Solid State Characterization of Pharmaceuticals -- Contents -- List of Contributors -- About the Editors -- Preface -- 1. Introduction to the Solid State - Physical Properties and Processes -- 1.1 Introduction -- 1.1.1 The Gas/Vapour and Liquid States -- 1.1.2 The Crystalline State -- 1.1.3 The Glassy State -- 1.2 Neutral Pharmaceutical Molecules -- 1.3 Thermodynamics and Phase Diagrams -- 1.3.1 Gibbs Phase Rule -- 1.3.2 One-Component (Unary) Systems -- 1.3.3 Two-Component (Binary) Systems -- 1.3.4 Three-Component (Ternary) Systems -- 1.4 Neutral Pharmaceutical Molecules in the Solid State -- 1.5 Salt Formation and Acid-Base Equilibrium -- 1.6 Polymorphs, Solvates and Mixed Crystals -- 1.6.1 Mixed Crystals -- 1.6.2 Solvates and Hydrates -- 1.7 Phase Transitions and Kinetics -- 1.7.1 Crystallization -- 1.7.2 Solid-to-Solid Phase Transitions -- 1.8 Screening for 'Polymorphs' (Ansolvates and Solvates) -- 1.9 Summary -- 1.10 Acknowledgements -- References -- 2. X-Ray Diffraction -- 2.1 Introduction -- 2.2 Generation and Properties of X-Rays -- 2.2.1 The Synchrotron -- 2.3 Crystal, Lattices, Unit Cells and Symmetry -- 2.3.1 Point Group Symmetry -- 2.3.2 Unit Cells and Crystal Lattices -- 2.3.3 Miller Indices -- 2.3.4 Space Group Symmetry -- 2.3.5 The Asymmetric Unit -- 2.4 The Interaction of X-rays with Crystals -- 2.4.1 X-rays and Atoms -- 2.4.2 X-Rays and Crystals -- 2.4.3 Determining Space Groups -- 2.5 Collecting Intensity Data for Single Crystals -- 2.6 Determining Crystal Structures -- 2.6.1 The Fundamental Equations of Crystallography and the Phase Problem -- 2.6.2 Data Resolution and Completeness -- 2.6.3 Methods of Solving Crystal Structures -- 2.6.4 Completing the Structure -- 2.6.5 Refinement and Validation -- 2.6.6 Small Crystals and the Synchrotron -- 2.6.7 Databases -- 2.6.8 Absolute Configuration -- 2.6.9 Polymorphism.

2.7 Powder Diffraction -- 2.7.1 Preferred Orientation -- 2.7.2 Data Collection -- 2.7.3 Qualitative Analysis: Pattern Matching -- 2.7.4 Compositions of Mixtures: Quantitative Analysis -- 2.7.5 Structure Solution from Powders -- 2.7.6 Powder Diffraction and Polymorphs -- 2.7.7 Nonambient Conditions -- 2.8 Amorphous Powders -- 2.9 Particle Size -- 2.10 Other Radiations: Neutrons and Electrons -- 2.10.1 Neutrons -- 2.10.2 Electrons -- References -- 3. Spectroscopic Characterization -- 3.1 Introduction and Theory -- 3.2 Electromagnetic Radiation -- 3.3 Vibrational Spectroscopy -- 3.3.1 Basic Instrument Configuration for Spectroscopy -- 3.4 Mid- and Near-Infrared Spectroscopy -- 3.4.1 Instrumentation -- 3.4.2 Attenuated Total Reflectance Spectrometry -- 3.4.3 Applications -- 3.4.4 Pharmaceutical Examples of the Use of ATR-FT-IR Spectroscopy -- 3.5 Near-Infrared Spectroscopy -- 3.5.1 Theory -- 3.5.2 Instrumentation -- 3.5.3 Qualitative and Quantitative Data Analysis -- 3.5.4 Pharmaceutical Applications -- 3.5.5 Polymorphism -- 3.5.6 Pseudopolymorphism, Hydrates and Solvates -- 3.5.7 Authentication of Medicines and Detection of Counterfeit and Clone Versions -- 3.5.8 Pharmaceutical Examples of the Use of NIR Spectrometry -- 3.6 Raman Spectroscopy -- 3.6.1 Theory -- 3.6.2 Instrumentation -- 3.6.3 Pharmaceutical Applications -- 3.6.4 Raman Spectrometry for Process Monitoring, Degradation, Stability and Crystallization -- 3.6.5 Polymorphism -- 3.6.6 Pseudopolymorphism -- 3.6.7 Process Analytical Technology -- 3.6.8 Raman Spectroscopy: Pharmaceutical Examples -- 3.7 Chemical Imaging and Mapping Microscopy -- 3.8 Nuclear Magnetic Resonance Spectroscopy -- 3.8.1 Pharmaceutical Applications -- 3.8.2 General Applications -- 3.8.3 Polymorphism -- 3.8.4 Drug Substance and Dosage Form Analysis -- 3.8.5 Conformation, Stereochemistry and Hydrogen Bonding Interactions.

3.9 Terahertz Pulsed Spectroscopy -- 3.9.1 Theory -- 3.9.2 Instrumentation -- 3.9.3 Sample and Instrument Preparation -- 3.9.4 Recent Developments in Instrumentation -- 3.9.5 Pharmaceutical Applications -- References -- 4. Thermal Analysis - Conventional Techniques -- 4.1 Introduction -- 4.2 Differential Scanning Calorimetry (DSC) -- 4.2.1 Heat Flow Measurements -- 4.2.2 Derivative Curves -- 4.2.3 General Practical Points -- 4.2.4 Encapsulation -- 4.2.5 Temperature Range -- 4.2.6 Scan Rate -- 4.2.7 The Instrumental Transient -- 4.2.8 Calibration -- 4.2.9 Factors Affecting Calibration -- 4.2.10 Double Furnace Design -- 4.2.11 Single Furnace Designs -- 4.2.12 Differential Thermal Analysis (DTA) -- 4.2.13 Modulated Temperature Profiles -- 4.2.14 Stepwise Methods -- 4.3 Thermogravimetric Analysis (TGA) -- 4.3.1 Instrument Design -- 4.3.2 TGA Calibration -- 4.3.3 Practical Points -- 4.3.4 Sample Interpretation -- 4.4 Dynamic Mechanical Analysis (DMA) -- 4.4.1 What is DMA? -- 4.4.2 How Does a DMA Work? -- 4.5 Determining the Melting Behaviour of Crystalline Solids -- 4.5.1 Evaluating the Melting Point Transition -- 4.5.2 Melting Point Determination for Identification of Samples -- 4.6 Polymorphism -- 4.6.1 Significance of Pharmaceutical Polymorphism -- 4.6.2 Thermodynamic and Kinetic Aspects of Polymorphism: Enantiotropy and Monotropy -- 4.6.3 Characterization of Polymorphs by DSC -- 4.6.4 Determining Polymorphic Purity by DSC -- 4.6.5 Interpretation of DSC Thermograms of Samples Exhibiting Polymorphism -- 4.7 Solvates and Hydrates (Pseudopolymorphism) -- 4.7.1 Factors Influencing DSC Curves of Hydrates and Solvates -- 4.7.2 Types of Desolvation/Dehydration -- 4.8 Evolved Gas Analysis (EGA) and Simultaneous Measurements -- 4.9 Amorphous Content -- 4.9.1 Introduction -- 4.9.2 Characterization of Amorphous Solids: The Glass Transition Temperature.

4.9.3 Quantification of Amorphous Content Using DSC -- 4.10 Purity Determination Using DSC -- 4.10.1 Types of Impurity -- 4.10.2 Differential Scanning Calorimetry Purity Method -- 4.10.3 Practical Issues and Potential Interferences -- 4.11 Excipient Compatibility -- 4.11.1 Excipient Compatibility Screening Using DSC -- References -- 5. Thermal Analysis - Dielectric Techniques -- 5.1 General Introduction -- 5.2 Common Background to the Techniques -- 5.3 Dielectric Spectroscopy -- 5.3.1 Interpretation of Data -- 5.3.2 Pharmaceutical Examples of Dielectric Spectroscopy -- 5.3.3 Analysis of Water Distribution and Mobility -- 5.3.4 Investigation of Molecular Mobility -- 5.3.5 Formulation, Characterization and Distribution of Materials -- 5.3.6 Experimental Issues -- 5.3.7 Advantages and Disadvantages of Dielectric Spectroscopy -- 5.4 Thermally Stimulated Current (TSC) Spectroscopy -- 5.4.1 Experimental Modes -- 5.4.2 Data Interpretation -- 5.4.3 Pharmaceutical Examples of the Use of TSC -- 5.4.4 Characterization of Amorphous Materials -- 5.4.5 Characterization of Polymorphic Materials -- 5.4.6 Experimental Issues -- 5.4.7 Advantages and Disadvantages of TSC -- 5.5 Overall Conclusions -- References -- 6. Isothermal Calorimetric Analysis -- 6.1 Introduction -- 6.1.1 Driving Forces - Thermodynamics -- 6.1.2 Kinetic Factors -- 6.2 Calorimetry: Principle of Measurement -- 6.2.1 Heat Conduction Isothermal Microcalorimetry -- 6.2.2 Power Compensation Isothermal Microcalorimetry -- 6.2.3 Instrumentation and Common Experiment Methodology -- 6.2.4 Calibration -- 6.3 Applications of IM for Characterization of Solid-State Pharmaceuticals -- 6.3.1 Detection and Characterization of Disorder in Processed Materials -- 6.3.2 Production of Amorphous Forms -- 6.3.3 Method 1: Direct Detection (Measurement) of Recrystallization.

6.3.4 Method 2: Indirect Detection of Recrystallization -- 6.4 Analysis of Solid-State Form Conversions -- 6.5 Analysis of Solid State Chemical Reactions -- 6.5.1 Solution Phase Reactions -- 6.6 Excipient Compatibility -- References -- 7. Calorimetric Methods - Solution Calorimetry -- 7.1 Introduction -- 7.2 The Principles of Solution Calorimetry -- 7.2.1 Semi-Adiabatic Solution Calorimeters -- 7.2.2 Heat-Conduction Calorimeters -- 7.2.3 Sample - Solvent Mixing -- 7.2.4 Calibration -- 7.3 Applications -- 7.3.1 Polymorphism -- 7.3.2 Determination of Degree of Crystallinity/Amorphous Content -- 7.3.3 Characterization of Interactions -- 7.3.4 Other Applications -- 7.4 Summary -- References -- 8. Vapour Sorption and Surface Analysis -- 8.1 Introduction -- 8.1.1 Background -- 8.1.2 Theory of Intermolecular Forces -- 8.1.3 Thermodynamics of Interfaces -- 8.1.4 Surface Energy -- 8.1.5 Comparison of Some Surface Characterization Methods -- 8.1.6 Solid State -- 8.2 Inverse Gas Chromatography -- 8.2.1 Introduction to IGC -- 8.2.2 Experimental Methodology -- 8.2.3 Theoretical Aspects of IGC -- 8.2.4 IGC Technique -- 8.2.5 Determination of Properties of Various Crystalline Forms -- 8.2.6 Surface Properties and Powder Processing -- 8.2.7 Recent Developments -- 8.2.8 Future Applications -- 8.3 Dynamic Vapour Sorption -- 8.3.1 Introduction -- 8.3.2 Fundamentals -- 8.3.3 Dynamic Vapour Sorption Instrumentation -- 8.3.4 Characterization of Solid State Materials -- 8.3.5 Gravimetric Dynamic Vapour Sorption Instruments Hyphenated With Other Analytical Methods -- 8.3.6 Amorphous Material Studies -- 8.3.7 Solute Permeability and Diffusion of Packaging Systems -- 8.3.8 Vapour Pressure Measurement Using Knudsen Effusion -- References -- 9. Microscopy -- 9.1 Introduction -- 9.2 The Microscope as an Analytical Tool -- 9.3 Which Microscope to Use? -- 9.4 Light Microscopy.

9.4.1 The Polarizing Light Microscope for Studying Solid-State Properties.