Computational Pharmaceutics Application of Molecular Modeling in Drug Delivery

Molecular modeling techniques have been widely used in drug discovery fields for rational drug design and compound screening. Now these techniques  are used to model or mimic the behavior of molecules, and help us study formulation at the molecular level. Computational pharmaceutics enables us to understand the mechanism of drug delivery, and to develop new drug delivery systems.

The book discusses the modeling of different drug delivery systems, including cyclodextrins, solid dispersions, polymorphism prediction, dendrimer-based delivery systems, surfactant-based micelle, polymeric drug delivery systems, liposome, protein/peptide formulations, non-viral gene delivery systems, drug-protein binding, silica nanoparticles, carbon nanotube-based drug delivery systems, diamond nanoparticles and layered double hydroxides (LDHs) drug delivery systems.

Although there are a number of existing books about rational drug design with molecular modeling techniques, these techniques still look mysterious and daunting for pharmaceutical scientists. This book fills the gap between pharmaceutics and molecular modeling, and presents a systematic and overall introduction to computational pharmaceutics. It covers all introductory, advanced and specialist levels. It provides a totally different perspective to pharmaceutical scientists, and will greatly facilitate the development of pharmaceutics. It also helps computational chemists to look for the important questions in the drug delivery field.

This book is included in the Advances in Pharmaceutical Technology book series.

Dr Defang Ouyang is at the Institute of Medical Sciences, University of Macau in China as well as Aston University, UK. He has a multi-disciplinary and unique background and expertise in both drug delivery and molecular modeling. He completed his PhD at The University of Queensland, Australia in 2010. Since joining Aston, he has pioneered the application of molecular modeling techniques in the field of drug delivery - "computational pharmaceutics", including cyclodextrin-drug complexes, solid dispersions, non-viral gene delivery systems and liposome formulations. So far, he has authored over 20 refereed publications, consisting of an invited book, a book chapter, invited reviews, journal articles, conference papers and patents.

Professor Sean C. Smith is at the School of Chemical Engineering, University of New South Wales, Australia. He was previously Director of the Center for Nanophase Materials Sciences at Oak Ridge National Laboratory, USA. He is firmly established internationally as a significant figure in the field of theoretical and computational chemistry. His contributions include theoretical studies of chemical reactions, material sciences, nano science and biological sciences. His publications include one book, three invited chapters, three invited reviews, and 203 refereed journal articles.

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

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

2.3 Examples of the Use of Crystal Energy Landscapes as a Complement to�@Solid Form Screening 18

2.4 Outlook 24

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

3.4 Characterization of Drug�]CD Complexes 38

3.5 Theoretical Progress of CD Studies 41

3.6 Future Prospects of Cyclodextrin Formulation 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

4.3 Simulations of Micellar Drug Delivery 63

4.4 Taxol 68

4.5 Summary and Conclusions 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

5.3 Thermodynamics of Solid Dispersions 85

5.4 Molecular Structure of Amorphous Solid Dispersions 89

5.5 Physical Stability of Solid Dispersions 91

5.6 Future Prospects 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

6.3 Model Membranes 105

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

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

7.3 Protein–Cosolvent Interactions 129

7.4 Protein–Protein Interactions 133

7.5 Informatics Studies of Protein Aggregation 136

7.6 Future Prospects 140

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

8.3 Summary 164

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

9.4 NDs as a Therapeutic Platform 187

9.5 Outlook 189

10 Molecular Modeling of Layered Double Hydroxide Nanoparticles for�@Drug Delivery 197
Vinuthaa Murthy, Zhi Ping Xu, and Sean C. Smith

10.1 Introduction 197

10.2 Basic Structure of LDH 198

10.3 Synthesis of LDH 199

10.4 Molecular Modeling Methodology 200

10.5 Conclusions 214

11 Molecular Modeling as a Tool to Understand the Role of Poly(Ethylene) Glycol in Drug Delivery 217
Alex Bunker

11.1 PEGylation in Drug Delivery 217

11.2 A Brief History of the Computational Modeling of PEG 220

11.3 Molecular Modeling Applied to the Role PEG Plays in Drug Delivery 221

11.4 Future Directions 224

12 3D Structural Investigation of�@Solid�@Dosage Forms 235
Xianzhen Yin, Li Wu, You He, Zhen Guo, Xiaohong Ren, Qun Shao, Jingkai Gu, Tiqiao Xiao, Peter York, and Jiwen Zhang

12.1 Structural Architectures of Solid Dosage Forms and Methods of Investigation– an Overview 235

12.2 Synchrotron Radiation X�]Ray Computed Microtomography 239

12.3 Principles and Procedures for SR�]μ Studies 239

12.4 3D Visualization and Quantitative Characterization 245

12.5 Future Prospects 258

13 Physiologically Based Pharmacokinetic Modelling in Drug Delivery 263
Raj K. Singh Badhan

13.1 Introduction 263

13.2 Modelling and Simulation Process 264

13.3 Pharmacokinetic Principles 264

13.4 Pharmacokinetic Modelling Approaches 267

13.5 Pharmacokinetic Software for Modelling 270

13.6 Developing a PBPK Model for an Orally Dosed Compound 270

13.7 Developing the Model 280

13.8 Summary 286

References 286

Index 293

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