Disordered Pharmaceutical Materials

A one-stop resource for researchers, developers, and post graduate students in pharmaceutical science. This handbook and ready reference provides detailed, but not overloaded information -- presenting the topic without unnecessarily complex formalism.
As such, it gives a systematic and coherent overview of disordered materials for pharmaceutical applications, covering fundamental aspects, as well as preparation and characterization techniques for the target-oriented development of drug delivery systems based on disordered crystals and amorphous solids. Special attention is paid to examine the different facets and levels of disorder in their structural and dynamic aspects as well as the effect of disorder on dissolution and stability. Chapters on processing induced disorder and on patenting issues round off the book. As a result the book helps overcoming the challenges of using these materials in the pharmaceutical industry.
For pharmaceutical and medicinal chemists, materials scientists, clinical physicists, and pharmaceutical laboratories looking to make better and more potent pharmaceuticals.

1 Some Facets of Molecular Disorder in Crystalline and Amorphous Pharmaceuticals 1
Marc Descamps and Jean-François Willart
1.1 The Crystal/Amorph Alternative 2
1.2 Characteristics of the Disorder in Glass Formers 28
Acknowledgments 51
References 51
2 Influence of Disorder on Dissolution 57
Khushboo Kothari and Raj Suryanarayanan
2.1 Introduction 57
2.2 Approaches to Enhance Solubility 59
2.3 Measuring the Solubility Advantage of Amorphous Compounds 64
2.4 Solid Dispersions 66
2.5 Polymer Properties 67
2.6 Drug?Polymer Interactions 70
2.7 Polymer Concentration 71
2.8 Other Formulation Components 73
2.9 Formulation Variables 74
2.10 Reliable Measurement of Supersaturation 75
2.11 Conclusion 76
References 77
3 Crystal Imperfections in Molecular Crystals: Physical and Chemical Consequences 85
William Jones and Mark D. Eddleston
3.1 Introduction 85
3.2 General Aspects of Defects in Crystals 87
3.3 Role of Imperfections in Reactivity and Stability ? Chemistry in the
Perfect and Imperfect Lattice 92
3.4 Role in Physical Processes 96
3.5 Concluding Remarks 99
References 99
4 Observation and Characterization of Crystal Defects in Pharmaceutical Solids 103
Mark D. Eddleston andWilliam Jones
4.1 Introduction 103
4.2 Techniques for Characterizing Defects within Crystals 104
4.3 Techniques for Characterizing Defects Emergent at Crystal Surfaces 119
4.4 Techniques for Quantifying Defect Densities within Crystals 125
4.5 The Complementarity of Techniques for Characterizing Defects 126
4.6 Summary and Outlook 127
Acknowledgment 128
References 128
5 "Enantiomeric Disorder" Pharmaceutically Oriented 135
Gerard Coquerel and Rui Tamura
5.1 Introduction 135
5.2 Introduction and Lexicon of Specific Terms Used among Chiral Molecules and Chiral Molecular Associations 135
5.3 Restrictions in Symmetry Operations Inside Crystal Lattices with an Enantiomeric Excess Different from Zero 136
5.4 Impact of Chirality on Phase Diagrams and the Gibbs?Scott Phase Rule 137
5.5 Competitions between Solid Solutions (Impact of Polymorphism on Solid Solutions) Application: Preferential Enrichment 149
5.6 Disorder at Level 3 Multiepitaxy between Enantiomers 154
5.7 Conclusion and Perspectives 156
Acknowledgments 157
References 157
6 Conformational Disorder and Atropisomerism in Pharmaceutical Compounds 161
Attilio Cesàro, Barbara Bellich, Giovanna Giannini, and Alessandro Maiocchi
6.1 Premise: Conformational Energy Barriers in FlexibleMolecules 161
6.2 Conformational Topology and Crystallization of Chain Molecules 162
6.3 Conformational Polymorphism and Crystallization of Flexible Molecules 165
6.4 Conformational Flexibility of Ring Molecules: Carbohydrates 170
6.5 Hindered Conformational Isomerism: Atropisomerism 172
6.6 Conclusion 178
Acknowledgments 180
References 180
7 Tautomerism in Drug Delivery 183
Zaneta Wojnarowska and Marian Paluch
7.1 Broadband Dielectric Spectroscopy as a Powerful Tool for Investigating the Tautomerization Process in Condensed Materials 187
7.2 Tautomerization Kinetics of Supercooled Pharmaceuticals 190
Acknowledgment 197
References 198
8 Disorders in Pharmaceutical Polymers 201
Emeline Dudognon and Sheng Qi
8.1 Polymers Architectures -
Structural Disorders 202
8.2 Structural States and Phases Transitions 205
8.3 Dynamic Disorders 213
8.4 Blends of Polymer and Small Molecules 221
8.5 Effect of the Structural Properties of Pharmaceutical Polymers on Their Physical Behavior 224
8.6 Concluding Remarks 234
References 235
9 Polymer Gels, Hydrogels, and Scaffolds ? An Overview 241
Madeleine Djabourov and Kawthar Bouchemal
9.1 Introduction 241
9.2 Gels and Hydrogels 243
9.3 Scaffolds 268
9.4 Conclusion 275
References 276
10 Use of the Pair Distribution Function Analysis in the Context of Pharmaceutical Materials 283
Pierre Bordet and PaulineMartinetto
10.1 Introduction 283
10.2 What Is the PDF? 284
10.3 How to Measure the PDF 288
10.4 Modeling of the PDF 290
10.5 Applications of PDF Analysis to Molecular and Pharmaceutical Compounds 292
10.6 Conclusion 297
Acknowledgments 298
References 298
11 Application of Broadband Dielectric Spectroscopy to Study Molecular Mobility in Pharmaceutical Systems 301
Katarzyna Grzybowska, Karolina Adrjanowicz, and Marian Paluch
11.1 Introduction to Broadband Dielectric Spectroscopy 301
11.2 Molecular Dynamics in Amorphous Pharmaceutical Systems 316
11.3 Molecular Mobility and Dielectric Response in Partially Ordered Pharmaceutical Systems 346
Acknowledgment 353
References 353
12 Raman Spectroscopy in Disordered Molecular Compounds: Application to Pharmaceuticals 361
Alain Hedoux
12.1 Introduction 361
12.2 Raman Spectroscopy 362
12.3 Analysis of Molecular Compounds by Raman Spectroscopy 370
12.4 Conclusion 388
References 388
XII Contents
13 Study of Disordered Materials by Terahertz Spectroscopy 393
Juraj Sibik and J. Axel Zeitler
13.1 Introduction 393
13.2 Exploration of Terahertz Dynamics Prior to THz-TDS 394
13.3 Response of Supercooled Liquids and Glasses at Terahertz Frequencies 397
13.4 Terahertz Studies of Disordered Molecular Solids 400
13.5 Organic Glass-Forming Liquids 404
13.6 Characterization of Disordered Biological and Pharmaceutical Systems 410
13.7 Outlook 416
References 418
14 Study of Disorder by Solid-State NMR Spectroscopy 427
Marco Geppi, Silvia Borsacchi, and Elisa Carignani
14.1 Introduction 427
14.2 Basics of Solid-State NMR 428
14.3 Static Disorder 433
14.4 Dynamic Disorder 448
14.5 A Case Study 458
14.6 Final Remarks and Future Perspectives 462
References 464
15 Processing-Induced Disorder in Pharmaceutical Materials 467
Sheng Qi
15.1 Introduction 467
15.2 Pharmaceutical Processing 468
15.3 Conclusion 484
References 485
16 Patenting of Inventions Relating to Solid Forms, with Special Considerations on Disordered Forms 491
Bertrand Gellie
16.1 Patentability of Disordered Crystals 493
16.2 Patentability of Co-crystals 496
16.3 Patentability of Amorphous Forms 500
16.4 Patenting (Disordered) Nanocrystals 509
16.5 Conclusions 511
Index 513

Marc Descamps is Professor for solid state physics and Head of the Technological Research Group "Therapeutic Materials" at the University of Lille, France. He is the author of more than 160 publications in international journals and he has collaborated with several large pharmaceutical companies. His research interests include: phase transitions in molecular materials, disordered crystals, molecular glasses and studies of the structural and dynamic properties of pharmaceutical solids by a variety of physicochemical techniques.