Computational Pharmaceutics Advances in Pharmaceutical Technology A Wiley Book Series Series Editors: Dennis Douroumis, University of Greenwich, UK Alfred Fahr, Friedrich–Schiller University of Jena, Germany Jűrgen Siepmann, University of Lille, France Martin Snowden, University of Greenwich, UK Vladimir Torchilin, Northeastern University, USA Titles in the Series: Hot‐Melt Extrusion: Pharmaceutical Applications Edited by Dionysios Douroumis Drug Delivery Strategies for Poorly Water‐Soluble Drugs Edited by Dionysios Douroumis and Alfred Fahr Forthcoming titles: Novel Delivery Systems for Transdermal and Intradermal Drug Delivery Edited by Ryan F. Donnelly and Thakur Raghu Raj Singh Pulmonary Drug Delivery: Advances and Challenges by Ali Nokhodhi and Gary P. Martin Computational Pharmaceutics Application of Molecular Modeling in Drug Delivery Edited by DEFANG OuyANG AND SEAN C. SMITH This edition first published 2015 © 2015 John Wiley & Sons, Ltd. 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Set in 10/12pt Times by SPi Global, Pondicherry, India 1 2015 Contents List of Contributors xi Series Preface xiii Preface xv Editors’ Biographies xvii 1 Introduction to Computational Pharmaceutics 1 Defang Ouyang and Sean C. Smith 1.1 What Is Computational Pharmaceutics? 1 1.2 Application of Computational Pharmaceutics 3 1.3 Future Prospects 4 References 4 2 Crystal Energy Landscapes for Aiding Crystal Form Selection 7 Sarah L. Price 2.1 Introduction 7 2.2 CSP Methods for Generating Crystal Energy Landscapes 10 2.2.1 Assessment of Flexibility Required in Molecular Model 11 2.2.2 Search Method for Generating Putative Structures 13 2.2.3 Methods for Computing Relative Crystal Energies 14 2.2.4 Comparing Crystal Structures, and Idealised Types of Crystal Energy Landscapes 16 2.2.5 Multicomponent Systems 17 2.3 Examples of the Use of Crystal Energy Landscapes as a Complement to Solid Form Screening 18 2.3.1 Is the Thermodynamically Stable Form Known? 18 2.3.2 Supporting and Developing the Interpretation of Experiments 20 2.4 Outlook 24 Acknowledgements 25 References 25 3 Solubilization of Poorly Soluble Drugs: Cyclodextrin‐Based Formulations 31 Sachin S. Thakur, Harendra S. Parekh, Carl H. Schwable, Yong Gan, and Defang Ouyang 3.1 Cyclodextrins in Pharmaceutical Formulations – Overview 31 3.2 Drug‐CD Complexes – Preparation Methods 35 3.3 Physicochemical Principles Underlying Drug‐CD Complexes 36 3.3.1 Inclusion Drug‐CD Complexes 36 3.3.2 Non‐inclusion Drug‐CD Complexes 37 vi Contents 3.4 Characterization of Drug‐CD Complexes 38 3.4.1 Thermo‐Analytical Methods 38 3.4.2 Microscopic Methods 39 3.4.3 Wettability/Solubility Studies 39 3.4.4 Chromatographic Methods 39 3.4.5 Spectroscopic Methods 40 3.4.6 X‐Ray Techniques 40 3.4.7 Other Techniques 41 3.5 Theoretical Progress of CD Studies 41 3.5.1 Quantum Mechanics 41 3.5.2 Molecular Dynamics Simulation 42 3.5.3 Monte Carlo Simulation 43 3.5.4 Docking Studies 43 3.5.5 Quantitative Structure–Activity Relationship 44 3.6 Future Prospects of Cyclodextrin Formulation 44 References 44 4 Molecular Modeling of Block Copolymer Self‐Assembly and Micellar Drug Delivery 53 Myungshim Kang, Dennis Lam, Dennis E. Discher, and Sharon M. Loverde 4.1 Introduction 53 4.2 Simulation Methods 58 4.2.1 All‐Atom Models 58 4.2.2 Coarse‐Grained Models 58 4.2.3 Mesoscale Methods: BD and DPD 60 4.2.4 Free Energy Methods 61 4.3 Simulations of Micellar Drug Delivery 63 4.3.1 Characterization of PCL Micelles with Simulation 63 4.3.2 Advantages of Worm‐Like Micelles, Breakup of Micelles 65 4.4 Taxol 68 4.4.1 Taxol Behavior in Membranes 71 4.4.2 Ligand‐Protein Binding 72 4.4.3 Taxol–Tubulin Binding 72 4.5 Summary and Conclusions 74 References 74 5 Solid Dispersion – a Pragmatic Method to Improve the Bioavailability of Poorly Soluble Drugs 81 Peng Ke, Sheng Qi, Gabriele Sadowski, and Defang Ouyang 5.1 Introduction of Solid Dispersion 81 5.2 Preparation Methods for Solid Dispersions 83 5.2.1 Melting Method 83 5.2.2 Solvent Method 84 5.2.3 Ball Milling 85 Contents vii 5.3 Thermodynamics of Solid Dispersions 85 5.4 Molecular Structure of Amorphous Solid Dispersions 89 5.5 Physical Stability of Solid Dispersions 91 5.5.1 Detection of Physical Instability of Amorphous Solid Dispersions 91 5.5.2 Glass Transition Temperature 92 5.5.3 Molecular Mobility and Structural Relaxation of Amorphous Drugs 93 5.5.4 Interactions between Drug and Polymer in Solid Dispersions 94 5.5.5 Characterization Phase Separation in Amorphous Solid Dispersion 95 5.6 Future Prospects 97 References 97 6 Computer Simulations of Lipid Membranes and Liposomes for Drug Delivery 101 David William O’Neill, Sang Young Noh, and Rebecca Notman 6.1 Introduction 101 6.2 Methodological Considerations 102 6.2.1 Representations of Model Lipids 102 6.2.2 Measurable Properties 103 6.3 Model Membranes 105 6.3.1 Phospholipid Bilayers 105 6.3.2 Liposomes 105 6.3.3 Skin–Lipid Membranes for Transdermal Drug Delivery 106 6.4 Small Molecule Uptake and Permeation across Membranes 108 6.5 Nanoparticle–Membrane Interactions 111 6.6 Mechanisms of Action of Chemical Penetration Enhancers 114 6.7 Future Challenges 116 Acknowledgements 116 References 116 7 Molecular Modeling for Protein Aggregation and Formulation 123 Dorota Roberts, Jim Warwicker, and Robin Curtis 7.1 Introduction 123 7.2 Protein Aggregation Pathways in Liquid Formulations 127 7.2.1 Multiple Pathways Can Lead to Protein Aggregation 127 7.2.2 Overview of Cosolvent Effects on Protein–Protein Interactions 128 7.3 Protein–Cosolvent Interactions 129 7.3.1 Lyotropic Series and Hofmeister Series Classifications of Ions 129 7.3.2 Modeling and Simulation of Ion–Interface Interactions 129 7.3.3 Ion Interactions with Protein Charged Groups 130 7.3.4 Protein Interactions with Other Excipients 132 7.4 Protein–Protein Interactions 133 7.4.1 The Osmotic Second Virial Coefficient and DLVO Theory 133 7.4.2 Incorporating Specific Salt and Ion Effects 134 viii Contents 7.4.3 Inclusion of Nonionic Excipients 135 7.4.4 Models Accounting for Anisotropic Protein–Protein Electrostatic Interactions 135 7.5 Informatics Studies of Protein Aggregation 136 7.5.1 Comparison with Modeling Used for Small Molecule Pharmaceutics 136 7.5.2 Prediction Schemes Deriving from Amyloid Deposition 137 7.5.3 Solubility Prediction Based on Sequence, Structural, and Surface Properties 137 7.6 Future Prospects 140 References 141 8 Computational Simulation of Inorganic Nanoparticle Drug Delivery Systems at the Molecular Level 149 Xiaotian Sun, Zhiwei Feng, Tingjun Hou, and Youyong Li 8.1 Introduction 149 8.2 Materials and Methods 152 8.2.1 Prepared Structures 152 8.2.2 MD Simulations 152 8.2.3 C omputational Simulation of Drug Delivery Strategies with CNTs 153 8.2.4 Computational Simulation of Drug Delivery Strategies with Graphene/GO 155 8.2.5 Computational Simulation of Drug Delivery Strategies with Silicon Nanomaterials 158 8.2.6 Computational Simulation of Drug Delivery Strategies with Au Nanomaterials 162 8.3 Summary 164 Acknowledgements 165 References 165 9 Molecular and Analytical Modeling of Nanodiamond for Drug Delivery Applications 169 Lin Lai and Amanda S. Barnard 9.1 Introduction 169 9.2 Structure of Individual NDs 170 9.3 Surface Chemistry and Interactions 172 9.3.1 Surface Passivation and Environmental Stability 173 9.3.2 Surface Functionalization 178 9.3.3 Consequences for Interactions and Self‐Assembly 180 9.4 NDs as a Therapeutic Platform 187 9.4.1 Simulations with Doxorubicin 187 9.4.2 Experimental Progress 187 9.5 Outlook 189 References 191