Drug Delivery Strategiesfor PoorlyWater-SolubleDrugsEditors

Dennis Douroumis and Alfred Fahr

ADVANCES IN PHARMACEUTICAL TECHNOLOGY

Drug Delivery Strategies for PoorlyWater-Soluble Drugs

Advances in Pharmaceutical TechnologyA Wiley Book Series

Series Editors:Dennis Douroumis, University of Greenwich, UKAlfred Fahr, Friedrich-Schiller University of Jena, GermanyJurgen Siepmann, University of Lille, FranceMartin Snowden, University of Greenwich, UK

Titles in the Series

Hot-Melt Extrusion: Pharmaceutical ApplicationsEdited by Dionysios Douroumis

Drug Delivery Strategies for Poorly Water-Soluble DrugsEdited by Dionysios Douroumis and Alfred Fahr

Forthcoming Title(s):

In Vitro Drug Release Testing of Special Dosage FormsEdited by Nikoletta Fotaki and Sandra Klein

Drug Delivery Strategiesfor Poorly

Water-Soluble Drugs

Edited by

DENNIS DOUROUMIS

School of Science, University of Greenwich, UK

and

ALFRED FAHR

Friedrich-Schiller University of Jena, Germany

A John Wiley & Sons, Ltd., Publication

This edition first published 2013C© 2013 John Wiley & Sons, Ltd.

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Library of Congress Cataloging-in-Publication Data

Drug delivery strategies for poorly water-soluble drugs / edited by Dennis Douroumis and Alfred Fahr.p. ; cm.

Includes bibliographical references and index.ISBN 978-0-470-71197-2 (cloth)I. Douroumis, Dennis. II. Fahr, Alfred.[DNLM: 1. Drug Delivery Systems. 2. Chemistry, Pharmaceutical–methods. 3. Drug Carriers–pharmacology.

4. Hydrophobic and Hydrophilic Interactions. 5. Solubility. QV 785]615.1–dc23

2012035502

A catalogue record for this book is available from the British Library.

ISBN: 9780470711972

Set in 10/12pt Times by Aptara Inc., New Delhi, India.

Excellence is an art won by training and habituation. We do not act rightly because wehave virtue or excellence, but we rather have those because we have acted rightly. We

are what we repeatedly do. Excellence, then, is not an act but a habit. (Aristotle,384–322 BC)

This book is dedicated to my beloved mother Eugenia for her continuous supportand unconditional love. It is also dedicated to my brother Bill and sister Angela for

their support and patience. Thank you all.

Doubt grows with knowledge.Johann Wolfgang von Goethe (1749–1832)

I thank my wife for her understanding for spending weekends in my home office forsetting and polishing this book. I apologize to my children Fabian and Sophie that their

dad was not ready on many weekends for playing and talking. I do hope, they willunderstand it in the near future somehow.

Contents

List of Contributors xviiSeries Preface xxiPreface xxiii

1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: BasicTheoretical Considerations and Modeling Concepts 1Sylvio May and Alfred Fahr

1.1 Introduction 11.2 Brief Reminder of Equilibrium Thermodynamics 31.3 Principles of Self-Assembly in Dilute Solutions 7

1.3.1 Linear Growth 91.3.2 Cooperative Assembly 10

1.4 Solubility and Partitioning of Drugs 111.4.1 Simple Partitioning Equilibria 111.4.2 Partitioning and Micellization 131.4.3 Hydrophobicity and Ordering of Water 15

1.5 Ways to Model Interactions in Colloidal Systems 161.5.1 Electrostatic Interactions: The Poisson–Boltzmann Model 171.5.2 Chain Packing Model 21

1.6 Kinetics of Drug Transfer from Mobile Nanocarriers 231.6.1 Collision Mechanism 251.6.2 Diffusion Mechanism 261.6.3 Internal Kinetics 26

1.7 Conclusion 29Acknowledgments 31References 31

2 Liposomes as Intravenous Solubilizers for Poorly Water-Soluble Drugs 37Peter van Hoogevest, Mathew Leigh and Alfred Fahr

2.1 Introduction 372.2 Intravenous Administration of Poorly Water-Soluble

Compounds (PWSC) 402.2.1 Solubilizing Vehicles with Precipitation Risk upon Dilution 412.2.2 Solubilizing Vehicles Maintaining Solubilization Capacity

upon Dilution 43

viii Contents

2.2.3 Mechanistic Release Aspects/Transfer Liposomal PWSC 452.2.4 In Vivo Consequences 522.2.5 Preclinical Parenteral Assessment Liposomal PWSC 56

2.3 Conclusion 59References 60

3 Drug Solubilization and Stabilization by Cyclodextrin Drug Carriers 67Thorsteinn Loftsson and Marcus E. Brewster

3.1 Introduction 673.2 Structure and Physiochemical Properties 683.3 Cyclodextrin Complexes and Phase Solubility Diagrams 723.4 Cyclodextrin Complexes 76

3.4.1 Self-Assembly of Cyclodextrins and their Complexes 763.4.2 Thermodynamic and Driving Forces for Complexation 76

3.5 Effects on Drug Stability 773.6 Cyclodextrins and Drug Permeation through Biological Membranes 803.7 Drug Solubilization in Pharmaceutical Formulations 82

3.7.1 Oral Drug Delivery 843.7.2 Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal

Drug Delivery 863.7.3 Ophthalmic Drug Delivery 873.7.4 Dermal and Transdermal Drug Delivery 873.7.5 Injectable Formulations 87

3.8 Toxicology and Pharmacokinetics 893.9 Regulatory Issues 903.10 Conclusion 91

References 91

4 Solid Lipid Nanoparticles for Drug Delivery 103Sonja Joseph and Heike Bunjes

4.1 Introduction 1034.2 Preparation Procedures for Solid Lipid Nanoparticles 104

4.2.1 Melt Dispersion Processes 1044.2.2 Other Top-Down Processes 1094.2.3 Precipitation from Homogeneous Systems 1114.2.4 Comparison of the Formulation Procedures and Scale-Up

Feasibility 1134.2.5 Further Processing of Solid Lipid Nanoparticle Suspensions 115

4.3 Structural Parameters and Their Influence on Product Quality andPharmaceutical Performance 1164.3.1 Particle Size and Size Distribution 1164.3.2 Surface Properties 1174.3.3 Solid State Properties of Solid Lipid Nanoparticles 1174.3.4 Particle Morphology and Overall Structure of the Dispersions 121

Contents ix

4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release 1234.4.1 Drug Incorporation 1234.4.2 In Vitro Drug Release 126

4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles 1294.5.1 In Vitro Behavior and Toxicity Studies 1294.5.2 Bioavailability and Pharmacokinetics 131

4.6 Conclusion 133References 133

5 Polymeric Drug Delivery Systems for EncapsulatingHydrophobic Drugs 151Naveed Ahmed, C.E. Mora-Huertas, Chiraz Jaafar-Maalej, Hatem Fessiand Abdelhamid Elaissari

5.1 Introduction 1515.2 Safety and Biocompatibility of Polymers 1525.3 Encapsulation Techniques of Hydrophobic Drugs 156

5.3.1 The Nanoprecipitation Method 1565.3.2 The Emulsification Methods 1585.3.3 Polymersome Preparation 1645.3.4 Supercritical Fluid Technology 1665.3.5 The Polymer-Coating Method 1675.3.6 The Layer-by-Layer Method 171

5.4 Behavior of Nanoparticles as Drug Delivery Systems 1735.4.1 Mean Size 1735.4.2 Zeta Potential 1735.4.3 Encapsulation Efficiency 1745.4.4 Drug Release Properties 1765.4.5 General Performance of the Nanoparticles 176

5.5 Conclusion 177References 180

6 Polymeric Drug Delivery Systems for EncapsulatingHydrophobic Drugs 199Dagmar Fischer

6.1 Introduction 1996.2 Drug Encapsulation by Monomer Polymerization 200

6.2.1 Emulsion Polymerization 2016.2.2 Interfacial Polymerization 2066.2.3 Interfacial Polycondensation 207

6.3 Polymeric Nanospheres and Nanocapsules Producedby Polymerization 209

6.4 Formulation Components 2106.5 Control of Particle Morphology 2126.6 Toxicity and In Vivo Performance 213

x Contents

6.7 Scale-Up Considerations 2146.8 Conclusion 217

Acknowledgements 217References 217

7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) forOral Bioavailability Enhancement of Poorly Soluble Drugs 225Dimitrios G. Fatouros and Anette Mullertz

7.1 Introduction 2257.2 Lipid Processing and Drug Solubilization 2267.3 Self-Emulsifying Drug Delivery Systems 227

7.3.1 Excipients Used in SEDDS 2277.3.2 Self-Emulsification Mechanism 2287.3.3 Physicochemical Characterization of SEDDS 2297.3.4 Drug Incorporation in SEDDS 231

7.4 In Vitro Digestion Model 2327.5 Enhancement of Oral Absorption by SEDDS 2357.6 Conclusion 238

References 239

8 Novel Top-Down Technologies: Effective Production of Ultra-FineDrug Nanocrystals 247C.M. Keck, S. Kobierski, R. Mauludin and R.H. Muller

8.1 Introduction: General Benefits of Drug Nanocrystals(First Generation) 247

8.2 Ultra-Fine Drug Nanocrystals (�100 Nm) andTheir Special Properties 248

8.3 Production of First Generation Nanocrystals: A Brief Overview 2508.3.1 Hydrosols 2508.3.2 Nanomorphs 2518.3.3 NanocrystalsTM by Bead Milling 2518.3.4 DissoCubes R© by High Pressure Homogenization 2518.3.5 NANOEDGE by Baxter 2528.3.6 Summary of First Generation Production Technologies 252

8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals 2528.4.1 Fine-Tuned Precipitation 2528.4.2 The SmartCrystal Concept 253

8.5 Conclusion 259References 259

9 Nanosuspensions with Enhanced Drug Dissolution Rates of PoorlyWater-Soluble Drugs 265Dennis Douroumis

9.1 Introduction 2659.2 Crystal Growth and Nucleation Theory 266

Contents xi

9.3 Creating Supersaturation and Stable Nanosuspensions 2699.4 Antisolvent Precipitation Via Mixer Processing 2729.5 Antisolvent Precipitation by Using Ultrasonication 2779.6 Nanoprecipitation Using Microfluidic Reactors 2789.7 Particle Engineering by Spray: Freezing into Liquid 2799.8 Precipitation by Rapid Expansion from Supercritical

to Aqueous Solution 2809.9 Conclusion 282

References 283

10 Microemulsions for Drug Solubilization and Delivery 287X.Q. Wang and Q. Zhang

10.1 Introduction 28710.2 Microemulsion Formation and Phase Behavior 289

10.2.1 Theories of Microemulsion Formation 28910.2.2 Structure of Microemulsions 28910.2.3 Phase Behavior 292

10.3 HLB, PIT and Microemulsion Stability 29310.4 Microemulsion Physico-Chemical Characterization 29310.5 Components of Microemulsion Formulations 295

10.5.1 Oils 29610.5.2 Surfactants 29810.5.3 Cosurfactants 30010.5.4 Drugs 302

10.6 Preparation Methods 30310.7 In Vitro and In Vivo Biological Studies 303

10.7.1 Microemulsions Used as an Oral Delivery System forPoorly Water-Soluble Compounds 303

10.7.2 Microemulsions Used as a Parenteral Delivery Systemfor Poorly Water-Soluble Compounds 311

10.8 Recent Developments and Future Directions 31410.8.1 Develop Cremophor-Free Microemulsions 31410.8.2 Dried O/W Emulsions for Oral Delivery of Poorly

Soluble Drugs 31510.8.3 Self-Microemulsifying Drug Delivery System (SMEDDS) 318References 319

11 Hot Melt Extrusion: A Process Overview and Use in ManufacturingSolid Dispersions of Poorly Water-Soluble Drugs 325Shu Li, David S. Jones and Gavin P. Andrews

11.1 Introduction: Present Challenges to Oral Drug Delivery 32511.2 Solid Drug Dispersions for Enhanced Drug Solubility 32711.3 Hot Melt Extrusion (HME) as a Drug Delivery Technology 329

11.3.1 Historical Review of HME 32911.3.2 Equipment 329

xii Contents

11.3.3 Screw Geometry 33111.3.4 HME Processing 33211.3.5 Product Characteristics 33511.3.6 Materials Commonly Used in HME for Solubility

Enhancement 33711.4 Solubility Enhancement Using HME 340

11.4.1 Product Structure 34011.4.2 HME Matrix Carriers 34111.4.3 HME for the Manufacture of Pharmaceutical Co-Crystals 343

11.5 Representative Case Studies with Enhanced Solubility 34411.5.1 Increased Dissolution Rate Due to Size Reduction or

De-Aggregation 34411.5.2 Increased Dissolution Rate Due to Drug Morphology

Change 34511.5.3 Controlled or Prolonged Release with Enhanced Release

Extent 34611.5.4 Complexation to Enhance Dissolution Performance 34611.5.5 Co-Crystal Formation 347

11.6 Conclusion 347References 348

12 Penetration Enhancers, Solvents and the Skin 359Jonathan Hadgraft and Majella E. Lane

12.1 Introduction 35912.2 Interactions of Solvents and Enhancers with the Skin 360

12.2.1 Small Solvents 36112.2.2 Solvents with Longer Carbon Chains 361

12.3 Skin Permeation Enhancement of Ibuprofen 36312.3.1 Infinite Dose Conditions 36412.3.2 Finite Dose Conditions 368

12.4 Conclusion 369References 369

13 Dendrimers for Enhanced Drug Solubilization 373Narendra K. Jain and Rakesh K. Tekade

13.1 Introduction 37313.2 Current Solubilization Strategies 37413.3 Origin of Dendrimers 37413.4 What Are Dendrimers? 37513.5 Synthesis of Dendritic Architecture 37513.6 Structure and Intrinsic Properties of Dendrimeric Compartments 37713.7 Dendrimers in Solubilization 37813.8 Factors Affecting Dendrimer-Mediated Solubilization and Drug

Delivery 381

Contents xiii

13.8.1 Nature of the Dendritic Core 38113.8.2 Dendrimer Generation 38213.8.3 Nature of the Dendrimer Surface 38213.8.4 Dendrimer Concentration 38213.8.5 pH of Solution 38313.8.6 Temperature 38413.8.7 Solvents 384

13.9 Drug–Dendrimer Conjugation Approaches 38613.9.1 Physical Loading: Complexation of Water-Insoluble Drugs 38613.9.2 Covalent Loading: Synthesis of Drug–Dendrimer

Conjugate 38913.10 Dendrimers’ Biocompatibility and Toxicity 393

13.10.1 PEGylation Technology: A Way to Enhance DendrimerSolubility and Biocompatibility 393

13.11 Classification of PEGylated Dendrimers 39413.11.1 PEGylated Dendrimer 39413.11.2 Drug-Conjugated PEGylated Dendrimer 39713.11.3 PEG Cored Dendrimer 39713.11.4 PEG Branched Dendrimer 39813.11.5 PEG-Conjugated Targeted Dendrimer 398

13.12 Conclusion 399References 400

14 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 411Swati Biswas, Onkar S. Vaze, Sara Movassaghianand Vladimir P. Torchilin

14.1 Micelles and Micellization 41114.1.1 Factors Affecting Micellization 41314.1.2 Thermodynamics of Micellization 414

14.2 Chemical Nature and Formation Mechanism of Polymeric Micelles 41614.2.1 Core and Corona of the Polymeric Micelles 41714.2.2 Block Co-Polymers as Building Block of Polymeric Micelles 418

14.3 Polymeric Micelles: Unique Nanomedicine Platforms 41914.3.1 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 421

14.4 Determination of Physico-Chemical Characteristicsof Polymeric Micelles 43014.4.1 Critical Micelle Concentrations (CMC) 43014.4.2 Particle Size and Stability 432

14.5 Drug Loading 43514.5.1 Drug-Loading Procedures 437

14.6 Biodistribution and Toxicity 43914.7 Targeting Micellar Nanocarriers: Example:

Drug Delivery to Tumors 44314.7.1 Passive Targeting 44314.7.2 Active Targeting: Functionalized Polymeric Micelles 445

xiv Contents

14.8 Site-Specific Micellar-Drug Release Strategies 44914.9 Intracellular Delivery of Micelles 45214.10 Multifunctional Micellar Nanocarriers 45314.11 Conclusion 455

References 455

15 Nanostructured Silicon-Based Materials as a Drug Delivery Systemfor Water-Insoluble Drugs 477Vesa-Pekka Lehto, Jarno Salonen, Helder A. Santos and Joakim Riikonen

15.1 Introduction 47715.2 Control of Particle Size and Pore Morphology 47815.3 Surface Functionalization 482

15.3.1 Stabilization 48215.3.2 Biofunctionalization 483

15.4 Biocompatibility and Cytotoxicity 48515.4.1 In Vitro Studies 48615.4.2 In Vivo and Ex Vivo Studies 490

15.5 Nanostructured Silicon Materials as DDS 49215.5.1 Drug-Loading Procedures 49215.5.2 Enhanced Drug Release 49515.5.3 Intracellular Uptake 500

15.6 Conclusion 502References 502

16 Micro- and Nanosizing of Poorly Soluble Drugs by GrindingTechniques 509Stefan Scheler

16.1 Introduction 50916.2 Kinetics of Drug Dissolution 51016.3 Micronization and Nanosizing of Drugs 510

16.3.1 Dissolution Enhancement by Micronization and Nanonization 51016.3.2 Dry and Wet Milling Technologies 51116.3.3 NanoCrystal R© Technology 512

16.4 Theory of Grinding Operations 51216.4.1 Fraction under Compressive Stress 51216.4.2 Brittle-Ductile Transition and Grinding Limit 51416.4.3 Milling Beyond the Brittle-Ductile Transition Limit 51616.4.4 Fatigue Fracture 51716.4.5 Agglomeration 51716.4.6 Amorphization 519

16.5 Influence of the Stabilizer 52016.5.1 Effects of Stabilization 52016.5.2 Steric and Electrostatic Stabilization 52116.5.3 Surfactants 52316.5.4 Polymers 527

Contents xv

16.6 Milling Equipment and Technology 52716.6.1 Grinding Beads 52716.6.2 Types of Media Mills 52816.6.3 Process Parameters 532

16.7 Process Development from Laboratory to Commercial Scale 53516.7.1 Early Development 53516.7.2 Toxicological Studies 53516.7.3 Clinical Studies 53616.7.4 Drying 53616.7.5 Further Processing of Drug Nanoparticles 536

16.8 Application and Biopharmaceutical Properties 53716.8.1 Oral Drug Delivery 53816.8.2 Parenteral Drug Delivery 54016.8.3 Extracorporal Therapy 542

16.9 Conclusion 543References 543

17 Enhanced Solubility of Poorly Soluble Drugs Via Spray Drying 551Cordin Arpagaus, David Rutti and Marco Meuri

17.1 Introduction 55117.2 Advantages of Spray Drying 55317.3 Principles and Instrumentation of Spray Drying Processes 553

17.3.1 Principal Function of a Spray Dryer 55317.3.2 Traditional Spray Dryers 55817.3.3 Recent Developments in Spray Drying 561

17.4 Optimizing Spray Drying Process Parameters 56317.4.1 Drying Gas Flow Rate (Aspirator Rate) 56317.4.2 Drying Gas Humidity 56317.4.3 Inlet Temperature 56417.4.4 Spray Gas Flow 56517.4.5 Feed Concentration 56517.4.6 Feed Rate 56517.4.7 Organic Solvent Instead of Water 566

17.5 Spray Drying of Water-Insoluble Drugs: Case Studies 56617.5.1 Nanosuspensions 56617.5.2 Solid Lipid Nanoparticles 56817.5.3 Silica-Lipid Hybrid Microcapsules 56817.5.4 Milled Nanoparticles 57017.5.5 Inhalation Dosage Forms 57117.5.6 Porous Products 57217.5.7 Microemulsions 57217.5.8 Application Examples: Summary 575

17.6 Conclusion 582References 583

Index 587

List of Contributors

Dr. Naveed Ahmed, University Lyon 1, Villeurbanne, CNRS, UMR-5007, Laboratoired’Automatique et de Genie des Procedes, France.

Dr. Gavin P. Andrews, The Drug Delivery and Biomaterials Research Group, The Schoolof Pharmacy, Queen’s University of Belfast, Northern Ireland.

Dr. Cordin Arpagaus, BUCHI Labortechnik AG, Flawil, Switzerland.

Dr. Swati Biswas, Center for Pharmaceutical Biotechnology and Nanomedicine, Depart-ment of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.

Dr. Marcus E. Brewster, Johnson & Johnson Pharmaceutical Research and Development,Beerse, Belgium.

Professor Heike Bunjes, Technische Universitat Braunschweig, Institut fur Pharmazeutis-che Technologie, Braunschweig, Germany.

Dr. Dennis Douroumis, School of Science, University of Greenwich, Chatham Maritime,ME4 4TB, Kent, UK.

Professor Abdelhamid Elaissari, University Lyon 1, Villeurbanne, CNRS, UMR-5007,Laboratoire d’Automatique et de Genie des Procedes, France.

Professor Dr. Alfred Fahr, Department of Pharmaceutical Technology, Institute forPharmacy, Friedrich-Schiller-University, Jena, Germany.

Dr. Dimitrios G. Fatouros, Department of Pharmaceutical Technology, School ofPharmacy, Aristotle University of Thessaloniki, Greece.

Professor Hatem Fessi, University Lyon 1, Villeurbanne, CNRS, UMR-5007, Laboratoired’Automatique et de Genie des Procedes, France.

Professor Dagmar Fischer, Department of Pharmaceutical Technology, Institute ofPharmacy, Friedrich-Schiller-University, Jena, Germany.

xviii List of Contributors

Professor Jonathan Hadgraft, Department of Pharmaceutics, School of Pharmacy,University of London, UK.

Dr. Chiraz Jaafar-Maalej, University Lyon 1, Villeurbanne, CNRS, UMR-5007, Labora-toire d’Automatique et de Genie des Procedes, France.

Professor Narendra K. Jain, Pharmaceutics Research Laboratory, Department of Phar-maceutical Sciences, Gour Central University, Sagar, India.

Dr. David S. Jones, The Drug Delivery and Biomaterials Research Group, The School ofPharmacy, Queen’s University of Belfast, Northern Ireland

Dr. Sonja Joseph, Technische Universitat Braunschweig, Institut fur PharmazeutischeTechnologie, Braunschweig, Germany.

Professor Cornelia M. Keck, Department of Applied Logistics and Polymer Sciences,Applied Pharmacy Division, University of Applied Sciences Kaiserslautern, Pirmasens,Germany; Institute of Biosciences (IBS), University Putra Malaysia (UPM), Serdang-KualaLumpur, Malaysia; and Department of Pharmaceutics, Biopharmaceutics & NutriCosmet-ics, Freie Universitat Berlin, Berlin, Germany.

Dr. Szymon Kobierski, Department of Pharmaceutics, Biopharmaceutics & NutriCosmet-ics, Freie Universitat Berlin, Berlin, Germany.

Dr. Majella E. Lane, Department of Pharmaceutics, School of Pharmacy, University ofLondon, UK.

Professor Vesa-Pekka Lehto, Department of Applied Physics, University of EasternFinland, Kuopio, Finland.

Dr. Mathew Leigh, Phares AG, Muttenz, Switzerland.

Dr. Shu Li, The Drug Delivery and Biomaterials Research Group, The School of Pharmacy,Queen’s University of Belfast, Northern Ireland.

Professor Thorsteinn Loftsson, Faculty of Pharmacy, University of Iceland, Reykjavik,Iceland.

Dr. Rachmat Mauludin, Department of Pharmaceutics, Universitas Pendidikan, Bandung,Indonesia.

Marco Meuri, BUCHI Labortechnik AG, Flawil, Switzerland.

Dr. C.E. Mora-Heurtas, University Lyon 1, Villeurbanne, CNRS, UMR-5007, Laboratoired’Automatique et de Genie des Procedes, France.

List of Contributors xix

Dr. Sara Movassaghian, Center for Pharmaceutical Biotechnology and Nanomedicine,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts,USA; and Department of Pharmaceutics, School of Pharmacy, Shaheed Beheshti Universityof Medical Sciences, Tehran, Iran.

Professor Rainer H. Muller, Department of Pharmaceutics, Biopharmaceutics & Nutri-Cosmetics, Freie Universitat Berlin, Berlin, Germany.

Professor Anette Mullertz, Bioneer: FARMA, Department of Pharmaceutics and Ana-lytical Chemistry, The Faculty of Pharmaceutical Science, University of Copenhagen,Copenhagen, Denmark.

Dr. Joakim Riikonen, Department of Applied Physics, University of Eastern Finland,Kuopio, Finland.

Dr. David Rutti, BUCHI Labortechnik AG, Flawil, Switzerland.

Assistant Professor Jarno Salonen, Department of Physics and Astronomy, University ofTurku, FI-20014 Turku, Finland.

Dr. Helder Santos, Division of Pharmaceutical Technology, Faculty of Pharmacy, Univer-sity of Helsinki, FI-00014 Helsinki, Finland.

Dr. Stefan Scheler, Sandoz GmbH, Kundl, Austria.

Dr. Hari Singh, Gour Central University, Sagar, India.

Dr. Rakesh K. Tekade, Pharmaceutics Research Laboratory, Department of Pharmaceuti-cal Sciences, Gour Central University, Sagar, India.

Professor Vladimir P. Torchilin, Center for Pharmaceutical Biotechnology andNanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston,Massachusetts, USA.

Dr. Peter van Hoogevest, Phares AG, Muttenz, Switzerland; and Department of Pharma-ceutical Sciences, Institute of Pharmaceutical Technology, University of Basel, Switzerland.

Dr. Onkar S. Vaze, Center for Pharmaceutical Biotechnology and Nanomedicine, Depart-ment of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.

Assistant Professor Xue-Qing Wang, School of Pharmaceutical Sciences, PekingUniversity, Beijing, China.

Professor Qiang Zhang, School of Pharmaceutical Sciences, Peking University, Beijing,China.

Series Preface

The series Advances in Pharmaceutical Technology covers the principles, methods andtechnologies that the pharmaceutical industry use to turn a candidate molecule or newchemical entity into a final drug form and hence a new medicine. The series will exploremeans of optimizing the therapeutic performance of a drug molecule by designing andmanufacturing the best and most innovative of new formulations. The processes associatedwith the testing of new drugs, the key steps involved in the clinical trials process and themost recent approaches utilized in the manufacture of new medicinal products will all bereported. The focus of the series will very much be on new and emerging technologies andthe latest methods used in the drug development process.

The topics covered by the series include:

Formulation: the manufacture of tablets in all forms (caplets, dispersible, fast-melting)will be described, as will capsules, suppositories, solutions, suspensions and emulsions,aerosols and sprays, injections, powders, ointments and creams, sustained release andthe latest transdermal products. The developments in engineering associated with fluid,powder and solids handling, solubility enhancement, colloidal systems including thestability of emulsions and suspensions will also be reported within the series. Theinfluence of formulation design on the bioavailability of a drug will be discussed andthe importance of formulation with respect to the development of an optimal final newmedicinal product will be clearly illustrated.

Drug Delivery: The use of various excipients and their role in drug delivery will bereviewed. Among the topics to be reported and discussed will be a critical appraisal ofthe current range of modified-release dosage forms currently in use and also those underdevelopment. The design and mechanism(s) of controlled release systems including;macromolecular drug delivery, microparticulate controlled drug delivery, the delivery ofbiopharmaceuticals, delivery vehicles created for gastro-intestinal tract targeted delivery,transdermal delivery and systems designed specifically for drug delivery to the lungwill all be reviewed and critically appraised. Further site-specific systems used for thedelivery of drugs across the blood–brain barrier including dendrimers, hydrogels andnew innovative biomaterials will be reported.

Manufacturing: The key elements of the manufacturing steps involved in the productionof new medicines will be explored in this series. The importance of crystallization;batch and continuous processing, seeding; mixing including a description of the keyengineering principles relevant to the manufacture of new medicines will all be reviewedand reported. The fundamental processes of quality control including good laboratorypractice (GLP), good manufacturing practice (GMP), Quality by Design (QbD), the

xxii Series Preface

Deming Cycle; Regulatory requirements and the design of appropriate robust statisticalsampling procedures for the control of raw materials will all be an integral part of thisbook series.

An evaluation of the current analytical methods used to determine drug stability, thequantitative identification of impurities, contaminants and adulterants in pharmaceuticalmaterials will be described as will the production of therapeutic bio-macromolecules,bacteria, viruses, yeasts, moulds, prions and toxins through chemical synthesis andemerging synthetic/molecular biology techniques. The importance of packaging includ-ing the compatibility of materials in contact with drug products and their barrier propertieswill also be explored.

Advances in Pharmaceutical Technology is intended as a comprehensive one-stop shop forthose interested in the development and manufacture of new medicines. The series willappeal to those working in the pharmaceutical and related industries, both large and small,and will also be valuable to those who are studying and learning about the drug developmentprocess and the translation of those drugs into new life-saving and life-enriching medicines.

Dennis DouroumisAlfred Fahr

Jurgen SiepmannMartin Snowden

Preface

In former times, formulation specialists were not yet exposed to the many problems andsubtleties that we face today in producing applicable drugs. In those ‘good old days’ thebest drugs were simply generated using polar media, either by extraction from plants orby synthetic methods. Later, towards the end of the last century, an ever growing numberof lipophilic drugs started to appear for oral as well as parenteral administration. Naturalsubstances, like cyclosporine or modifications of aromatic structures that render selecteddrugs even more lipophilic, began to enter the vanguard of the blockbuster class. Storiesabout the difficulties of absorption in the gut or the bad pharmacokinetic profiles of thesedrugs have entered the body of canonical knowledge in many pharmaceutical companies.Desperate attempts to formulate these insoluble drugs – such as ‘encapsulating’ themin Swiss chocolate to get an oral delivery – are well remembered in the correspondingpharmacists’ clubs.

This situation has changed with the advent of the new millennium in two ways:

1. The percentage of new drug molecules that are insoluble in water has risen to about 40%in total; in various therapeutic areas this percentage has even reached 80–90%. Why isthis so? Perhaps the best explanation is the invention of the so-called High ThroughPutScreening (HTPS) method. Here, a variety of substances are tested (for cases of morethan 100,000 per day, the method is re-named ‘ultra-HTPS’) for their activity with regardto certain biochemical targets (alternatively a cell, organ, or organism). This often favorsthe selection of drugs with higher lipophilicity, as most target sites – for example, theactive center of an enzyme or a membrane protein – tend to be more accessible tolipophilic drugs, which runs in parallel to non-solubility. Adding to the difficulties for aformulation specialist, oral bioavailability is not among the primary aims of the HTPSprocedure.

2. Pharmaceutical scientists have responded to this challenge in the past few decades bydeveloping a variety of formulation principles for these poorly water-soluble drugs.Insoluble drugs should be made dissolvable by physico-chemical or biological means(e.g. transfer to gut cell membranes (p.o.) or lipoproteins (i.v.)) in order to arrive at thepharmacological target in appreciable amounts.

Even though some advertisements of excipient producers do suggest this, there is no ultimatesingle solution for insoluble drugs (as evidenced by the variety of methods presented inthis book). On the other hand, there is the old saying that if there is more than one solutionfor a problem, there is likely no solution at all.

xxiv Preface

Therefore, a pharmacist who has to design and develop a formulation for an insolubledrug has to be aware of all the characteristics of the drug, s/he also has to have a profoundknowledge of the available and feasible formulation options. To this end, s/he is likelyto end up studying the literature in depth, as there are few other resources available thatprovide comprehensive surveys written by the experts in the field. The present book triesto fill this gap.

The book begins with some theoretical considerations, thereby introducing and dis-cussing basic concepts such as solubility and hydrophobicity, and also provides a mod-eling framework for nanocarriers and their interactions with drug and the environment(Chapter 1).

Several chapters (2, 3–6, 13, 14) show how cyclodextrins, dendrimers, micelles, lipo-somes, solid lipid nanoparticles, and polymeric systems can overcome the solubility prob-lem for insoluble drugs by using carrier systems mostly intended for the parenteral route.The carrier systems may be composed of either complex single molecules as hosts (e.g.dendrimers) or an assembly of rather simple molecules (e.g. micelles), or a combination ofboth. The complex interplay between host and drug often plays a crucial role in the successof such formulations and is extensively discussed in the respective chapters, along withdetailed production procedures.

Microemulsion technology serves both the parenteral and the oral administration routefor insoluble drugs, as is demonstrated in Chapter 10. Upon the addition of water, anhy-drous (micro)emulsions may spontaneously emulsify. This process is used to produceself-emulsifying drug delivery systems (SEDDS) that are mainly used for oral delivery; seethe discussion in Chapter 7.

Another feasible approach to improving the solubility of orally administered drugs is thesize reduction of solid-state particles, yielding a large specific surface area. In Chapters 8,9, 16 and 17, the production of nano-sized particles is described, using several differentapproaches (milling techniques, nanocrystals, nanosuspensions, and spray drying). Theamorphous state of, for example, spray-dried particles and nanosuspensions may increasethe solubility further and this is discussed thoroughly in the respective chapters.

Hot melt extrusion (solid dispersion technology) is, like the other methods describedhere, already on the market and attracting ever more attention as a method to enhance thebioavailability of problematic drugs. This is thoroughly described in Chapter 11.

Mesoporous silica nanoparticles (Chapter 15) are an interesting experimental formulationfor increasing the solubility of insoluble drugs – they hold promising potential for the future.

Finally, Chapter 12 demonstrates that skin delivery of highly insoluble drugs is equallyas challenging as other administration routes.

The different methods described in this book share the underlying goal of improving thesolubility and the dissolution rate of poorly water-soluble drugs. We wish to point out that,especially for colloidal systems, these methods can be combined with targeting approaches.Targeting constitutes a fast-growing research field in its own right; its inclusion was outsidethe scope of the present book.

The interested reader may notice that the chapters integrate with each other. This indeedis the intention of the book as it likely facilitates the decision on which method mightbe worth trying for a given formulation problem. We emphasize that despite the effortsof all authors – including their careful descriptions, practical tips, and even theoreticalconsiderations – finding the right formulation may in the end still be a matter of educated

Preface xxv

trial and error. Yet, even in this case, we are confident that this book will speed up theprocess.

The editors thank all the contributors for their time and effort in composing this com-pendium, for presenting the current state of the art in formulating insoluble drugs for oral,parenteral and topical administration, and for providing the reader with practical guidelineson how to start a formulation task.

1Self-Assembled Delivery Vehicles forPoorly Water-Soluble Drugs: Basic

Theoretical Considerations andModeling Concepts

Sylvio May and Alfred Fahr

1.1 Introduction

Poor solubility is a well-recognized property of many drug molecules [1]. Unprotectedadministration of poorly water-soluble drugs is problematic. Aggregation, precipitation,uncontrolled binding, and direct exposure to a harsh biological environment render thisprocess inefficient. The putative ‘solution’ of using higher drug concentrations narrowsthe window between a therapeutic success and unwanted side effects such as locally toxicdrug levels. It comes as no surprise that the administration of poorly water-soluble drugscan benefit dramatically from using delivery vehicles. Such vehicles can, in principle, bedesigned not only to encapsulate a drug and protect it from biological defense mecha-nisms, but also to release the drug in a controlled manner at the target site and then to berecycled through biodegradation. Different types of delivery vehicles are currently beinginvestigated, including microemulsions [2,3], gels [4], micelles [5,6], liposomes [7], poly-mersomes [8], dendrimers [9], and nanopcrystals [10], or lipid nanoparticles [11]. Notably,most of these are self-assembled structures. Self-assembly is an ubiquitous process in cellu-lar systems, most strikingly perhaps in the cell membrane where a matrix (lipids) containshighly specialized functional units (poorly water-soluble proteins). Functionalization is anadvantage that is also increasingly integrated into drug delivery vehicles. As an example

Drug Delivery Strategies for Poorly Water-Soluble Drugs, First Edition. Edited by Dennis Douroumis and Alfred Fahr.© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

2 Drug Delivery Strategies for Poorly Water-Soluble Drugs

we mention liposomes, which were originally designed as long-circulating transport vehi-cles for drug molecules [12]. Extending the circulation time by decorating the liposomesurface with PEG-chains (stealth liposomes [13]) can be viewed as the first step towardfunctionalization. Currently designed liposomes raise the concept of functionalization to anew height: they contain targeting ligands and carry out stimuli-sensitive triggering of thedrug release [14–16].

Optimizing drug delivery vehicles is promising but also challenging. Self-assemblednanostructures are soft and responsive materials, where entropy becomes an importantfactor for structure and stability. It is virtually impossible to manipulate one propertywithout affecting others (and sometimes this has drastic implications as one of the authorsvividly recalls the disintegration of an entire colloidal formulation upon the replacement ofa single -H group by an -OH group in a 1 kDalton drug molecule). Nanocarrier propertiesare affected by a range of interactions that are well known from colloidal science, includingsolvation energies, electrostatic and van der Waals interactions, depletion and packingeffects, etc. [17, 18]. Appreciation and understanding of these interactions are likely toreflect upon nanocarrier design and optimization. For example, one of the challenges thatdrug encapsulation in nanocarriers faces is related to the retention of the drug in the carrier.A lipophilic drug does not necessarily remain in a rigid lipophilic matrix [19] but is rapidlysqueezed out, whereas soft structures (like liposomal membranes) tend to increase theresidence time in the membrane. What physical mechanisms underlie the ability of softrather than rigid self-assembled structures to accommodate small lipophilic drugs? Andwhat physical properties determine the release? The latter question relates to the fact thata carrier keeping the drug completely in the interior will ultimately prevent a therapeuticeffect. The authors’ experience with a liposomal formulation of a peptide showed anincrease of lifetime from 3 mins to 24 hours in blood, but there was no pharmacologicalactivity, as the liposomes with the drug inside were eliminated without releasing the drugto blood components or organs. Other practical hurdles are discussed, for example, by vanHoogevest et al. [20].

The present chapter presents a conceptual framework for physics-based modelingapproaches of self-assembled nanoscaled carrier systems that are associated with lipophilicdrugs. Our focus is clearly on the basic physics and underlying concepts [21]. We start withan account of basic thermodynamic relations (Section 1.2) which we subsequently exploitto discuss principles of self-assembly (Section 1.3) and the partitioning of drug moleculesinto self-assembled carrier systems (Section 1.4). The energetics of individual deliveryvehicles depends on a multitude of inter-molecular interactions; of these we discuss elec-trostatics and the packing of chain-like molecules (Section 1.5). We finally consider kineticproperties of drug transfer from mobile nano-carriers to a target system (Section 1.6). Notethat none of the sections aims to give a comprehensive account of the available theoreticalconcepts (for more comprehensive accounts and discussions of specific applications, see[21–24]). However, for those subjects that we discuss, it is our goal not only to state the finalresults but also provide some guidance through the physical and mathematical basis of theirderivation. We shall focus on simple and generic models, namely those that highlight theunderlying physical principles, thereby excluding more advanced theoretical concepts andatomistic simulations. In summary, the present chapter approaches the pharmaceutical sci-entist who is interested in the process of developing theoretical models for self-assembleddelivery vehicles of drug molecules from first principles.