepts Associated with Solubility 307 17.3 Prediction of Aqueous Drug Solubility 308 17.4 Solubility of Pharmaceutical Solid Forms 310 17.5 Solubility Determination Using the Shake-Flask Method 311 17.6 High-throughput Screening of Solubility 312 17.7 Solubility Measurement of Metastable Forms 313 17.8 Kinetic Solubility Measurement 314 17.9 Solubility Determination of Drugs in Polymer Matrices 315 17.10 Dissolution Testing 316 17.11 Nonsink Dissolution Test 320 17.12 Biorelevant Dissolution Test 321 17.13 Intrinsic Dissolution Studies 324 17.14 Summary 325 18 Physical Stability of Solids 329 18.1 Introduction 329 18.2 Underlying Basis for Physical Instability in Pharmaceutical Systems 330 18.3 Disorder in Crystals 331 18.4 Quantitative Determination of Partially Amorphous Material in Crystals 333 18.5 Phase Transformation 335 18.5.1 Solid-state Crystallization 335 18.5.2 Solvent-mediated Phase Transformations 338 18.6 Examples of the Role of Process-induced Disorder in Solid-state Physical Instability in Pharmaceutical Systems 339 18.7 Poor Wettability of Solids During Dosage Form Processing and Administration 341 18.8 Considerations in Evaluating Solid-state Physical Stability 345 19 Chemical Stability of Solids 349 19.1 Introduction 349 19.2 Examples of Chemical Reactivity in the Solid State 349 19.3 Some General Principles That Establish the Rate of Chemical Reactions in Solution 352 19.4 Some General Principles Governing the Rates of Solid-state Reactions 355 19.5 The Role of Crystal Defects in Solid-state Reactions 356 19.6 Chemical Reactivity in the Amorphous Solid State 360 19.7 Chemical Reactivity and Processed-induced Disorder 363 19.8 The Effects of Residual Water on Solid-state Chemical Reactivity 364 19.9 Drug–Excipient Interactions 369 19.10 Summary 371 20 Solid-State Properties of Proteins 375 20.1 Introduction 375 20.2 Solution Properties of Proteins 375 20.3 Amorphous Properties of Proteins 379 20.4 Crystalline Properties of Proteins 381 20.5 Local Molecular Motions and the Dynamical Transitional Temperature, T d 382 20.6 Solid-state Physical and Chemical Stability of Proteins 384 20.7 Cryoprotection and Lyoprotection 385 21 Physical and Chemical Properties of RNA Therapeutics 389 21.1 Introduction 389 21.2 Mode of Action 389 21.2.1 Antisense RNA 390 21.2.2 Small Interference RNA 390 21.2.3 Messenger RNA 391 21.2.4 Crispr 392 21.3 Building Blocks and Primary Structure 392 21.4 RNA Structure in Solution 394 21.4.1 Hydrogen Bonding 395 21.4.2 Stacking Interaction 395 21.4.3 Ionic Interaction 395 21.4.4 RNA Secondary and Tertiary Structure 396 21.5 RNA Stability in Solution 398 21.6 Solid-state Properties 400 21.7 Pharmaceutical Development 402 21.7.1 Drug Delivery Challenges and Current Platforms 402 21.7.2 How to Make RNA Therapeutics 403 21.7.3 Characterization of mRNA LNPs 404 21.7.4 Stability of mRNA LNPs 406 21.7.5 Lyophilization of mRNA LNPs 407 21.8 Summary 408 22 Solid Form Selection of Active Pharmaceutical Ingredients 411 22.1 Introduction 411 22.2 Solid Form Selection 411 22.3 Amorphous Form Screening 413 22.4 Salt Selection 414 22.5 Cocrystal Screening 417 22.6 Polymorph Screening 419 22.7 Slurrying 420 22.8 High-Throughput Screening 421 22.9 Crystallization in Confined Space 422 22.10 Nonsolvent-based Polymorph Screening 423 22.11 Polymer-induced Heteronucleation 424 22.12 Physical Characterization 425 22.13 Thermodynamic Stability and Solid Form Selection 426 22.14 Summary 427 23 Final Stage Drug Substance Manufacturing and Control 431 23.1 Introduction 431 23.2 Crystallization and Impurity Purge 431 23.3 Removal of Residual Solvents 434 23.4 Control of Genotoxic Impurities 436 23.5 Control of N-Nitrosamines 437 23.6 Chiral Separation Through Salt and Cocrystal Formation 438 23.7 Preparation of the Final Solid Form 441 23.8 Particle Size and Shape Control During Crystallization 444 23.9 Powder Agglomeration and Caking 447 23.10 Milling and Micronization 448 23.11 Impact of Process Impurities on Crystallization 449 23.12 Summary 450 24 Solid-State Mixture Analysis 455 24.1 Introduction 455 24.2 Limitations of Wet Chemistry 455 24.3 Pharmaceutical Analysis in the Solid State 456 24.3.1 Sample Preparation 456 24.3.2 Data Collection 456 24.3.3 Data Transformation 457 24.3.4 Calibration Model Development and Validation 457 24.4 Measurement of Amorphous Content 459 24.5 Detection of Crystallinity 462 24.6 Quantification of Mixtures of Polymorphs 464 24.7 Salt and Free Form Composition 466 24.8 Analysis of Particulate Contaminants in Drug Products 467 24.9 Process Analytical Technology 470 24.9.1 Physical and Chemical Attributes of a Process 471 24.9.2 Selection of Process Analyzers 471 24.9.3 Location of the Process Analyzer 473 24.9.4 Development of Analytical Models for Process Monitoring 474 24.9.5 Validation 475 24.10 Summary 476 25 Drug Product Development 479 25.1 Chemistry, Manufacture, and Control 479 25.2 Preformulation 481 25.3 Drug–Excipient Compatibility 482 25.4 Solid Dispersions 484 25.5 Abuse-Deterrent Dosage Forms 489 25.6 Drug-Eluting Stents 491 25.7 Dry Powder Inhalers 494 25.8 Lyophilization of Biopharmaceutical Products 497 25.9 Oral Delivery of Peptides 500 25.10 Injectable Drug–Device Combination Products 502 25.11 Control of N-Nitrosamine in Drug Product 504 25.12 Summary 506 26 Quality by Design 511 26.1 Introduction 511 26.2 QbD Wheel 511 26.3 Learning Before Doing 514 26.4 Risk-based Orientation 516 26.5 API Attributes and Process Design 517 26.6 Development and Design Space 517 26.7 Process Design – Crystallization 520 26.8 Phase Transformations During Wet Granulation 521 26.9 Dissolution Tests with an IVIVC for QbD 522 26.10 Summary 525 Index 527