Title Details

Vijay Kumar Thakur (Ph.D.) is a Staff Scientist in the School of Mechanical and Materials Engineering at Washington State University, U.S.A. He has published more than 100 research articles, patents and conference proceedings in the field of polymers and materials science and has published ten books and 25 book chapters on the advanced state-of-the-art of polymers/ materials science. He has extensive expertise in the synthesis of polymers (natural/ synthetic), nano materials, nanocomposites, biocomposites, graft copolymers, high performance capacitors and electrochromic materials.

Manju Kumari Thakur works in the Department of Chemistry, Himachal Pradesh University, Simla, India.

Preface xvii

1 Particle Engineering of Polymers into Multifunctional Interactive Excipients 1
Sharad Mangal, Ian Larson, Felix Meiser and David AV Morton

1.1 Introduction 1

1.2 Polymers as Excipients 3

1.3 Material Properties Affecting Binder Activity 6

1.3.1 Particle Size 6

1.3.2 Deformation Mechanisms 7

1.3.3 Glass Transition Temperature (Tg) 8

1.4 Strategies for Improving Polymeric Filler-Binder Performance for Direct Compression 8

1.4.1 Interactive Mixing 12

1.4.2 Challenges to Interactive Mixing 13

1.4.3 Controlling Interparticle Cohesion 14

1.5 Preparation and Characterization of Interactive Excipients 14

1.5.1 Particle Size and Size Distribution of Excipients 15

1.5.2 Effect of L-leucine on Surface Morphology 16

1.5.3 Effect of L-leucine on Surface Composition 16

1.5.4 Effect of L-leucine on Surface Energy 17

1.5.5 Effect of L-leucine on Interparticle Cohesion 18

1.6 Performance of Interactive Excipients 18

1.6.1 Blending Ability 18

1.6.2 Effect on Flow 20

1.6.3 Binder Activity 20

1.7 Investigation of the Effect of Polymer Mechanical Properties 23

1.8 Conclusion 25

References 26

2 The Art of Making Polymeric Membranes 33
K.C. Khulbe, T. Matsuura and C. Feng

2.1 Introduction 33

2.2 Types of Membranes 35

2.2.1 Porous Membranes 35

2.2.2 Nonporous Membranes 36

2.2.3 Liquid Membranes (Carrier Mediated Transport) 36

2.2.4 Asymmetric Membranes 36

2.3 Preparation of Membranes 36

2.3.1 Phase Inversion/Separation 37

2.3.2 Vapor-Induced Phase Separation (VIPS) 37

2.3.3 Thermally-Induced Phase Separation (TIPS) 37

2.3.4 Immersion Precipitation 38

2.3.5 Film/Dry Casting Technique 38

2.3.6 Track Etching 39

2.3.7 Electrospinning 39

2.3.8 Spraying 42

2.3.9 Foaming 42

2.3.10 Particle Leaching 43

2.3.11 Precipitation from the Vapor Phase 43

2.3.12 Emulsion Freeze-Drying 43

2.3.13 Sintering 44

2.3.14 Stretching 44

2.3.15 Composite/Supported 44

2.3.16 Mixed Matrix Membranes (MMMs) 45

2.3.17 Hollow Fiber Membranes 46

2.3.18 Metal-Organic Frameworks (MOFs) 48

2.4 Modification of Membranes 49

2.4.1 Modification of Polymeric Membrane by Additives/Blending 49

2.4.2 Coating 50

2.4.3 Surface Modification by Chemical Reaction 50

2.4.4 Interfacial Polymerization (IP)/Copolymerization 50

2.4.5 Plasma Polymerization/Treatment 52

2.4.6 Surface Modification by Irradiation of High Energy Particles 52

2.4.7 UV Irradiation 53

2.4.8 Ion-Beam Irradiation 53

2.4.9 Surface Modification by Heat Treatment 53

2.4.10 Graft Polymerization/Grafting 53

2.4.11 Other Techniques 53

2.5 Characterization of Membrane by Different Techniques 54

2.5.1 Conventional Physical Methods to Determine Pore Size and Pore Size Distribution 55

2.5.2 Morphology 58

2.5.3 Thermal Properties 60

2.5.4 Mechanical Properties 60

2.6 Summary 61

References 62

3 Development of Microstructuring Technologies of Polycarbonate for Establishing Advanced Cell Cultivation Systems 67
Uta Fernekorn, Jörg Hampl, Frank Weise, Sukhdeep Singh, Justyna Tobola and Andreas Schober

3.1 Introduction 67

3.2 Material Properties of Polycarbonate 71

3.2.1 Physical Properties 71

3.2.2 Chemical Properties 72

3.2.3 Biological Properties 72

3.3 Use of Polycarbonate Foils in Structuration Processes 75

3.3.1 Hot Embossing 75

3.3.2 Thermoforming 77

3.4 Simulation of Microstructuring of a Polycarbonate Foil 79

3.5 Chemical Functionalization of Polycarbonate 81

3.6 Surface Micropatterning of Polycarbonate 84

3.7 Application Examples 86

3.7.1 3D Liver Cell Cultivation in Polycarbonate Scaffolds 86

3.7.2 3D Lung Cell Cultivation in Semi-Actively Perfused Systems 87

3.7.3 Guiding 3D Cocultivation of Cells by Micropatterning Techniques 87

3.8 Conclusion and Further Perspectives 88

Acknowledgements 89

References 89

4 In-Situ Gelling Thermosensitive Hydrogels for Protein Delivery Applications 95
Roberta Censi, Alessandra Dubbini and Piera Di Martino

4.1 Introduction 96

4.2 Polymers for the Design of Hydrogels 97

4.2.1 Polymer Architectures 97

4.2.2 Natural, Synthetic and Hybrid Hydrogels 97

4.2.3 Crosslinking Methods 99

4.2.4 Thermogelling Polymer Hydrogels 100

4.3 Pharmaceutical Applications of Hydrogels: Protein Delivery 107

4.3.1 Strategies for Protein Release from Hydrogels 109

4.4 Application of Hydrogels for Protein Delivery in Tissue Engineering 112

4.5 Conclusions 113

References 114

5 Polymers as Formulation Excipients for Hot-Melt Extrusion Processing of Pharmaceuticals 121
Kyriakos Kachrimanis and Ioannis Nikolakakis

5.1 Introduction 121

5.1.1 Overview of Hot-Melt Extrusion (HME) 121

5.1.2 Solubility/Dissolution Enhancement by Solid Dispersions 123

5.2 Polymers for HME Processing 127

5.2.1 Basic Requirements 127

5.2.2 Suitability – Examples 128

5.3 Polymer Selection for the HME Process 130

5.3.1 Thermodynamic Considerations – Drug-Polymer Solubility and Miscibility 130

5.4 Processing of HME Formulations 135

5.4.1 Physical Properties of Feeding Material – Flowability, Packing and Friction 135

5.5 Improvements in Processing 141

5.5.1 Equipment Modifications 141

5.5.2 Plasticizers 142

5.6 Conclusion and Future Perspective 144

References 144

6 Poly Lactic-Co-Glycolic Acid (PLGA) Copolymer and Its Pharmaceutical Application 151
Abhijeet Pandey, Darshana S. Jain, Subhashis Chakraborty

6.1 Introduction 151

6.2 Physicochemical Properties 152

6.3 Biodegradation 153

6.4 Biocompatibiliy, Toxicty and Pharmacokinetics 154

6.5 Mechanism of Drug Release 155

6.6 PLGA-Based DDS 157

6.7 Bone Regeneration 158

6.8 Pulmonary Delivery 160

6.9 Gene Therapy 162

6.10 Tumor Trageting 162

6.11 Miscellaneous Drug Delivery Applications 164

6.12 Conclusion 165

References 165

7 Pharmaceutical Applications of Polymeric Membranes 173
Stefan Ioan Voicu

7.1 Introduction 173

7.2 Obtaining Pure and Ultrapure Water for Pharmaceutical Usage 178

7.3 Wastewater Treatment for Pharmaceutics 180

7.4 Controlled Drug Delivery Devices Based on Membrane Materials 183

7.5 Molecularly Imprinted Membranes 185

7.6 Conclusions 190

References 191

8 Application of PVC in Construction of Ion-Selective Electrodes for Pharmaceutical Analysis: A Review of Polymer Electrodes for Nonsteroidal, Anti-Inflammatory Drugs 195
Joanna Lenik

8.1 Introduction 195

8.2 Properties and Usage of Poly(vinyl)chloride (PVC) 197

8.3 PVC Application and Properties in Construction of Potentiometric Sensors for Drug Detection 199

8.3.1 Role of Polymer Membrane Components 202

8.4 Ion-Selective, Classic, Liquid Electrodes (ISEs) 205

8.5 Ion-Selective Solid-State Electrodes 206

8.5.1 Ion-Selective Coated-Wire Electrodes (CWE) 206

8.5.2 Ion-Selective BMSA Electrodes 207

8.5.3 Electrodes Based on Conductive Polymers (SC-ISEs ) 208

8.6 Application of Polymer-Based ISEs for Determination of Analgetic, Anti-Inflammatory and Antipyretic Drugs: Literature Review (2000-2014) 211

8.6.1 Electrodes for Determination of Narcotic Medicines 211

8.6.2 Electrode Sensitive to Dextromethorphan 211

8.6.3 Electrode Sensitive to Tramadol 212

8.6.4 Electrodes for Determination of Non-Narcotic Drugs 212

8.6.5 Salicylate Electrode 214

8.6.6 Ibuprofen Electrode 214

8.6.7 Ketoprofen Electrodes 216

8.6.8 Piroxicam Electrode 216

8.6.9 Tenoxicam Electrode 217

8.6.10 Naproxen Electrodes 217

8.6.11 Indomethacin Electrodes 217

8.6.12 Sulindac Electrode 218

8.6.13 Diclofenac Electrodes 218

8.7 Conclusion 218

References 222

9 Synthesis and Preservation of Polymer Nanoparticles for Pharmaceutical Applications 229
Antonello A. Barresi, Marco Vanni, Davide Fissore and Tereza Zelenková

9.1 Introduction: Polymer Nanoparticles Production 229

9.2 Production of Polymer Nanoparticles by Solvent Displacement Using Intensive Mixers 238

9.2.1 Influence of Polymer-Solvent Type and Hydrodynamics on Particle Size 243

9.2.2 Dependence on Operating Conditions – Polymer and Drug Concentration, Solvent/Antisolvent Ratio, Processing Conditions 248

9.2.3 Process Design: Selection of Mixing Device, Scale Up and Process Transfer 256

9.3 Freeze-Drying of Nanoparticles 264

9.4 Conclusions and Perspectives 268

Acknowledgements 272

References 272

10 Pharmaceutical Applications of Maleic Anhydride/Acid Copolymers 281
Irina Popescu

10.1 Introduction 281

10.2 Maleic Copolymers as Macromolecular Drugs 283

10.3 Maleic Copolymer Conjugates 285

10.3.1 Polymer-Protein Conjugates 286

10.3.2 Polymer-Drug Conjugates 288

10.4 Noncovalent Drug Delivery Systems 291

10.4.1 Enteric Coatings 291

10.4.2 Solid Dispersions 292

10.4.3 Polymeric Films and Hydrogels 293

10.4.4 Microspheres and Microcapsules 294

10.4.5 Nanoparticles 295

10.4.6 Micelles 295

10.5 Conclusion 296

References 296

11 Stimuli-Sensitive Polymeric Nanomedicines for Cancer Imaging and Therapy 311
F. Perche, S. Biswas and V. P. Torchilin

11.1 Introduction 311

11.2 Pathophysiological and Physical Triggers 314

11.2.1 Acidosis 314

11.2.2 Reductive Stress 319

11.2.3 Tumor Hypoxia 320

11.2.4 Cancer Associated Extracellular Enzymes 322

11.2.5 Magneto-Responsive Polymers 324

11.2.6 Temperature-Sensitive Dendrimers 325

11.2.7 Photoresponsive Polymers 326

11.3 Stimuli-Responsive Polymers for Patient Selection and Treatment Monitoring 327

11.3.1 Selection of Patients Amenable to Nanomedicine Treatment 328

11.3.2 Selection of Patients for pH-Sensitive Nanocarriers 329

11.3.3 Selection of Patients for Redox-Sensitive Nanocarriers 329

11.3.4 Mapping of Dominant Active Pathways Using Enzyme-Sensitive Probes 330

11.3.5 Selection of Patients for Molecularly-Targeted Therapies 330

11.3.6 Evaluation of Response to Treatment 331

11.4 Conclusions and Future Perspectives 331

Acknowledgments 333

References 333

12 Artificial Intelligence Techniques Used for Modeling of Processes Involving Polymers for Pharmaceutical Applications 345
Silvia Curteanu

12.1 Introduction 345

12.2 Artificial Neural Networks 347

12.2.1 Elements and Structure 347

12.2.2 Working Methodology 349

12.2.3 Variants of ANN Modeling 350

12.3 Support Vector Machines 352

12.3.1 General Aspects 352

12.3.2 SVM Modeling Methodology 353

12.4 Modeling of Processes Involving Polymers for Pharmaceutical Applications 354

12.4.1 Neural Networks Used for Modeling of Processes Involving Pharmaceutical Polymers 354

12.4.2 Support Vector Machines Used for Modeling of Processes Involving Pharmaceutical Polymers 359

12.5 Conclusion and Future Perspective 360

References 361

13 Review of Current Pharmaceutical Applications of Polysiloxanes (Silicones) 363
Krystyna Mojsiewicz-Pieñkowska 13.1 Introduction 363

13.2 Variety of Polysiloxane – Structure, Synthesis, Properties 364

13.2.1 Basic Silicone Chemistry 364

13.2.2 Properties of Silicones 364

13.3 Polysiloxanes as Active Pharmaceutical Ingredient (API) 368

13.3.1 Mechanism of Action of Dimethicone and Simethicone 370

13.3.2 Current Legislative Standards Related to Oral Application of Dimethicone and Simethicone (PDMS) 370

13.3.3 Admissible Doses for Dimethicone and Simethicone (PDMS) 372

13.4 Polysiloxanes as Excipients 373

13.4.1 Skin Adhesive Patches 375

13.4.2 Carrier for Controlled-Release Drugs 375

13.5 Conclusion and Future Perspective 377

References 378

14 Polymer-Doped Nano-Optical Sensors for Pharmaceutical Analysis 383
M. S. Attia and M. S. A. Abdel-Mottaleb

14.1 Introduction 383

14.1.1 Sol-Gel Process 383

14.1.2 Molecular Imprinting Nanomaterial Polymer 386

14.1.3 Poly(methyl methacrylate) Polymer (PMMA) 390

14.2 Processing 392

14.2.1 Sol-Gel Technique 392

14.2.2 Molecular Imprinted Nanomaterials 394

14.2.3 Preparation of Optical Sensor Doped in PMMA Matrix 396

14.2.4 Determination of Pharmaceutical Drug in Pharmaceutical Preparations 396

14.2.5 Determination of Pharmaceutical Drug in Serum Solution 397

14.3 Application of Optical Sensor for Pharmaceutical Drug Determination 397

14.3.1 TEOS-Doped Nano-Optical Sensor for Pharmaceutical Determinations 397

14.3.2 Molecular Imprinted Nano-Polymer 401

14.3.3 Sensor Embedded in Polymethymethacrylate 404

14.4 Conclusion 405

References 405

15 Polymer-Based Augmentation of Immunosuppressive Formulations: Application of Polymer Technology in Transplant Medicine 411
Ian C. Doyle and Ashim Malhotra

15.1 Introduction 411

15.2 Polymer-Based Immunosuppressive Formulations 414

15.2.1 Sirolimus 414

15.2.2 Cyclosporine A 424

15.2.3 Tacrolimus 429

15.2.4 Mycophenolic Acid 431

15.3 Conclusion and Future Perspective 433

References 434

16 Polymeric Materials in Ocular Drug Delivery Systems 439
M. E. Pina, P. Coimbra, P. Ferreira, P. Alves, A. I. Figueiredo and M. H. Gil

16.1 Introduction 439

16.2 A Brief Description of Ocular Anatomy and Physiology 440

16.2.1 Anatomy of the Human Eye 440

16.2.2 Routes of Ocular Drug Delivery 441

16.2.3 Barriers in Ocular Drug Delivery 444

16.3 Polymeric Ocular Drug Delivery Systems 445

16.3.1 Non-Biodegradable Polymeric Ocular Drug Delivery Systems 446

16.3.2 Biodegradable Polymeric Ocular Drug Delivery Systems 449

16.4 Conclusion and Future Perspective 455

References 455

Index 459