Drug Delivery Strategies for PoorlyWater-Soluble Drugs -- Contents -- List of Contributors -- Series Preface -- Preface -- 1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: Basic Theoretical Considerations and Modeling Concepts -- 1.1 Introduction -- 1.2 Brief Reminder of Equilibrium Thermodynamics -- 1.3 Principles of Self-Assembly in Dilute Solutions -- 1.3.1 Linear Growth -- 1.3.2 Cooperative Assembly -- 1.4 Solubility and Partitioning of Drugs -- 1.4.1 Simple Partitioning Equilibria -- 1.4.2 Partitioning and Micellization -- 1.4.3 Hydrophobicity and Ordering of Water -- 1.5 Ways to Model Interactions in Colloidal Systems -- 1.5.1 Electrostatic Interactions: The Poisson-Boltzmann Model -- 1.5.2 Chain Packing Model -- 1.6 Kinetics of Drug Transfer from Mobile Nanocarriers -- 1.6.1 Collision Mechanism -- 1.6.2 Diffusion Mechanism -- 1.6.3 Internal Kinetics -- 1.7 Conclusion -- Acknowledgments -- References -- 2 Liposomes as Intravenous Solubilizers for Poorly Water-Soluble Drugs -- 2.1 Introduction -- 2.2 Intravenous Administration of Poorly Water-Soluble Compounds (PWSC) -- 2.2.1 Solubilizing Vehicles with Precipitation Risk upon Dilution -- 2.2.2 Solubilizing Vehicles Maintaining Solubilization Capacity upon Dilution -- 2.2.3 Mechanistic Release Aspects/Transfer Liposomal PWSC -- 2.2.4 In Vivo Consequences -- 2.2.5 Preclinical Parenteral Assessment Liposomal PWSC -- 2.3 Conclusion -- References -- 3 Drug Solubilization and Stabilization by Cyclodextrin Drug Carriers -- 3.1 Introduction -- 3.2 Structure and Physiochemical Properties -- 3.3 Cyclodextrin Complexes and Phase Solubility Diagrams -- 3.4 Cyclodextrin Complexes -- 3.4.1 Self-Assembly of Cyclodextrins and their Complexes -- 3.4.2 Thermodynamic and Driving Forces for Complexation -- 3.5 Effects on Drug Stability.

3.6 Cyclodextrins and Drug Permeation through Biological Membranes -- 3.7 Drug Solubilization in Pharmaceutical Formulations -- 3.7.1 Oral Drug Delivery -- 3.7.2 Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal Drug Delivery -- 3.7.3 Ophthalmic Drug Delivery -- 3.7.4 Dermal and Transdermal Drug Delivery -- 3.7.5 Injectable Formulations -- 3.8 Toxicology and Pharmacokinetics -- 3.9 Regulatory Issues -- 3.10 Conclusion -- References -- 4 Solid Lipid Nanoparticles for Drug Delivery -- 4.1 Introduction -- 4.2 Preparation Procedures for Solid Lipid Nanoparticles -- 4.2.1 Melt Dispersion Processes -- 4.2.2 Other Top-Down Processes -- 4.2.3 Precipitation from Homogeneous Systems -- 4.2.4 Comparison of the Formulation Procedures and Scale-Up Feasibility -- 4.2.5 Further Processing of Solid Lipid Nanoparticle Suspensions -- 4.3 Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance -- 4.3.1 Particle Size and Size Distribution -- 4.3.2 Surface Properties -- 4.3.3 Solid State Properties of Solid Lipid Nanoparticles -- 4.3.4 Particle Morphology and Overall Structure of the Dispersions -- 4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release -- 4.4.1 Drug Incorporation -- 4.4.2 In Vitro Drug Release -- 4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles -- 4.5.1 In Vitro Behavior and Toxicity Studies -- 4.5.2 Bioavailability and Pharmacokinetics -- 4.6 Conclusion -- References -- 5 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs -- 5.1 Introduction -- 5.2 Safety and Biocompatibility of Polymers -- 5.3 Encapsulation Techniques of Hydrophobic Drugs -- 5.3.1 The Nanoprecipitation Method -- 5.3.2 The Emulsification Methods -- 5.3.3 Polymersome Preparation -- 5.3.4 Supercritical Fluid Technology -- 5.3.5 The Polymer-Coating Method -- 5.3.6 The Layer-by-Layer Method.

5.4 Behavior of Nanoparticles as Drug Delivery Systems -- 5.4.1 Mean Size -- 5.4.2 Zeta Potential -- 5.4.3 Encapsulation Efficiency -- 5.4.4 Drug Release Properties -- 5.4.5 General Performance of the Nanoparticles -- 5.5 Conclusion -- References -- 6 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs -- 6.1 Introduction -- 6.2 Drug Encapsulation by Monomer Polymerization -- 6.2.1 Emulsion Polymerization -- 6.2.2 Interfacial Polymerization -- 6.2.3 Interfacial Polycondensation -- 6.3 Polymeric Nanospheres and Nanocapsules Produced by Polymerization -- 6.4 Formulation Components -- 6.5 Control of Particle Morphology -- 6.6 Toxicity and In Vivo Performance -- 6.7 Scale-Up Considerations -- 6.8 Conclusion -- Acknowledgements -- References -- 7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs -- 7.1 Introduction -- 7.2 Lipid Processing and Drug Solubilization -- 7.3 Self-Emulsifying Drug Delivery Systems -- 7.3.1 Excipients Used in SEDDS -- 7.3.2 Self-Emulsification Mechanism -- 7.3.3 Physicochemical Characterization of SEDDS -- 7.3.4 Drug Incorporation in SEDDS -- 7.4 In Vitro Digestion Model -- 7.5 Enhancement of Oral Absorption by SEDDS -- 7.6 Conclusion -- References -- 8 Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals -- 8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) -- 8.2 Ultra-Fine Drug Nanocrystals (_100 Nm) and Their Special Properties -- 8.3 Production of First Generation Nanocrystals: A Brief Overview -- 8.3.1 Hydrosols -- 8.3.2 Nanomorphs -- 8.3.3 NanocrystalsTM by Bead Milling -- 8.3.4 DissoCubes R _ by High Pressure Homogenization -- 8.3.5 NANOEDGE by Baxter -- 8.3.6 Summary of First Generation Production Technologies -- 8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals.

8.4.1 Fine-Tuned Precipitation -- 8.4.2 The SmartCrystal Concept -- 8.5 Conclusion -- References -- 9 Nanosuspensions with Enhanced Drug Dissolution Rates of Poorly Water-Soluble Drugs -- 9.1 Introduction -- 9.2 Crystal Growth and Nucleation Theory -- 9.3 Creating Supersaturation and Stable Nanosuspensions -- 9.4 Antisolvent Precipitation Via Mixer Processing -- 9.5 Antisolvent Precipitation by Using Ultrasonication -- 9.6 Nanoprecipitation Using Microfluidic Reactors -- 9.7 Particle Engineering by Spray: Freezing into Liquid -- 9.8 Precipitation by Rapid Expansion from Supercritical to Aqueous Solution -- 9.9 Conclusion -- References -- 10 Microemulsions for Drug Solubilization and Delivery -- 10.1 Introduction -- 10.2 Microemulsion Formation and Phase Behavior -- 10.2.1 Theories of Microemulsion Formation -- 10.2.2 Structure of Microemulsions -- 10.2.3 Phase Behavior -- 10.3 HLB, PIT and Microemulsion Stability -- 10.4 Microemulsion Physico-Chemical Characterization -- 10.5 Components of Microemulsion Formulations -- 10.5.1 Oils -- 10.5.2 Surfactants -- 10.5.3 Cosurfactants -- 10.5.4 Drugs -- 10.6 Preparation Methods -- 10.7 In Vitro and In Vivo Biological Studies -- 10.7.1 Microemulsions Used as an Oral Delivery System for Poorly Water-Soluble Compounds -- 10.7.2 Microemulsions Used as a Parenteral Delivery System for Poorly Water-Soluble Compounds -- 10.8 Recent Developments and Future Directions -- 10.8.1 Develop Cremophor-Free Microemulsions -- 10.8.2 Dried O/W Emulsions for Oral Delivery of Poorly Soluble Drugs -- 10.8.3 Self-Microemulsifying Drug Delivery System (SMEDDS) -- References -- 11 Hot Melt Extrusion: A Process Overview and Use in Manufacturing Solid Dispersions of Poorly Water-Soluble Drugs -- 11.1 Introduction: Present Challenges to Oral Drug Delivery -- 11.2 Solid Drug Dispersions for Enhanced Drug Solubility.

11.3 Hot Melt Extrusion (HME) as a Drug Delivery Technology -- 11.3.1 Historical Review of HME -- 11.3.2 Equipment -- 11.3.3 Screw Geometry -- 11.3.4 HME Processing -- 11.3.5 Product Characteristics -- 11.3.6 Materials Commonly Used in HME for Solubility Enhancement -- 11.4 Solubility Enhancement Using HME -- 11.4.1 Product Structure -- 11.4.2 HME Matrix Carriers -- 11.4.3 HME for the Manufacture of Pharmaceutical Co-Crystals -- 11.5 Representative Case Studies with Enhanced Solubility -- 11.5.1 Increased Dissolution Rate Due to Size Reduction or De-Aggregation -- 11.5.2 Increased Dissolution Rate Due to Drug Morphology Change -- 11.5.3 Controlled or Prolonged Release with Enhanced Release Extent -- 11.5.4 Complexation to Enhance Dissolution Performance -- 11.5.5 Co-Crystal Formation -- 11.6 Conclusion -- References -- 12 Penetration Enhancers, Solvents and the Skin -- 12.1 Introduction -- 12.2 Interactions of Solvents and Enhancers with the Skin -- 12.2.1 Small Solvents -- 12.2.2 Solvents with Longer Carbon Chains -- 12.3 Skin Permeation Enhancement of Ibuprofen -- 12.3.1 Infinite Dose Conditions -- 12.3.2 Finite Dose Conditions -- 12.4 Conclusion -- References -- 13 Dendrimers for Enhanced Drug Solubilization -- 13.1 Introduction -- 13.2 Current Solubilization Strategies -- 13.3 Origin of Dendrimers -- 13.4 What Are Dendrimers? -- 13.5 Synthesis of Dendritic Architecture -- 13.6 Structure and Intrinsic Properties of Dendrimeric Compartments -- 13.7 Dendrimers in Solubilization -- 13.8 Factors Affecting Dendrimer-Mediated Solubilization and Drug Delivery -- 13.8.1 Nature of the Dendritic Core -- 13.8.2 Dendrimer Generation -- 13.8.3 Nature of the Dendrimer Surface -- 13.8.4 Dendrimer Concentration -- 13.8.5 pH of Solution -- 13.8.6 Temperature -- 13.8.7 Solvents -- 13.9 Drug-Dendrimer Conjugation Approaches.

13.9.1 Physical Loading: Complexation of Water-Insoluble Drugs.