Innovative dosage forms : design and development at early stage 9783527812172, 3527812172

Table of contents :
Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development / MHD Bashir Alsirawan, Anant Paradkar --
Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route / Sanket Shah, Abhijit Date, Renè Holm --
Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products / Ankit Sharma --
Preclinical Formulation Assessment of NCEs / Raju Saka, Priyadarshini Sathe, Wahid Khan, Sachin Dubey --
Regulatory Aspects for Formulation Design - with Focus on the Solid State / Michael Gruss --
Insight into Innovative Applications of Parenteral Formulations / Clara Fernandes --
Assessing Pharmacokinetics of Various Dosage Forms at Early Stage / Susanne Bonsmann, Joachim Ossig --
Transdermal Medical Devices: Formulation Aspects / Mayank Singhal, César E S Jimenez, Maria Lapteva, Yogeshvar N Kalia --
Physical Characterization Techniques to Access Amorphous Nature / Aniket Sabnis, Niten Jadav, Tim Gough, Adrian Kelly, Anant Paradkar --
Design and Development of Ocular Formulations for Preclinical and Clinical Trials / Mathieu Schmitt --
Preclinical Safety Aspects for Excipients: Oral, IV, and Topical Routes / Florian Engel --
Formulation of Therapeutic Proteins: Strategies for Developing Oral Protein Formulations / Saurabh Patil, Aditya Narvekar, Amita Puranik, Ratnesh Jain, Prajakta Dandekar.

Citation preview

Innovative Dosage Forms

Methods and Principles in Medicinal Chemistry Edited by R. Mannhold, H. Buschmann, Jörg Holenz Editorial Board G. Folkerts, H. Kubinyi, H. Timmerman, H. van de Waterbeemd, J. Bondo Hansen

Previous Volumes of this Series: Gervasio, F. L., Spiwok, V. (Eds.)

Vaughan, T., Osbourn, J., Jalla, B. (Eds.)

Biomolecular Simulations in Structure-based Drug Discovery

Protein Therapeutics

2018 ISBN: 978-3-527-34265-5 Vol. 75

Sippl, W., Jung, M. (Eds.)

Epigenetic Drug Discovery 2018 ISBN: 978-3-527-34314-0 Vol. 74

2017 ISBN: 978-3-527-34086-6 Vol. 71

Ecker, G. F., Clausen, R. P., and Sitte, H. H. (Eds.)

Transporters as Drug Targets 2017 ISBN: 978-3-527-33384-4 Vol. 70

Martic-Kehl, M. I., Schubiger, P.A. (Eds.) Giordanetto, F. (Ed.)

Early Drug Development 2018 ISBN: 978-3-527-34149-8 Vol. 73

Animal Models for Human Cancer Discovery and Development of Novel Therapeutics 2017 ISBN: 978-3-527-33997-6 Vol. 69

Handler, N., Buschmann, H. (Eds.)

Drug Selectivity 2017 ISBN: 978-3-527-33538-1 Vol. 72

Holenz, Jörg (Ed.)

Lead Generation Methods and Strategies 2016 ISBN: 978-3-527-33329-5 Vol. 68

Innovative Dosage Forms Design and Development at Early Stage

Edited by Yogeshwar G. Bachhav

Series Editors Dr. Raimund Mannhold

Rosenweg 7 40489 Düsseldorf Germany Dr. Helmut Buschmann

Aachen, Germany Sperberweg 15 52076 Aachen Germany Dr. Jörg Holenz

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.:

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GSK R&D Neurosciences TAU 1250 S. Collegeville Road, PA United States

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Volume Editor

Bibliographic information published by the Deutsche Nationalbibliothek

Dr. Yogeshwar G. Bachhav

Adex Pharmaceutical Consultancy Services, C-201 Bharatkhand CHS Tilaknagar, Chembur 400089 Mumbai India

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

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978-3-527-34396-6 ePDF ISBN: 978-3-527-81220-2 ePub ISBN: 978-3-527-81218-9 oBook ISBN: 978-3-527-81217-2 Cover Design SCHULZ Grafik-Design,

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Contents Preface xvii 1

Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development 1 MHD Bashir Alsirawan and Anant Paradkar

1.1 1.1.1 1.1.2 1.1.2.1 1.1.2.2 1.1.3 1.1.3.1 1.1.3.2 1.1.4 1.1.5 1.1.5.1 1.1.5.2 1.1.5.3 1.2 1.2.1 1.2.2 1.2.3 1.2.3.1 1.2.3.2 1.2.3.3 1.3

Introduction 1 Background 1 Types of Polymorphism 2 Conformational Polymorphism 2 Packing Polymorphism 4 Thermodynamic-Based Classification of Polymorphism 4 Enantiotropic Polymorphism 4 Monotropic Polymorphism 5 Concomitant Polymorphism 6 Debatable Polymorphism Cases 7 Tautomeric Polymorphism or Tautomerism 7 Enantiomerism/Stereoisomerism 7 Pseudopolymorphism 8 Polymorphism Impact on Drug/Excipient Properties 9 Physicochemical Properties 10 Mechanical Properties 11 Impact of Polymorphism on In Vivo Performance 13 Effect of Polymorphism on Solubility 14 Effect of Polymorphism on Dissolution Rate/Solubility Kinetics 17 Effect of Polymorphism on Bioavailability 20 Critical Impact of Polymorphic Form of API on Processing and Formulation 22 Process-induced Transformation Types 23 Grinding-induced Transitions 23 Granulation-induced Transitions 25 Tableting-induced Transition 30 Freeze-drying-induced Transition 32 Spray-drying-induced Transitions 33 Supercritical-fluid-induced Transitions 35 Conclusion 37 References 38

1.3.1 1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.1.6 1.4

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2

Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route 49 Sanket Shah, Abhijit Date, and Renè Holm

2.1 2.2 2.3 2.4 2.5 2.5.1 2.5.2 2.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2.5.2.5 2.5.3 2.5.3.1 2.5.3.2 2.5.3.3 2.5.3.4 2.5.3.5 2.6 2.6.1 2.6.2 2.6.2.1 2.6.2.2 2.6.2.3 2.6.3 2.6.3.1 2.6.3.2 2.7 2.7.1 2.7.2 2.7.3 2.7.4 2.8 2.8.1 2.8.2 2.8.3 2.9 2.9.1 2.9.2 2.9.3 2.10

Introduction 50 Quality by Testing (QbT) and Quality by Design (QbD) 50 Linking the Formulation to the Clinical Phase 52 Defining the Formulation Strategy 55 Nanosuspensions 58 Description 58 Method of Manufacturing 59 Top-Down Methods 59 Wet Media Milling Technology 60 High-pressure Homogenization 61 Bottom-Up Methods 62 Methods Utilizing a Hybrid Approach 63 Characterization of Nanosuspensions 63 Particle Size, Polydispersity Index, and Particle Morphology 63 Surface Charge 63 Particle Morphology 64 Solid-state Properties 64 Saturation Solubility and Dissolution Velocity 64 Solid Dispersion 64 Description 65 Method of Manufacturing 66 Melting/Fusion 66 Solvent Evaporation 67 Coprecipitation 67 Characterization 68 Investigation of Crystallinity 68 Investigation of Molecular Arrangement 69 Lipid-Based Drug Delivery Systems 69 Description 70 Method of Manufacture 71 Characterization 75 Role of API Property on Lipid-Based DDS 76 Micellar System 76 Description 76 Formulation Development and Optimization 80 Characterization 81 Mesoporous Silica Particles 81 Description 82 Method of Manufacturing and Characterization 83 Case Study on the in Vivo Efficacy of Mesoporous Silica Particles 84 Conclusion 84 References 85

Contents

3

Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products 91 Ankit Sharma

3.1 3.2

Introduction 91 Reactive Impurities in the Excipients and Their Impact on Drug Stability 92 Impact of Reactive Impurities on Drug–Excipient Compatibility 93 Physical Interactions 93 Chemical Interactions 94 Oxidative Degradation 94 Peroxides 95 Transition Metal Impurities 96 Condensation Reactions 99 Aldehyde Impurities 99 Reducing Sugars 102 Organic Acids 103 Hydrolytic Degradation 105 Risk Assessment for API Incompatibilities and Mitigation Strategies 107 Assessment of Incompatibilities of API with Excipients 108 Design and Selection of Drug Substance 109 Formulation Strategies to Circumvent API Degradation 110 Inhibition of Oxidative Degradation 110 Initiation Inhibitors 111 Propagation Inhibitors 111 Selection of Antioxidant 112 Super-Refined Excipients 113 Polyethylene Glycols (PEG) 114 Polysorbates 114 Fatty Acids 115 Packaging and Storage 115 Concluding Remarks 116 References 116

3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.3.7 3.3.8 3.3.9 3.3.10 3.4 3.5 3.6 3.7 3.8 3.8.1 3.8.2 3.8.3 3.9 3.9.1 3.9.2 3.9.3 3.10 3.11

4

Preclinical Formulation Assessment of NCEs 119 Raju Saka, Priyadarshini Sathe, Wahid Khan, and Sachin Dubey

4.1 4.2

Introduction 120 Significance of Various Properties of NCEs in Early Drug Discovery 122 Solubility 123 Permeability 124 Stability 125 Formulation Strategies to Improve Properties of NCEs 125 pH Modification 127 Cosolvents 127

4.2.1 4.2.2 4.2.3 4.3 4.3.1 4.3.2

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Contents

4.3.3 4.3.4 4.3.5 4.3.6 4.3.7 4.3.8 4.4 4.4.1 4.4.1.1 4.4.2 4.4.3 4.4.3.1 4.4.3.2 4.4.3.3 4.4.3.4 4.4.3.5 4.4.4 4.4.5 4.4.6 4.4.7 4.4.8 4.5 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 4.5.6 4.5.7 4.5.8 4.5.9 4.6

Cyclodextrins 128 Surfactants 128 Suspensions and Nanosuspensions 129 Emulsions and Microemulsions 130 Solid Dispersions 130 Liposomes 131 Preclinical Formulation Assessment of Oral, Parenteral, and Topical Dosage Forms 131 Oral Formulations 131 Formulation Development 132 Parenteral Formulations 134 Topical Formulations 135 Structure of Skin and Effect on Permeation 136 Formulation Effect 136 Skin Metabolism 136 Formulation Development 136 Formulation Approaches 137 Excipients 138 Characterization and Stability of Preclinical Formulations 140 Formulation Selection for Pharmacokinetic Studies 141 Formulation Selection for Pharmacodynamic Studies 142 Formulation Development for Toxicity Studies 142 Case Studies 143 Case 1: Use of Surfactant to Prevent Precipitation of API in Cosolvent-Based Formulations 143 Case 2: Topical Gel Microemulsion Formulation of Lipophilic Drug WHI-07 144 Case 3: Salt Approach to Improve the Bioavailability of the Poorly Soluble Drug 144 Case 4: Use of SMEDDS Dosage Form to Improve Bioavailability 145 Case 5: Micronized Suspension of Poorly Soluble Lead Compounds Using Wet Milling Technique 145 Case 6: Polymer Addition in Cyclodextrin-Based Formulations and pH Adjustment 146 Case 7: Cyclodextrin Complexation to Improve Topical Delivery of a Poorly Soluble Compound 146 Case 8: Use of Solublizers and Their Effect on PK of Preclinical Lead Candidates 147 Case 9: Self-nanoemulsifying Drug Delivery Systems (SNEDDS) to Improve Solubility and Bioavailability 147 Conclusion and Future Perspectives 148 References 148

5

Regulatory Aspects for Formulation Design – with Focus on the Solid State 155 Michael Gruss

5.1 5.2

The Understanding of “Regulatory” 156 Formulation Design 157

Contents

5.3 5.4 5.5 5.6 5.6.1 5.6.2 5.6.2.1 5.6.2.2 5.6.2.3 5.6.3 5.6.4 5.6.4.1 5.6.4.2 5.7 5.7.1 5.7.2 5.8 5.8.1 5.8.2 5.8.3 5.9 5.9.1 5.9.1.1 5.9.1.2 5.9.1.3 5.9.2 5.9.2.1 5.9.2.2 5.9.3 5.9.4 5.9.5 5.9.5.1 5.9.5.2 5.9.5.3 5.9.5.4

5.9.6 5.9.6.1 5.9.6.2 5.9.6.3 5.9.6.4 5.9.6.5 5.9.6.6 5.9.6.7

An Extended Timescale 158 Solubility Data 158 Impact of Solubility and Dissolution Rate on Formulation Design 162 Single and Multicomponent Systems 163 Introduction 163 Scientific Point of View 164 Polymorphism 164 Polyamorphism 165 Multicomponent Compounds – Salt, Co-crystal, Solvate, and Hydrate 165 Fate and Pathway of a Compound During Development 166 Regulatory Point of View 167 Patents 167 Pharmacopeias 168 Analytical Techniques for the Characterization of the Solid State 168 Scientific Literature 168 Pharmacopeias 169 Control of Solid-state Constitution 171 The Process – from Synthesis to Patient 171 Change of Properties and Constitution 173 Need for Control of Solid-State Properties During the Process and Supply Chain 173 Regulatory Consideration of Solid Compounds 174 Definitions for Solid Compounds 174 Co-crystals and Solvates 174 Salts and Co-crystals 174 Polymorphism 175 Common Technical Document (CTD) – M4Q 175 CTD – Section 3.2.S – Drug Substance 175 CTD – Section 3.2.P – Drug Product 177 Guideline on the Chemistry of Active Substances 178 Guideline on Quality of Transdermal Patches 180 Quality Guidelines 181 ICH Q1A (R2) Stability Testing of New Drug Substances and Products 182 ICH Q1B Photostability Testing 182 ICH Q1C Stability Testing: Requirements for New Dosage Forms 183 ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 183 EMA – Consideration and Perspective 188 Abridged Applications 188 New Active Substance (NAS) Status 188 Marketing Authorization Application (MAA) 189 Co-crystals and GMP Manufacturing 189 Active Substance Master File (ASMF) 190 Pharmaceutical Acceptance 190 Compounds Containing More than One Therapeutic Moiety 190

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5.9.7 5.9.7.1 5.9.7.2 5.9.7.3 5.9.7.4 5.9.7.5 5.9.7.6 5.9.8 5.10

FDA – Consideration and Perspective 190 Sources for Information 190 Naming of Drug Substances and Drug Products 191 Investigational New Drug Application (IND) 192 Marketing Authorization Application – New Drug Application (NDA) 194 ANDA – Abbreviated New Drug Applications 194 Regulatory Classification of Pharmaceutical Co-crystals and Salts 196 Similarities and Differences Between the Regulative Systems in the EU and United States 197 Conclusions and Recommendations 198 Disclaimer 198 References 198

6

Insight into Innovative Applications of Parenteral Formulations 209 Clara Fernandes

6.1 6.2

Introduction 209 Factors Affecting Development of Sustained-/Controlled-Release Formulations 209 Overview of Sustained and Controlled Release Parenteral Formulations 213 Suspension Based Formulations 213 Nanosuspension Based Formulations 213 Microsuspension Based Formulations 214 Particulate System Based Formulations 215 Polymer Nanoparticles Based Formulations 215 Lipid Nanoparticles Based Formulations 217 Inorganic Nanoparticles Based Nanoparticles 217 Case Studies 219 Nanosuspension Formulation of Paclitaxel – Abraxane 219 219 PLGA Depot Based Formulation of Triptorelin – Trelstar Microemulsion Formulation of Propofol 220 Inorganic Metal Nanoparticle Based Formulation for Parenteral Applications 220 Polymeric Formulation of Glatiramer 221 Conclusion 222 Future Prospects 222 References 222

6.3 6.3.1 6.3.1.1 6.3.1.2 6.3.2 6.3.2.1 6.3.2.2 6.3.2.3 6.4 6.4.1 6.4.2 6.4.3 6.4.4 6.4.5 6.5 6.6

®

®

7

Assessing Pharmacokinetics of Various Dosage Forms at Early Stage 227 Susanne Bonsmann and Joachim Ossig

7.1 7.2

Introduction 227 Definition of Pharmacokinetics 229

Contents

7.2.1 7.2.1.1 7.2.1.2 7.2.1.3 7.2.2 7.2.2.1 7.2.2.2 7.2.2.3 7.2.2.4 7.2.2.5 7.2.2.6 7.2.3 7.2.3.1 7.2.3.2 7.2.3.3 7.3 7.3.1 7.3.2 7.3.3 7.3.4 7.4

ADME Parameters 229 Absorption 229 Distribution 230 Metabolism and Excretion 231 Pharmacokinetic Parameters 231 Plasma Concentration Time Profile 231 Area Under the Curve (AUC) 232 Bioavailability (BA) 233 Volume of Distribution (V d ) 234 Clearance (Cl) 234 Half-life (T 1/2 ) 235 PK Studies During Drug Development 236 ADME in Vitro Studies 236 In Vitro Models 237 In Vivo Studies 238 Case Studies 241 Case Study 1 241 Case Study 2 241 Case Study 3 242 Case Study 4 243 Summary 243 References 243

8

Transdermal Medical Devices: Formulation Aspects 245 Mayank Singhal, César E. S. Jimenez, Maria Lapteva, and Yogeshvar N. Kalia

8.1 8.2 8.2.1 8.2.1.1 8.2.1.2 8.2.2 8.2.2.1 8.2.2.2

Introduction 246 Microneedles 247 Delivery Using Solid Microneedles: Skin Pretreatment 248 Delivery of Low-Molecular-Weight Compounds 248 Delivery of High-Molecular-Weight Compounds 251 Delivery Using Coated Microneedles 252 Delivery of Low-Molecular-Weight Compounds 252 Delivery of High-Molecular-Weight Compounds: Formulation Challenges Related to the Formulation of Coated Microneedles – A Case Study 252 Delivery Using Dissolvable Microneedles 254 Delivery of Low-Molecular-Weight Compounds 254 Delivery of High-Molecular-Weight Compounds: Formulation Challenges Related to the Formulation of Dissolvable Microneedles – A Case Study 255 Delivery Using Hollow Microneedles 255 Delivery of Low-Molecular-Weight Compounds 255 Delivery of High-Molecular-Weight Compounds 256 Delivery of Vaccines 257 Modalities of Microneedle Use 259 Perspectives in Microneedle-Mediated Transdermal Delivery 259 Laser-Assisted Ablation: Skin Pretreatment 260

8.2.3 8.2.3.1 8.2.3.2

8.2.4 8.2.4.1 8.2.4.2 8.2.5 8.2.6 8.2.7 8.3

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Contents

8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.4.6

Laser–Skin Interaction 261 Formulation Aspects 262 Perspective 263 Iontophoresis 263 Clinical Benefits of Iontophoresis in Transdermal/Topical Delivery 264 Selection of Drug Candidates 265 Iontophoretic Device Formulation Characteristics: Compositions and Challenges 265 Earlier Approved Commercial Devices 266 Smart Ionto System Features 268 Perspectives 269 References 269

9

Physical Characterization Techniques to Access Amorphous Nature 281 Aniket Sabnis, Niten Jadav, Tim Gough, Adrian Kelly, and Anant Paradkar

9.1 9.1.1 9.1.2 9.1.3 9.1.4

Introduction 282 Limitations of the Amorphous Form 285 Stabilization of the Amorphous Form 285 Solid Dispersion 285 Factors Affecting Solubility of API in the Form of Solid Dispersions 287 Limitations 289 Co-Amorphous 289 Screening Techniques for Amorphization 290 Amorphization: Solution-Based Techniques 291 Melting and Quench Cooling 291 Spray-Drying 292 Freeze-Drying 293 Flash Evaporation/Rotary Evaporation 294 Supercritical Fluid Processing 294 Amorphization: Solid-State Techniques 294 Dehydration of Crystalline Hydrates 294 Milling 294 Vacuum Compression Molding 296 Hot Melt Extrusion 296 Characterization of Amorphous Materials 298 X-Ray Powder Diffraction (XRPD) 299 Thermal Methods 302 Differential Scanning Calorimetry 302 Dynamic Mechanical Thermal Analysis 305 Perfusion/Solution Calorimetry 307 Density Measurements 310 Sorption Technique: Dynamic Vapor Sorption (DVS) 310 Vibrational Spectroscopy 312 Mid-Infrared Spectroscopy 313

9.1.5 9.1.6 9.2 9.2.1 9.2.1.1 9.2.1.2 9.2.1.3 9.2.1.4 9.2.1.5 9.2.2 9.2.2.1 9.2.2.2 9.2.2.3 9.2.2.4 9.3 9.3.1 9.3.2 9.3.2.1 9.3.2.2 9.3.3 9.3.4 9.3.5 9.3.6 9.3.6.1

Contents

9.3.6.2 9.3.6.3 9.3.6.4 9.4 9.5

Raman Spectroscopy 316 Near-Infrared Spectroscopy 318 Terahertz Spectroscopy 319 Summary 321 Future Prospects 322 References 323

10

Design and Development of Ocular Formulations for Preclinical and Clinical Trials 331 Mathieu Schmitt

10.1 10.2 10.3 10.4 10.4.1 10.4.2

Introduction 331 Ocular Anatomy and Physiology 332 Ocular Routes of Administration 336 Drug Discovery in Ophthalmology 337 Repositioning of Existing Drugs from Other Disease Area 337 Optimization of Compound Class to Enhance Selectivity, Tolerance Profile, and Efficacy 338 Specific Development 339 Topical Drug Administration 340 Ocular Bioavailability 340 Drug Design 340 Prodrugs 342 Physiological Factors 343 Formulation and Drug Delivery Systems 344 In Situ Gelling Systems 344 Emulsion 346 Nonaqueous Solutions 347 Polymeric Micelles and Dendrimers 348 Cyclodextrins 349 Multiparticulate Drug Delivery Systems 351 Sustained-release Strategies for Anterior Segment 352 Patient Compliance Through Packaging 354 Posterior Segment Delivery 356 In Situ Depot 357 Prodrugs 357 Intraocular Implants/Microparticles 358 Conclusion 360 References 361

10.4.3 10.5 10.5.1 10.5.2 10.5.3 10.5.4 10.5.5 10.5.5.1 10.5.5.2 10.5.5.3 10.5.5.4 10.5.5.5 10.5.5.6 10.5.5.7 10.5.6 10.6 10.6.1 10.6.2 10.6.3 10.7

11

Preclinical Safety Aspects for Excipients: Oral, IV, and Topical Routes 367 Florian Engel

11.1 11.2 11.3 11.4 11.4.1

Introduction 368 General Considerations 369 Undesired Side Effects of Excipients 370 Novel Excipients 371 Regulatory Requirements 372

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11.5 11.5.1 11.5.1.1 11.5.1.2 11.5.1.3 11.5.1.4 11.5.1.5 11.5.1.6 11.5.1.7 11.5.2 11.5.3 11.5.4 11.5.5 11.6

Rationale in Selecting an Excipient 375 Data Sources 376 Inactive Ingredient Database (IID) 376 Pharmacopoeias 376 Generally Recognized as Safe (GRAS) 376 Handbook of Pharmaceutical Excipients 377 STEP Database 377 Other Databases 377 In Silico 378 Strategies to Determine “Estimated Safe Excipient Doses” 378 Special Considerations for Oral Use 381 Special Considerations for Intravenous Use 381 Special Considerations for Topical Use 385 Conclusions 386 References 387

12

Formulation of Therapeutic Proteins: Strategies for Developing Oral Protein Formulations 391 Saurabh Patil, Aditya Narvekar, Amita Puranik, Ratnesh Jain, and Prajakta Dandekar

12.1 12.1.1 12.1.2

Introduction 392 Use of Proteins for Different Therapeutic Indications 392 Importance of Physicochemical Properties on Preformulation and Formulation Development of Protein Therapeutics 394 Stability Constraints and Formulation Challenges 395 Current Market Status and Opportunities of Therapeutic Proteins 396 Current Technologies for Protein Formulation Development 398 Current Approaches in Oral Delivery of Proteins for Enhanced GIT Absorption 400 Types of Proteins Used in Therapeutic Indications 400 Important Physicochemical Properties of Proteins for Formulation Development 402 Existing Route of Administrations of Protein Formulations 404 Developmental Aspects of Oral Protein Formulations 405 Resource Requirements for Manufacturing of Protein-Based Formulations 406 Stability Concerns of Proteins in the Gastrointestinal Tract (GIT) 407 Physical Barriers to Delivering Proteins and Peptides 407 Unstirred Layer of Intestinal Fluid 407 Epithelial Cell Membrane 407 Biochemical Barriers to Proteins and Peptides 409 Formulation Strategies for the Oral Delivery of Proteins and Peptides 409 Peptidase/Enzyme Inhibition Approaches 409 Use of Permeation Enhancers 410 Modification of the Physicochemical Properties 411

12.1.3 12.1.4 12.1.5 12.1.6 12.2 12.3 12.4 12.5 12.5.1 12.5.2 12.5.3 12.5.3.1 12.5.3.2 12.5.3.3 12.5.4 12.5.4.1 12.5.4.2 12.5.5

Contents

12.5.5.1 12.5.5.2 12.5.5.3 12.5.6 12.5.6.1 12.5.6.2 12.5.6.3 12.5.6.4 12.5.6.5 12.5.7 12.5.8

PEGylation 411 Alteration of Amino Acids 412 Hydrophobization 412 Use of Particulate Formulations 412 Microemulsions 413 Solid Lipid Core Particles 414 Liposomes 414 Nanoparticles 415 Microspheres/Microparticles 416 Colon-Targeted Delivery Systems for Proteins and Peptides 416 Mucoadhesive Polymeric Systems and Stimuli-Responsive Hydrogels 417 12.5.9 Cell-Penetrating Peptides 417 12.5.10 Prodrug Approach 417 12.6 Clinical Application of Oral Protein Formulations 418 12.7 Case Studies of Oral Protein Formulations 418 12.7.1 Case Study I: Cyclosporine A 418 12.7.2 Case Study II: Oral Insulin 421 12.7.3 Case Study III: Prodrug Approach – Desmopressin 422 12.8 Conclusion 422 References 423 Index 433

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Preface Drug discovery and development is an outstandingly complex task. Technological innovations in biology, chemistry, and medicine have provided the pharmaceutical industry with a wealth of targets and molecules, with the potential to treat diseases formerly assumed intractable to drug therapy. The consequential increase in complexity, both in terms of the molecules and their biological targets, combined with the increasing need to work in an efficient and cost-constrained environment has necessitated an evolution in the role of pharmaceutical sciences in discovery support. Because more and more drug candidates in the pipeline pose constraints such as poor solubility and stability, the development of an overall formulation strategy to support in vivo studies should be considered carefully as it can reduce cycle time and resources. The in vivo studies performed in the preclinical setting can broadly be classified as pharmacology, pharmacokinetic, and toxicology studies. The goals and challenges of these studies are diverse. Therefore, drug developers must consider many aspects when positioning a preclinical drug candidate to succeed in first-in-human clinical trials. Besides many other factors, a biopharmaceutical assessment of drug substances is crucial for different phases of the development process. In an early phase, pharmaceutical profiling should help to rate candidate molecules in terms of their “drug-like” properties. The first step for a new molecule moving out of the discovery phase is the preformulation studies, or developability assessment. Indeed, preformulation work lays the foundation for choosing the right salt and polymorph, delivery technology, and formulation strategies. Formulation approaches to deliver molecules in the preclinical setting include, besides many other innovative forms, the more traditional ones like suspensions, solutions, and amorphous dispersions administered as solids or in aqueous vehicles. Nowadays, advanced systems such as nanosuspensions and silica particles are also explored for this purpose. The goals of preformulation studies are to choose the correct form of the drug substance, evaluate its physical and chemical properties, and generate a thorough understanding of the material’s stability under the conditions that will lead to the development of a practical drug delivery system. Preformulation is a science that

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serves as a big umbrella for the fingerprinting of a drug substance or product both at the early and later stages of development in pharmaceutical manufacturing. Traditionally, pharmaceutical scientists participated in the discovery teams only in the later phases of lead development or in the lead optimization phase, and their role was largely to assess the development risks (developability) of the molecule advancing to clinical dosing. These activities, while important, have been augmented to include early discovery formulation support related to building a basic understanding of biology through in vivo target validation and demonstration of proof of mechanism. The book in hand, edited by a very experienced pharmaceutical scientist with many years of experience in this preformulation field, has pointed out with the selected chapters a comprehensive view of actual research filed in this area. In particular, the following chapters are enclosed: • Impact of the polymorphic form of the drugs/NCEs on the preformulation and formulation development • Regulatory aspects for formulation design – with focus on the solid state • Effect of residual reactive impurities in excipients on the stability of pharmaceutical products • Assessing pharmacokinetics of various dosage forms at early stage • Preclinical safety assessment for excipients; oral, IV, and topical routes • Preclinical formulation assessment of NCEs • Strategies for the formulation development of poorly soluble drugs via oral route • Physical characterization techniques to access amorphous nature • Design and development of ocular formulations for preclinical and clinical trials • Insights into innovative applications of parenteral formulations • Transdermal medical devices: formulation aspects • Formulation of therapeutic proteins: strategies for developing oral protein formulations The series editors are confident that this book and the highly actual topics will provide valuable benefits to interdisciplinary drug discovery teams working in industry and academia. Last but not least, we thank Yogeshwar Bachhav for excellently editing this volume as well as Frank Weinreich and Stefanie Volk from Wiley-VCH for their valuable contributions to this project. September 2018 Düsseldorf, FRG Aachen, FRG Boston, USA

Raimund Mannhold Helmut Buschmann Jörg Holenz

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development MHD Bashir Alsirawan and Anant Paradkar Center for Pharmaceutical Engineering Sciences, University of Bradford, Richmond Road, Bradford BD7 1DP, UK

1.1 Introduction Polymorphism is a well-established phenomenon which describes the ability of a solid-state molecular structure to be repetitively positioned in at least two different arrangements in three-dimensional space. These different arrangements can result in different sets of physicochemical properties of the same molecular structure, which can significantly affect material behavior during handling, processing, and storing. Hence, polymorphism is crucial for many applications, including the pharmaceutical industry. Most drugs, whether already produced or newly discovered candidates, and usually referred to as new chemical entities (NCEs), are found as solids under normal conditions of temperature and pressure. Eighty-five percent of active pharmaceutical ingredients (APIs) display pseudopolymorphism, including 50% having real polymorphism [1]. In addition, Cruz-Cabeza et al. have listed polymorphic incidence of single-component NCEs from the Cambridge Structure Database (CSD), European Pharmacopeia, and data from the extensive screening procedures performed in Roche and Lilly (Table 1.1) [2]. Consequently, polymorphism must be taken into consideration during every processing stage starting from early steps such as preformulation and formulation development, passing through processing, manufacturing, and storage, and eventually until consumption in humans. 1.1.1

Background

Polymorphism has been discussed and investigated by many reports [3–7]. Moreover, several definitions were made depending on the researcher or the field of research; McCrone (1965) defined polymorphism thus: “Polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecule of that compound in the solid state.” Buerger defined polymorphism of a crystal as “molecular arrangements having different properties.” The definition by Purojit and Venugopalan states it is the “ability of a substance to exist as two or more crystalline phases that have different Innovative Dosage Forms: Design and Development at Early Stage, First Edition. Edited by Yogeshwar G. Bachhav. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

Table 1.1 Polymorphism incidence for single-component NCE from several data source.

Source

Number of single NCEs

Polymorphism occurrence (%)

CSD

5941

37

European Pharmacopeia 2004

598

42

Roche

68

53

Lilly

68

66

arrangements or conformations of the molecules in the crystal lattice” [3]. IUPAC defined the phase transition between polymorphs as the “reversible transition of a solid crystalline phase at a certain temperature and pressure (the inversion point) to another phase of the same chemical composition with a different crystal structure” [8]. Other definitions were similar to those previously mentioned, such as different crystal arrangements for the same chemical composition [9], or crystal systems of same elemental structure but with unlike unit cells [4]. Desiraju has debated the experimentality of McCrone’s definition depending on previous observations of polymorphism cases where coexistence of two polymorphs within the same crystal is found with no distinctive phase separation or, in other cases, where two structures are very similar with a barely identified difference (divergence). Desiraju has suggested setting criteria to differentiate whether two arrangements are genuine polymorphs or belong to the same solid phase [6]. The first reported polymorphism event was discovered with calcium carbonate in 1788 by Kalporoth. In 1832, benzamide was the first organic molecule the polymorphism of which was observed by Wöhler and Liebig [10]. The first crystal structure of polymorphic form determined by X-ray diffraction was for resorcinol in 1938 [11]. Although the term polymorphism seems specific, there is confusion around designating different structures as polymorphs. Moreover, reports follow different terminology rules depending on the fields of interest and background. To mitigate this confusion, other terms have arisen such as pseudopolymorphism or solvatomorphism. However, several reports do not encourage using these terms as it may create further confusion [7, 12]. 1.1.2

Types of Polymorphism

If we stick to the pure definition of polymorphism and exclude chemically nonsimilar structures, there are two primary types of polymorphism, conformational and packing polymorphism. 1.1.2.1

Conformational Polymorphism

This type of polymorphism resulted in molecules having flexible moieties which, in turn, have rotatable bonding. The rotational movement of a single bond in the molecular structure leads to a symmetry change and produces a new

1.1 Introduction

configuration, and, subsequently, a change in lattice packing [13]. A typical example of conformational polymorphism is ranitidine hydrochloride, which has two polymorphs, form 1 and form 2. Both phases are monoclinic, with the same space group but with only a difference in the conformation and disorder of nitroethenediamine moiety (Figure 1.1) [14]. Triamcinolone acetonide acetate, a drug commonly used for rheumatoid arthritis, exists in three polymorphic forms A, B, and C and a monohydrate; all these forms exhibit conformational variations (Figure 1.1) which result in different packing (Figure 1.2) [15]. Figure 1.1 Molecular structure of triamcinolone polymorphs A (light blue), B (red and green), C (orange), and MH (blue). Source: Buˇcar et al. 2015 [14] and Wang et al. 2017 [15]. Adapted with permission of ACS. C

A

D

B

E

a

b

b

a

c c Form A

a

Form B

b

b

a

c c

Form C

MH

Figure 1.2 Lattice packing of triamcinolone acetonide acetate polymorphs. Source: Wang et al. 2017 [15]. Adapted with permission of ACS.

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1.1.2.2

Packing Polymorphism

In this type, the configuration and bond orientation between two structures is identical, yet the arrangement and backing of this conformation in a three-dimensional structure is not similar. Most of the pharmaceutical materials have flexible moieties; thus, it is rare to observe packing polymorphism in the field. Donepezil, which is used in the palliative treatment of Alzheimer’s disease, has two packing polymorphs, forms K and F. The conformation similarity of the two forms was investigated by superimposing their structure using Mercury 3.3, a 3D structure visualization and measurement program. Root-mean-square deviation (RMSD) was then calculated and found to be insignificant (0.0624 Å) supporting the identical confirmation (Figure 1.3) [16]. 1.1.3

Thermodynamic-Based Classification of Polymorphism

Polymorphic interconversion is primarily governed by the thermodynamic state of the material, and as per thermodynamic rules, both temperature and pressure determine the thermodynamic stability of a certain polymorph. Polymorphism type depends on the nature of solid-phase transition with respect to temperature or pressure and can be divided into monotropic and enantiotropic (Figure 1.4). Understanding and identifying the transition nature of polymorphs is crucial for establishing optimum parameters for crystallization, screening [17], processing, and storage of active ingredients and excipients [18, 19]. 1.1.3.1

Enantiotropic Polymorphism

In enantiotropic polymorphism, one polymorph (let us call it form I) is considered the most stable at a certain temperature and pressure, at which the other polymorph (form II) is not stable, usually called metastable. On the other hand, the metastable form II becomes stable when reaching different temperature or pressure zones or reaching transition temperature T t or pressure Pt .

(a)

(c)

(b)

Figure 1.3 Superimposed view of donepezil form F (blue) and form K (red); (a) crystallographic A axis view, (b) 90∘ angle view where an axis is horizontally positioned, the packing of two polymorphs are translated (green double-headed arrows). However, (c) superimposed molecular structures show identical conformations, meaning that the two phases are packing polymorphs. Source: Part et al. 2016 [16]. Adapted with permission of American Chemical Society.

1.1 Introduction

Free energy (kJ/mol)

ΔHf, FI

ΔHf, FII

Liq

ΔHt

FII FI

Temp

Tt

Free energy (kJ/mol)

Monotropic

Enantiotropic

ΔHf, FII

ΔHf, FI

FII FI

Temp

TFI TFII

(a)

Liq

TFII

TFI

(b)

Figure 1.4 Phase energy versus temperature diagram for the (a) enantiotropic and (b) monotropic interconversion for two polymorphic phases FI and FII.

Simultaneously, the stable form I becomes metastable and a phase transition from form I to form II takes place. In some cases, a third polymorph (form III) is found and it has a third temperature or pressure zone, above specific transition temperature or pressure, where it becomes the most stable among others. 1.1.3.2

Monotropic Polymorphism

This type describes the case where one polymorph is considered the most stable in a wide range of temperatures reaching high transition levels, higher than the melting point of the other forms which are all considered to be metastable polymorphs under their melting point. Two thermodynamic rules can be applied, which basically rely on thermal analysis to distinguish the type of polymorphism. These rules are heat of fusion and heat of transition, and may be referred to as Burger–Ramberger rules [20]. To describe these rules, let us propose two polymorphs form I and T FII T t form II, where form I is more stable under normal temperature or before heating. The heat of fusion rule states that if the polymorph with the higher melting point has lower fusion enthalpy compared to the other form, the relationship between the two polymorphs is enantiotropic. However, if the higher melting point form has higher enthalpy of fusion, the polymorphism is monotropic. In the case of the heat of transition rule, polymorphs I and II are monotropic if the transition from form II to I is exothermic; or enantiotropic if the transition from form I to II is endothermic. It should be noted that the interconversion is reversible in enantiotropic systems and irreversible in monotropic polymorphism [4]. Moreover, enantiotropic polymorphs have a defined transition temperature (Figure 1.3) and can be determined experimentally. Conversely, monotropic systems have no observable transition temperature, yet there is a theoretical transition point that can be calculated using the Bauer–Brandl equation (1.1): Ttr =

T T ΔHm,I − ΔHm,II T T ΔHm,I ∕Tm,I − ΔHm,II ∕Tm,II

(1.1)

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation T T where ΔHm,I and ΔHm,II are the melting enthalpy of forms I and II, respectively, and Tm, I and Tm, II are the melting points of forms I and II, respectively.

1.1.4

Concomitant Polymorphism

Concomitant polymorphism describes the case where more than one solid phase displays simultaneous nucleation and crystal growth under the same conditions and within the same batch. The reason behind concomitant polymorphism is a struggle between kinetically and thermodynamically stable polymorphs [21]. In other words, the kinetic and thermodynamic phases have a slight free energy difference [22]. This event may occur momentarily as the kinetically stable phase could convert rapidly to the thermodynamically stable phase, and in most cases the event is temporary and not observed due to the polymorphic conversion with time, or after predisposition to water or solvent (recrystallization or dissolution) [21]. The appearance of concomitant polymorphism can depend on the nature of crystallization solvent, temperature, and solution concentration [23]. Concomitant polymorphism poses a challenge to preformulation scientists when controlling the formation of a specific and desired polymorph. Several cases of APIs which exhibit concomitant polymorphism have been reported. A concomitant polymorphism of methoxyflavone, a nonsteroidal anabolic flavone, was reported. Thermodynamically stable form A and kinetically form B have a negligible difference in lattice energies and appear simultaneously after crystallization (Figure 1.5). Form B can transform to form A under the influence of temperature [24]. The relative nucleation and crystal growth rate is a crucial factor in controlling polymorphic appearance; furthermore, higher growth rate will govern the presence of the phase at the end of crystallization. Two polymorphs of donepezil, forms I and II, can appear concomitantly. The nucleation rate of form I is slower than that of form II, yet crystal growth is

Figure 1.5 Concomitant polymorphism after crystallization of methoxyflavone form A (bulk shape) and form B (needle shape). Source: Gong et al. 2016 [24]. Adapted with permission of American Chemical Society.

1.1 Introduction

higher in form I. As a result, form I appears at the beginning of the process followed by form II, which dominates its presence at the end of the process [16]. 1.1.5

Debatable Polymorphism Cases

These types are considered by many researchers as imperfect or pseudopolymorphism. Unlike the known variations found in basic polymorphism, the structures under this category have variations within the chemical structure which results in a change in crystal confirmation of packing. 1.1.5.1

Tautomeric Polymorphism or Tautomerism

Tautomerism is a simultaneous interconversion of isomeric organic compounds resulting from proton transfer caused by the presence of strong electronegative atoms such as O or N. Tautomerism depends on the presence of weakly acidic functional groups such as amines, amides, ketones, and lactams. The transformations are classified as chemical reactions and primarily consist of interconverting pairs such as keto-enol, oxime-nitroso, amine-imine, amide-imidic acid, and lactam-lactim reaction (Figure 1.6). Tautomerism transition occurs at solution or melt state, where the reaction is at equilibrium, while at solid state, the crystallization of different tautomers causes a unit cell structure producing polymorphs with tautomeric origin. Ranitidine hydrochloride form 2 is found to consist of a tautomeric mixture (50 : 50) of enamine and nitronic acid, which takes place in the nitroethenediamine group [26]. In addition, omeprazole tautomerism takes place in solution state with 5-methoxy–6-methoxy transition. However, in solid state, both tautomers exist continuously at the molecular level or as solid solution (Figure 1.7) [27]. 1.1.5.2

Enantiomerism/Stereoisomerism

The concept describes structures having a similar composition of atoms and bonding; however, they differ in the three-dimensional arrangement or orientation of the atoms. This type of structural change is also considered a chemical reaction as it requires the deconstruction of a covalent bond to allow a new covalent bond to form, resulting in a configuration that is the mirror image of the first structure. Most organic molecules that comprise asymmetric or chiral carbon exhibit this phenomenon, and therefore are named chiral. OH

O

OH

N

Keto

Enol

Oxim

NH2

NH

N

NH

Imine

O

Nitroso

O

OH

HN CI

Amine

N

N CI

Lactam

Lactim

Figure 1.6 Examples of tautomeric reactions. Source: Braga et al. 2014 [25]. Adapted with permission of Bentham Science Publishers Ltd.

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation 17 CH3 16 H3C

14 CH3 O

O 11

H3C 12 15

10

3 N S

8

9 N

3a

4 5

O

16 H 3C

2 1 N

7a

7

O

14 CH3 O

11

10

H 3C 12 15

6

13

H

13

9 N

3 N S

8

3a

4 5

2 1 N H

7a

7

6

O CH3 17

Figure 1.7 Tautomeric forms of omeprazole; 5-methoxy tautomer in form V (right), and 6-methoxy tautomer in form I (left). Source: Bhatt et al. 2007 [27]. Adapted with permission of Royal Society of Chemistry. L

O N H

O

O

N

N

H O

O

H O O

D

O

Figure 1.8 Enantiomerism of L-thalidomide and D-thalidomide.

N H

Enantiomerism is a crucial property in the pharmaceutical and pharmacological fields, as nearly 50% of the drugs are chiral and 90% of them are marketed as racemate equimolar mixtures (containing both isomers). Moreover, different isomers exhibit different pharmacokinetic and pharmacodynamic properties. The advancement in chiral drug design has produced safer and more effective candidates [28]. One of the examples of chiral or enantiomeric drugs is thalidomide which displays two enantiomers, (S)-thalidomide and (R)-thalidomide (Figure 1.8). Thalidomide was used for motion sickness, but it turned out that l-isomer is teratogenic and the therapeutic activity comes from the d-isomer. 1.1.5.3

Pseudopolymorphism

The utilization of the term pseudopolymorphism supports part of the definition of polymorphism “having the same chemical composition” as it describes molecules with different crystal structures caused by the presence of a secondary

1.2 Polymorphism Impact on Drug/Excipient Properties

Figure 1.9 Representation of pseudopolymorphism events which involve the incorporation of a heterostructure within the crystal lattice compared to polymorphism.

Polymorphism

Pseudopolymorphism

Hydration Drug

Solvation Water

Solvent

Cocrystal Coformer

(a)

(b)

Figure 1.10 Packing polymorphism of caffeine: glutaric acid cocrystal, (a) FI and (b) FII. Source: Trask et al. 2005 [33]. Adapted with permission of American Chemical Society.

heterostructure within the crystal lattice (e.g. water, solvent, coformer, etc.) (Figure 1.9) [12]. However, the U.S. Food and Drug Administration (FDA) still consider hydrates, solvates, cocrystals, and amorphous phase as polymorphs [29–31]. However, some of these forms such as cocrystals tend to be polymorphic with their own structure [32]. For example, caffeine: glutaric acid cocrystal displays enantiotropic packing polymorphism; stable FII and metastable FI (Figure 1.10) [33, 34].

1.2 Polymorphism Impact on Drug/Excipient Properties Different molecular conformation or packing for a compound provides specific characteristics and hence it necessitates formulation to utilize certain handling,

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processing, or storage procedures. These characteristics can be categorized as physicochemical or mechanical properties, which are described in detail further.

1.2.1

Physicochemical Properties

Physicochemical properties are related to both physical and chemical features of molecular structure (e.g. presence of hydrophobic/hydrophilic groups, interand intramolecular bonding, crystal structure, etc.). Physicochemical properties include melting point, density, hygroscopicity, refractive index, surface activity, crystal habit, color, physical stability, and performance properties. Later involve solubility, dissolution rate, and bioavailability (which are interrelated). These properties are further described in detail due to their importance in pharmaceutical development (see Section 2.3). The difference in melting points originates from the variation in molecular interaction and lattice energy among polymorphs. Refractive index can be defined as the ratio of light speed in a vacuum to the speed of light within the crystal at a certain wavelength and temperature. Anisotropic crystals obtain multiple refractive index values, and hence are called birefringent, whereas isotropic crystals obtain a single refractive index, and thus are called non-birefringent. Refractive index is mainly determined by crystal structure and molecular arrangements; therefore, different polymorphs will exhibit different refractive index and birefringence. This property can be detected by polarized light microscopy, and it is used to identify different polymorphs or phase transitions Crystal color and shape are primarily dependent on the molecular conformation or packing in the crystal lattice which results in different macroscopic orientation within the crystal structure. Crystal color can be determined depending on how the light is absorbed and reflected by the crystal lattice, which changes according to lattice conformation [35, 36]. Crystal morphology is dictated by the crystal growth mechanism of crystal nuclei faces. Therefore, the growth of crystal nuclei having different crystal packing results in morphological variations. Triamcinolone exhibits three polymorphs and a monohydrate having different crystal shapes (Figure 1.11) [15] Hygroscopicity is the measure of moisture uptake, sorption, and retention from the atmosphere (humidity), neighboring liquids (mostly water), or solids in contact. Both thermodynamic and kinetic factors are involved in this process. Hygroscopicity is a crucial property in pharmaceutical development as it has a direct impact on other properties such as solubility, dissolution rate, and stability [37]. Dynamic vapor sorption is a very popular technique in assessing the hygroscopicity of materials; it measures the mass change as a function of relative humidity level (RH, %) at isothermal conditions, called sorption isotherms [38]. Different polymorphs can show varied moisture uptake behavior. This can be attributed to the variation in lattice structure, intermolecular interactions, and positioning of hydrophilic/hydrophobic molecular arrangement. Dynamic vapor sorption analysis of amisulpride forms I and II (Figure 1.12) shows that moisture uptake by form II is lower compared to that of form I [39].

1.2 Polymorphism Impact on Drug/Excipient Properties

(001)

(20–1) (011)

(011) (0–11)

(001)

(011)

(101)

(–101) (0–11)

(a)

(b)

50 μm

Form A

(110)

(c)

50 μm

(d)

50 μm

Form B

(01–1)

Form C

50 μm

MH

Figure 1.11 Predicted morphology and optical images of triamcinolone form A, B, C, and monohydrate (MH). Source: Wang et al. 2017 [15]. Adapted with permission of American Chemical Society. 0.35

Change in mass (%)

0.30

Form I Form II

0.25 0.20 0.15 0.10 0.05 0.00 0

20

40

60

80

100

RH (%)

Figure 1.12 Dynamic vapor sorption isotherm of amisulpride forms I and II at 25 ∘ C. Source: Zhang and Chen 2017 [39]. Adapted with permission of Elsevier.

1.2.2

Mechanical Properties

Mechanical properties are related to crystal behavior while subjected to mechanical stress such as compression or shear forces. These properties include plasticity, tensile strength, compressibility, or overall manufacturability. Different polymorphs that exhibit variations in terms of morphology, structural geometry, presence of defects or slip planes, density, or lattice strength mostly obtain different mechanical properties.

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Morphology change caused by polymorphism can affect flowability and compressibility. However, the crystal shape can be changed while preserving the polymorph integrity using various crystal engineering approaches [40]. The presence of slip planes has been linked by many reports to superior compactability. Slip planes are comprised of crystallographic planes having the most vulnerable bonds attaching them to other planes. Slip planes accommodate compression force and use it to slide over neighboring planes, improving compressibility and deformation. However, active slip planes should be distinguished because the presence of weak hydrogen bonding across the plane can prevent plane sliding, thereby making it inactive. For example, ranitidine FI, although it contains slip planes within its crystal lattice, displays poor deformation which may be attributed to the presence of weak hydrogen bonding (Figure 1.13) [41]. The most popular example is the change in mechanical properties among paracetamol polymorphs. Metastable orthorhombic form II crystal structure is superior in compressibility compared to the monoclinic form I [42]. Therefore, polymorphic composition should be monitored and controlled before initiating direct compression of paracetamol. Form II obtains slip planes which enhance its deformation and plasticity, producing more coherent compacts [43]. Furthermore, sulfathiazole form III tablets were found to have the highest crushing force due to the presence of the slip plane in form III crystal structure which grants it excellent compressibility [44]. Variations in molecular density due to different crystal packing between polymorphs can also affect compressibility. It is proposed that stable polymorphs obtain denser packing and stronger intermolecular interactions which are more difficult to deform as in the case of metoprolol [45]. Other reports also found that true density negatively impacts compressibility but improves compactability, which results in higher tensile strength, as was the case with ranitidine polymorphs [46]. In addition, clopidogrel exhibits high true density in metastable form I, which results in low compressibility; yet it displays better properties for tableting compared to the less dense stable form II. It should be noted that form II structure involves stronger hydrogen bonding, which is reflected by the higher heat of fusion compared to form I.

(a)

(b)

Figure 1.13 Crystal structure of ranitidine form I with (a) slip planes (yellow box) and (b) presence of weak hydrogen bonding (yellow dots). Source: Khomane and Bansal 2013 [41]. Adapted with permission of Elsevier.

1.2 Polymorphism Impact on Drug/Excipient Properties

(a)

(d)

1000 μm

1000 μm

(b)

(e)

1000 μm

1000 μm

(c)

(f)

1000 μm

1000 μm

Figure 1.14 3D images of clopidogrel polymorphs after compression, (left) form I, and (right) form II, (a) and (d) are the overall particle content in tablets, (b) and (e) uncompressed or particles present in tablet core; (c, f ) are compressed particles at the surface on the tablet. Source: Yin et al. 2016 [47]. https://creativecommons.org/licenses/by/4.0/(CC BY 4.0).

Further investigation was performed on clopidogrel compressibility using synchrotron radiation X-ray microtomography (SR-μ CT) and 3D reconstruction analysis. This revolutionary and nondestructive method enables the visualization and quantification of deformation after compression. Form II shows better deformation and compressibility compared to form I. Moreover, the distribution of particles within the tablet was different among the two polymorphs. Deformation was assessed on the basis of change of sphericity, volume, and ellipsoid parameters. Deformation of form I particles was found to be mediated by plastic–elastic mechanism, while form II exhibits brittle fracture mechanism [47]. SR-μ CT tomographic 3D images show how form I disc-shaped particles got flattened, while form II particles were crushed and lost their shape (Figure 1.14). 1.2.3

Impact of Polymorphism on In Vivo Performance

The development of drugs with appropriate in vivo performance and pharmacokinetics to satisfy the regulatory guidelines is paramount in the pharmaceutical industry. Furthermore, the selection of a specific polymorph of API for final

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product manufacturing could have a significant impact on the in vivo profile of that drug product. Polymorphism can alter both solubility and chemical stability of the compound, which are great influencers of bioavailability. 1.2.3.1

Effect of Polymorphism on Solubility

Solubility, from the perspective of solid polymorphism, is a thermodynamic concept that describes the case where solid-state solute and liquid solvent coexist in equilibrium state. Equilibrium state indicates that the two phases have equal temperatures, pressures, and free energies. Solubility is an intensive property which is independent of the amount of solute but rather is affected by the nature of the solid phase. Poorly soluble compounds are commonly divided into brick dust or grease ball materials. The brick dust materials have strong lattice energies which make it difficult to break the structure within the solvent. Grease ball materials are extremely hydrophobic and have low affinity to aqueous media including gastrointestinal fluids. The two effects could be concomitant in the case of NCEs with poor solubility, necessitating the application of further formulation techniques. Intrinsic solubility is governed by the Gibbs free energy of solubilization (ΔGsol ), which should obtain a value less than 0 for the solubility reaction to take place. ΔGsol can be mathematically obtained using the general Eq. (1.2). ΔGsolu = ΔHsolu − TΔSsolu

(1.2)

where ΔHsolu is the solubility enthalpy, ΔSsolu is the entropy of solubilization, and T is the temperature in kelvin. Solubilization enthalpy (ΔHsolu ) can be defined as the amount of energy, or heat, absorbed or released to initiate the solubility reaction. ΔHsolu could have a positive or a negative value, if the reaction is endothermal or exothermal, respectively. ΔHsolu is mainly composed of two parts (Eq. (1.3)), crystal lattice enthalpy ΔHlatt , which is related to the cohesion energy within solute particles, and solvation enthalpy ΔHsolv which is related to solute–solvent interactions. ΔHsolu = −ΔHlatt + ΔHsolv

(1.3)

ΔHlatt , in the case of solid-state materials, where pressure and volume change can be neglected, is the energy required to form the lattice structure when gaseous phases bond together. Since bonding formation is an exothermic process, ΔHlatt always obtains a negative value; hence, −ΔHlatt is always positive. Equation (1.3) involves two competing forces at equilibrium state, the solute–solute bonding ΔHlatt , which is governed by the physical bonding within the crystal structure, and solute–solvent bonding ΔHsolv which is related to the solute–solvent chemical affinity or polarity (high affinity means ΔHsolv is highly negative, while low affinity means a low negative or a positive value). If solute–solvent affinity is high enough to overcome lattice energy, the negativity of Hsolv overcomes the −ΔHlatt value. This will result in a negative value of ΔHsolu , meaning that overall solubilization is exothermal. Moreover, the solubilization will occur spontaneously as, according to Eq. (1.2), the ΔGsolu value will obtain a negative value. On the other hand, if the lattice energy, or −ΔHlatt value, is high enough to overcome ΔHsolv , ΔHsolu will obtain a positive value. In this case, based on

1.2 Polymorphism Impact on Drug/Excipient Properties

Eq. (1.2) and depending on the entropy–temperature value TΔSsolu , two scenarios are possible. The first is that TΔSsolu is high enough to overcome ΔHsolu , leading to a negative ΔGsolu , which means that solubilization is endothermic and can occur spontaneously provided enough energy is supplied to the reaction. The second scenario happens if TΔSsolu cannot overcome ΔHsolu , resulting in a positive ΔGsolu , and thus solubility does not take place. Therefore, ΔHsolu is crucial for the formulators, and it is targeted to enhance the solubility either by reducing lattice energy (decreasing −ΔHlatt ) or by increasing the affinity between the solute and solvent (decreasing ΔHsolv ). Lowering lattice energy is performed by manipulating the solute physical structure, such as converting to amorphous form, solvate, salt, cocrystal, or the polymorph. Nevertheless, changing the solute–solvent interaction is associated with changing chemical composition, e.g. complexation, ionization, micellar solubilization, and prodrug formation. Polymorphism, which results in different molecular conformation or packing, leads to a change in the lattice energy value and therefore a change in the solubility. The metastable form at a certain temperature has lower lattice energy than the stable form, and hence has higher solubility at the same temperature. In addition, the solubility differences between several polymorphs have been investigated and it was found that the solubility ratio between metastable and stable forms ranges from 1: 1–10 times [48]. Form C of phenylbutazone is 1.5 times more soluble than form A. Ritonavir, a protease inhibitor, has two polymorphs, the stable form II and metastable form I, which have significant solubility differences, approximately 4 : 1 in ethanol/water mixtures [49]. Conventional solubility determination has been discussed by many reviews and it involves preparing a saturated solution of the desired solute–solvent system using a shake-flask method. This is done by adding excess of solute to the solvent, agitation, or stirring for a certain time at a certain temperature and pressure, and subsequent filtration. If the solvent is aqueous, pH measurement or adjustment must be performed using a pH meter, and standard buffer systems, respectively. The next step is to determine the concentration of aliquots, which is measured using gravimetric, spectroscopic, or chromatographic techniques. Commonly, the solubility is investigated using the range of solvents (mostly water, buffers, and ethanol), temperatures, and pH level [50]. The process is exhaustive, stagnant, and requires a decent amount of sample, which is difficult to supply in the early stages of drug development. In addition, it requires expertise in the solid–liquid equilibria (SLE) field, including phase rule, phase diagrams, and thermodynamics. Moreover, solubility determination of metastable polymorphs is very tricky in terms of physical stability as metastable polymorphs tend to undergo solution-mediated phase transformation and convert to the stable form. The solubility of polymorphic materials can be determined using thermal methods or be predicted using computational and mathematical models. Experimental thermal data can be utilized assuming that crystal lattice cohesion is the only controlling factor. In this case, solubility is referred to as ideal solubility (Sideal ). Lattice energy can be represented as the melting or fusion enthalpy, neglecting heat capacity change after melting, and used to calculate the

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ideal solubility using the van ’t Hoff equation (1.4). The equation is a deferential correlation between solubility/temperature change and enthalpy of fusion. d ln Sideal ΔHfus = dT RT 2

(1.4)

where ln S is the natural logarithm of fractional solubility, T is the temperature in kelvin, R is the ideal gas constant, and ΔHfus is the enthalpy of fusion, which can be also referred to as enthalpy of melting. Enthalpy of melting can be determined experimentally using differential scanning calorimetry (DSC). Moreover, the van ’t Hoff equation is integrated to produce Eq. (1.5) ) ( ΔHm Tm − T ln Sideal = − (1.5) R TTm where ΔHm is the melting enthalpy and Tm and T are the melting point and temperature, respectively. However, this method discards the contribution of the solvent–solute effect which is necessary to obtain realistic solubility (Eq. (1.6)). ln Srealistic = ln Sideal − ln 𝛾

(1.6)

where 𝛾 the activity coefficient of solute in the solvent. The van ’t Hoff equation (1.7) can be also employed to calculate the enthalpy of solubilization, depending on two solubility values at two distinct temperatures which are determined either experimentally or computed via prediction models. In this case, the solubility values are considered realistic, and thus the enthalpy value can be referred to as solubilization instead of melting enthalpy as the solvent contribution is present [51]. ( ) S1 T1 T2 ΔHsolu = R ln (1.7) T1 − T2 S2 Solubility prediction of NCEs before conducting experimental measurement can save a lot of time and effort by avoiding to deal with extremely low-soluble candidates and focusing on the development of more suitable compounds. Quantum-mechanics-dependent computational methods such as lattice energy minimization algorithms combined with molecular dynamics (MD) can determine predicted solubility curves [51]. Moreover, mathematical models such as modified Apelblat equation, λh equation, van ’t Hoff equation, ideal model, Wilson model, nonrandom twoliquid model (NRTL), and universal quasichemical model (UNIQUAC) are used to predict solubility curves as a function of temperature (kelvin). The calculated values are commonly used to correlate experimental data and to calculate solubilization enthalpy, entropy, and Gibbs free energy. For example, experimental solubility of pioglitazone form II [52] in several solvents (Figure 1.15a) was calculated as a function of temperature and correlated to 𝜆h, van ’t Hoff, and ideal model with good agreement. Furthermore, the van ’t Hoff equation was applied to calculated solubilization enthalpy, entropy, and Gibbs free energy depending on the linear relationship between the natural logarithm of experimental solubilities and reciprocal of temperature (Figure 1.15b). Enthalpy

1.2 Polymorphism Impact on Drug/Excipient Properties

18 16 14

103x1

12 10 8 6 4 2 0 –2 280

290

310

320

330

0.0034

0.0035

0.0036

300 T/K

(a) –4 –5

Inx1

–6 –7 –8 –9 –10 –11 0.0031 (b)

0.0032 0.0033 –1

T /K

–1

Figure 1.15 (a): Experimental solubility of pioglitazone form II in ◾, N,N-dimethylacetamide; •, methanol; ▴, dimethyl sulfoxide; ▾, acetic acid. Solid lines are predicted values using the van’t Hoff model. (b) van’t Hoff plot: natural logarithm of experimental mole fraction solubility vs reciprocal of temperature (K) of pioglitazone form II. Source: Tao et al. 2013 [52]. Adapted with permission of American Chemical Society.

of solubilization can be calculated from the slope of the van’t Hoff plot. Similarly, the polymorphic solubilities of buspirone hydrochloride [53], mefenamic acid [54], and clopidogrel [55] in several solvents were investigated experimentally and correlated with the mathematical models. 1.2.3.2

Effect of Polymorphism on Dissolution Rate/Solubility Kinetics

Dissolution is the kinetic definition of solubility and is related to the mechanism or the way the solute dissolves in the solvent. Assessment of dissolution rates or kinetics is paramount during formulation development studies, especially for solid-state formulations.

17

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

Diffusion constant and kd

Bulk solution Ct

Saturated solubility Cs

Figure 1.16 A representation of diffusion layer dissolution, solute particles (black shapes) obtain a diffusion layer (dark blue areas) within solvent (light blue). In addition, the effect of particle shape and size on the surface area is presented.

Dissolution rate can be represented mathematically as the change in solute mass with time (dm/dt). Moreover, for pharmaceutical proposes, dissolution is widely determined using the Noyes–Whitney equation (1.8) which is derived on the basis of the diffusion layer theory [56]. The theory (Figure 1.16) predicts the formation of a saturated solution layer over the solute’s solid particles which acts as an intermediate phase through which the solute molecules are diffused to bind with the solvent molecules, and hence the name diffusion layer. dm (1.8) = Akd (Cs − Ct ) dt where A is the solute surface area, k d is the rate constant, and Cs is the saturated concentration or solubility of the drug in the solvent or biological fluid, and Ct is the drug concentration at time t. The equation states that the dissolution rate is proportional to the surface area, solubility, and to the concentration difference between the diffusion layer and solvent bulk. Surface area is basically related to particle size, shape, and surface; therefore, particles with elongated shapes, having a small particle size, or a rough surface, will obtain a relatively large surface area, and hence a large dissolution rate. Solubility is a major factor determining the dissolution rate, which is discussed in detail in Section 2.3.1. In addition, concentration difference and rate constant k d control the extent and rate of diffusion from saturated layer to bulk solution. Rate constant is related to diffusion coefficient D and the thickness of diffusion layer (Eq. (1.9)): (1.9)

kd = D∕h 2

Diffusion constant (unit: m /s) is the proportionality factor between molecular flux from the diffusion layer and the concentration difference between diffusion layer and bulk solution. Diffusion constant follows the Arrhenius equation as follows (Eq. (1.10)): −E D = D e A∕(𝜅T) (1.10) 0

1.2 Polymorphism Impact on Drug/Excipient Properties

where D0 is the maximum diffusivity at infinite temperature, EA is the diffusion activation energy (unit: J/atom), T is the temperature (kelvin), and 𝜅 is the Boltzmann constant. From the equation, it can be noticed that temperature is also a factor in determining the dissolution rate through the diffusion constant. The dissolution test of pharmaceutical dosage forms is performed using four pharmacopeial apparatuses. Sink condition, which means dissolution medium volume, should be at least five times larger than the volume required to obtain a saturated solution, and is mandatory while performing dissolution testing. The purpose is to avoid reaching saturation levels in the bulk solution, which will significantly slow down the dissolution process [57]. Intrinsic dissolution rate (IDR) testing involves compressing the powder of the solute into flat disks which are held by rotating dies and through which a single surface with known area is exposed to the dissolution medium. This process eliminates the impact of particle size and shape and hence enables the formulator to compare the effect of crystal arrangement or lattice energy between different polymorphs. Polymorphism can impact the dissolution rate of drugs by affecting solubility due to the change in lattice energy (see Section 2.3.1). In addition, polymorphism can affect crystal shape, thus affecting the particle surface area [15]. Examples in the literature with respect to the dissolution of polymorphic drugs such as carbamazepine [58], spironolactone [59], phenobarbital [60], triamcinolone (Figure 1.17), and mebendazole [61] reveal that metastable forms have a superior dissolution rate over stable forms. However, the metastable form of theophylline anhydrate was surprisingly found to have a significantly slower dissolution rate compared to the stable form. It was found that the metastable form rapidly converts to the monohydrate form in the medium which has a slow dissolution rate [62]. 25

Concentration (μg/ml)

20 Form C

15

Form B Form A MH

10

5

0 0

60

120

180

240

300

Time (min)

Figure 1.17 Dissolution profile of triamcinolone forms A, B, C, and monohydrate (MH). Source: Wang et al. 2017 [15]. Adapted with permission of American Chemical Society.

19

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

1.2.3.3

Effect of Polymorphism on Bioavailability

Bioavailability is represented as drug concentration levels in the blood versus time and is expressed as the area under the curve (AUC; concentration X time). Both solubility and dissolution rate are crucial for bioavailability. This is mostly emphasized in the Biopharmaceutical Classification System (BCS), which divides drugs into four classes based on solubility and permeability level (Table 1.2). BCS class 2 (majority) and class 4 exhibit poor bioavailability and thereby reduced therapeutic response. Polymorphism modification, as discussed earlier, can improve bioavailability by enhancing both solubility and dissolution rate [63] as it influences both lattice energy and crystal habit (Figure 1.18). Chloramphenicol palmitate form B shows a significantly higher blood level in humans compared to form A. Following the administration of a single oral dose using form B, mean blood serum concentration of 22 mcg/ml was observed compared to 3 mcg/ml in the case of from A [64]. Moreover, three mebendazole polymorphs (A, B, and C) were tested in vivo for pharmacokinetics, brain penetration in the case of glioblastoma, and medulloblastoma (central nervous system [CNS] cancers). Polymorphs were separately administered via oral route into the GL261 glioma mouse model to assess therapeutic and toxic effects; polymorph concentrations in plasma and brain were analyzed using liquid chromatography/mass spectroscopy LC/MS. Oral administration of pure forms B or C has improved Table 1.2 Biopharmaceutical classification system. Class

Solubility

Permeability

Class 1

High

High

Class 2

Low

High

Class 3

High

Low

Class 4

Low

Low

Bioavailability

Absorption

Dissolution

Distribution

Crystal shape

Metabolism

Particle size

Polymorphism Solubility Solvation ethalpy

Exertion

Lattice enthalpy

Diffusivity

Figure 1.18 A schematic presentation showing different factors affecting solubility, dissolution, and bioavailability. Both solubility and dissolution rate are major integrated factors for bioavailability. Polymorphism has a dual impact on both lattice enthalpy and crystal shape affecting both solubility and dissolution.

1.2 Polymorphism Impact on Drug/Excipient Properties

Plasma level

(b) Distribution of MBZ polymorphs MBZ-A MBZ-B MBZ-C

3000 2000 1000 0 0

5

10 15 Time (h)

(c)

Conc. (ng/ml or ng/g)

Conc. (ng/ml)

(a)

2500 2000

MBZ-A MBZ-B MBZ-C

1500 1000 500 0

20

n a n a n a ai m ai m ai m Br las Br las Br las P P P At 6 h

Survival of GL261 glioma Percent survival

100

Con (m=29.5d) MBZ-A (m=29d) n = 6 MBZ-B (m=45d) n = 5 *P = 0.04 MBZ-C (m=48.5d) n = 6 **P = 0.004 MBZ-B vs. MBZ-C P = 0.72

80 60 40 20 0 0

20 40 60 Days after tumor implantation

Figure 1.19 In vivo performance of mebendazole polymorphs (A, B, and C). (a): plasma concentrations of polymorphs, (b): distribution of polymorphs between plasma and brain tissues, and (c): therapeutic impact of polymorphs represented by GL261-uc glioma implanted mice survival percent vs time (Kaplan–Meier curves) after mebendazole administration compared to placebo control and P values of forms B and C versus control and form B vs C are mentioned. Median survival days (m) for each form are mentioned. Note: One mouse died after one-day administration of form B due to its toxicity; therefore, n = 5. Source: Adapted from [65] after permission and modification.

survival in mice compared to form A. While both forms reach high plasma levels (high AUC) effective concentration level (above IC50 ) in brain tissues, form C is more efficient in crossing blood–brain barrier (BBB) than form B with higher brain-to-plasma ratio (B/P) of 0.82 (Figure 1.19). Nevertheless, form B displays high toxicity compared to other polymorphs [65]. It is highly implausible that polymorphs retain their crystal structure after dissolving in gastrointestinal liquids. However, the variation in pharmacokinetic and therapeutic effects substantially pertains to the in vivo performance of polymorphs. Moreover, mebendazole is a class II drug, meaning that solubility (dissolution) is the rate-limiting step in drug absorption. Indeed, the in vitro performance of mebendazole polymorphs [61] shows that the order of dissolution rate is C > B > A. This could help to explain polymorphic behavior in vivo; more specifically, the superior BBB penetration of form C could be due to the highest dissolution rate among other polymorphs. Oral administration of methoxyflavone (a nonsteroidal anabolic isoflavone) in rats shows that the metastable form B has a faster absorption rate as it reached maximum concentration after 5 minutes compared to 29 minutes in stable form A (Figure 1.20). However, form A displays a higher AUC and C max [24].

21

1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

Figure 1.20 Plasma concentration–time curves of methoxyflavone polymorphs forms A and B. Source: Adapted from Gong et al. 2016 [24] after permission.

20 Form A Form B

15 Peak area

22

10 5 0 0

20

40

60

Time (min)

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation Polymorphic forms of active ingredients can be obtained deliberately, or serendipitously; also, it can transform immediately or sluggishly at any stage of drug development or manufacturing. Polymorphic transition may be triggered using the simplest processing method, e.g. mixing, drying, milling, or even with time. In contrast, other polymorphic transformations require the existence of extremely specific conditions of temperature, or pressure such as the case of monotropic polymorphs of rotigotine [66, 67]. The main difficulty is that most of the polymorphic transition cases take place spontaneously and in an unexpected manner. This is mainly due to the lack of thermodynamic data for API, and less evidence of screening or equilibrium testing during the early stage of drug development, or API has a relatively stable (or stubborn) kinetic polymorph. The presence of a stubborn polymorph is mostly observed in monotropic polymorphs. The classical example to represent this case is of ritonavir, a drug first marketed by Abbott; the dosage form contained form I API. However, a thermodynamically more stable form II started to appear and replaced form I, which caused a regulatory catastrophe as batches failed the dissolution test owing to the poor solubility of form II compared to form I [49, 66]. Therefore, understanding of such behavior is crucial in process design and product development. Two main mechanisms are involved in polymorphic transformation: reconstructive mechanism (nucleation and crystal growth) and topotactic/epitactic mechanism. The reconstructive mechanism is one of the most common for polymorphic transitions and it causes the breakdown of the original crystal structure. The topotactic/epitactic mechanism is responsible for the singlecrystal-to-single crystal (SCSC) polymorphism where polymorphs have similar structures [68]. Epitaxy indicates that there is crystal lattice matching between the two interconverting phases, leading to buildup of the new form on the interface of the original, parent, lattice. For example, fingolimod hydrochloride under elevated temperature undergoes single crystal – single crystal form I to form II polymorphic transformation [69]. In either case, the transformation involves reaching an equilibrium state between two competing phases, and this is either driven thermodynamically or kinetically. Transformations are related to many factors which need to be taken

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

into consideration, such as number of polymorphs, enantiotropic/monotropic relation, degree of crystallinity, presence of an amorphous or a disordered phase, hygroscopicity, solubility, dissolution rate, nucleation and growth rates, or melting point, etc. Since the late 1990s, process-induced transformation (PIT) has gained a lot of interest among researchers. To gain a comprehensive understanding about PIT, it is extremely valuable to cover both thermodynamic and kinetic aspects of polymorphic transition under process conditions [70]. PIT is based on the fact that any process can exert thermal or mechanical force on drug particles. This force can challenge the physical structure and bring it inward or outward equilibrium. This equilibrium can be influenced by the presence of other components, such as excipients, solvents, or humidity. At the end of the process, the force impact on the physical structure is withdrawn; however, the physical structure is either resistant to force which will return to its original equilibrium, and remain intact, or is vulnerable to force, bounded by the new equilibrium, and undergoes transformation. Five scenarios can take place during a PIT event, (Figure 1.21); 1. The metastable form is driven into equilibrium and after force dissipation it transforms to the more thermodynamic stable form. 2. The stable form is driven into equilibrium by force, and after dissipation, the stable form relaxes back to its original arrangement. 3. The system is brought into equilibrium region where the metastable becomes more thermodynamically favored, and after force dissipation, the form is trapped as the kinetic stable form. 4. Another type of force (e.g. pressure) could produce a new type of equilibrium, either forming a new component or the transition nature is changed (e.g. from enantiotropic to monotropic, resulting in an irreversible transition). 5. During the process, a heterogeneous component is added to the system which takes part in a new equilibrium, producing a multicomponent form or it acts as a reaction intermediate which facilitates the formation of a new form. All these scenarios are primarily dependent on the following: • Nature of the molecule: thermodynamic aspects, e.g. crystal structure, lattice energy, solubility, and kinetic aspects, e.g. nucleation rate, growth rate, and relaxation time; • Nature of processing: e.g. thermal, mechanical, compressional, and process kinetics such as force application rate, force dissipation rate; • Presence of additives: e.g. moisture, solvents, excipients which may cause a change in the composition of the system and is classified as the thermodynamic factor. 1.3.1 1.3.1.1

Process-induced Transformation Types Grinding-induced Transitions

Grinding provides mechanical stress to the solid particles constituting the system. Moreover, thermal impact can rise during the process due to friction-forcemediated temperature. Grinding-induced transitions are mostly mediated by the formation of an amorphous or a disordered phase [71].

23

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

(a)

(d)

or

Force 1 (b)

Force +

Relaxed

Trapped

or Solvent

Force 2

Relaxed

Trapped

(c)

Relaxed

(e)

Trapped Force 3

Figure 1.21 Chart summarizing all possible PIT mechanisms; (a): starting compound either metastable (purple) or stable (black). (b): applying force to (a) will result in equilibrium, and after force dissipation (green arrows) the system either will trap the force and result into kinetic stable form or it will relax into thermodynamic stable form. (c): Applying different force (force 2) could result in a new equilibrium having new component, in this illustration, a new metastable form exists. After force dissipation, the system will follow same steps as (b). (d): New equilibrium is formed due to the presence of a heterogeneous component (solvent, moisture, additive, etc.), which either participates as a discrete component or as an intermediate. Acting as an intermediate could result in producing a different equilibrium which enables forming a normally inaccessible phase, such as monotropic metastable forms. (e): Another type of force may transform the equilibrium into monotropic transition which is irreversible.

During grinding, mechanical force is injected into the crystal lattice which develops a local strain. As the force increases, the strain zone increases or a new strain zones appears. If the structural and energetic differences between the two phases are small, the lattice accommodates the energy and forms a new arrangement which obtains higher potential energy (metastable form). However, in most cases, the structural and energetic differences are large enough, so the developed strain overcomes lattice cohesion resulting in the crystal destruction and producing either deformed small crystals of the new phase, or an amorphous phase which, in later stages, recrystallizes to the new phase [70]. Ribavirin enantiotropic R-II stable form at room temperature (above T g ) transforms completely to the metastable form R-I after milling for 15 minutes (Figure 1.22), while no transformation was observed when unprocessed R-II was kept at above transition temperature, around 70 ∘ C, for seven days.

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

Normalized intensity (a.u.)

Cryomilled 120 min Cryomilled 60 min 270 min 180 min 60 min R-II (before milling) Simulated R-I Simulated R-II 6.0

9.4

12.8

16.2

19.6 23.0 Position 2θ (°)

26.4

29.8

33.2

Figure 1.22 PXRD pattern showing phase transformation of ribavirin R-II to metastable R-I after 60, 180, and 270 minutes of milling; and amorphization of R-II after cryomilling for 120 minutes. Source: Vasa and Wildfong 2017 [72]. Adapted with permission of Elsevier.

This indicates that mechanical stress introduced by milling is necessary to overcome the energy barrier for the transition. However, cryomilling at −196 ∘ C, below T g to exclude temperature effect, of R-II resulted in an amorphous phase after two hours, suggesting a reduction in molecular mobility which prevented the recrystallization process (Figure 1.22). Moreover, this indicates that the milling-induced conversion is mediated by formation of the amorphous phase [72]. Excipients can influence polymorphic stability during co-milling. For instance, the effect of organic (starch and hydroxy propyl cellulose (HPC) and inorganic (silicone dioxide and calcium biphosphate) excipients on polymorphic transition of gabapentin was compared during milling with excipient free samples. The results show partial conversion of stable form II to metastable form III after milling only for the samples containing excipients. In addition, the transition level is dependent on excipient type, but there was no impact of type of excipient (organic vs inorganic) on the transition degree. The presence of CaHPO4 and SiO2 produced 39 ± 0.40, and 8.7 ± 0.12 mol% of FIII, respectively. Moreover, the presence of starch and HPC produced 21 ± 0.50 and 33 ± 0.31 mol% of FIII, respectively [73]. 1.3.1.2

Granulation-induced Transitions

The granulation process is defined as agglomeration of powder into larger aggregates termed as granules. Methods used for granulation are dry, wet, and melt granulation; and it involves the use of mechanical and thermal forces. In addition, the presence of a solvent in wet granulation changes the thermodynamic composition of the system, leading to the evolution of solution-mediated transformation.

25

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

Wet Granulation Wet granulation can be performed in the pharmaceutical

industry using several techniques and instruments; however, this chapter restricts the description to the most commonly used techniques. And these include high-shear granulation, twin-screw granulation, and fluid-bed granulation. These techniques are complex processes and generally constitute wetting the powder with binding liquid (granulation liquid) to form large agglomerates, then applying shear force (not in fluid-bed granulation) to break the agglomeration into granules, and applying thermal energy to dry the granules. Both high-shear and twin-screw granulation share similar wetting steps, but vary in the type of applied shearing force. The high-shear granulator, as indicated by the name, applies a high level of shear force using rapid rotating blades, called impellers, whereas the twin-screw granulator applies a lower shearing force using two oppositely revolving screws. Along the screw’s axis, different configurations can be present to function as conveying, mixing, and shearing components. Fluid-bed granulation is performed by suspending the powder in a flowing air stream called a fluid bed, inside a vessel while granulation liquid is sprayed, which results in forming larger aggregates in a stage called spraying. Subsequently, the drying stage is performed by increasing inlet air temperature. Fluid-bed granulation has advantages in obtaining homogeneous granule size distribution compared to other methods. Each technique has key process parameters that affect physicochemical properties of API, including polymorphism (Table 1.3). It is crucial to understand the impact of each parameter on triggering or preventing polymorphic change, and on the nature and amount of phase transition to enable the formulators to tune the parameters depending on the desired polymorphic outcome. This is achieved by correlating the parameters with thermodynamic and kinetic factors (Table 1.4) since they govern the polymorphism process. In wet granulation, the solvent can interact with the active material either by incorporating in the crystal lattice forming a hydrate or solvate, or dissolving the material which may lead to the recrystallization of the drug into different phases (e.g. stable, metastable, and amorphous). Metastable to stable phase conversion is very common [74] and is mainly caused by reaching saturation levels of stable form after metastable is dissolved in granulation liquid (the stable form is less soluble than the metastable form). Solubility of the metastable in the selected granulation liquid (at specific temperature) during wetting or drying is an important thermodynamic parameter. Table 1.3 Key process parameters for each type of wet granulation. High-shear granulation

Twin-screw granulation

Fluid-bed granulation

• Granulation liquid addition rate • Wetting time • Mixing speed • Impeller speed

• Granulation liquid addition method • Granulation liquid viscosity • Powder feed rate • Screw configuration • Screw speed

• • • • •

Inlet air temperature Air flow rate Atomization pressure Spraying nozzle position Spraying rate of granulation liquid • Drying time

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

Table 1.4 Thermodynamic and kinetic factors that are related to process parameters and control polymorphism events. Thermodynamic factors

Kinetic factors

• The solubility of drug or formulation components in the granulation liquid • Drying temperature • Amount or composition fraction of the components (i.e. dose or powder/granulation liquid ratio) • Quantity of the mechanical force

• Granulation, drying, sieving time • Dissolution rate of solids in the granulation liquid • Particle size • Nucleation and growth rates of involved phases • Relaxation time

Kinetically, granulation time, dissolution rate of the metastable phase, drying rate, and relaxation times (molecular mobility) of both phases determine the type of recrystallized phase. For example, mefenamic acid undergoes phase transformation from metastable form II to stable form I during the wetting step. The effect of granulation liquid type (ethanol or water) and temperature on transition rate was investigated [75]. As a result, form II conversion rate is proportional to temperature and it is faster in ethanol compared to water, which is attributed to the faster dissolution rate in ethanol [54]. The conversion rate followed the three-dimensional nuclei growth Avrami model (Figure 1.23). If metastable is the desired phase, a granulation solvent having no or little solubilizing properties should be used. However, solvents used in granulation are limited (water and ethanol) due to toxicity issues. Alternatively, avoiding polymorphic conversion is attempted by trapping the phase kinetically and preventing the nucleation of the stable phase. Granulation time (which covers wetting, mixing, and shearing times) is set to minimize the dissolved amount (by slowing time of contact of metastable phase with granulation liquid). Moreover, drying time must be set below the relaxation time of the metastable phase so it does not have enough time to relax back to the stable form when crystallizing out of the granulation liquid. If kinetic control is not sufficient to control the 1.0

0.8 [–In (1 – x)]1/3

Figure 1.23 Transformation rates of mefenamic acid form II to form I following the Avrami model; squares, triangles, and circles represent temperatures 37, 33, and 28 ∘ C respectively. Source: Otsuka 2004 [76]. Adapted with permission of Elsevier.

0.6

0.4

0.2

0 0

100

200 Time, h

300

400

27

28

1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

desired polymorphic form, other granulation techniques can be considered, such as dry granulation. In contrast, stable to metastable transition during wet granulation is less common. However, it can take place if the stable form gets dissolved completely or partially in the granulation liquid. Subsequently, the metastable becomes the stable form (which is thermodynamically favored) either by reaching supersaturation levels or high temperatures (e.g. during drying) which promote the nucleation of the metastable form. Finally, the metastable phase is trapped kinetically, e.g. high drying rate, or nucleation and growth rate of the metastable phase is higher. This type of conversions can be prevented by slowing the drying process or limiting the amount of dissolved stable form. For example, the stable γ-glycine at room temperature converts to metastable α-glycine at high temperatures. D. Davis et al. monitored the phase transformation of glycine using NIR spectroscopy and powder X-ray diffraction (PXRD) during the drying step using a fluid-bed dryer during wet granulation. High drying rates overcome the slow rate of solution-mediated transformation from metastable to stable form and result in the formation of metastable α-glycine after drying [77]. As solvent is present during the process, the formation of solvate or, more commonly, hydrate should not be ruled out. In most of the cases, the hydrate is the stable form under wet conditions, which either remains stable after the process or it acts as an intermediate phase which transforms either into stable or metastable phase. An example of stable – hydrate – metastable phase transformation is piracetam; it has five polymorphs and two hydrates (mono- and di-) and is highly soluble in water. Form III, the most stable, was subjected to varying amounts of water during the wetting stage. As the amount of water increases, more monohydrate formation is observed, even after the drying step. However, when monohydrate was left at ambient temperature (20 ∘ C), metastable form II crystals were detected (Figure 1.24) [78]. In contrast, chlorpromazine hydrochloride shows the example of metastable – hydrate – stable. During wet granulation with water, metastable form II is subjected to phase conversion to form I hemihydrate which dehydrates under room temperature to stable form I [79]. Dry Granulation Dry granulation provides a solvent-free environment and is dedicated to improving the compressibility and flowability of materials that are unstable to solvent presence or to high levels of temperature during the drying process. The process is mainly performed by compressing the powder into large masses using roller compaction or slugging techniques using the dry binders. Subsequently, the large masses are shattered into smaller aggregates or granules [80]. Phase transformation during dry grinding is not common as the employed pressure is relatively low (8 MPa) [81] compared to the pressure used in tableting (200 MPa to 4 GPa), where most of the polymorphic transitions occur. For example, no polymorphic conversion was observed after roller compaction of theophylline [80], whereas theophylline monohydrate undergoes dehydration during tableting at 50–196 MPa and transforms to the metastable anhydrous form which it spontaneously converts to the stable form II phase. It was found that as compression pressure increases at fixed tablet thickness, the

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

FIII

0.48 ml/gsolid

0.56 ml/gsolid Progression of time

Counts (a.u.)

0.02 ml/gsolid

FII 11

13

15

17

19

21

23

25

27

2θ (°)

Figure 1.24 PXRD patterns of piracetam form III after wetting with increasing amount of water showing the formation of monohydrate phase once the water is added. The three patterns from the bottom show monohydrate transformation to metastable FII at ambient conditions. Source: Potter et al. 2017 [78]. Adapted after permission and modification of Elsevier.

mechanism changes from two-dimensional (at 50 MPa) to three-dimensional (at 98 MPa) [82]. Melt Granulation Melt granulation is performed by adding a meltable binder

(polymer or wax) to the powder mixture followed by raising the temperature of the mixture to allow the liquidation of the binder, forming a pasty mass or large agglomerates which are subjected to shear force to break them into granules. This can be accomplished using a jacketed high-shear mixer or hot melt extrusion (HME). Process parameters include granulation temperature, powder feeding rate, and screw or impeller speed. Interestingly, the type, concentration of binder, and drug–binder interaction can have an impact on the degree of transition. For example, caffeine form II to form I transition is more pronounced using a high level of Soluplus , according to DSC analysis (Figure 1.25) where no transition peak was observed [83]. Mechanical and thermal stresses contribute to the transformations during the process. The most common transformations are the enantiotropic thermal transitions where the metastable phase transforms into stable phase at high temperature, which subsequently either converts back or, in most cases, remains trapped after the process. Kulkarni et al. [84] suggested that the dry surrounding

®

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

2.0

(a) 142.56°C 14.70J/g 162.76°C (b)

Heat flow (W/g)

30

139.21°C 14.03J/g

147.86°C (c)

143.03°C 11.96J/g 162.58°C (d)

(e)

144.04°C

138.58°C 8.924J/g

0.2 100 Exo Up

150 Temperature (°C)

200 Universal V4.5A TA Instruments

Figure 1.25 DSC thermograms of (a) transition endotherm of pure caffeine form II into form I, (b) granules of form II and low-level poly ethylene glycol (PEG), (c) form II and low-level Soluplus, (d) FII and high-level PEG, and (e) form II and high-level Soluplus where transition peak has disappeared, indicating that form II is completely transformed into form I after melt granulation. Source: Monteyne 2016 [83]. Adapted with permission of Elsevier.

conditions at metastable formation onset assist in preventing the transformation to the stable form. The researchers have investigated the polymorphic transformation of artemisinin orthorhombic polymorph to high-temperature stable triclinic polymorph using HME. This technique can produce a pure metastable form that resists solid-state conversion over a year, much greater than the metastable formed by regular solvent evaporation techniques. In addition, the HME process is easy to scale up and parameters such as temperature, screw speed, and configuration can be adjusted to control the produced polymorph. All these features make the HME technique an ideal option to be used in the development of resistant metastable polymorphs. 1.3.1.3

Tableting-induced Transition

Tableting-induced transition introduces pressure and thermal and mechanical forces into the system (tablet mass). Pressure influence may generate new transformation routes which produce solid phases that are not obtained during other processes (e.g. thermal) (Figure 1.26). Phase transformation during compression is very common, and it can generate unexpected new phases. For example, caffeine [18, 85], chlorpropamide [86–88], paracetamol [89], and fluconazole [90] all are subjected to phase transformation under high pressure. Factors that mostly control the transition are the crystal structure of the sample and the compression/decompression protocol. Thermodynamically, phases having lower molar volumes tend to be more stable at high pressure.

Solid phase I

a

Phase II

Meltin g

Pressure

Figure 1.26 Pressure–temperature phase diagram of an enantiotropic polymorph compound under the influence of temperature and pressure. Dotted arrows show paths of solid phase transitions; (a) shows that solid phase II to I transition can be mediated by pressure only; (b) shows the transition of I to II path mediated by both temperature and pressure.

So trans lid itio n

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

Liquid b

g

ilin

Gas

Su

bli m

at

ion

Bo

Temperature

However, kinetic factors have a huge role in controlling phase transformation during compression. More specifically, nucleation of the new phase must take place to initiate the reaction. However, due to confined space generated by the increasing pressure, nucleation may be hindered leading to transition being prevented, i.e. the energy barrier cannot be overcome without nucleation. Therefore, high-pressure-induced transformation can take place in the presence of crystal seed [91], under melt (due to friction-mediated heating) [92], saturation conditions [93], or partial presence of amorphous phase [94], all of which grant flexibility in the molecular movements, thus facilitating the nucleation process. Otherwise, in the dry state, transition can occur under exceptional conditions of rapid pressure onset and slow pressure dissipation, which allows more time for molecular rearrangement. For example, paracetamol monoclinic form I to orthorhombic form II interconversion is thermodynamically favored under high pressure (c. 4 GPa) as the latter possesses lower molar volume (by 3.5%). However, it requires a large degree of crystal rearrangement and crushing of many hydrogen bonds which leads to inconsistent transformation results [89]. In addition, the transition kinetics are primarily controlled by nucleation rate. The direct compression of caffeine form I, the metastable form at ambient conditions, resulted in a significant increase in transition to stable form II compared to uncompressed mixtures and regardless of the diluent type. However, the increase in compression force or velocity did not affect the transition degree [95]. Moreover, the transition takes place homogeneously at both tablet core and surface, meaning that distribution of compression force also does not affect the degree of transition. The polymorphic conversion keeps progressing for both powder and tablets, after compression, until reaching a plateau. However, the compression impact caused a significant increase in both degree and progressivity of the conversion [18]. Transition kinetics were assessed experimentally using DSC, and transformation rate curves were fitted in good agreement with the Johnson–Mehl Avrami (JMA) stretched exponential model, which expresses that transformation rate

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

is solely dictated by nucleation rate (excluding growth rate) due to constraint geometry conditions during compression (Eq. (1.11)): X(t) = 1 − e

[ ( )n ] − 𝜏t

(1.11)

N

where X(t) is the transformed volume fraction, 𝜏 N is the form II nucleation rate constant, t is the time, and n is the exponent which is either equal to or less than 1. The study also investigated different types of diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate which deform plastically and are subjected to fragmentation under compression, respectively. Both diluents have less impact on the pressure-induced transition compared to direct pressure (Figure 1.27). 1.3.1.4

Freeze-drying-induced Transition

Freeze drying or lyophilization involves freezing of aqueous solutions of drugs and, subsequently, drying (in multiple steps) is performed by dropping pressure below vapor pressure of the solvent (water) to allow the ice to detach and sublimate away from the solute. Thermodynamically, the freezing process causes the formation of ice crystals, which form a highly concentrated solute state called freeze. On the other hand, the drying process can increase molecular mobility which can disturb the molecular interactions within the solute. The impact of freezing and drying processes on phase transformation is dependent on the type of solute, composition of the formula, solute concentration, solution pH, and Volume fraction of the transformed phase X (%)

32

1.0

0.8

78 wt% CFI-MCC in powder (exp.)

Xreg 78 wt% CFI-MCC in powder (model)

78 wt% CFI-MCC in tablets (exp.)

Xreg 78 wt% CFI-MCC in tablets (model)

80 wt% CFI-DCPA in powder (exp.)

Xreg 80 wt% CFI-DCPA in powder (model)

80 wt% CFI-DCPA in tablets (exp.)

Xreg 80 wt% CFI-DCPA in tablets (model)

0.6

0.4

0.2

0.0 0

50

100

150

200

Time (days)

Figure 1.27 Volume fraction transformation as a function of time for caffeine form I (CFI) to form II in tablets and uncompressed powder mixed with two diluents, microcrystalline cellulose (MCC) and anhydrous dibasic calcium phosphate (DCPA) with content 78 and 80 wt% of CFI, respectively. Solid and dotted lines are the calculated values from stretched exponential equation for uncompressed powder and tablets, respectively. Source: Juban et al. 2016 [18]. Adapted with permission of Elsevier.

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

process parameters. During freezing, the solute either crystallizes with the ice, as in the case of mannitol [96] and glycine [97], or it get trapped as an amorphous phase, as in cephalosporins, sucrose, and peptides. However, the drying stage can induce crystallization of the amorphous phase. Kinetic factors have a huge role in controlling the solid-state phase during freeze drying. Cooling rate, drying rate, and nucleation and growth rates all contribute to the resulting phase. These factors and others such as onset of ice and solute nucleation, and end point of sublimation can be monitored using NIR and Raman spectroscopy [98]. Commonly, the final product of freeze drying tends to be the amorphous phase [99]. For instance, irrespective of initial solution concentration, pentamidine isethionate trihydrate is formed using a low freezing rate which dehydrates during the drying step into a partially crystalline metastable form B. On the other hand, using a high cooling rate, the amorphous phase is formed which transforms into stable form A after the drying step. Forms A and B are monotropically related, and form B transforms slowly to form A during storage [100]. The process was simulated and monitored using variant temperature – powder X-ray diffraction (VT-PXRD) (range −190–300 ∘ C) which starts from 10% w/v drug solution and is cooled slowly, while trihydrate peaks started to appear followed by dehydration to partially crystalline form B after drying (Figure 1.28a), which may support the polymorphic transformation of form B into A. However, increasing pressure during primary drying from 100 to 500 mTorr (Figure 1.28b) prevented the dehydration process and produced the highly crystalline trihydrate form [101]. The interaction between different solutes in the multicomponent formulation can cause a preferential solid-state formation. For example, the presence of anticancer drug cyclophosphamide with mannitol during lyophilization led to the selective formation of pure metastable δ-mannitol, while lyophilization of mannitol alone produced a mixture of stable β-mannitol and minor amounts of the δ-form. This was attributed to cyclophosphamide’s ability to inhibit the nucleation of β-mannitol during freeze drying, which is considered as the rate-limiting step in the solution-induced δ- to β-phase transition [102]. 1.3.1.5

Spray-drying-induced Transitions

Spray drying shares an attribute similar to that of the freeze-drying process. It is performed by spraying a solution or dispersion of the active material at controlled temperature and under conditions which cause rapid removal of solvent and formation of spherical dry powder mostly with improved morphology, flowability, and dissolution properties. Critical process parameters include air flow rate, air humidity, inlet temperature, atomization type and flow, and feed rate, which are adjusted to control particle size, size distribution, porosity, moisture content, yield, and solid form [103]. Solid-phase transformation during spray drying is highly common and mostly generates physical structures having higher potential energy including amorphous [104, 105] and metastable phases. This is due to the rapid evaporation of solvent during atomization process and high temperature which thermodynamically favors the formation of high-energy phases. The most common example is the spray-dried amorphous lactose which has superior properties in terms of flowability and compressibility [106]. In addition, carbamazepine form IV can

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

(a)

Trihydrate Form B Ice Secondary drying

25°C, 15 min 0°C, 15 min

Primary drying Annealing Freezing

Intensity (a.u.)

–10°C, 30 min –30°C, 45 min –30°C, 15 min –25°C, 60 min –25°C, 0 min –45°C, 30 min –3°C, 15 min 3°C, 15 min

10

15

20

25

30 Trihydrate

(b)

Hexagonal ice

Intensity (a.u.)

34

25°C, 15 min 0°C, 15 min –10°C, 30 min –30°C, 45 min –25°C, 30 min –45°C, 15 min –3°C, 15 min

5

10

15

20 2θ (°)

25

30

Figure 1.28 Variable temperature X-ray diffraction (VT-XRD) patterns of freeze-dried pentamidine solution. Freezing, annealing, primary, and secondary drying steps are indicated. Same conditions were applied in the case of (a) and (b), except that primary drying was performed under 100 mTorr in (a), while the primary drying in (b) was performed under 500 mTorr. Source: Sundaramurthi et al. 2012 [101]. Adapted with permission of Elsevier.

conventionally only be obtained using the polymers; however, the spray-drying process enables formation of this form using the drug solution in methanol [107]. The efficient control of process parameters can assist in producing the desired phase. For example, changing drying temperature during spray drying of phenylbutazone resulted in producing different polymorphic phases [108]. The effect of formulation additive on phase transformation has been investigated in spray drying. The presence of pH-adjusting buffers can affect the solid phase of glycine obtained after spray drying. Spray drying of glycine aqueous solution with no pH control (6.2) resulted in the formation of α-glycine, while γ-glycine is formed if pH is adjusted to below or above 6.2 with HCl and NaOH. The pH of the system affects the thermodynamic formation of α-glycine dimer [109]. Sulfamethoxazole polymorphism during spray drying is highly affected by

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

the presence of cellulose acetate phthalate (CAP) and talc. Spray drying of drug aqueous dispersion with CAP resulted in an amorphous phase, whereas drug dispersion with talc resulted in stable form I to metastable form II conversion. This was ascribed to the ability of these additives to form an interaction with the drug and disturb its structure during the process [110]. Pyrazinamide (PZA) metastable γ-form, produced by spray drying, undergoes transition to stable δ-form after 14 days. This transition can be prevented by adding 5% w/w 1,3-dimethylurea (DMU) during the spray-drying process and it helped obtain a stable γ-form over 12 months. It was found that 1,3-dimethylurea entraps the metastable phase, preventing any interaction at its surface (Figure 1.29). Furthermore, addition of polyvinyl pyrrolidone (PVP) instead of 1,3-dimethylurea during spray drying results in the formation of δ-form [111]. 1.3.1.6

Supercritical-fluid-induced Transitions

Supercritical technology is a green, solvent-free, and single-step process that utilizes a gas after reaching the supercritical state, at a point which exceeds the critical temperature, and pressure values. At supercritical point, the border between gaseous and liquidus phases diminishes and is called supercritical fluid. This state combines a group of properties for both liquid and gas phases including density

Y (μm)

(a)

(c)

PZA-δ (1055 cm–1– δ ring) PVP (935 cm–1– δ C-H)

–25 –20 –15 –10 –5 0 5 10 15 20 25 30

(b) PZA-δ (from Raman image)

PZA-δ 600 –20

0 X (μm)

20

800

* Trace of PVP

–25

1000

1200

1400

1600

1400

1600

Wavenumber (cm–1)

PZA-γ (1055 cm–1– δ ring)

–20

DMU-HT (935 cm–1– υsC-N)

–15 –10

(d)

0

Intensity (a.u)

Y (μm)

–5 5 10 15 20

PZA-γ (from Raman image)

PZA-γ

25 30 –20

0 X (μm)

20

600

800

* Trace of DMU

1000

1200

Wavenumber (cm–1)

Figure 1.29 Raman mapping image of pyrazinamide (PZA) spray dried with polyvinyl pyrrolidone (PVP) (a) and extracted Raman spectrum compared to reference spectra of δ-form (b). Raman mapping image of PZA spray dried with dimethylurea (DMU) (c), and (d) extracted spectra compared to reference γ-form (d). Source: Baaklini et al. 2015 [111]. Adapted with permission of Elsevier.

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1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation

of liquids and viscosity, and compressibility of gases. These properties enable the dense gas to dissolve the solid materials; simultaneously, like gases, its volume changes upon changing pressure which changes its density and thus its dissolving ability. This technology is used in separation, chemical synthesis, and powder technology. In pharmaceutical development, supercritical fluid is employed in particle design, micronization, and drying to obtain the desired physicochemical properties such as particle size, shape, dissolution, and stability [112, 113]. Moreover, one application that makes supercritical fluid a unique method is its ability to control and produce a pure polymorphic form in a short time and under moderate temperature and pressure values [114]. The use of supercritical CO2 (scCO2 ) as fluid constitutes 98% of pharmaceutical processing due to its economic, nontoxic, and ease of handling, plus achieving a CO2 critical state is facile as critical temperature and pressure of CO2 are 38 ∘ C and 7.4 MPa, respectively [113]. Two types of scCO2 processing are mainly used; in the first type, the drug is dissolved or liquefied in scCO2 fluid. Subsequently, the solution is rapidly depressurized through atomization in a process called rapid expansion of the supercritical solution (RESS). This process reduces the drug solubility in scCO2 , leading to its precipitation as new solid particles having special properties [115]. Flufenamic acid metastable form I undergoes phase transition after RESS into stable form III. Key process parameters are extraction pressure, pre-expansion temperature, crystallization temperature, and capillary tube dimensions, where sc-CO2 depressurization takes place before reaching the expansion chamber [116]. It is believed that this transformation is thermodynamically driven as the lower soluble form III starts to nucleate before form I. However, RESS requires sufficient solubility of the drug in the sc-CO2 (called ideal solute); however, not all drugs have this property. Therefore, the supercritical anti-solvent (SAS) was developed to enable the use of sc-CO2 for drugs that are poorly soluble in sc-CO2 (called nonideal). The method involves dissolving the drug in a suitable solvent, and then the scCO2 is used as antisolvent for precipitating the drug. SAS techniques can have many variations, yet the most commonly used for polymorphic control [117] is solution-enhanced dispersion by supercritical fluid ( SEDS), which was invented by Hanna and York [118]. The process is performed by co-atomization of the drug solution and scCO2 via a coaxial nozzle into a mixing chamber at a controlled temperature and pressure. This allows the scCO2 to be transferred at high speed into a drug solution, forming small droplets and a rapid nucleation rate [119]. Theoretically, these conditions favor the formation of a metastable or an amorphous phase. PXRD analysis of baicalein powder after micronization using SEDS shows a reduction in crystallinity [120], which is a common observation also found for other drugs such as tretinoin and acetaminophen [121]. A novel minocycline β-form was produced using the ethanol–CO2 system, which shows a higher melting point, 247 ∘ C, compared to the commercial α-form, 187 ∘ C [114]. Conventional supercritical antisolvent method SAS can trigger stable to metastable polymorphic transformation for indomethacin (triclinic γ- to monoclinic α-form) [122], carbamazepine (monoclinic FIII to trigonal FII), and theophylline (orthorhombic FII to polymorphic mixture) [123].

1.4 Conclusion

Process parameters of SEDS such as drug supersaturation, composition of solvent, flow rate, temperature, and pressure can contribute to polymorphism control. For example, acetaminophen polymorphism can be controlled by changing the type of solvent in the initial solution. Use of acetone resulted in the formation of orthorhombic form II, while ethanol favors the formation of monoclinic form I [124]. Etoposide stable form I was found to convert to metastable form II, which are monotropically related. Form II exhibits higher solubility and dissolution rate compared to FI [125, 126]. The effect of supercritical gas type on polymorphism has been investigated for carbamazepine, indomethacin, and theophylline [127, 128]. scCO2 reactivity in comparison to inert supercritical nitrogen (scN2 ) was investigated using solution-enhanced atomization (SEA) technique which, except for theophylline, produced the same results using both gases. Thus, this implies that transformation is mediated by the atomization process and the results can be reproduced using conventional spray drying. To investigate the difference obtained with theophylline, a new processing method was applied which utilizes a smaller sc-CO2 volume (1 cm3 ); and the sc-CO2 -solution mixing step takes place before atomization, producing a suspension. This method is called atomization of antisolvent-induced suspension (ASAIS) and it is used to investigate the impact of CO2 before atomization. Parameters such as temperature, pressure, initial solution concentration, liquid flow, flow residence time, volume of mixing chamber, and nozzle orifice diameter are involved in the investigation. ASAIS using sc-CO2 resulted in theophylline transformation [127], indicating the impact of sc fluid on crystal structure. Polymorphs I, and III, and a dihydrate form of carbamazepine which is classified as BCS class 2 were thoroughly investigated in terms of in vitro and in vivo performance. Oral administration of the three phases at dose 40 mg resulted in similar AUC values. However, increasing the dose to 200 mg resulted in significant differences with AUC (unit: μg h/ml) values, form I (9.10) followed by form III (6.33), and then dehydrate (4.39). Moreover, it was found that form III transforms rapidly into dehydrate form in gastrointestinal fluid, which may explain the differences in the in vitro performance compared to the in vivo where form III obtained a higher rate compared to form I [58].

1.4 Conclusion Polymorphism is a type of physical structure variation caused by the difference in conformational or packing arrangements, which involves a change in noncovalent bonding only. This event can be classified into several categories depending on type of structures and thermodynamic properties. Other types are being regarded as nonideal polymorphism due to the presence of chemical variations like a modification in covalent bonding, or the presence of a heterostructure within the crystal lattice. Polymorphism has a significant impact on the physicochemical and mechanical properties of API or excipients which in turn affect in vivo performance. On the other hand, extensive care is being

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taken during the processing of formulation components that are prone to phase transition. These transitions can occur at any stage of formulation. In order to achieve total control and to prevent any unwanted effect from polymorphic transformation during formulation, the following aspects should be considered: 1. NCEs or excipients must be subjected to sufficient preformulation testing and screening to explore all possible forms and to understand the relation and transition nature between these phases. At this step, two things must be assessed, whether the compound undergoes polymorphic transition within the range of temperature and pressure attained during processing. Secondly, if polymorphic transformation will result in a significant impact on the stability, handling, efficacy, and safety of the dosage form. 2. Selection of specific polymorphic phase with desired physicochemical and mechanical properties to be targeted in the final dosage form. Subsequently, thermodynamic and kinetic properties of targeted NCE or excipient phase should be identified. 3. Optimization of process thermodynamic and kinetic parameters with relevance to thermodynamic and kinetic properties of the selected polymorph. The optimization should aim to obtain the targeted phase at the end of the process. 4. The final dosage form should contain the targeted phase, which remains stable throughout storage and administration stages. No significant change should be observed for the in vivo performance or mechanical properties. Despite the vast volume of literature reported regarding polymorphism, this phenomenon is still a subject of significant interest and requires enormous amount of investigation. Therefore, further investigation and reports in the future are expected to emerge whether it deals with existing issues, discovery of new polymorphic forms, or innovating new techniques to improve properties, processing, or stability.

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2 Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route Sanket Shah 1 , Abhijit Date 2 , and Renè Holm 1,3 1 Johnson & Johnson, Drug Product Development, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium 2 University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Department of Pharmaceutical Sciences, 200 W. Kawili Street Hilo, HI 96720, USA 3 University of Roskilde, Department of Science and Environment, Universitetsvej 1 4000, Denmark

List of Abbreviations

AFM API BCS CMC CPPs CQAs CTD DCS DDS DoE DSC GIT GRAS HLB ICH IIG LFCS NCE NDA PAT PDI PET QbD QbT QTPP RESOLV RESS

atomic force microscopy active pharmaceutical ingredient biopharmaceutics classification system critical micelle concentration critical process parameters critical quality attributes common technical document developability classification system drug delivery system design of experiments differential scanning calorimetry gastrointestinal tract generally regarded as safe hydrophilic lipophilic balance International Conference for Harmonization FDA’s inactive ingredient database lipid formulation classification system new chemical entity new drug application process analytical tool polydispersity index positron emission topography quality by design quality by testing quality target product profile rapid expansion of supercritical solutions into a liquid solvent rapid expansion of supercritical solution

Innovative Dosage Forms: Design and Development at Early Stage, First Edition. Edited by Yogeshwar G. Bachhav. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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SAS SEDDS SEM SMEDDS TEM TEOS USP XRPD

supercritical antisolvent precipitation self-emulsifying drug delivery system scanning electron microscopy self-microemulsifying drug delivery system transmission electron microscopy tetraethoxysilane United States pharmacopeia X-ray powder diffraction

2.1 Introduction Oral drug delivery is the preferred route for drug administration due to increased patient safety and compliance, and reduced production costs compared to topical and parenteral drug delivery [1]. Upon ingestion of an oral dosage form, the drug must undergo disintegration and dissolution in the gastrointestinal (GI) fluid to reach systemic circulation as only molecules in solution state are able to permeate the intestinal epithelial wall [2]. It is generally recognized that the rate and extent of drug absorption is controlled by two fundamental parameters: drug solubility and permeability [3]. As increasing numbers of new drug candidates have limited oral bioavailability because of poor water solubility, the development of strategies to improve the dissolution profile of these drugs is one of the biggest challenges facing the pharmaceutical industry today [4]. The solubility and/or dissolution rate of a drug can either be increased through material engineering such as crystal modification, salt formation, amorphization, particle size reduction, or through different “enabling” formulation techniques such as solid dispersions, cyclodextrin complexations, and lipid-based formulations [5, 6]. The aim of this chapter is to describe the essential elements concerning formulation development during drug development such as quality by design (QbD), formulations for different clinical phases, and, finally, the formulation technologies available for poorly soluble compounds to provide an insight into the formulation selection strategy.

2.2 Quality by Testing (QbT) and Quality by Design (QbD) The regulatory expectation in pharmaceutical development (and thereby formulation development) is described in the International Conference for Harmonization (ICH) Q8 (R2) guideline. More precisely, it also provides guidance to draft formulation development aspects to support the establishment of the design space investigated, and not only the specifications and manufacturing controls in the applications for new drug applications (NDAs), i.e. section 3.2.P.2 in module 3 of the Common Technical Document (CTD) [7]. Further, the guideline introduces the concept of QbD and how it is perceived from a regulatory perspective. The guideline does not only define that the pharmaceutical development in NDAs should follow the principles of QbD but

2.2 Quality by Testing (QbT) and Quality by Design (QbD)

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Table 2.1 Differences in applications of quality by test (QbT) and quality by design (QbD) paradigms. Factor

QbT

QbD (at an extreme)

Experimental design

One variable evaluated at a time – minimum product knowledge

Multivariate experiments – extensive product knowledge

Development focus

Focus on optimization and reproducibility of process

Focus on control strategy and robustness of process

Testing paradigm

End-product testing

On-line process analytical tool (PAT) tools utilized

Control strategy

Primary control through final product specifications

Final product specifications part of overall control strategy

Release strategy

Final product quality controlled by in-process and end-product testing

Final product quality ensured through risk-based control strategy since product and processes are well understood Real-time release testing with possible reduction of end-product testing

Life-time quality management

Quality over product lifecycle managed through problem solving and corrective action

Quality over product lifecycle managed through preventive action and continuous improvement

also provides the drug development companies with the option to choose an empirical approach to product development, or a combination of both. Empirical product development, also termed quality by testing (QbT), has historically been the regulatory paradigm; see Table 2.1 for a comparison of QbT and QbD. In short, the strategy ensures product quality through raw material testing, drug substance specification, a fixed drug product manufacturing process, in-process controls, and, in particular, end-product testing [8]. The thinking behind this quality approach is that if all elements are standardized, the process should run consistently throughout its lifecycle. The success of this approach, however, relies on the possible variability in the process that can be controlled by end-product testing. While the QbT has been the backbone of quality in the pharmaceutical industry for decades, benchmarking of the industry with other industries highlighted that the existing approach has numerous disadvantages, such as innovation inertia and an increased documentation burden for both the pharmaceutical industry and the regulatory agencies, which has resulted in the introduction of QbD [9, 10]. The basic rationale behind the QbD concept was that most quality problems relate to the initial product development and there is a resultant reluctance with regard to continuous improvements for existing marketed products. Hence, quality should be designed into the product [11, 12] and a more flexible system needed to be established for post-approval changes. Changes made within this design space are not subject to regulatory approval and should deliver a consistent product quality. This design space is normally defined using design of experiments (DoE); however, this approach is not equal to QbD and will normally also be applied in a QbT approach.

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Pharmaceutical QbD should therefore be considered a systematic, proactive, scientific, and risk-based approach to formulation development. It has its emphasis on product and process variables and these are used as control strategies. Development starts with the quality target product profile (QTPP) with the purpose of identifying characteristics critical to quality from the patient’s perspective, e.g. the time between doses in a pulsatile release formulation to ensure optimal treatment. This information must then be translated into critical quality attributes (CQAs) that the final product should fulfill and how critical process parameters (CPPs) may be varied to consistently produce a product with the desired characteristics [8]. Ideally, under the QbD paradigm, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables; end-product testing is only conducted to confirm the quality of the product. Specifications should be defined on the basis of relevance to in vivo performance, e.g. dissolution, as well as variations within the defined, approved formulation and process design space. For a pharmaceutical drug product, such as an immediate release (IR) tablet produced by wet granulation, many raw material and processing variables will exist. Consequently, getting to a required level of understanding that provides sufficient insight into all CQAs of the product may be overwhelming. Modeling a nonlinear response surface would require an optimization design (e.g. a central composite face, with 11 experiments/batches if 3 center points were to be included). During early formulation development, such a design is often unrealistic to conduct due to limited active pharmaceutical ingredient (API) availability (often restricted by API route optimization, in parallel with the pharmaceutical development activities). More formulation and process understanding can certainly mitigate this challenge. This can be achieved by working with established platform technologies and applying prior knowledge, which is work from legacy products or formulation platforms. QbD is, in principle, a term related to a regulatory submission, but the outcome is generated through the entire development phase. The different development phases may define different requirements to the formulation (see next section), so the formulation used at the different clinical phases may vary significantly to fit the purpose of the study. Exploring the full design space is a larger effort, so the concepts of DoE can be applied at all stages of formulation development; however, a full QbD is only developed for the formulation to be marketed.

2.3 Linking the Formulation to the Clinical Phase The clinical development program has several purposes, but it is through these studies that the safety and efficacy of new potential therapeutic compounds is established. This is performed under very controlled conditions, with the purpose of determining the compounds’ safety (tolerability and acceptability) and efficacy as a new medication. Typically, the clinical development is divided into four phases, as summarized in Table 2.2;

Table 2.2 Phases of clinical development and the overall insights obtained from the trials.

Important readout

Approximate number of subjects/ patients

Study conducted in healthy volunteers unless special reasons defined the studies to be conducted in patients (e.g. oncology)

PK parameters

20–60

Sometimes explorative clinical effects

Escalating single-dose with placebo control. Normally randomized and double blind

Typical adverse effects In exceptional cases, PD measurements

Ib

As phase Ia

Design largely as in phase Ia, with the exception that the dosing is repeated over an extended period

As phase Ia

30–100

IIa

Safety and efficacy

Studies conducted in patients with dose assumed to provide clinical effect based on nonclinical studies and potential phase I studies. Often placebo-controlled, randomized double blind, but open label also possible

Typical adverse events

50–300

Studies conducted in patients with selected doses compared to placebo or standard treatment

Dose–response relationships for statistical analysis

Often placebo-controlled, randomized double blind, but open label also possible

Confirmation of clinical dose for optimum efficacy, safety, and tolerability

Clinical phase

Ia

IIb

Aim

Design

Safety, tolerability, as well as PK to help define the studies in patients

Dose selection to support registration

Preliminary evidence of efficacy (“proof of concept”) Potential PK parameters, if included in clinical design 150–750

III

Efficacy and safety data to support registration

Studies conducted in patients including diverse groups (e.g. age, ethnicity, etc.). Dose level as defined from phase IIb with placebo and/or standard treatment. Randomized double blind, but open label also possible

Measurements for evaluating safety and efficacy statistically compared to placebo and/or existing therapies

500–2 500+

IV

Post-marketing surveillance to continuously monitor adverse effects and toxicity

Treated patients

Adverse effects and events

10 000+

PK, pharmacokinetics; PD, pharmacodynamics.

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• Phase I: first administration in humans to evaluate safety and pharmacokinetic properties, usually conducted in healthy volunteers; • Phase II: early exploration and dose-finding studies in patients with continued focus on safety and efficacy; • Phase III: larger clinical studies in patients to demonstrate safety in efficacy in a larger number of patients; • Phase IV : post-marketing safety monitoring of patients. The clinical trials are performed as per the international guidelines defined in the good clinical practice. Phase I studies are conducted to obtain information about the compounds’ safety, tolerability, and pharmacokinetic profile. As the behavior of the compound is unknown, the starting dose is defined as 1/50 to 1/100 of the no adverse effect level (NOAEL) defined in the toxicological studies. The first studies in humans includes single dosing of the compound, phase Ia. The dose is slowly increased; and if safety or tolerability issues arise, the escalation is stopped. After this, the study follows the phase Ib, where the compound is administered repeatedly at the same dose – again with escalation of the dose, to evaluate the safety, tolerability, and pharmacokinetics of the compound after repeated administration. Due to the study design of the phase I studies, there is often a need for a wide dose span as well as a need for large flexibility in the dose to get an optimal study design. The phase I studies are conducted in specialized phase I units; hence, medication of the volunteers is done under very controlled conditions. This, together with the need for a large dose flexibility, a relative large attrition rate of compounds entering phase I, and limited availability of the compound for the formulation development normally means that the formulation used in this phase of the development program is as simple as possible and non-optimized for use (e.g. sometimes produced under less controlled conditions). These formulations may include powder in a bottle for reconstitution, solutions both in cosolvents or aqueous systems, or very simple solid dosage forms as powder in capsules, etc. Phase IIa studies, also often termed “proof of concept,” are a critical study conducted in patients to verify the pharmacological target. The patients are followed up closely during the study, but they are normally responsible for their own medication, which will often be taken home by the patient. The dose is defined on the basis of the pharmacokinetic insight potentially supported with other studies such as positron emission topography (PET)-assisted topography studies; however, the dose is relatively fixed when compared to the phase I studies. The formulation for this development stage can still be suboptimal, e.g. high pill burden, low API availability, and chances of failure due to less efficacy (possibly due to unknown pharmacological target). If the intended dosage form is a solid form, this will normally be used at this stage; however, formulation optimization may not have been completed at this stage. After a successful proof of concept, the dose-range-finding studies, phase IIb, follows. These studies are conducted in a larger patient population and the patients normally bring their medication home. These studies are considered pivotal and will hence support the clinical evaluation of the compounds’ efficacy

2.4 Defining the Formulation Strategy

in the dossier, so, if possible, the final or close to final formulation is used for these studies. The phase III studies are larger studies conducted in patients to ensure the compounds’ efficacy and safety; and as the data goes into the dossier, they are normally conducted with the final formulation. In cases where the use of a final formulation is not possible, bridging studies can be made between a developmental formulation and the final formulation by bioequivalence studies or, in extreme cases, through clinical efficacy studies. However, as this comes at a significant cost, there are several advantages in ensuring that formulation and critical process work is conducted before entering the clinical phase III studies.

2.4 Defining the Formulation Strategy A larger pool of information about the drugs’ biopharmaceutical behavior is already available upon selection of the molecule for development (in most of the drug development companies). And this knowledge is further expanded through the toxicological studies and clinical phase I studies. This prior knowledge, together with insight into the drugs’ physicochemical properties, forms the foundation for the formulation strategy, i.e. which dosage form to be developed and choice of technology. Upon administration, a tablet or capsule disintegrates into granules or primary particles upon contact with fluids in the gastrointestinal track. From the granules/primary particles, the drug will dissolve/solubilize at a rate determined by the compounds’ physicochemical properties (such as pKa, solubility, etc.) as well as the size of the drug particles. After the dissolution, the compound is ready for absorption; hence, one of the first essential elements for determination of the formulation strategy is the compounds’ solubility in the gastrointestinal fluids (in relation to dose of compound). Another important parameter is the permeability, one of two parameters reflected in the biopharmaceutics classification system (BCS) . Normally, the simplest technology shall be used to develop early formulation, e.g. immediate-release tablet can be used. Leane et al. suggested a manufacturing classification system for immediate-release formulations to classify technologies based on the projected doze, API particle size, morphology, API form, API flowability, etc., but, ultimately, organizational experiences and technologies available are also an important parameter of the specific technology chosen [13]. For compounds where the treatment will be positively affected by extending the release, e.g. for compounds with a suboptimal plasma half-life, a controlled-release formulation strategy will normally be chosen. Also, within this group of formulations, many technologies exist, e.g. eroding tablets and control by coating, and decisions are defined by clinical needs, costs, and available technologies. As mentioned, compounds need to be solubilized to get absorbed; and as more and more compounds have low aqueous solubility, there has been a larger focus on available formulation strategies for this class of compounds. The BCS categorizes API based on its permeability and solubility into four

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Dose/solubility ratio 10 Predicted Peff in humans (cm/s × 10–4)

56

Using jejunal solubility, typically FaSSIF 37 °C

250

500

1000

10 000

IIa (dissolution rate limited)

I Good solubility Good permeability

100 000

II Poor solubility Good permeability

IIb (solubility limited)

1

III

IV

Good solubility Poor permeability

Poor solubility Poor permeability

0.1

Figure 2.1 The biopharmaceutics classification system (BCS) is shown in black and the modifications from the BCS to the DCS are shown in blue. Source: Adapted from Butler and Dressman [14].

main categories, viz. APIs that are highly soluble/highly permeable, poorly soluble/highly permable, highly soluble/poorly permeable, and poorly soluble/poorly permeable. Butler and Dressman suggested a developability classification system (DCS) based on the BCS to help with this (see Figure 2.1) by subclassifying low-soluble high-permeable compounds into class IIa and IIb based on whether the drugs show dissolution rate-limited or solubility-limited absorption, respectively [14]. For class IIa compounds, particle engineering technologies may be sufficient to drive the exposure, i.e. by milling, which does not add a larger complexity to the pharmaceutical processing, so if possible, this will normally be selected. The class IIb compounds need technologies which will facilitate the dissolution step and hence the focus on the formulation options described in this chapter. Various technologies can be used for the compounds with solubility-limited absorption, including lipid-based formulations and amorphous solid dispersions. There are various limitations to the different technologies that can define whether they can be used or not, e.g. for lipid-based formulation, a sufficient solubility in the lipids is needed. Technical feasibility as well as organizational experience and access to technologies define preferred options that vary from company to company; however, due to the complexity of these formulations, they will normally only be selected as a last resort. Figure 2.2 explains a classification based on the thermodynamic energy input for formulating various drug delivery strategies. This information can be used to correlate the physicochemical properties of the API and the formulation of a thermodynamically stable strategy.

High Nanosuspensions thermodynamic Nanosuspensions are high energy systems, as the particle size reduction is brought about by high energy input techniques. The small size thus obtained is stable due Brownian motion. However, there is always a interplay between Brownian motion and the fact that the system would look to achieve a low energy. One indication, energy systems to of the system attaining low energy, is increase in particle size over storage. One way to arrest the increase in particle size of a nanosuspension is optimizing the surfactant concentration and/or having a narrow polydispersity index.

Emulsions prepared by energy input Emulsion are systems in which the active is dissolved in suitable oil followed by high energy input process leading to formation of, preferably submicron, oil droplets stabilized by a layer of a surfactant. Although, the active is dissolved in an oil, lowering its thermodynamic energy, the high energy input methods introduces a high potential energy in the system which is stabilized by a layer of surfactant. Optimal surfactant concentration and type as well as a monodisperse system is key to a stable emulsion. Such type of emulsions are stable to infinite dilutions.

Solid dispersion Solid dispersion are systems in which the active is dispersed in a polymer in an amorphous state. It is one of the methods of improving the solubility of the active. As the active is in a amorphous state in the polymer matrix, it is in a high energy state and would always want to come to a more stable crystalline state. Stable solid dispersions are prepared by optimizing the active to polymer ratio and processing technique.

Metastable polymorphs As the name suggest, metastable polymorphs, are in a most high energy state and has a higher chance to revert back to a more stable polymorph. Owing to higher solubility of metastable polymorphs, they are perfered over more stable polymorphs for BCS class II molecules as the absorption of such systems is dissolution rate limited.

Low thermodynamic energy systems

Microemulsions/nanoemulsions Microemulsions are submicron systems in which the active is dissolved in an oil droplet stabilized by surfactant. A point-of-differentiation from nanoemulsions, is that no high energy input techniques are used to reduce the microemulsions to a submicron range. In general, the types and concentration of surfactants used are higher for microemulsions compared to nanoemulsions. Microemulsions are unstable to infinite dilution.

Lipid based systems Lipid based systems is broad term that encompasses multiple technologies. In most of these technologies, the active is dissolved in a solid and/or liquid lipid stabilized by a layer of surfactant and hence the thermodynamic energy of these systems is low. A stabilizing effect is also obtained by use of stabilizers.

Figure 2.2 Classification based on the thermodynamic energy of the system.

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2 Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route

Table 2.3 List of key oral nanosuspension-based pharmaceutical products [15].

Drug

Approval year

Final dosage form

Rapamycin/sirolimus

2000

Tablet

Aprepitant

2003

Capsules

Tricor

Fenofibrate

2004

Tablet

Triglide

Fenofibrate

2005

Tablet

Megestrol acetate

2005

Liquid nanosuspension

Trade name

®

Rapamune

® ® ® ®

Emend

Megace

ES

2.5 Nanosuspensions Drugs that have limited aqueous solubility and dissolution rate-limited absorption can lead to issues such as low oral bioavailability, intraindividual (fed/fasted state) and/or interindividual variability, slow onset of action, and lack of dose proportionality [15]. The development of nanoscale drug particles or nanosuspensions is one of the promising strategies to improve the oral bioavailability of such drugs. Over the past two decades, academia and pharmaceutical industry have extensively investigated the potential of nanosuspensions to improve oral delivery of a variety of therapeutic agents belonging to BCS class II (or BCS class IV in some cases) [15–17]. The commercial availability of several oral pharmaceutical products containing “drug nanosuspensions” (Table 2.3) is sufficient to indicate the utility and translational potential of “drug nanosuspensions” as a strategy to salvage the new chemical entities (NCEs) with limited aqueous solubility and dissolution rate-limited absorption. 2.5.1

Description

In the pharmaceutical arena, the term “nanosuspensions” generally refers to a colloidal dispersion of nanosized drug particles in liquid media that contains a suitable stabilizer or a mixture of stabilizers. Typically, the average particle size of “pharmaceutical nanosuspensions” is in the range of 200–600 nm. The liquid media used for generation of nanosuspensions can be aqueous or nonaqueous (polyethylene glycol, or oils) depending on end application [18]. The term “nanosuspensions” encompasses nanosized drug particles that are in the crystalline, partially amorphous, or amorphous state. Unlike most other nanoformulation strategies such as liposomes, micelles, or polymeric/lipid nanoparticles, nanosuspensions do not contain any carrier; instead, nanosuspensions contain a relatively small amount of the stabilizer(s) that adsorbs onto the drug surface to prevent particle agglomeration during manufacturing and storage. Hence, nanosuspensions typically have a very high drug loading (∼30–50% w/w) unlike other formulation strategies such as liposomes, polymeric/lipid nanoparticles, lipid-based oral formulations, and solid dispersions, and they can deliver a relatively high concentration of

2.5 Nanosuspensions

the drug at the site of action compared to the aforementioned formulation strategies [15]. Furthermore, nanosuspensions can also reduce the potential adverse effects emanating due to the high concentration of carriers/excipients. “Nanosuspension” is an effective strategy to improve oral delivery of drugs that exhibit limited aqueous solubility and poor solubility/miscibility with polymer or lipid matrices or organic solvents. The advantages associated with the use of nanosuspensions are (i) enhanced dissolution velocity due to dramatic increase in the surface area, (ii) increased saturation solubility of the drug, (iii) increased adhesion to the gastrointestinal mucosa, (iv) improved oral bioavailability, (v) reduction in variability in the drug absorption, (vi) rapid onset of action (compared to drug suspensions), (vii) long-term physical stability, (viii) ease of scale-up and large-scale manufacturing, and (ix) amenability to transformation into solid oral dosage forms [15–17, 19, 20]. Thus, “nanosuspension” is an attractive strategy to reduce the number of failing NCEs due to their poor biopharmaceutical properties. 2.5.2

Method of Manufacturing

The methods of manufacturing nanosuspensions are broadly divided into (i) top-down methods, (ii) bottom-up methods, and (iii) methods utilizing a hybrid approach [21–23]. In the top-down method, micron-size or larger drug particles are broken down into nanosized drug particles using various particle reduction methodologies. Top-down methods are primarily used for the manufacture of most of the currently available nanosuspension-based pharmaceutical products. In bottom-up methods, nanosuspensions are generated by the controlled precipitation of the drug dissolved in a suitable solvent(s) or supercritical fluid in the presence of a suitable stabilizer(s). 2.5.2.1

Top-Down Methods

Based on the mechanism used for the particle-size reduction, top-down methods can be further divided into (i) wet media milling and (ii) high-pressure homogenization. The top-down methodologies offer development of nanosuspensions with high drug loading. Furthermore, they are also suitable for the drugs that exhibit poor solubility in organic solvents that are commonly used for bottom-up techniques. Typically, the top-down techniques generate considerable heat during the manufacturing of nanosuspensions, which can be detrimental to thermolabile drugs/NCEs [22, 23]. In addition, top-down methods, because of intensive mechanical forces involved in the particle size reduction, may also lead to product contamination due to erosion of materials used in these processes. The top-down methodologies have evolved over the years, and now it is possible to control the manufacturing temperature of nanosuspensions to enable formulation of thermolabile drugs into nanosuspensions and also to minimize/avoid the contamination of the final product due to erosion of the materials used for the manufacturing [21]. With the currently available technologies, these concerns are not a major roadblock for

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the top-down methods, as evident by currently available parenteral products like INVEGA SUSTENNA and INVEGA TRINZA .

®

2.5.2.2

®

Wet Media Milling Technology

®

Wet media milling technology is also referred to as NanoCrystal technology. Elan Drug Technologies own the patent for this technology [21]. In this process, the drug nanosuspensions are manufactured in the media mill, which consists of a milling chamber, milling shaft, and recirculation chamber, as shown in Figure 2.3. In this process, the drug/NCE candidate is suspended in a stabilizer solution into the milling chamber that consists of suitable milling beads (milling media). The mixture is agitated for a suitable time frame to obtain drug nanosuspensions [19, 21, 23, 25]. The particle size reduction achieved in this process is a result of the impact, friction, and shear forces generated from the collision among milling beads, drug particles, and the wall of the milling chamber. This method is very simple, and it can be used to manufacture nanosuspensions at the laboratory scale or even at a very large scale (500–1000 kg of drug nanosuspension per batch) [25]. It is possible to obtain smaller and fairly monodisperse drug nanosuspensions using the wet media milling technology. Furthermore, unlike the high-pressure homogenization method, prior micronization of the drug is not required to successfully achieve manufacturing of drug nanosuspensions. The process of wet media milling involves the use of the milling beads (milling media) to accomplish particle size reduction of drugs to the nanoscale. Various inert materials such as highly cross-linked polystyrene, ultradense ceramic, yttrium-stabilized zirconia, zirconium oxide, and glass beads can be used as the milling media. Recirculation chamber

Coolant

Large drug Charged with drug, crystals water, and stabilizer

Milling chamber Nanocrystals Milling shaft

Screen-retaining milling media chamber Milling media

Motor

Figure 2.3 Wet media milling process to manufacture nanosuspensions. Source: Reprinted from [24].

2.5 Nanosuspensions

The processing time to obtain nanosuspensions using wet media milling can range from 30 minutes to several hours, and it depends on factors such as drug physicochemical properties and the concentration, material, and size of milling beads and the required particle size of nanosuspensions [19, 21, 23, 25]. As the milling process can also lead to changes in the polymorphic form of the API, it is important to optimize the parameters of the media milling process to avoid/minimize the polymorphic changes in the product. The manufacturing of many existing nanosuspension-based pharmaceutical products involves the use of wet media milling (NanoCrystal) technology [25]. In a nutshell, the wet media milling technology can be easily utilized for the “nanosuspension development” of NCEs for preclinical as well as clinical evaluations. 2.5.2.3

High-pressure Homogenization

The process of high-pressure homogenization involves passage of the micronized drug suspension through an orifice of appropriate size under high pressure. The particle size reduction in the high-pressure homogenization is achieved due to particle collision and/or cavitation, and the operating pressure of the high-pressure homogenizers can be as high as 1500 bar. To achieve effective particle size reduction, it is important to micronize the drug before subjecting it to the process of high-pressure homogenization. Furthermore, suitable homogenization pressure and multiple homogenization cycles may be necessary to obtain nanosuspensions with desired particle size and homogeneity. High-pressure homogenization can be achieved using jet-stream homogenizers such as microfluidizer (Microfluidics Inc., USA) or piston-gap homogenizers. The process of manufacturing nanosuspensions using the microfluidization method is also called insoluble drug-delivery particle (IDD-PTM ) technology and it is currently owned by Skyepharma PLC, Canada [23, 26, 27]. Depending on the liquid media used for manufacturing nanosuspensions, the piston-gap homogenization process is termed as either DissoCubes or NanoPure technology (PharmaSol GmBH, Germany). DissoCube technology uses aqueous vehicles, whereas NanoPure technology uses nonaqueous vehicles (PEG or oils) for manufacturing nanosuspensions [19, 21–23, 26]. In the microfluidization process, a micronized drug suspension containing a stabilizer is passed through an interaction chamber of appropriate geometry at a very high speed and under high pressure. The sudden change in the direction of the flow of the drug suspension due to the geometry of the interaction chamber causes collisions between particles and the chamber wall, thus leading to the particle size reduction [23, 27]. Commercially available tablets containing fenofibrate nanosuspensions (Triglide ) are manufactured using the IDD-P technology [26]. The piston-gap homogenization method is depicted in Figure 2.4. As shown in Figure 2.4, a suspension containing micron-size drug particles in a stabilizer solution is transported by a piston through a small homogenization gap (5–20 μm) at a high velocity in the homogenizer. This phenomenon leads to the formation of gas bubbles (process of cavitation), and the cavitation along with particle collision, shear forces, and turbulent flow generated during the homogenization process are responsible for the comminution of drug particles,

®

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Impact ring

Figure 2.4 Schematics of piston-gap homogenization method. Source: Reprinted from [24].

Valve seat

Valve

Nanoparticles

Microparticles

leading to formation of nanosuspensions [19, 21–23, 26]. Piston-gap homogenizers are capable of operating at homogenization pressure between 100 and 2000 bar, and they can process sample size ranging from 3 ml to as high as 1000 l [19, 21–23, 26]. Thus, high-pressure homogenizers can also be very useful for developing nanosuspensions of the NCE for preclinical and clinical studies. 2.5.2.4

Bottom-Up Methods

In the bottom-up methods, the drug is dissolved in an appropriate solvent or a mixture of solvents containing a stabilizer, and the drug nanosuspension is obtained by the controlled precipitation/crystallization of the drug with the help of a suitable mechanism. The bottom-up methods face problems such as lack of precise control on solid-state properties of the drug during crystallization and growth of particles, use of a relatively high amount of organic solvents, and limitations of the processes available for the solvent removal. Depending on the methods used for drug solubilization and/or precipitation of drugs, the bottom-up methods can be further classified into (i) solvent antisolvent methods, (ii) supercritical fluid-based methods, and (iii) cryogenic methods [23]. Drug precipitation with the help of antisolvent addition is one of the most commonly used bottom-up techniques used for generating nanosuspensions. However, this method often leads to the formation of the metastable amorphous particles that convert rapidly to larger crystalline agglomerates [22, 28]. Supercritical fluid-mediated precipitation methods have also been used for generating nanosuspensions. These methods typically use supercritical carbon dioxide as a solvent for the drug, and after solubilization of drug in the supercritical fluid, various techniques such as rapid expansion of supercritical solution (RESS), rapid expansion of supercritical solutions into a liquid solvent (RESOLV), and supercritical antisolvent precipitation (SAS) are used to obtain nanosized drug particles [28–30]. Recently, cryogenic methods such as spray freeze-drying and emulsion freeze-drying have also been used to obtain drug nanosuspensions [23, 31]. Bottom-up techniques have been greatly explored at the laboratory scale but their scale-up is usually problematic.

2.5 Nanosuspensions

2.5.2.5

Methods Utilizing a Hybrid Approach

To minimize/avoid drawbacks of the top-down methods such as long milling time or multiple homogenization cycles, hybrid or combination methods have been developed. Baxter has developed a patented hybrid method (NANOEDGE ) that uses a combination of bottom-up and top-down techniques. In addition, optimally designed combination methods can also yield smaller sized nanosuspensions. NANOEDGE involves solubilization of the drug into a suitable solvent or mixture solvents and subsequent precipitation of the drug into soft (amorphous/partially amorphous) microcrystals using a suitable antisolvent. This mixture is then subjected to the top-down techniques such as high-pressure homogenization to obtain stable crystalline nanosuspensions [32]. The solvent in the final nanosuspension is removed with the help of suitable technologies. The hybrid approaches utilize a combination of spray drying-high pressure homogenization (H42 technology) [22], freeze drying-high pressure homogenization (H96 technology) [22], high speed stirring-high pressure homogenization (ARTcrystal technology), and wet media milling-high pressure homogenization (smartCrystal technology) [33, 34].

®

®

2.5.3

®

Characterization of Nanosuspensions

Manufactured nanosuspensions need to be characterized for a variety of parameters to ensure their suitability for the desired application and long-term stability. 2.5.3.1

Particle Size, Polydispersity Index, and Particle Morphology

Nanosuspensions are characterized for the average particle size and polydispersity index (PDI) as they influence various properties such as saturation solubility, dissolution velocity, physical stability, and in vivo performance. The PDI is the measure of homogeneity of nanosuspensions and it influences the long-term physical stability of the nanosuspensions. The target PDI value for the nanosuspensions ranges between 0.1 and 0.25 and it indicates a narrow particle size distribution. The particle size and the PDI of nanosuspensions are typically measured by the dynamic light scattering or photon correlation spectroscopy (PCS) [35]. For nanosuspensions intended for parenteral or pulmonary delivery, techniques such as laser diffractometry or Coulter counter analysis can be used to identify larger particles (e.g. particles >1 μm for parenteral) in the nanosuspension formulations. 2.5.3.2

Surface Charge

The surface charge (also known as zeta potential) of the nanosuspensions is determined by measuring the electrophoretic mobility of the nanosuspension in an electric field. The zeta potential governs the physical stability of the nanosuspension and can help predict long-term stability. The stabilizers used for the nanosuspensions as well as the chemical structure of the drug can influence the zeta potential. Typically, to obtain a nanosuspension with good physical stability, a zeta potential value of ±30 mV is required for the electrostatically stabilized nanosuspensions, whereas sterically stabilized nanosuspensions can have a zeta potential value of ±20 mV [19].

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2.5.3.3

Particle Morphology

While previously described techniques such as PCS or laser diffractometry are useful for the rapid determination of the average particle size of the nanosuspensions, they typically presume that the nanosuspensions are perfectly spherical in morphology, which is seldom true. In many cases, needle-shaped, or irregular-shaped particles can be observed, which is dependent on the shape of the starting material. As there is a growing role for particle shape in the biodistribution and cellular uptake of the nanosuspensions (e.g. longer rods are efficiently taken up by the macrophages compared to the shorter rods), characterization of particle morphology with the help of suitable microscopy techniques is essential. Depending on the physical state of the nanosuspension-based product (liquid or transformed solid), various microscopy techniques such as transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) can be used to visualize the morphology of nanosuspensions [35]. These microscopic techniques can also help ascertain the robustness of the average particle size data. 2.5.3.4

Solid-state Properties

The nanosuspensions are characterized by solid-state properties such as degree of crystallinity and the presence of polymorphs or pseudopolymorphs such as solvates or hydrates. The solid-state properties of the nanosuspensions can influence their long-term storage stability and dissolution rate. The current manufacturing methods can lead to generation of crystalline, amorphous, or partially amorphous nanosuspensions. Generally, crystalline nanosuspensions are desired as they are thermodynamically most stable compared to the amorphous or partially amorphous nanosuspensions. X-ray powder diffraction (XRPD), thermal analytical techniques (differential scanning calorimetry, DSC or thermogravimetry), and vibrational spectroscopy (infrared and Raman) are the most commonly used methods to determine and monitor the solid-state properties of nanosuspensions [35]. 2.5.3.5

Saturation Solubility and Dissolution Velocity

Increases in saturation solubility and in dissolution velocity are the key advantages of nanosuspensions that are responsible for their improved biological performance. Hence, the developed nanosuspensions should be characterized by the saturation solubility and dissolution velocity. The saturation solubility of the nanosuspensions in physiological buffers of different pH values is determined at 37 ∘ C using the shake-flask method. The in vitro dissolution profile of the nanosuspensions or nanosuspensions-based solid formulations can be determined at 37 ∘ C in physiological buffers of different pH values using United States pharmacopeia (USP) type I, II, or IV dissolution apparatus with suitable modifications [19].

2.6 Solid Dispersion One of the potential strategies to overcome the poor oral bioavailability associated with BCS class II compounds is utilization of the amorphous form

2.6 Solid Dispersion

of the drug. The amorphous form of a drug has higher free energy than its crystalline counterpart, which will increase the apparent solubility and dissolution rate. However, the amorphous form is thermodynamically unstable and tends to crystallize over time with the subsequent loss of the solubility and dissolution rate advantages. Thus, in order to avoid crystallization during storage, the drug can be dispersed in a hydrophilic carrier, also known as a solid dispersion [36]. 2.6.1

Description

The term solid dispersion covers a range of different systems, and based on their molecular arrangement and physicochemical properties, solid dispersions can be classified into four diverse types, as described in Table 2.4. The number of components in a solid dispersion is not limited; however, for the sake of simplicity, the diverse types and subtypes are here defined on the basis of the binary systems of drug and carrier. Crystalline solid dispersions, in which both drug and carrier are present in the crystalline state, can be divided into eutectic and monotectic systems. A eutectic mixture is a mixture of two crystalline components that are miscible in the liquid state, but completely immiscible in the solid state. At a specific compound-dependent mixing ratio, referred to as the eutectic point, the mixture exhibits one single melting point and forms a homogenous liquid mixture that will phase separate simultaneously upon cooling [37, 38]. If the two crystalline components have a degree of miscibility in the solid state, a fraction of the drug may be molecularly dispersed in the carrier to form a solid solution. Amorphous suspensions are comparable to eutectic mixtures. However, eutectic mixtures contain two amorphous phases that are immiscible in the solid state, while an amorphous suspension is heterogeneous on a molecular level. Due to the inherent unstable nature of the amorphous form, these systems will almost inevitably crystallize over time. To overcome crystallization, the drug can be molecularly dispersed in a carrier in which it is miscible to form a homogeneous single-phase amorphous solid dispersion. However, even though the molecular mobility in an amorphous solid dispersion is often reduced by the carrier, these systems may also be unstable and phase separate into an amorphous suspension and eventually crystallize [39, 40]. Physical stability can only be ensured if the drug is solubilized in the amorphous carrier below its equilibrium solubility in the carrier, a system known as a glass solution. Consequently, glass solutions are thermodynamically stable. Table 2.4 Classification of solid dispersions. 1 phase

2 phases

Crystalline

Solid solution

Eutectic mixture

Amorphous

Amorphous solid dispersion or glass solution

Amorphous solid suspension

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2.6.2

Method of Manufacturing

Amorphous character can generally be induced in two fundamentally diverse ways: the thermodynamic and the kinetic path. The kinetic path is an approach where particle size reduction and loss of molecular order in a bulk powder is introduced over time. This approach requires high energy or pressure input and includes technologies such as high-pressure homogenization and different milling methods. The thermodynamic path involves formation of the amorphous state from a solution state and hence the energy input for amorphization of the API is limited. The thermodynamic path is the more popular of the two paths to prepare amorphous solid dispersions and is commonly divided into solvent-based and melt-based technologies. The solvent-based technologies include spray-drying, coprecipitation, supercritical fluid extraction, electrospinning, and freeze-drying; and the melt-based technologies include melt agglomeration, spray congealing, and melt extrusion [41]. The selection of a suitable processing technology for the preparation of amorphous solid dispersions depends on the desired outcome and the physicochemical properties of both the drug and polymer such as their T m or T g , thermal stability, and solubility/stability in organic solvents albeit with additional considerations to cost and organizational strategy. In the following section, the three main methods of large-scale production of solid dispersions are briefly described. Other methods naturally exist at the laboratory scale; however, these are not described here. 2.6.2.1

Melting/Fusion

The simplest way to produce an amorphous solid dispersion is using the melting or fusion method, where a drug and polymer are heated to a combined melt and rapidly solidified by cooling. If cooling of the melt through the supercooled liquid state exceeds the rate of crystallization, the drug and polymer may be kept in the glassy state. Therefore, adequate mixing of the drug and polymer in the melting and rapid cooling phase is essential to form homogeneous amorphous solid dispersions [42]. Several different methods have been proposed on the basis of fusion, and they differ by the way the compounds are mixed and cooled. Powders can be readily produced if the melt is spray cooled, a process conceptually similar to spray-drying where the melt is sprayed into a chamber that is continuously perfused with chilled air, causing the droplets to solidify almost instantly into spherical particles with good flow properties [43]. However, a more frequently used method in the pharmaceutical industry is hot melt extrusion. In a normal hot melt extrusion operation, a physical mixture of crystalline drug and polymer is introduced via a hopper into an extruder, containing a heated barrel and one or two rotating screws that transport the material down the barrel. The mixture is then subjected to mechanical forces as well as being heating to yield a well-mixed melt, forced through a die and formed or cut into the desired shape and size. The combination of a rotating screw and a heated barrel results in a high shear stress, which allows for intimate mixing of the components, and the short residence times reduce the chance of thermal degradation [44]. Compared to the traditional fusion methods, hot melt extrusion enables continuous

2.6 Solid Dispersion

manufacturing, which makes it suitable for large-scale production. Nevertheless, application of the fusion method requires that the drug and polymer are completely miscible and thermally/chemically stable in the liquid state, and therefore it is only applicable to drugs with relatively low melting points and are not thermolabile [45]. Despite these limitations, the application of the hot melt extrusion technology for commercial manufacturing of amorphous solid dispersions is well documented and includes marketed products such as Casemet (nabilone) and Kaletra (lopinavir/ritonavir).

®

®

2.6.2.2

Solvent Evaporation

In the solvent evaporation method, the drug and polymer are dissolved in a common solvent, which is then rapidly evaporated. If the solvent evaporation is fast enough and the drug and polymer are miscible in the solid state, the drug will be kinetically trapped in the polymeric matrix in a solution-like solid state. Several different solvent evaporation methods have been proposed and they differ by the type of solvent used and the conditions under which the solvent is evaporated. Due to the very fast solvent evaporation, spray-drying is the most successful solvent-based method to prepare amorphous solid dispersions. In this process, which is often complex, a solution of drug and polymer in a volatile organic solvent is atomized into fine droplets by applying a force (pneumatic, centrifugal, or vibrational) in a drying chamber that is continuously perfused with conditioned drying gas (often inert nitrogen gas). This causes the solvent to evaporate and the droplets to solidify into spherical particles, which are then separated from the gas using a cyclone and/or a filter bag. Even though the processing temperature in a normal spray-drying operation is relatively high, the product rarely reaches temperatures above 50 ∘ C because the heat transfer associated with evaporation causes the temperature of the surrounding gas to drop [46]. Hence, compared to the fusion method, the thermal decomposition of thermosensitive drugs and polymers may be prevented as evaporation of organic solvents can be performed at comparatively low temperatures. Spray-drying has been applied for large-scale production of amorphous solid dispersions, and commercially available products such as Incivel (telaprevir) and Tibotec (etravirine) use the technology [6]. This technique is not suitable for drugs that have poor/low solubility in organic solvents and/or there is a concern on the use of organic solvents in manufacturing process owing to organizational strategy. A consideration for this technique is use of organic solvents belonging to class 2 or class 3.

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2.6.2.3

®

Coprecipitation

In the coprecipitation method, drug and polymer are dissolved in a common organic solvent and slowly added to a large volume of antisolvent, causing simultaneous precipitation of drug and polymer. The resulting suspension is then filtered and washed to remove residual solvents before it is dried to yield a fine powder referred to as a microprecipitated bulk powder [41]. The rate of precipitation is dependent on the solubility of the drug and polymer in the antisolvent. If the precipitation is fast enough, the microprecipitate will become amorphous. The selection of a suitable solvent and antisolvent is crucial for the quality of the amorphous solid dispersion; and as they are washed out, the

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solvents can be less volatile than those used for solvent evaporation methods. The coprecipitation method is advantageous compared to techniques such as melt extrusion and spray-drying for compounds that have high melting points and low solubility in conventional volatile organic solvents. The marketed amorphous solid dispersion of vemurafenib (Zelboraf ) is manufactured using the precipitation method [47]. A consideration for this technique is the use of organic solvents belonging to class 2 or class 3.

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2.6.3

Characterization

Solid dispersions are generally amorphous systems which are disordered, with random molecular configurations and packing of the components. These systems may possess local and short-range order or residual crystallinity, and different density regions which add to the formulation complexity. For these reasons, obtaining insight into the formulation is important to address optimization of a solid dispersion system. The complexity of the analytical testing may vary depending on the development stage. However, successful formulation development depends on the sound understanding of the formation of the amorphous system, residual crystallinity and interaction between the polymer and compound, and ensuring a uniform formulation. This knowledge forms the basis for development and helps define important formulation and process parameters such as concentration of polymer and drug spray rate, etc. In the following section, commonly used analytical techniques to characterize solid dispersions are described. 2.6.3.1

Investigation of Crystallinity

A poor selection of factors such as carrier (polymer), drug loading, and process control during manufacturing of amorphous solid dispersions may generate a crystalline drug in the product. Even the trace levels of crystalline drug may function as seeds for recrystallization during in vitro dissolution or upon long-term storage and, of course, it might occur during in vivo passage of the drug product. The recrystallization phenomenon may have considerable influence on the product performance. Therefore, several techniques are frequently used to investigate the presence of crystalline drug in the solid dispersion formulation. X-ray Powder Diffraction (XRPD) XRPD is the most widely used and perhaps the

most definitive technique used for the detection of crystalline material in an amorphous solid dispersion. Absence of clear Bragg’s peaks and observation of a halo structure suggest that a formulation contains only amorphous material. Calibration curves can be generated to quantify the degree of crystallinity by mixing crystalline and amorphous compounds in various ratios. Although a debated approach, it is the only method which can be validated for analysis of the product. The limit of quantification is typical in the range of 5% of total crystalline content and can vary from one compound to other. Raman and Infrared Spectroscopy IR and Raman spectroscopy can be used

to detect the variations in vibrational energy between the amorphous and

2.7 Lipid-Based Drug Delivery Systems

crystalline materials. Crystalline materials normally produce sharp peaks, while amorphous materials generate broader peaks. In principle, the calibration model used for XRPD can also be used for spectroscopic method of analysis. Differential Scanning Calorimetry (DSC) During the DSC analysis, samples are

heated at a constant rate, heat flow is constantly monitored, and the temperatures where events occur are recorded. Thermal events relevant for amorphous solid dispersions are glass transition, (re)crystallization, and melting, which can be used to quantify the crystallinity of the formulations. Besides this, information on decomposition can be obtained, which can be used for the selection of production process. Other Techniques Various other techniques that can be used to detect the crystallinity of a sample are polarized microscopy, water vapor sorption for hygroscopic materials, or isothermal microcalorimetry; however, these techniques are complex for general applications. 2.6.3.2

Investigation of Molecular Arrangement

An optimal solid dispersion is physically stable and maintains supersaturation during the period of drug absorption. To achieve this supersaturation state, a careful selection of polymer and drug loading is needed depending on the drug’s specific physicochemical properties. Desired physical stability can be obtained when the drug is molecularly dispersed in a polymer matrix with appropriate intermolecular interactions between the two components. Therefore, it is of high importance to gain insight into the arrangement in the amorphous system using spectroscopic methods such as IR and Raman spectroscopy [48]; solid-state nuclear magnetic resonance (NMR) can also be used to investigate these interactions [49]. Dissolution Methods Dissolution test can be used to gain insight into the potential

in vivo performance of a formulation; and, of course, for solid dispersions this is obviously the case. An important parameter to be investigated for solid dispersion is the formulation’s ability to maintain a supersaturated solution for a sufficient period. This property allows absorption of the compound; hence, the non-sink dissolution conditions should be defined to evaluate this specific parameter. Use of biorelevant media (such as FassGF and FassIF) and a period of three to four hours’ dissolution study should be considered to simulate the intestinal conditions as well as the potential residence time in the small intestine, where the formulations should ensure the supersaturated state.

2.7 Lipid-Based Drug Delivery Systems Lipid-based drug delivery system (DDS), as the name suggests, comprises all the drug delivery techniques which use a solid and/or a liquid lipid to improve/ modulate the bioavailability of the active compound. Drug delivery technologies that can be categorized as lipid-based include oily solutions, solid lipid

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nanoparticles, nanostructured lipid carriers, nanoemulsions, microemulsions, self-emulsifying drug delivery systems (SEDDSs) and self-microemulsifying drug delivery systems (SMEDDSs), micellar systems, and, to some extent, solid dispersions (especially when the carrier used is solid lipid). However, we discuss micellar systems as a separate topic as they are a broad topic in the defined scope of this chapter. Here, we focus on lipid-based systems that are classified in the Pouton lipid formulation classification system (LFCS) [50]. 2.7.1

Description

Lipid-based systems have been traditionally classified into four main categories, viz. type I through to type IV, also known as LFCS. Readers are advised to refer the following articles [50–52] for a detailed understanding of this classification system. In short, these LFCS types are based on the increasing hydrophilic content of the formulation, with type I having the least hydrophilic content and type IV having the highest hydrophilic content. Type I lipid formulations contain oils that need to be digested by the gastrointestinal tract (GIT) to form micelles or mixed micelles and thus absorbed. For very potent or low-dose actives, this type of formulation strategy is ideal, as the development part involves only solubilization of the active in a suitable oil followed by stability studies. Type II lipid-based DDSs consist of mixtures of lipids and water-insoluble surfactants that have a hydrophilic lipophilic balance (HLB) value less than 12. In vivo, this system self-emulsifies into oil-in-water emulsions with some energy input via GI motility. Type III lipid formulations contain water-soluble surfactants with HLB value more than 12 along with cosolvents such as ethanol, propylene glycol, or PEGs. These formulations spontaneously self-emulsify upon contact with an aqueous environment in vivo. Depending on the particle size of the globule formed, the type III systems are classified as SEDDS (>200 nm) or SMEDDS (5 g/kg [54]

Bioavailability enhancer, solubilizer

Capryol PGMC

Propylene glycol monocaprylate (type I)

L

6.0

—

Bioavailability enhancer, solubilizer

Lauroglycol 90

Propylene glycol monolaurate (type II)

L

3.0

Oral, rat, >2 g/kg

Bioavailability enhancer/solubilizer

Lauroglycol FCC

Propylene glycol monolaurate (type I)

L

4.0

Oral, rat, 2 g/kg

Bioavailability enhancer

Labrafac PG

Propylene glycol dicaprylocaprate

L

2.0

—

Bioavailability enhancer/solubilizer

Labrafil M1944CS

Oleoyl polyoxyl-6 glycerides

L

9.0

Oral, rat, >20 g/kg

Reduced hepatic metabolism due to increased lymphatic uptake

Labrafil M 2125CS

Linoleoyl polyoxyl-6 glycerides

L

9.0

—

Reduced hepatic metabolism due to increased lymphatic uptake

Capmul MCM

Medium chain mono- and diglyceride of C8 and C10 chain

L

5.0–6.0

Oral, rat, >5 g/kg

Emulsifier and lipophilic surfactant, Improves permeation and, consequently, oral bioavailability and also acts as a solubilizer

Miglyol 810 and 812

Caprylic/capric triglyceride

L

1.0

Oral, rat, >5 g/kg i.p., rat, >8 g/kg

Absorption promoter in GIT and when used topically, parenteral nutrition, solvent for certain APIs

Tween 80/ Polysorbate 80

Polyoxyethylene 20 sorbitan monooleate

L

15.0

Oral, rat, 25 g/kg i.v., rat, 1.8 g/kg i.p., rat, 6.8 g/kg

Emulsifying, wetting, and dispersing agent

Tween 20/ polysorbate 20

Polyoxyethylene 20 sorbitan monolaurate

L

16.7

Oral, rat, 37 g/kg i.v., mouse, 1.42 g/kg

Emulsifying, wetting, and dispersing agent

Labrasol

Caprylocaproyl macrogol-8 glycerides

L

12.0

Oral, rat, >22 g/kg

Bioavailability and permeation enhancer, emulsifier and surfactant

Trade name

Chemical name

Capryol90

Kolliphor HS 15

Polyoxyl 15 hydroxy stearate

SS

14.0–16.0

Oral, rat, >20.6 g/kg

Emulsifying, wetting, and dispersing agent

Kolliphor EL, ELP

Polyoxyethylene 35 castor oil

L

12.0–14.0

Oral, rat, >6.4 g/kg

Emulsifying, wetting, and dispersing agent

Kolliphor RH 40

Polyoxyl 40 hydrogenated castor oil

P/L

14.0–16.0

Oral, rat, >20 g/kg

Emulsifying, wetting, and dispersing agent

Transcutol P and Transcutol HP

Diethylene glycol monoethyl ether

L

—

Oral, rat, >5 g/kg dermal, rat, 6 g/kg

Solubilizing agent

Soluphor P

2-Pyrrolidone

L

—

Oral, rat, >2 g/kg dermal, rabbit, >2 g/kg

Solubilizing agent

Pharmasolve V

N-Methylpyrrolidone

L

—

Oral, rat, 3.9 g/kg i.p., rat, 2.5 g/kg i.v., rat, 0.08 g/kg

Solubilizing agent

Glycofurol

Tetrahydrofurfuryl alcohol polyethylene glycol ether

L

—

i.v., mouse, 3.5 ml/kg

Solubilizing agent

PEG 200–400

Polyethylene glycols

L

—

PEG 200, oral, rat, 28 g/kg PEG 300, oral, rat, 27.5 g/kg PEG 400, oral, mouse, 28.9 g/kg

Solubilizing agent, improves permeation

Propylene glycol

2-Hydroxypropanol

L

—

22 g/kg

Solubilizing agent, improves permeability of skin and mucosa

LCTs (soybean oil, corn oil, safflower oil, fish oil)

Glycerides of long chain fatty acids (C16–C20)

L

3.0–7.0

Soybean oil, i.v., rat, 16.5 g/kg

Useful for parenteral nutrition, useful for improving oral and topical permeation

Safflower oil, i.p., mouse, >50 g/kg a) L, liquid; S, solid; P, paste; SS, semisolid. This is a suggestive list. Source: Adapted from [55] with permission from Springer Nature.

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Table 2.6 The lipid formulation classification system: characteristic features, advantages, and disadvantages of the four essential types of “lipid” formulations. Formulation type

Composition

Characteristics

Advantages

Disadvantages

Type I

Oils without surfactants (e.g. tri-, di-, and monoglycerides)

Nondispersing, requires digestion

GRAS status; simple; excellent capsule compatibility

Formulation has poor solvent capacity unless drug is highly lipophilic

Type II

Oils and waterinsoluble surfactants

SEDDS formed without water-soluble components

Unlikely to lose solvent capacity on dispersion

Turbid o/w dispersion (particle size 0.25–2 μm)

Type III

Oils, surfactants, cosolvents (both water-insoluble and watersoluble excipients)

SEDDS/ SMEDDS formed with water-soluble components

Clear or almost clear dispersion; drug absorption without digestion

Possible loss of solvent capacity on dispersion; less easily digested

Type IV

Water-soluble surfactants and cosolvents (no oils)

Formulation disperses typically to form a micellar solution

Formulation has good solvent capacity for many drugs

Likely loss of solvent capacity on dispersion; may not be digestible

Source: Reprinted from [50] with permission from Elsevier.

mixing equipment, a homogenizer is also a prerequisite in the manufacture of type II systems. In a type III system, the active is dissolved in a mixture of oil, water-soluble surfactant (HLB > 12), and a cosolvent. The role of the cosolvent is to reduce the interfacial tension between the oil phase and the aqueous phase. The use of a hydrophilic surfactant aids in the formation of spontaneous emulsion. If the particle size of an emulsion formed is >200 nm, it is considered an SEDDS. And the systems with particle size 4) is favorable for lipid-based DDS [50, 61]

Melting point

Compounds with low melting point are favored for lipid-based DDS, as the energy required for solubilization is low and hence a more physically stable system can be obtained

Dose

Potent drugs (drugs with low dose) are ideal candidates for lipid-based DDS, due to the possibility of loading all the doses within the lipidic excipients

2.7.4

Role of API Property on Lipid-Based DDS

Apart from the formulation variables, drug-related factors are also important to consider prior to development of lipid-based DDSs (see Table 2.8). However, the list is indicative and it is very rare that a formulator comes across an active with all the desired properties. Nevertheless, it is an interplay of these properties of drugs that define successful development of a stable lipid-based DDS. For example, a drug with very poor solubility in lipids and/or surfactant, can still be developed in a lipid-based DDS provided the dose is low (potent compound), as the low solubility is still sufficient to deliver the desired dose.

2.8 Micellar System Micellar systems, although a type IV LFCS, is being discussed as a separate topic owing to vast formulation-related information available for the perusal of a formulation scientist and owing to a more often used formulation strategy in the earlier stage of the drug development process. 2.8.1

Description

Micellar systems are DDSs where the drug is surrounded by a layer of one or more surfactants in an aqueous environment. These systems can be used to improve the solubility of actives belonging to BCS class II or IV. In most of the micellar systems, the active is located inside the hydrophobic core of the surfactant. The surfactant molecule is composed of a hydrophilic head and a hydrophobic tail.

2.8 Micellar System

A unique property of surfactants is HLB value and it is based on the ratio of the area of the hydrophilic head to that of the lipophilic tail. In general, the lower the HLB value, the bigger is the hydrophobic tail in terms of hydrodynamic area, and hence the surfactant is more hydrophobic-loving. Two or more surfactants with differing HLB values can be mixed to obtain the ideal surfactant ratio for effective drug solubilization. When two or more surfactants are used to achieve drug solubilization, such systems are called mixed micelles. Micellar systems improve the solubility of the active by decreasing the interfacial energy between the hydrophobic active and the hydrophilic aqueous environment by way of micelle formation. Figure 2.5 gives an overview of the various micelle formation configuration. Surfactants are the primary components of a micellar system, and they are classified as nonionic, cationic, anionic, or zwitterionic. Every class of surfactant presents some pros and cons; however, nonionic surfactants are the least toxic followed by anionic surfactants, polymeric surfactants, and cationic surfactants. Nonionic surfactants are without any charge in aqueous environments and they are subdivided into water-insoluble and water-soluble surfactants. Apart from the low toxicity, these surfactants show better excipient–excipient and drug–excipient compatibility and stability. Figure 2.6 summarizes the valuable information about different classes of surfactants. A crucial factor in the selection of surfactants is the critical micelle concentration (CMC). At or above the CMC, individual surfactant molecules arrange themselves into micelles, the shape of which can range from spherical to cylindrical or cubic phase. Below the CMC, surfactant molecules exist as individual monomers. The different techniques used to measure the CMC include surface tension, osmometry, and dynamic light scattering. Apart from the inherent property of the surfactants, the CMC is also affected by external factors such as temperature, pH, presence of salts, and the physicochemical property of the active to be loaded within the micelles. As a rule of thumb, lower CMC means that a lower amount of surfactant is required to achieve micelle formation and hence the surfactant has better solubilization potential. The next important parameter considered during the design of the micellar system is the size of micelles and the aggregation number. Aggregation number is an indication of the number of individual surfactant molecules coming together to form the micellar structure and can be calculated as per Eq. (2.1)1 . Aggregation number =

Molecular weight of micelle Molecular weight of surfactant

(2.1)

Micellar size is indicative of the stability of the micellar system and the effective particle size of micelles formed upon in vivo exposure. The physicochemical property of the drug can have an influence on the micelle size as well as concomitant increase in aggregation number, meaning more numbers of surfactant monomers are required for creation of a micellar structure. As more and more surfactant molecules are used to deliver the hydrophobic drugs, understanding the relationship of aggregation number and micellar stability can 1 The molecular weight of micelles can be found out using dynamic light scattering, sedimentation equilibrium, or small-angle X-ray scattering.

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(a)

H

Nonionic surfactant molecule Anionic surfactant molecule Counterion Water molecule

(b)

(c)

Ionic surfactant molecule Water molecule

(d)

(e)

Figure 2.5 (a) Spherical micelle of an anionic surfactant (left) and a nonionic surfactant (right). (b) Schematic representation of the structures of surfactant aggregates in dilute aqueous solutions. Shown are aggregates that are spherical, globular, and spherocylindrical micelles and spherical bilayer vesicles. (c) Lamellar mesophases of an ionic surfactant. (d) Schematic representation of solubilization of hydrophobic molecules in surfactants giving rise to type I aggregates, referred to as swollen aggregates. The solubilizates are present in the surfactant tail region which extends over the entire volume of the aggregate. The smaller dimension characterizing the aggregate is limited by the length of the surfactant tail and (e) Structure of surfactant aggregates wherein the type II mode of solubilization occurs, also referred to as microemulsions. In these structures, the solubilizates are present both within surfactant tail region and in a domain made up of only the solubilizate. The solubilizate domain constitutes the core of the aggregate in the first structure shown and is a spherical shell region separating the two surfactant layers in the second structure shown. The dimensions of the aggregates are not limited by the extended length of the surfactant tail. Source: Reprinted with permission from Taylor & Francis from [62].

Surfactants

Nonionic surfactants Surfactant head group has no charged groups

Water insoluble Usually lipid-based hydrophobic tail. Eg.: fatty alcohols, glyceryl esters, fatty acid esters

Water soluble Usually polyoxyethylene groups attached via an ether linkage to the alcohol groups. Eg. Tweens

Anionic surfactants Surfactant head group has net negative charge

Cationic surfactants Surfactant head group has net positive charge

Zwitterionic surfactants Surfactant head has a pH-dependent positive or negative charge

Salts of weak carboxylic acids are formed by the hydrolysis of fats (triglycerides) by sodium hydroxide. Sulfonates, such as sodium docusate and decane sulfonate, widely used in pharmaceutical systems

Examples include amine, quaternary ammonium, and pyridiniumions. The use in pharmaceutical systems is limited to antimicrobial preservation

Such as amino acids, betaines, carnitines, and phosphatidylcholines

Figure 2.6 Classification of surfactants based on charge. Source: Modified from [62].

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help a formulation scientist design a robust micellar system [62]. Other factors that affect the performance of the surfactant are the packing parameter and the HLB value. The packing parameter, a semiquantitative parameter, is related to the shape and size of the micellar system, meaning the type of three-dimensional orientation the surfactant molecules like to take in an aqueous environment ranging from sphere-like, cylinder-like, or lamellar-sheet-like micelles. This parameter is dependent on the surfactant hydrophobic tail volume and length of the surfactant hydrophobic tail. The HLB scale for surfactants is a unitless scale used to classify the surfactants based on the ability to like a lipophilic or hydrophilic environment. A surfactant with an HLB value between 1 and 10 is considered lipophilic, whereas a surfactant with an HLB value greater than 10 is considered a hydrophilic surfactant [62]. 2.8.2

Formulation Development and Optimization

The method of producing a micellar system is relatively simple and straightforward. The primary data package needed to initiate a screening of probable surfactants is the preformulation data of the drug such as log P, pH-solubility curve, stability, solubility in aqueous and nonaqueous solvents, and melting point. This information helps the formulation scientist select the right surfactant type with the correct HLB value, which would provide the best solubilization result for the drug under consideration. The next step would be to identify surfactants based on different chemical class and charge, as described in Figure 2.6. Another consideration while making this choice of surfactant is the safety of the surfactant in preclinical and clinical settings, and the inactive ingredient database (IIG) from the U.S. Food and Drug Administration (FDA) can be helpful to decide the upper concentration of the surfactant. Once selection of surfactants is performed, the next step is to determine the solubility of the drug in the surfactant or a mixture of surfactants. The surfactant or the surfactant mixture showing desired solubility is further evaluated for chemical compatibility over accelerated conditions. The best drug–surfactant combination is selected for further prototype formulation development. Other excipients such as antioxidants, sweeteners, and taste masking agents can also be added from a physical and chemical compatibility as well as patient compliance point of view. Once a stable micellar system is developed, the next step is to design the product ready for administration. One of the possibilities is to fill the liquid surfactant-active-excipient mixture in a soft gelatin capsule. Another way can be to adsorb the liquid surfactant-active-excipient mixture on an inert carrier such as silicon dioxide or dextrin, and the powder can be filled in the hard gelatin capsules or developed as a tablet for ease of administration. In case of polymeric micelles where the surfactant is polymeric in nature, the process of micelle formation slightly differs as the polymeric surfactants are usually solid in nature, e.g. poloxamers. There are two main methods to produce polymeric micelles. The first method involves dissolving the polymeric surfactant and active in water; this is a straightforward technique and suitable for less hydrophobic materials. The second method involves use of organic solvents where the active and polymer are dissolved in a common solvent followed by

2.9 Mesoporous Silica Particles

Table 2.9 Characterization considerations for a micellar system. Characterization

Relevance to micellar system

Particle size

Particle size is an essential in-process control and quality assurance. It helps ensure batch-to-batch reproducibility

Microscopy

Techniques such as polarized light microscopy, SEM, TEM, and cryoTEM may help to understand the packing structure of the micelles in liquid phase and the different micellar structures. This information helps in accurate description of the formulation development

X-ray scattering

This technique helps identify the packing parameter and the thickness of the micellar layer

Calorimetry

Differential scanning calorimetry helps identify the phase separation

Rheology

Rheology can play a key role in determining the packing of the micellar systems, as different surfactants have different packing in an aqueous environment. It can be also an important in-process control tool

Effect of dilution

The micellar system upon exposure to GIT is subject to dilution, which might lead to precipitation of the active instead of micellization. Hence, it is important to determine the effect of dilution

removal of the organic solvent. The active–polymer mixture thus obtained can be filled in a hard gelatin capsule for oral administration [63–65]. 2.8.3

Characterization

Apart from the chemical analysis such as assay, purity, and ICH stability, there are additional techniques to evaluate the stability of the micellar systems. Table 2.9 lists them in more detail.

2.9 Mesoporous Silica Particles Silicon dioxide (SiO2 ), commonly referred to as silica, is widely present in the earth’s crust but is also found in plants, cereals, fruits, and living organisms [66]. Silica has a long history of use and regulatory approval in the manufacturing of oral solid dosage forms mainly as a glidant to improve powder flow properties. Silica, due to its relatively high surface area, has been also used as a carrier to improve the dissolution rate and subsequently oral delivery of a variety of hydrophobic drugs [67]. Furthermore, it can also be used as an adsorbent to transform liquid/semisolid for lipid-based formulations to solid formulation. However, silica (commercial name: Aerosil , Cab-O-Sil , HDK) used in the pharmaceutical industry hitherto, is a nonporous amorphous fumed silica (colloidal SiO2 ) [67]. In the pharmaceutical arena, mesoporous silica particles are regarded as the second-generation and high-performance silicon dioxide materials mainly due to their very high surface area compared to the nonporous fumed silica which results in enhanced drug-carrying capability and drug delivery [66–69].

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2.9.1

Description

Mesoporous silica particles have a pore diameter ranging from 2 to 50 nm; typically, these pores are uniform in size and are arranged in a highly ordered manner in the silicon matrix when studied by X-ray crystallography [65, 67]. Due to this specialized mesoporous structure, mesoporous particles tend to have high pore volume and 1.5–5-fold higher surface areas than the nonporous silica materials such as Aerosil [67]. Due to the porous nature and high surface area, a significantly higher amount of the drug (and even biomolecules) can be loaded (adsorbed) onto the mesoporous silica particles (∼50% w/w) [66–69]. Furthermore, the presence of silanol functional group (Si-OH) on the inner and outer surface of the mesoporous silica particles allows for (covalent) conjugation of the drug/biomolecules to the particles which can further (i) improve drug loading capability, (ii) enable delivery of multiple drugs with diverse physicochemical properties, and (iii) help with tuning the drug release [66–69]. As mesoporous particles retain integrity in the presence of organic solvents, they allow for a wide choice of organic solvents to load the hydrophobic drugs into the mesoporous silica particles based on the solubility characteristics of the drug [67]. After drug loading, the drug molecules are caged and stabilized within the silica mesopores in the noncrystalline (or amorphous) form, leading to a higher drug dissolution rate. The mesoporous silica particles containing non-swellable silica network or larger pore size can efficiently prevent the loaded drugs/biomolecules from the enzymatic degradation and deactivation that can occur in the different physiological fluids. Tu et al. synthesized mesoporous silica nanoparticles with higher pore size that are capable of encapsulation and tunable release of a variety of biomolecules such as bovine serum albumin, lysozyme, and catalase [70]. The excellent structural stability of mesoporous silica particles on the storage makes them more advantageous than the conventional solid dispersions which may suffer from problems such as solid-state phase separation on storage [66–69]. To date, several types of mesoporous silica particles with different pore (i) volume, (ii) shape, (iii) size, and (iv) arrangement have been developed for a variety of applications including oral drug delivery. Based on the pore arrangement, the mesoporous silica particles are divided into the ordered and non-ordered mesoporous silica particles, and both the types have been evaluated as drug carriers [66, 67]. Examples of the ordered mesoporous silica materials include a rage of particles developed by Mobil Corporation such as Mobil Crystalline Material (MCM)-41 containing well-ordered hexagonal mesopores and MCM-48 containing cubic mesopores [66–69]. Santa Barbara Amorphous (SBA)-15 is material developed by the investigators at the University of California at Santa Barbara that contains hexagon-shape ordered silica mesopores [66–69]. These materials have been used for many applications including drug delivery. Non-ordered mesoporous silica materials such as Syloid and Sylysia have also been developed for a variety of applications including use as drug carrier [67]. Recently, excipient companies have focused on the development of mesoporous silica materials specifically suited for pharmaceutical applications. The examples include Parteck SLC (Merck Millipore Corp., Germany), Syloid silica (Grace Pharmaceuticals, MD, USA), and Sylysia (Fuji Sylysia Chemical Ltd., Japan) [67].

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2.9 Mesoporous Silica Particles

Several clinical studies are being carried out to ascertain the in vivo advantage of the mesoporous silica particles as drug carriers. Compared to the strategies, oral drug delivery using mesoporous silica particles is in its nascence and there are no FDA-approved commercial products based on mesoporous silica particles yet. 2.9.2

Method of Manufacturing and Characterization

Generally, surfactant-micelle- and/or liquid-crystal-mediated templating is used to fabricate mesoporous silica particles. Both the methods involve the hydrolysis and condensation of silica precursors such as tetraethoxysilane (TEOS) in the presence of a structure-directing agent which leads to a hybrid gel referred to as mesophase [66, 68]. Subsequently, processes such as calcination or solvent extraction are carried out to obtain mesoporous materials [66, 68]. The schematics of the process is shown in Figure 2.7. Several parameters such as pH; temperature; aging time; type of silica precursor; the nature, type, and concentration of the surfactant; and the ratio of the silica precursor and the structure-directing agents influence the physicochemical properties of the mesoporous silica particles [68]. To manufacture drug-loaded mesoporous silica particles, various methods such as melt processing, solvent immersion, supercritical fluid-based particle engineering, co-spray-drying, hot melt extrusion, and fluid-bed processing can be used [67, 71]. Mesoporous silica particles are typically characterized for various parameters such as particle size and morphology, pore size and morphology, pore volume, surface area, surface silanol groups, and drug loading. The techniques such as DSC and XRD (X-ray diffraction) are used for the characterization of the amorphous nature of the drug incorporated into mesoporous silica particles. Drug-loaded mesoporous silica particles are further characterized for the in vitro drug release studies and in vivo performance [66–69]. Iyotropic liquid-crystalline phase (shown 2D hexagonal) Spherical micelle

Composite: inorganic mesostructured solid/surfactant

O O Si O O

Rod-shaped micelle

(a)

O O Si O O

O O Si O O

Mesoporous material (shown MCM-41)

O O Si O O

Removal of the surfactant

Silica precursor (shown: TEOS)

(b)

Figure 2.7 Formation of the mesoporous silica particles with help from structure-directing agents: (a) true liquid crystal template mechanism and (b) cooperative liquid crystal template mechanism. Source: Reprinted from [66] with permission from Elsevier.

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Fenofibric acid plasma concentration (μg/ml)

84

0.05 0.04 Fenofibrate-OMS – 33.5 mg 0.03

Lipanthyl® – 67 mg

0.02 0.01 0.00 0

12

24

36

48

60

72

84

96

Time (h)

Figure 2.8 Mean (n = 12) plasma concentration versus time profiles after single administration of one capsule containing 33.5 mg of fenofibrate formulated with ordered mesoporous silica (fenofibrate-OMS) or one capsule containing 67 mg of fenofibrate (Lipanthyl). Data normalized to 1 mg dose to ascertain rate and extent of absorption. Source: Reprinted from [74] with permission from Elsevier.

2.9.3

Case Study on the in Vivo Efficacy of Mesoporous Silica Particles

As the applications of mesoporous silica particles as drug carriers are in nascence, there are limited studies available on the in vivo performance of the mesoporous silica particles on oral administration [72, 73]. Recently, Bukara et al. evaluated the potential of ordered mesoporous silica material to improve oral bioavailability of fenofibrate (a hydrophobic antihyperlipidemic drug) in a proof-of-concept study in humans [74]. The investigation involved a single oral administration of 33.5 mg of fenofibrate loaded onto the mesoporous silica particles or Lipanthyl (capsules containing 67 mg of micronized fenofibrate) to 12 healthy and overnight fasted volunteers. Interestingly, fenofibrate-loaded mesoporous silica particles showed a significantly higher rate and extent of absorption (77% enhancement in the C max /dose, 0.75 hours reduction in the t max , and 54% enhancement in the AUC0–24 h /dose) compared to the marketed fenofibrate formulation (Figure 2.8). This study clearly established the potential of mesoporous silica particles in the oral delivery of hydrophobic drugs with dissolution rate-limited bioavailability.

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2.10 Conclusion Poor aqueous solubility, slow dissolution rate, and poor permeability have been and will continue to be the roadblocks in the drug development process. Previously, the primary focus used to be the manipulation of physicochemical properties of the NCEs to improve their developability, and this approach was insufficient to address the attrition faced by the drug development process. The repurposing of novel but commercially viable drug delivery strategies as “enabling” formulation strategies represents a paradigm shift in the drug development process. Various commercially viable or emerging “enabling” formulation strategies such as nanosuspensions, solid dispersions, lipid-based DDSs, micellar

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3 Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products Ankit Sharma Amgen Research, Department of Therapeutic Discovery-Medicinal Chemistry, 360 Binney Street, Cambridge, MA 02142, USA

3.1 Introduction A pharmaceutical drug product consists of an active pharmaceutical ingredient (API) and excipients that constitute the bulk of a drug product. Excipients are often added to enhance drug performance by providing uniformity, solubility, and stability to the API in the dosage form [1]. Excipients also aid in improving the appearance, taste and drug product manufacturing process. From the patient’s safety and efficacy point of view, a pharmaceutical drug product should exhibit batch-to-batch uniformity in delivering the API at the projected rate and amount throughout the product’s shelf life [2]. Therefore, excipients play a critical role in drug performance by ensuring uniformity and stability [3]. Excipients are generally considered pharmacologically inert components, but have the potential to significantly influence drug performance. The chemical functional groups present in the excipients can participate in different types of physical or chemical interactions with the API. Physical interactions between the excipient and the API can modulate the pharmacokinetic profile of the API including its bioavailability, whereas chemical interactions between the two may lead to degradation of the drug product. These degradation products can significantly influence the safety profile of the pharmaceutical product while reducing efficacy due to loss of the active ingredient. These effects are illustrated in more detail in Sections 3.3.1 and 3.3.2. Excipients also contain traces of unknown chemical impurities that are formed either during the manufacturing process or through gradual degradation during storage. These impurities can significantly influence the efficacy and stability of the drug product, which is needed for the desired therapeutic effect [4]. Although the physicochemical properties of commonly used excipients are well documented, data regarding the identity and/or chemical reactivity of the residual impurities in the excipients is often unknown. Chemically, these impurities often behave differently than the excipient and may cause unexpected incompatibilities with the API or other excipients present in the pharmaceutical drug product. For example, povidone and crospovidone are commonly used in oral solid dosage forms as a binder and disintegrant, respectively. Although Innovative Dosage Forms: Design and Development at Early Stage, First Edition. Edited by Yogeshwar G. Bachhav. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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these excipients are chemically inert, they often contain trace levels of aldehydes as impurities. Such impurities can react with various nucleophilic functional groups like amines present in APIs, leading to degradation of the drug product. Therefore, such an API–excipient combination should be avoided. In recent years, both the pharmaceutical industry and health care authorities have expressed significant interest in controlling the quality of the pharmaceutical product during storage. This goal could be achieved by developing precise and validated analytical methods to control the level of impurities present in the pharmaceutical product during drug release [5]. Further, knowledge of incompatible API–excipient combinations and mechanism of degradation pathways could help in designing a robust pharmaceutical product. For this purpose, stability tests have been designed to evaluate the compatibility of each excipient–API combination under accelerated aging conditions [6]. These studies not only facilitate the identification and characterization of relevant drug degradation products but also help in elucidating rational degradation pathways and residual impurities liable for such a degradation pattern. This knowledge could assist in selecting compatible API–excipient combinations and thus help in streamlining the drug development process. The initial part of this chapter focuses on residual impurities commonly present in excipients and the reactivity of these impurities that leads to degradation of the drug product. We also discuss various strategies used to understand the mechanism of such degradation pathways and the use of this knowledge in identifying incompatibilities between drug–excipient combinations. The latter part of this chapter focuses on various measures and mitigation strategies that are often employed to prevent API degradation, as well as the role of environmental factors packaging and storage conditions in ensuring the quality of a pharmaceutical drug product.

3.2 Reactive Impurities in the Excipients and Their Impact on Drug Stability The presence of residual reactive impurities in excipients has confounding effects on pharmaceutical drug development [4]. Even the most commonly used excipients may contain a reactive impurity that could interact with the novel scaffolds present in the API or investigational compounds (drugs under development). Such compounds often contain chemical scaffolds with suboptimal structure that are more susceptible to degradation. This vulnerability of the API toward degradation adds more complexity to the formulation development process. Specifically, in the case of highly potent drugs, where low doses require higher quantities of excipients (diluent), even a small amount of reactive impurities in excipients can lead to significant degradation of the API. The tolerance of residual impurities present in the excipients with APIs of varying types and doses makes it hard to define compendial limits for these unknown impurities. Prior knowledge of the interactions between these reactive impurities and the labile functional groups in APIs can help in addressing potential drug–excipient incompatibility issues.

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility The interaction of excipients or impurities present in excipients with the API can be divided into two main categories: physical interactions and chemical interactions. 3.3.1

Physical Interactions

Physical interactions are noncovalent types of interactions of APIs with excipients or the reactive impurities derived from the excipient. These interactions are often electrostatic in nature, and include hydrogen bonds, ion pairs, dipole–dipole interactions, van der Waal–type interactions, and π-effects like π–π, cation–π, and anion–π-type interactions. Collectively, these interactions can have two major impacts on the overall drug product. First, they can alter the uniformity of the dose without affecting the chemical composition of the API. Second, they can affect the rate of dissolution and release of the API from the drug product, and, in certain cases, have detrimental effects on product performance. Several of these cases involve magnesium stearate, which is commonly used as a flow promoter (lubricant) in solid oral dosage forms, but may cause tablet hardening and therefore poor dissolution of the API from the tablets and capsules. In a well-reported example, increase in the concentration of magnesium stearate in formulations of the nonsteroidal anti-inflammatory drug (NSAID) indomethacin resulted in decreases in the dissolution rate of the API at higher concentrations [7]. It was postulated that the collapse of the matrix structure resulted in formation of a stronger film at the surface, causing slower wettability and retardation of indomethacin dissolution. In another example, activity of the antibacterial cetylpyridinium chloride was reduced when magnesium stearate was used as a lubricant in its tablet form [8]. The ionic interaction between cetylpyridinium cation and stearate anion results in agglomeration of the antibacterial on magnesium stearate particles, limiting its dissolution and diffusion, and hence its bioavailability and observed antibacterial activity. Therefore, the effect of magnesium stearate on drug product behavior needs to be carefully monitored. Microcrystalline cellulose (MCC) is another excipient commonly used as a binder or filler in solid oral dosage forms. The binding properties of MCC may be attributed to the presence of many free hydroxyl residues on its surface. During tablet production, under the compression forces, MCC particles come into close contact and form multiple hydrogen bonds with each other, leading to the formation of strong compacts. However, this phenomenon can produce similar interactions with the functionality present in the API. As expected, high concentrations of MCC in drug tablets and capsules often leads to the slow disintegration and dissolution of drug products containing polar functionality into aqueous media [3f ]. As an example, Steele et al. observed significant variations in the absorption of tacrine hydrochloride, used as a model amine-containing drug, onto 21 MCC-based samples in aqueous solution [9]. Swelling of MCC is

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observed in aqueous solution due to the strong hydrogen bonding of hydroxyl functional groups present in MCC with the solvent, with swelling values ranging from 0.2 to 0.8 ml/g [10]. Such changes to the viscous layer can potentially affect drug release, and are particularly problematic whenever MCC is used with a highly potent compound at low dose. To address this issue, disintegrants are typically included in the formulation to achieve the desired disintegration and dissolution rates whenever MCC is used as a binder. 3.3.2

Chemical Interactions

Drug substances invariably contain functional groups that interact with biological targets to produce the desired physiological effects. These same functional groups can make APIs susceptible toward chemical reactions with the excipients or residual impurities present in excipients, leading to undesirable degradation of the drug substances. The extent and impact of these degradation processes are also influenced by external factors such as the ratio of API to excipient, and environmental factors such as light, moisture, pH, and temperature. Preformulation studies using accelerated and stress stability conditions should be executed during the early stages of drug development to select compatible drug–excipient combinations. In this section, the discussion is centered on the various types of chemical degradation pathways of APIs that result from the presence of trace amounts of reactive impurities in excipients. These degradation pathways are typically associated with certain types of impurities present in excipients and functional groups present in APIs. This section also addresses the sources of these impurities and their role in promoting such chemical degradation processes of the APIs. 3.3.3

Oxidative Degradation

Oxidative degradation is perhaps one of the most common pathways for drug degradation caused by reactive impurities [10]. Oxidation reactions of organic molecules involve complex mechanisms that result in either the removal of electrons or electropositive atoms, or the addition of electronegative atoms like oxygen and the halogens. These reactions involve the oxidation of susceptible functional groups like aldehydes, alcohols, phenols, amines, anilines, thiols, and thiophenols present in APIs and excipients, leading to the degradation of drug substances (Figure 3.1). Oxidation: Increase oxygen content and reduce hydrogen content

[O]

[O] R–CH3

[H]

R–CH2OH

[H]

[O] R–CHO

[H]

R–CO2H

Reduction: Increase hydrogen content and reduce oxygen content

Figure 3.1 Different oxidation stages of organic molecules.

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

Several pharmaceutical excipients contain trace redox-active impurities such as peroxides, hydroperoxides, or transition metals that can trigger oxidative degradation of the API or the excipients themselves, and ultimately result in the degradation of the drug product. Oxidative degradation can also result in the formation of new reactive impurities that could form adducts with the API, resulting in its degradation. Oxidative degradation of povidone and polyethylene glycol (PEG) excipients, for example, result in the formation of formaldehyde, acetaldehyde, and formic acid (Scheme 3.1) [10]. These reactive impurities may undergo condensation reactions with susceptible functional groups present in the API, triggering its degradation. These degradation pathways are discussed in more detail in the following sections. H O

HO

O

O

n

OH

m

I = radical initiator I O O

HO

n

O

O

OH

O2

m

HO

O n

O O

O

OH

m

RH H HO

O +

O n

O

H

O

HO O H

–H2O OH

m

HO

O n

O

O

OH

m

Scheme 3.1 Oxidative degradation of polymeric excipients.

Polymeric excipients such as PEG and polyvinylpyrrolidone (povidone, PVP) are often prepared using peroxides or transition metals like iron or copper to initiate living polymerization reactions. These initiators, or the residual living radicals in the polymerized excipients, are hard to eliminate from the final products, and are hence considered as the primary source of oxidation. Environmental factors such as light, air, pH, and moisture greatly affect the reactivity of these oxidative impurities with the excipient or the API [11]. For example, molecular oxygen present in the air may react with the initiators or residual living radicals to form peroxy radicals, which in turn react with oxidizable APIs or excipients to generate additional free radicals leading to further decomposition of the API or the excipients [10b]. 3.3.4

Peroxides

As mentioned in Section 3.3.3, peroxide impurities are commonly found in polymeric excipients in the form of either hydroperoxide (ROOH) or hydrogen peroxide (HOOH). Peroxides may be used as bleaching agents in cellulosic excipients, but are more often introduced during the manufacture of polymeric excipients like PEG, polysorbates (e.g. Tween 80), PVPs, and ethylene

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oxide–based materials to initiate the polymerization process of their respective monomers. Peroxides can also be generated through autoxidation of polymeric excipients like povidone, PEG, and crospovidone in the presence of molecular oxygen, leading to further degradation of the excipients. This autoxidation process may be accelerated by environmental factors such as exposure to light, air, and moisture; changes in pH and temperature; mechanical stress or pressure; and the presence of reducing agents (e.g. Udenfriend reaction vide infra). The high sensitivity of the autoxidation process to environmental factors leads to significant variation in the amount of peroxide observed during the storage of polymeric excipients. Such variability also results in varied outcomes for drug–excipient compatibility trials, and therefore makes it hard to define rational limits on permissible levels of peroxide impurities [12]. In one such drug–excipient study, Hartauer et al. reported incompatibilities between raloxifene hydrochloride and two commonly used excipients, povidone and crospovidone, in the tablet formulation [13]. These incompatibilities were attributed to the residual peroxide impurities present in these excipients, and led to the formation of N-oxo raloxifene as a degradation product (Scheme 3.2). The degradation product was characterized by comparing its spectroscopic and chromatographic data to that of synthetic N-oxo raloxifene. This report also highlighted a direct correlation between the amount of peroxide observed and the quantity of N-oxo raloxifene formed under accelerated storage conditions [13]. The authors advocated that formulation scientists should use drug–excipient studies to set rational limits on peroxide impurities in polymeric excipients in order to control the formation of such degradation products. HO

HO

S

S

OH

OH [O]

O N

O

O

N O Raloxefine

O N-oxo raloxifene

Scheme 3.2 Oxidative degradation of raloxifene.

In another study, Cory et al. concluded that the presence of residual peroxide impurities in polymeric excipients such as PEG and polysorbate 80 (Tween 80) were responsible for the oxidative degradation of ibuprofen tablets stored under accelerated degradation conditions (40 ∘ C/75% relative humidity [RH]) [14]. As shown in Scheme 3.3, four major degradation products were formed under these accelerated conditions. 3.3.5

Transition Metal Impurities

Transition metals have revolutionized organic synthesis by catalyzing various chemical transformations, including those used in the manufacturing processes of APIs and excipients. Among the transition metals, iron and copper are the

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

CO2H

[O] O +

CO2H

CO2H +

OHC

CO2H

+ OH

O

Scheme 3.3 Oxidative degradation of ibuprofen in the presence of polymeric excipients.

most widely reported metal impurities found in excipients and APIs. Transition metals such as these have the ability to change oxidation states, either by donating electrons (oxidation) or by accepting electrons (reduction), at different stages of a chemical reaction’s catalytic cycle. Such reactivity often results in the oxidative degradation of drug products, even when the metals are present in trace amounts. These metals may also react with other impurities present in excipients such as peroxides to generate highly reactive hydroxyl radicals, thereby accelerating oxidative degradation in chemical processes known as Fenton-type reactions (Figure 3.2). As an example, Dong et al. reported that in the presence of iron and nickel chloride salt as metallic impurities, the oxazolidinone-based antibacterial drug candidate RWJ416457 undergoes oxidative degradation to form the two isomeric aldehydes shown in Scheme 3.4 [15]. Mechanism

Fenton reaction OH +

HO OH + Fe(II)

OH + Fe(III)

O2 + Fe2+(L)

O2 + Fe3+(L) Fe2+(L)

Udenfriend reaction O2 + Fe2+(L) + H2O

R H

+ O2 + 2H

OH + Fe3+(L)

Ascorbic acid

Fe3+(L) + H2O2 R

+ H2O2

O2 + H2O2

or hν

Fe3+(L)

A

Fe2+(L)

L = chelating agent; R—H = API or excipient; A = antioxidant

Figure 3.2 Mechanism of the transition-metal-mediated oxidative degradation of drug product. R

F N N

N

R

Free radical oxidation

N N

CHO H N

R

O

RWJ416457 R=

N

F O NHAc

Scheme 3.4 Oxidative degradation of RW416457.

+

N N

N H CHO

F

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Another common mode of transition-metal-mediated degradation of drug product involves the direct reaction of transition metal impurities with molecular oxygen to generate highly reactive oxygen species [11]. This chemical process is known as the Udenfriend reaction and has three key components: (i) a transition metal ion, typically iron or copper; (ii) a chelating agent, which is especially needed in iron-catalyzed reactions; and (iii) an antioxidant or a reducing agent, which can be an excipient or the drug substance itself. Chelating agents and antioxidants are often used in formulations to extend the shelf life of potentially labile drug products. However, as shown in Figure 3.2, the combination of these three components can result in the formation of highly reactive oxygen species by a multistep process that leads to degradation of the drug product. To start with, the metal ion in a reduced oxidation state forms a complex with the chelating agent. Then, this complex activates molecular oxygen in its ground state by transferring an electron to oxygen and generating a superoxide anion radical. The anion radical thus formed can be reduced by another iron complex, auto-disproportionate to form hydrogen peroxide, or abstract a hydrogen radical from the excipient or drug substance, thus causing their degradation and the formation of hydrogen peroxide. In turn, the hydrogen peroxide may undergo a Fenton-type reaction with reduced iron complex, resulting in the generation of highly reactive hydroxyl radicals, which again can cause rapid oxidative degradation of the drug product. Finally, oxidized Fe(III) complexes can be recycled to Fe(II) complexes by a reducing agent such as ascorbic acid to reinitiate the Udenfriend reaction and complete the catalytic cycle. As mentioned earlier, environmental factors can play an important role in initiating degradation pathways. In particular, oxidative degradation reactions mediated by transition metals are highly sensitive to air and light. In one preformulation study, Reed et al. observed that a drug candidate was unstable to citrate buffer at pH 6.0 [16]. Although the structure of the API was not revealed, it was reported that it does not contain any chromophore that absorbs light in the range of the International Conference for Harmonization (ICH) photostress conditions (wavelength > 300 nm). The authors attributed the drug’s instability to Udenfriend-type reactions that occurred in the liquid formulation containing citrate buffer and trace amounts of iron upon exposure to light. In this example, it was proposed that the citrate ion acts as a chelating agent to form [Fe(II)–citrate] complex. This complex could then be responsible for the production of superoxide anion, hydrogen peroxide, and hydroxyl radical via a Fenton-type reaction, and in turn the oxidative degradation of the drug candidate. This step also results in the formation of [Fe(III)–citrate] complex, which could be converted back to the [Fe(II)–citrate] complex via photochemical reduction in the presence of a citrate anion to complete the catalytic cycle. Therefore, the citrate anion acts both as a chelator and reducing agent under photostress conditions and its presence in formulation during photoexposure makes the drug product intrinsically vulnerable to oxidative degradation. Furthermore, high catalytic reactivity of iron ions in oxidative photochemical Udenfriend reactions led to significant API degradation even

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

at low concentrations (∼1 ppb). Under accelerated photochemical degradation conditions, as defined by the ICH, 50 ppb of iron ion was enough to cause up to 20% degradation of the drug product. These findings clearly indicate the challenges associated with developing stable formulations of drugs that require combinations of such polymeric excipients and chelating antioxidants. Chelating agents such as ethylenediaminetetraacetic acid (EDTA) can also promote Udenfriend reactions. In one such study, Wu et al. reported that EDTA led to accelerated oxidative degradation of bortezomib [17]. In another study, Grubstein and Milano found that EDTA can enhance the photosensitivity of IV formulations of epinephrine containing sodium metabisulfite by promoting Udenfriend-type reactions [18]. Therefore, certain combinations of chelating agents and antioxidants can increase the intrinsic vulnerability of drug products toward oxidative degradation. A deeper understanding of the source and mechanism of oxidative degradation can help in designing robust formulations. 3.3.6

Condensation Reactions

Condensation reactions are reactions in which two or more molecules combine to form a larger molecule, often with the loss of a small molecule like water as a by-product. This type of degradation pathway involves the formation of adducts between reactive impurities present in excipients with APIs, resulting in degradation of the latter. The adduct thus formed can have different efficacies, physiochemical properties, and safety profiles compared to the unaltered drug product. This is especially true for drug products containing low overall doses of highly potent APIs, or simply high API-to-excipient ratios, where even small amounts of reactive impurities may lead to significant degradation of the API. Degradative condensation reaction pathways are typically observed whenever excipient impurities containing electron-deficient functional groups such as aldehydes, carboxylic acids, esters, and α,β-unsaturated carbonyls were combined with APIs containing electron-rich functionalities. These reactions may be subclassified by the functional groups or structural moieties involved in the degradation of the drug product, the most common of which are described in the following sections. 3.3.7

Aldehyde Impurities

The aldehyde functional group is one of the most common structural features found in impurities present in pharmaceutical excipients. Oxidative processes similar to those described in the previous section are often responsible for generating these impurities by degrading excipients such as MCC, crospovidone, hydroxypropyl cellulose (HPC), PEG, polysorbates, starch, lactose, and benzyl alcohols. The most common types of aldehyde impurities present in these excipients are formaldehyde, acetaldehyde, benzaldehyde, and furfural. Even in trace amounts, these highly electrophilic reactive impurities can adversely affect the stability and thereby the efficacy of drug products by forming adducts with

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electron-rich or nucleophilic moieties present in APIs. In one such example, Nassar et al. reported that formaldehyde formed adducts with the investigational drug candidate BMS-204352 whenever PEG 300 and polysorbate 80 were used as excipients (Scheme 3.5a) [19]. The degradation of BMS-204352 to its corresponding hydroxymethylated derivate was also observed, and this product was characterized by mass spectroscopy, nuclear magnetic resonance (NMR), chromatography, and comparison to a reference standard. In a second example, Wang et al. identified the formation of a formaldehyde adduct during long-term stability studies of AvaproTM (Irbesartan) in a low-dose film-coated tablet form (Scheme 3.5b) [20]. Formation of this degradation product was attributed to formaldehyde impurities derived from PEG that were present in the tablet’s coating material, OpadryTM II white. Absence of a degradation product in a redesigned formulation prepared by eliminating PEG further supports this hypothesis. OH

H N

F3C

O

HCHO

F3C

N O

F

(a)

F

BMS-204352 N N N N H

N N N N H Tautomerism

O

N N

HCHO O

H

N N N N H

N NH

O

N N

OH

(b)

Scheme 3.5 Mechanism of degradation of (a) BMS-204352 and (b) irbesartan.

In addition to reacting directly with APIs, formaldehyde may also be oxidized in air to form formic acid. As a result, excipients having residual formaldehyde also contain formic acid as an impurity. The combination of these two impurities can lead to methylation of amine functional groups present in APIs by a process known as the Eschweiler–Clarke reaction. In the example shown in Scheme 3.6, the appetite suppressant fenfluramine reacts with formaldehyde to form an iminium intermediate that undergoes reduction with formic acid impurities present in the formulation to form N-methyl fenfluramine [21]. Furfuraldehyde and 5-hydroxymethyl-2-furfuraldehyde (HMF) are aromatic aldehyde impurities commonly observed in excipients derived from plant sources. These impurities are typically generated during the manufacture of spray-dried lactose and MCC, which require harsh hydrolytic conditions, and, in particular, heating with strong acids such as sulfuric acid. These aldehydes can react in a manner similar to formaldehyde to produce imines (Schiff bases), or the combination of formaldehyde and formic acid to produce alkylated amines,

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

H N

F3C

+

CH2 + N

F3C

–H2O

HCHO

O +

H

O

–H+

H

F3C

CH2 N+

F3C

Me N

–CO2

Scheme 3.6 Formation of N-methyl fenfluramine through Eschweiler–Clarke-type reaction.

often resulting in the visual discoloration of the drug product. For example, the antiepileptic drug vigabatrin reacts with HMF impurities present in MCC to generate the alkylated degradation product shown in Scheme 3.7a [22]. OH O NH2

Microcrystalline cellulose

O O

OH + O

H

HN

OH

OH

(a)

O OH O

F

F

O N O

+ OH

O H

OH

N O

OH

Haloperidol

(b)

Cl

Cl

Scheme 3.7 Degradation of (a) vigabatrin and (b) haloperidol by 5-hydroxymethyl2-furfuraldehyde (HMF) as impurity.

In another example, Janicki et al. reported that the antipsychotic drug haloperidol reacts with HMF to form the Claisen–Schmidt-type condensation product shown in Scheme 3.7b [23]. As one might expect, environmental factors such as moisture content, microenvironmental pH, and the concentrations of the salt or free base forms of a drug relative to the excipients can have a strong influence on the extent of degradation of the API via such alkylation and condensation pathways. In some cases, excipients containing aldehyde functionalities can form adducts with an API, leading to degradation. One typical example is the flavoring agent vanillin, which contains an aldehyde functional group and commonly reacts with nucleophilic primary amine functional groups present in APIs to form imines. The degradation of APIs can also result in the formation of aldehyde impurities. As an example, hydrochlorothiazide (HCTZ) undergoes slow hydrolysis in the presence of moisture to form formaldehyde. This aldehyde impurity can in turn react with the disintegrant sodium starch glycolate (SSG),

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which results in its cross-linking and ultimately slows the dissolution rate of the remaining API. 3.3.8

Reducing Sugars

Excipients derived from polysaccharides are commonly used in oral dosage forms and are generally considered nonreactive in crystalline form. Despite the chemical inertness of the excipients themselves, they often contain trace levels of reducing sugars that are known to be incompatible with amine-containing drugs [1f ]. The reducing sugar impurities are typically generated during production of the cellulosic excipients, and formed under forcing hydrolytic or mechanochemical conditions that invoke strong acids, high-pressure grinding, or ball milling. Environmental factors such as acidity, temperature, and humidity can also favor the hydrolytic cleavage of polysaccharide excipients and generate reducing sugars as impurities. One excipient affected by such impurities is MCC, which often contains trace levels (40–80 ppm) of glucose as a result of its manufacturing process. Polysaccharide excipients like mannitol are also regularly contaminated by monosaccharides such as mannose and glucose in a similar manner. Starch, in particular, is known to degrade into smaller chains as it is prepared from plants in a multistep process involving coarse milling, water washing, wet sieving, and centrifugal separation. Naturally occurring disaccharides such as lactose are also often used as excipients in pharmaceutical formulations, but can themselves act as reducing sugars and lead to the degradation of APIs containing amines. The major degradation pathway by which APIs containing primary or secondary amine functional groups react with reducing sugar impurities is known as the Maillard reaction [24]. As shown in Figure 3.3, the reaction sequence begins with the replacement of a hydroxyl group in a reducing sugar, such as lactose, with an amino group present in the API to form an N-glycoside (glycosylamine) intermediate. This amine intermediate may undergo rearrangement

HO HO

O

R OH Lactose

OH R HN 1 O + R2

−H2O

HO HO

O

R1 N R

2

H2O

O

R

R1 N R

HO HO

2

OH OH

O

R OH

OH N-Glycoside (glycosylamine)

−H2O

Multiple degradation products

O HO

R1 N R

O

2

OH OH 1-Amino-1-deoxy-2-ketose R

Figure 3.3 Mechanism of Maillard degradation reaction.

H2O

R1 N R

HO HO

2

O

OH

R OH

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

under either acidic or basic conditions to produce a 1-amino-1-deoxy-2-ketose intermediate. This rearrangement is also known as Amadori rearrangement. The ketose intermediate thus formed can then undergo any number of parallel or consecutive reactions to form brown-colored pigments. As such, degradation via this Maillard reaction pathway results in a “browning” effect, and the extent to which it occurs often depends on environmental conditions such as local pH, moisture content, and drug concentration. One such example of an API that is susceptible to Maillard-type degradation is pregabalin, an anticonvulsant drug used for treatment for neuropathic pain. It was found that pregabalin degraded into seven different products whenever lactose was used as an excipient [25]. Characterization of these products supported the reaction of the primary amine present in pregabalin with lactose and other reducing sugar impurities present in lactose, such as galactose and glucose, leading to degradation of the API. Another such example was reported by George et al. for the degradation of vigabatrin; this antiepileptic drug reacts with glucose and other monosaccharide impurities present in Avicel , a type of MMC, by a similar sequence, resulting in browning of the tablet form of vigabatrin upon aging [22]. Protein- and peptide-based drugs containing N-terminal amino groups or lysine residues are also highly susceptible to a specific type of Maillard degradation pathway known as glycation. This process may occur either in vitro or in vivo, and results in the formation of advance glycation end (AGE) products [26]. Due to the inherent incompatibility of amine-containing peptides and reducing sugars, excipients well known to be contaminated with reducing sugar impurities or are reducing sugars themselves are generally avoided in the formulations of peptide-based drugs to avoid degradation of the final drug products.

®

3.3.9

Organic Acids

Organic acids such as formic acid, acetic acid, monochloroacetic acid, glycolic acid, succinic acid, and phthalic acid are the most common acidic impurities present in pharmaceutical excipients. These organic acid impurities are typically formed during the oxidative degradation of polymeric excipients under aerobic conditions. As discussed earlier in this chapter, the oxidative degradation of PEG and polysorbate excipients, in particular, initially results in the formation of aldehyde impurities that can undergo further oxidation to form both formic and acetic acid. Organic acid impurities may also be introduced in trace amounts during the manufacture of polymeric excipients as residual monomers (or, more generally, reactants), excess reagents, reaction byproducts, or solvents. For example, acetic acid is typically found in polyvinyl alcohol (PVA) as a by-product of its manufacturing process, that is, the hydrolysis of polyvinyl acetate. As another example, monochloroacetic acid is regularly found in solid oral dosage forms that include croscarmellose sodium as a superdisintegrant. During the production of croscarmellose sodium, sodium monochloroacetate reacts

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with nucleophilic hydroxyl groups present in cellulose to form sodium carboxymethylcellulose (SCMC) and glycolic acid as a by-product. The glycolic acid thus formed catalyzes the cross-linkage to form internally cross-linked SCMC. Any excess amount of monochloroacetic reactant or glycolic acid is typically retained by the product polymer, and can subsequently react with nucleophilic sites present in APIs, leading to their alkylation and subsequent degradation. Although monochloroacetic acid reacts with APIs in a very specific manner, organic acid impurities can more generally react with APIs by sundry esterification, transesterification, and amidation pathways. For example, Waterman et al. reported that formic acid reacts with the anti-smoking medication varenicline to form N-formylvarenicline, as shown in Figure 3.4 [27]. In addition to reacting as an electrophile, formic acid may serve as a hydride donor and promote the methylation of APIs, as described in the previous section. Accordingly, Waterman described the reaction of varenicline with a combination of formaldehyde and formic acid impurities in the final drug product, leading to the formation of N-methylvarenicline via tandem condensation and Eschweiler–Clarke reactions. Residual carboxylic acid impurities present in enteric polymer coatings can also migrate into core tablets and lead to degradation of pharmaceutical drug products. For example, in the case of duloxetine hydrochloride, its tablet form contains the enteric polymers hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP), which are often contaminated with trace amounts of succinic acid and phthalic acid, respectively. These organic acids have been found to react with duloxetine in separate amidation reactions to form the adduct shown in Figure 3.5a,b, and ultimately result in degradation of the API [28]. In addition to the alkylation and amidation reactions described thus far, organic acid impurities may lead to the degradation of the drug product without forming adducts with the API. As an example, Fukuyama et al. described how formic acid impurities promote the optical isomerization of FK480, a non-peptide antagonist of cholecystokinin (CCK)-A receptors (Figure 3.5c) [29]. The authors observed that the formulation of this drug candidate containing PEG 400 and glycerol resulted in the isomerization of the asymmetric carbon atom located within its pyrrolobenzodiazepine core. Fortunately, the authors

NH

HCO2H

H2O

OH

O N

N

H N-Formylvarenicline

OH H2CO H2O OH N

H+

CO2

+ N

– O

H O

N N-Methylvarenicline

Figure 3.4 Mechanism of formation of N-methyl varenicline via Eschweiler–Clarke-type degradation reaction.

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

O

(a)

O

O

N CO2H S Duloxetine-succinic acid adduct

O

CO2H

N S (b) Duloxetine-phthalic acid adduct

F N H O N (c)

N H O FK480

H N

Figure 3.5 Chemical structure of (a) HPMCAS, (b) HPMCP, (c) FK480; degradation products of duloxetine hydrochloride.

observed retardation of the rate of isomerization whenever amino acids were added to the capsule formulation to neutralize the formic acid impurities.

3.3.10

Hydrolytic Degradation

Hydrolytic degradation is the most commonly reported degradation pathway for drugs [30]. The prevalence of such degradation is due to two major reasons. First, APIs often contain functional groups – such as epoxides, esters, amides, lactones, sulfamides, and phosphates – that are susceptible to hydrolysis. Second, APIs have easy access to moisture due to the ubiquitous presence of water in formulations and the surrounding atmosphere. Many drug products also inherently contain water, as APIs or excipients may be produced in hydrate forms. Predictably, environmental factors such as pH and temperature can play an important role in the hydrolytic degradation of drug products. Both acidic and basic conditions, as well as the presence of metal ion impurities in excipients or the API, are known to catalyze hydrolysis reactions according to the mechanisms shown in Figure 3.6a. Furthermore, nucleophilic impurities present in final drug products can also promote the hydrolysis of APIs by forming intermediates that are more susceptible to hydrolysis than the starting API via a series of addition and elimination steps outlined in Figure 3.6b. As an example, Serajuddin et al. observed the hydrolytic degradation of fosinopril sodium whenever magnesium stearate was used as a lubricant in formulation [31]. As shown in Scheme 3.8, degradation of the API in the presence of magnesium ion results in the formation of three distinct products. The authors proposed that the metal impurity promotes degradation of the drug molecule either by direct acid-catalyzed hydrolysis, or via a series of bond rearrangement and hydrolysis reactions.

105

Acid-and base-catalyzed hydrolysis Mn+

M

O R

H X

O

H

O

–H+ R

X

R

OH

H

O

–MX

OH

R

O

H

O

O

H

X OH

– OH

X

R

Mn+ = H+, Mg2+, Fe2+, Fe3+, Cu2+, etc. X = OR, NR1R2, SR

(a)

Nucleophile-assisted degradation H

O

O

H R

(b)

X

Nu

– –OH

H R

O

H

O X Nu

H R

Nu

O

H R

O

Nu OH

O

–HNu R

OH

Nu = Nucleophile

Figure 3.6 (a) Mechanism of acid- or base-catalyzed hydrolytic degradation of a drug product and (b) nucleophile-assisted hydrolytic degradation.

3.4 Risk Assessment for API Incompatibilities and Mitigation Strategies

O Na

O

N O

P O

O

O

O Fosinopril sodium [Mg2+]

O P HO

O Na +

N

O O

O

O Na +

N

O P OH HO

O O

Scheme 3.8 Hydrolytic degradation of fosinopril sodium in the presence of magnesium stearate.

3.4 Risk Assessment for API Incompatibilities and Mitigation Strategies As discussed in the previous sections, residual reactive impurities present in excipients can cause gradual degradation of the APIs upon storage. The degradation products thus formed can alter the toxicological and pharmacological profile of the drug product. As defined by the ICH Q3B guideline, complete structural determination and toxicological assessment is required for any degradation product observed above the threshold limit. In most cases, the amount of degradation observed is directly proportional to the amount of residual reactive impurities present in the excipients. Further, the amount of these residual impurities in excipients not only varies with commercial sources but significant variation was also observed within the same batch upon storage. These variations cause variability in the amount of degradation of APIs leading to inconsistencies in product shelf life. Considering all these factors, development of a stable and robust formulation has become one of the major challenges in the pharmaceutical industry. In the earlier sections of this chapter, different types of reactive impurities and degradation pathways were discussed. The following sections focus on various mitigation strategies often employed to prevent such degradation of the drug product. Initial mitigation strategies include modifications in the API or the formulation while taking into account the chemical nature of the API and the mechanism of degradation pathway observed. These strategies are often employed in early drug developmental stages and are discussed in

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Sections 3.6–3.8. The other set of strategies require improvement in excipient quality, product manufacturing processes, packaging, and storage conditions. These strategies are often employed in later stages of product development and are discussed in Sections 3.9 and 3.10.

3.5 Assessment of Incompatibilities of API with Excipients Excipient selection is one of the most critical steps in formulation development. Excipients are selected not only on the basis of their functional requirements in the formulation but also on their compatibility with the API. To assess drug–excipient incompatibilities, various accelerated stability tests and/or stress tests are designed. These studies enforce degradation of the API in the presence of the excipient under extreme environmental conditions [6]. According to the ICH definition, the accelerated test conditions are defined as Studies designed to increase the rate of chemical degradation or physical change of an active drug substance or drug product using exaggerated storage conditions as part of the formal, definitive, storage program. These data, in addition to long-term stability studies, may also be used to assess longer-term chemical effects at non-accelerated conditions and to evaluate the impact of short-term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes. And the stress tests are defined as Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. Stress testing is likely to be carried out on a single batch of the drug substance. The testing should include the effect of temperatures (in 10∘ C increments (e.g., 50∘ C, 60∘ C)) and humidity (e.g. 75 percent relative humidity or greater) where appropriate, oxidation, and photolysis on the drug substance can take place. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values either in solution or suspension. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B Photostability Testing of New Drug Substances and Products. Examining degradation products under stress conditions is useful in establishing degradation pathways and to develop and validate suitable analytical procedures. However, such examination may not be necessary for certain degradation products if it has been

3.6 Design and Selection of Drug Substance

demonstrated that they are not formed under accelerated or long-term storage conditions. Results from these studies will form an integral part of the information provided to regulatory authorities. As defined in the ICH guidelines, the accelerated tests are designed to predict degradation products under fast aging conditions. In contrast, stress tests are predictive tools designed for scientific exploration of intrinsic stability of drug substance for research investigation to discover stability issues under forced degradation conditions. Typically, stress tests are part of developmental studies to examine stability under conditions more severe than accelerated tests. Severity of these stress tests can sometimes result in degradation products that are not relevant under regular or long-term storage conditions or even under accelerated environmental conditions. These severe conditions may also cause degradation of the degradation products that might have formed under accelerated conditions. In certain cases, these results could overpredict the liabilities of certain degradation pathways. Therefore, a careful analysis of degradation products and mechanisms is essential to employ appropriate mitigation strategies.

3.6 Design and Selection of Drug Substance As described in the previous section, stress tests or accelerated tests are designed to identify potential degradation products, which in turn assist in establishing the mechanism of degradation. Once the mechanism of degradation of the API is elucidated, it can be used to identify the reactive soft spots present in the API that may cause degradation. Structural modification in the API can then be employed to improve stability and suppress degradation. However, such modifications can have a detrimental impact on safety, efficacy, and other pharmacokinetic properties of drug substance. A similar strategy is employed in optimizing metabolic stability in early lead optimization. In fact, the degradation products obtained from stress tests (in vitro) and drug metabolism (in vivo) often indicate common soft spots in the initial lead compound. Therefore, combining early lead optimization attempts to improve metabolic stability with the attempts to counter the degradation of the API in dose form, could aid in achieving a more robust design of the drug candidate with desirable chemical stability while maintaining the potency and other desirable absorption, distribution, metabolism, and excretion (ADME) properties. One such example is betamethasone dipropionate, a drug commonly used for the treatment of inflammatory disorders. Betamethasone dipropionate belongs to the family of corticosteroid drugs containing a cross-conjugated 2,5-cyclohexadienone that undergoes facile photodegradation to form isomeric products (Figure 3.7a) [32]. Such photoisomerizations of cross-conjugated cyclohexadienones had been proposed to take place via n–π* triplet excited state. Photoisomeric degradation of such corticosteroid drugs could be avoided by introduction of a heavy atom such as chloride at the nearby 9-position. The presence of a heavy atom presumably leads to quenching of the triplet excited

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3 Effect of Residual Reactive Impurities

O

O HO

O H N

O HN O

R R = H; Cl; F O 9-Substituted betamethasone (a) dipropionate

H2 N CH3CO2H

N O

NHCO2Bu CO2Me

O

DMP 754

(b)

Figure 3.7 Chemical structures of (a) betamethasone dipropionate (R = H) and (b) DMP 754.

state and hence no photoisomeric degradation was observed. Conversely, this 9-chloro-betamethasone dipropionate undergoes degradative epoxidation via elimination of chloride at the 9-position to form 9,11-epoxide. Interestingly, replacement of the 9-chloride (9-Cl) with a more electronegative atom to form 9-F-betamethasone dipropionate led to termination of degradation through the epoxide formation pathway; however 9-F-betamethasone dipropionate undergoes facile photoisomerization leading to degradation. This example represents the most common predicament often faced by scientists during drug development, where the solution to one problem leads to another. In such cases, very often, toxicological profiles of degradant and intended use dictate the selection of the API. In another example, Badawy et al. described an alternative approach to improve stability of an antagonist prodrug (DMB 754, Figure 3.7b) developed for glycoprotein IIb/IIIa receptor [33]. Badawy had observed that the ester prodrug (DMP 754) achieved maximum stability at approximately pH of 4. The use of the mesylate salt instead of the corresponding acetate salt could provide lower microenvironment pH that favors maximum stability. Therefore, changing the counterion of a prodrug provides an alternative strategy for maximizing drug product stability.

3.7 Formulation Strategies to Circumvent API Degradation Excipients are introduced in a formulation to fulfill its functional requirements such as improvement in solubility, bioavailability, and for assistance in controlled release of the API. As a mitigation strategy, excipients can also be introduced to improve drug stability by inhibiting drug degradation pathways. The following section focuses on the excipients that are added in the formulation to improve stability of the API, particularly toward oxidative degradation.

3.8 Inhibition of Oxidative Degradation Residual reactive impurities in excipients, such as heavy metal(s) and peroxides, can initiate radical-mediated oxidative degradation reactions. These degradative

3.8 Inhibition of Oxidative Degradation

processes are accelerated by environmental factors such as heat and exposure to air or light and are difficult to control experimentally, especially for complex formulations. To prevent such degradation pathways, early tactics are directed toward identifying the type of residual reactive impurity that causes the degradation. The identification of residual impurities is crucial in the selection of an antioxidant or a stabilizer to completely suppress degradation. For example, a transition-metal-initiated oxidative degradation can be quenched by addition of chelating agents like EDTA; however, a peroxide-initiated oxidative degradation reaction may require an antioxidant such as butylated hydroxytoluene (BHT); this is further discussed in the following sections. Typically, a radical-mediated oxidative degradation reaction can be inhibited at various stages of radical chain reaction, namely, initiation, propagation, or the termination step. 3.8.1

Initiation Inhibitors

The initiation step of a radical oxidative degradation process can be suppressed by eliminating the initiators like peroxides and/or deactivating residual transition metal ions such as copper or iron present in the formulation. Chelating agents such as EDTA, citric acid, carvedilol, and tartaric acid are commonly used to suppress transition-metal-initiated oxidative degradation. In one such example, Won et al. reported inhibition of oxidative degradation of RG-12915, a highly potent antagonist of 5-hydroxytryptamine 3 (5-HT3) receptor, by the addition of EDTA (Scheme 3.9) [34]. H N

H N

O

[Cu]

N O

[O]

N O

H N

O O

RG-12915

O Cl

Cl

Cl

O

N O

O OH

HO

Scheme 3.9 Copper-catalyzed oxidative degradation of RG-12915.

RG-12915 undergoes copper-catalyzed oxidation at both the dihydrobenzofuran and quinuclidine moieties, as shown in Scheme 3.9. EDTA forms a coordinatively saturated complex with metallic impurities, thus preventing substrates from binding to the metal center, leading to inhibition of oxidative degradation. In another study, addition of EDTA (as chelating agent) in the formulation of the antitumor drug 9-hydroxyellipticine suppressed oxidative degradation of API [35]. 3.8.2

Propagation Inhibitors

The propagation stage of a radical chain reaction can be inhibited by introducing antioxidants that possess lower reduction potentials than the substrate (API).

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For example, phenolic antioxidants can reduce peroxy radicals formed during API degradation to a relatively inert phenolic radical, thus ensuring inhibition of propagation. Ascorbic acid, thiols (such as thioglycerol and thioglycolic acid), sulfites, and phenols (such as propyl gallate, hydroxyanisole, and BHT) are often used as reducing antioxidants in formulation. These antioxidants compete with the API to get preferentially oxidized and hence shield the drug from oxidative degradation. For example, polysorbates are amphipathic nonionic surfactants commonly used in protein formulation. These polymeric excipients contain peroxide impurities that lead to oxidative degradation of proteins. In one such example, oxidative degradation of therapeutic proteins such as recombinant human ciliary neurotrophic factor (rhCNTF) and recombinant human nerve growth factor (rhNGF) was observed when polysorbate 80 (Tween 80) was used as the excipient [3g]. The oxidation of these proteins was prevented by addition of antioxidants such as BHT, cysteine, glutathione, and methionine in the formulation. In another example, oxidative degradation of simvastatin (lovastatin), a hydroxymethylglutaryl coenzyme A reductase (HMG-CoA) inhibitor was inhibited by the addition of α-tocopherol (vitamin E) as antioxidant [36]. 3.8.3

Selection of Antioxidant

The selection of an antioxidant not only requires consideration of the relative concentration and oxidation potential of the antioxidant with respect to the API but also the mechanism of degradation. One such example was discussed in Section 3.8.1, where EDTA was used to inhibit oxidative degradation of experimental drug RG-12915. When EDTA was replaced with propyl gallate as an antioxidant, it only inhibited oxidation at the benzofuran moiety and oxidation of the quinuclidine moiety was still observed (Scheme 3.9). This example clearly highlights the importance of understanding the mechanism of oxidation for selecting an appropriate antioxidant. Drug products may contain different types of residual impurities that may require a combination of antioxidants. Chelating agents and reducing agents (antioxidants) are often used in combination to effectively inhibit oxidative degradation of the drug product. In some cases, however, combinations of these excipients can cause activation of autoxidative degradation instead of inhibition. Such a seemingly paradoxical situation could be explained by the Udenfriend reaction. As discussed in Section 3.3.5, ionic iron impurities in the presence of chelating agents can catalyze the activation of molecular oxygen to generate peroxides that could initiate (or accelerate) oxidative degradation of the API. Therefore, the combination of an antioxidant and the chelator in a formulation can increase the risk of oxidative degradation of a drug product. Other reducing agents such as phenols or certain preservatives, such as m-cresol and chlorocresol, are also capable of reducing Fe(III)(chelator) complex to Fe(II)(EDTA) complex and thereby promoting oxidative degradation. Therefore, in order to employ an appropriate mitigation strategy for oxidative degradation, it is important to identify residual impurities that cause such degradation. In some cases, the oxidized forms of the antioxidant can also cause degradation of the API. For example, Zhang et al. observed the formation of a new

3.9 Super-Refined Excipients N O

OH [O]

O [O]

HNO3 Cl

N + Cl O

BHT

BHT phenolic radical

Quinone methide

Cl

Cl

Miconazole Nitrate

OH

N Cl

N Cl O

Cl

Cl

Figure 3.8 Mechanism of degradation of miconazole nitrate in the presence of BHT as excipient.

degradation product of miconazole nitrate (an antifungal drug) while developing a petrolatum-based topical ointment formulation. The authors observed the formation of an adduct of miconazole nitrate with the oxidized form (quinone methide intermediate) of antioxidant 2,6-di-tertbutyl-4-methylphenol (BHT) under accelerated stability test conditions (40 ∘ C/75% RH), as shown in Figure 3.8 [37]. It was postulated that the adduct formed by nucleophilic addition of the imidazole functional group present in the API to the methylene of electrophilic quinone methide intermediate resulted in the formation of C—N bond, as shown in Figure 3.8. The structure of the adduct was later assigned by comparing mass and NMR spectrometry data with the reference compound. This example again highlights the importance of understanding the nature of the antioxidant to prevent drug degradation.

3.9 Super-Refined Excipients As discussed earlier, many commonly used excipients like PEG, polysorbates, and povidone contain varying amounts of peroxide and aldehyde impurities. The variability in residual impurities can have a detrimental impact on the choice of excipients during the product development process. In many cases, incompatible excipients are often avoided unless a suitable substitute is available. One of the ways to circumvent these problems is to start with the lowest possible residual impurities in excipients, i.e. by utilizing super-refined excipients. In recent years, super-refined excipients have become increasing popular due to their ability to provide robust pharmaceutical formulation. Super-refined excipients are generated by reducing the amount of polar and oxidative impurities such as transition metal ions, peroxides, aldehydes, and acids present in commonly used excipients

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3 Effect of Residual Reactive Impurities

without changing their chemical composition. The removal of residual impurities from the excipient provides a significant improvement in API stability, resulting in improved bioavailability and product shelf life. Super-refined excipients also reduce cellular irritation caused by residual reactive impurities present in excipients and thus minimize issues observed at the site of application or injection of the drug, especially for parenteral products. Use of super-refined excipients also reduces the impact of color, taste, and odor, which is linked with unrefined grade of excipients. And, finally, not so surprisingly, it also improves the shelf life of the drug product. Super-refined excipients can help in avoiding many potential complications that arise from residual impurities present in commonly used excipients e.g. variable drug degradation. In this section, some of the commonly used excipients and their super-refined alternatives are discussed in detail. 3.9.1

Polyethylene Glycols (PEG)

Super-refined PEG 300, 400, and 600 are highly purified PEGs with low levels of aldehydes and peroxides impurities [38]. Super-refined PEG 400 NF contains approximately 50% less peroxide and formaldehyde contaminants compared to a standard pharmaceutical grade excipient both initially and even after storage for four weeks. Formaldehyde impurities in standard pharmaceutical grade PEG are known to cross-link gelatin capsule shells, leading to slow dissolution and retarded drug release [39]. As mentioned, use of super-refined excipients minimizes the cross-linking of the gelatin shell and thus prevents the complications associated with the low drug release. In another example that was discussed in Section 3.3.7, residual formaldehyde impurities in PEG cause degradation of BMS-204352 by forming a hydroxymethyl derivative degradation product [19]. The authors also conducted a formaldehyde spiking experiment that involved addition of variable amounts of formaldehyde in drug formulation. A direct correlation between the levels of formaldehyde and the formation of the hydroxymethyl degradant was observed. These results clearly highlight the importance of lowering residual impurities and therefore support the use of super-refined PEG instead of standard pharmaceutical grade PEG to circumvent the degradation of the API. 3.9.2

Polysorbates

Polysorbates (Tween 20 and Tween 80) are another important class of excipients that are widely used in protein formulations [4b, 40]. As described earlier, polysorbates are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan. These excipients are typically introduced in formulation to protect the protein against surface adsorption, agitation-induced aggregation under various processing conditions, such as refolding, filtering, storage, freeze thawing, and reconstitution. Several protein pharmaceutical products contain polysorbate 20 (polyoxyethylene sorbitan monolaurate, Tween 20) and polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80) as inactive pharmaceutical ingredients. Like other polymeric excipients, polysorbates also contain residual peroxide impurities that may cause degradation of

3.10 Packaging and Storage

the APIs. As mentioned earlier, the amount of residual peroxide impurities played an important role in determining shelf life. In one such example, Ha et al. conducted a study to evaluate the effect of peroxide level in polysorbate 80 on protein degradation under a variety of storage conditions using IL-2 mutein as a model protein [40]. A significant increase in IL-2 mutein oxidation at a higher level of peroxides in polysorbate 80 in both liquid and solid states was observed. In another study, Singh et al. have demonstrated that the photostability of a proprietary IgG1 monoclonal antibody formulation was greatly affected by the residual peroxide and quality (grade/vendor) of polysorbate 80 [41]. Clearly, the use of super-refined grade polysorbates with minimal peroxide impurities could circumvent such complications and improve the overall shelf life of the drug product. 3.9.3

Fatty Acids

Fatty acids like oleic acid are often used to enhance drug absorption in topical, transdermal, and oral dosages and are typically used in self-emulsifying drug delivery systems (SEDDSs) to improve the bioavailability of poorly water-soluble drugs. It can also be used as a solubilizer and an emulsifying agent, and can be employed in pulmonary and nasal delivery systems. Fatty acids also contain polar residual impurities such as peroxide, aldehydes, etc. that promote degradation of the API. Super-refined oleic acid NF is often used as a highly purified alternative to normal grade oleic acid to ensure formulation stability. Replacement of a nonrefined oleic acid with super-refined oleic acid NF in in vitro settings resulted in reduction of intercellular leakage and therefore exhibited reduced skin irritation. In one such example, Statham et al. reported impaired stability of imiquimod (an immunomodulator drugs) when oleic acid was used in the formulation [42]. Authors attributed this impaired stability of a drug product to the polar residual impurities present in the oleic acid that led to degradation of imiquimod, thereby destabilizing the formulated product. As expected, when refined oleic acid was used in the formulation, the authors observed improved stability of the drug product. These findings again emphasize on the importance of the careful screening of excipient quality to develop a stable and robust formulation.

3.10 Packaging and Storage Packaging and storage are two important components of mitigation strategies to ensure stability of drug product throughout its shelf life. As discussed in previous sections, environmental factors such as exposure to oxygen/air, moisture, light, and elevated temperature can initiate and/or accelerate the degradation of API, triggering variability in drug product shelf life. Primary packaging and storage conditions may play a critical role in preventing the exposure to any of these elements to the drug product, thereby ensuring stability of the drug product without any modification in drug formulation [16]. For example, for a moisture and oxygen/air-sensitive drug product, use of oxygen- and water-impermeable

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packaging under inert gas environment could help in avoiding the degradation of the drug product. In certain cases, oxygen scavengers or desiccants such as silica gel can be co-packaged with the dosage form to ensure an adequate shelf life [43]. Consequently, the selection of suitable primary packaging and storage conditions requires consideration of the mechanism of API degradation and the effect of environmental factors on potential degradation pathways, associated cost for packaging, intended use, and shelf life of the drug product.

3.11 Concluding Remarks In this chapter, we have discussed various types of residual reactive impurities in excipients and their confounding effects on stability, efficacy, safety, and overall performance of pharmaceutical products. Even a most commonly used excipient may contain certain residual reactive impurities that could cause degradation of the drug product. Further, significant variation in the amount of these residual impurities in the excipients with respect to the storage and change of batch and manufacturer poses an additional challenge in developing a robust pharmaceutical product. Super-refined excipients can help in avoiding many potential complications arising from residual impurities present in commonly used excipients. However, as we have discussed in earlier sections, even small amounts of residual impurities can lead to significant degradation of the drug product. Therefore, identification of the reactive impurity that causes degradation and understanding the mechanism of degradation are essential for designing a robust drug product or selecting a suitable mitigation strategy to prevent degradation of the pharmaceutical product.

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182–188. (b) Zarmpi, P., Flanagan, T., Meehan, E. et al. (2017). Eur. J. Pharm. Biopharm. 111: 1–15. (c) Constantinides, P.P., Chakraborty, S., and Shukla, D. (2016). AAPS Open 2: 3. (d) Rowe, C.R., Sheskey, P.J., and Quinn, M.E. (2009). Handbook of Pharmaceutical Excipients. Washington, DC: American Pharmacists Association, Pharmaceutical Press. (e) Wasylaschuk, W.R., Harmon, P.A., Wagner, G. et al. (2007). J. Pharm. Sci. 96: 106–116. (f ) Kibbe, A. (2000). Handbook of Pharmaceutical Excipients, 3e, 102–106. Washington, DC: American Pharmaceutical Association. 2 (a) Kuentz, M., Holm, R., and Elder, D.P. (2016). Eur. J. Pharm. Sci. 87: 136–163. (b) Rantanen, J. and Khinast, J. (2015). J. Pharm. Sci. 104: 3612–3638. (c) Moreton, C. (2010). Am. Pharm. Rev. Part IV 18–21. 3 (a) Hotha, K.K., Roychowdhury, S., and Subramanian, V. (2016). Am. J. Anal. Chem. 07 (01): 34. (b) Dave, V.S., Saoji, S.D., Raut, N.A., and Haware, R.V. (2015). J. Pharm. Sci. 104: 906–915. (c) Siew, A. and Peters, R. (2014). Pharm. Technol. (3): 12–15. (d) Liltorp, K., Larsen, T.G., Willumsen, B., and Holm, R.

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4 Preclinical Formulation Assessment of NCEs Raju Saka 1 , Priyadarshini Sathe 1 , Wahid Khan 1 , and Sachin Dubey 2 1 National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmaceutics, NH 9, Kukatpally Industrial Estate, Balanagar, Hyderabad 500037, India 2 Glenmark Pharmaceuticals, S.A., Formulation, Analytical and Drug Product Development (Biologics), Chemin de la Combeta 5, 2300 La Chaux-de-Fonds, Switzerland

List of Abbreviations

NCE IND NDA DMSO PK PD IP SC ADME DSC BCS FaSSIF FeSSIF P-gp PAMPA PG DMA PEG CDs HPβCD SBEβCD CMC MC SEDDS SMEDDS GRAS SNEDDS

new chemical entity investigational new drug new drug application dimethyl sulfoxide pharmacokinetics pharmacodynamics intraperitoneal subcutaneous absorption distribution metabolism excretion differential scanning calorimetry Biopharmaceutics Classification System fasted-state simulated intestinal fluid fed-state simulated intestinal fluid P-glycoprotein parallel artificial membrane permeability assay propylene glycol N,N-dimethyl acetamide polyethylene glycol cyclodextrins hydroxypropyl-β-cyclodextrin sulfobutylether-β-cyclodextrin critical micellar concentration methyl cellulose self-emulsifying drug delivery system self-microemulsifying drug delivery system generally recognized as safe self-nanoemulsifying drug delivery systems

Innovative Dosage Forms: Design and Development at Early Stage, First Edition. Edited by Yogeshwar G. Bachhav. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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SUV LUV MLV API i.v. EPO EDTA LD50 ED50 USP PDR FDA IIG NMP XRD SEM TEM NMR FTIR NOAEL GI ISPB HIV PVP Na-CMC

small unilamellar vesicles large unilamellar vesicles multilamellar vesicles active pharmaceutical ingredient intravenous erythropoietin alfa ethylenediaminetetraacetic acid lethal dose 50 effective dose 50 United States Pharmacopeia Physicians’ Desk Reference Food and Drug Administration Inactive Ingredients Guide N-methylpyrrolidone X-ray diffraction scanning electron microscopy transmission electron microscopy nuclear magnetic resonance Fourier transform infrared spectroscopy no observed adverse effect level gastrointestinal isotonic Sorensen’s phosphate buffer human immunovirus polyvinylpyrrolidone sodium carboxyl methyl cellulose

4.1 Introduction The process of developing a new chemical entity (NCE) into a pharmaceutically acceptable formulation involves numerous critically validated procedures to bring it into the market all the way through preclinical and clinical investigation. A typical investigational new drug (IND) development consists of initial screening of NCEs and subsequent promotion of these compounds to preclinical drug development stage followed by clinical investigation for safety and efficacy [1]. If the compound is found to be safe and effective in all the three clinical trial phases (I, II, and III), it will be then filed for new drug application (NDA) [2]. This development and regulatory process involves financial costs at a magnitude of hundreds of millions to over a billion US dollars. The majority of INDs were abandoned due to unacceptable safety and efficacy. Typically, the success rates of compounds from discovery phase to preclinical phase ranges from 1 in 100 [3] to 1 in 5000 [4] compounds. The success rate is typically higher at clinical stages, where it is 13% for phase I, 40% for phase II, and 80% for phase III clinical studies. From the given data, it can be assumed that 1 in 25 IND designated compounds reach the market. Financial aspects also govern major drug discovery programs. Only one in four approved NCEs are expected to meet the revenue targets [5].

4.1 Introduction

This is a major issue since the innovator has invested large amounts of capital on the product. The high cost of drug development is due to higher attrition rates of NCEs in both discovery and preclinical phases [6]. The overall IND withdrawals/failures are above 40% of all the IND applications filed. This explains the magnitude of attritions between NCEs [7]. This also indicates poor in vitro and in vivo correlations employed while selecting the NCEs for further evaluation. Many pharmaceutical companies are trying to reduce developmental costs by optimizing critical performance characteristics for an NCE. Apart from chemistryand pharmacology-related attritions, the NCEs are also abandoned due to poor physicochemical properties and poor dosage form performance. In the early days of drug discovery, drug chemistry was given more importance while formulation aspects were less focused on. With the advent of combinatorial chemistry, the activity is being given utmost importance when compared with physicochemical properties, which are highly neglected. Hence, the majority of the candidates are administered as solutions in dimethyl sulfoxide (DMSO) and other organic solvents which are poorly characterized. This led to poor understanding of pharmacokinetics (PK) and pharmacodynamics (PD) due to the dose variation and toxicity associated with the use of organic solvents [8]. This led to withdrawal of compounds from later stages as they posed unpredictable properties not fully understood by the scientists. In recent years, however, to avoid such issues, the formulation development scientist was also involved in the discovery phase to select the suitable vehicle for preclinical studies in the early discovery phase [9, 10]. This led to development of early formulations or discovery formulations. The formulation development scientists are actively involved in improving the solubility, permeability, and stability of the NCEs for animal studies in the early stages itself. Hence, these formulations were popularly termed as “preclinical formulations” or “discovery formulations” [11]. Preclinical formulations are newly introduced activities which are part of drug discovery and development programs of major pharmaceutical firms. These are introduced for enhancing stability, solubility, and in vivo exposure of NCEs to advance PD, PK, and toxicological aspects [12]. Major aspects of developing and characterizing preclinical formulations (Table 4.1) include the following: (a) Sufficient in vivo exposure: Essential as sufficient concentration of the compound should be available at the target site to elicit activity. This is useful to optimize the PD of the candidate drug. (b) Accurate dosing: Use of cosolvents in the initial PD studies presents challenges in accurate dosing, dose–response profile, and stability profile of the candidate drugs. Preclinical formulations are designed with an objective of reducing dose inequalities and optimizing the dose–response relationship along with establishing the stability profile of the drug for short-term storage. (c) Minimizing excipient-related interventions in safety and efficacy: In early days of drug discovery, the drugs are administered by solubilizing in organic solvents (e.g. DMSO). This created numerous hurdles to evaluate the toxicity of drugs as the vehicle is itself toxic to animals. In this regard, preclinical formulations are designed to maintain maximum biocompatibility and in vivo tolerability.

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Table 4.1 Use of preclinical formulations with respect to the study goals [13]. Optimization and candidate selection

Hit screening

Lead candidate screening

I. Pharmacodynamics • Proof of concept/ target validation • Limited to a few compounds with limited druggability (drug-like properties) • Single-dose studies • Non-oral routes of dosing commonly used, such as intraperitoneal (IP) or subcutaneous (SC) routes • Frequently high concentrations needed at the target

• Hits from cell-based potency screening tested for in vivo activity • Wide range of concentrations to test for activity, target selectivity, and durability • Time course and dose range assessments to understand on-target and off-target effects • Some studies with non-oral formulations (e.g. IP or SC route) • Formulation recommendation is based on assessment of selected compounds from each class and effect of vehicles • Physical and chemical stability data is generated

• Non-oral route of administration is less practiced as the oral route is of clinical interest • Studies focused on a thorough assessment of in vivo pharmacology for selection of clinical candidates

• PK assessment in rodents to get basic understanding of clearance mechanisms and PK properties as they relate to scaffolds • Goal is to facilitate lead selection from a specific scaffold • Scaffold-wise formulation recommendation supported by physicochemical properties of representative compounds • Basic crystallinity data on compounds of interest for formulation requirements and/or absorption modeling

• Rodent and non-rodent PK studies with dogs as the most common non-rodent species • Absorption and metabolism parameters must be in specified limit for oral dosing • Solubility and solid-state data on material in dog studies is essential • High emphasis on the absorbable dose in humans • Formulation or study design options for overcoming PK variability associated with dog gastric pH

II. Pharmacokinetics • Assessment of ADME of tool compounds in rodents

ADM, absorption distribution metabolism excretion.

4.2 Significance of Various Properties of NCEs in Early Drug Discovery During the late 1980s and early 1990s, the major breakthrough achieved in the high-throughput screening of lead molecules helped in rapid screening of libraries for potential leads. During this phase, emphasis was given on the potency rather than on the prerequisites for physicochemical properties. This led to problems in later stages of drug development and resulted in the rejection of the majority of the NCEs during the late stages of drug development. Initially, drug-like properties were proposed to screen thousands of molecules from the

4.2 Significance of Various Properties of NCEs in Early Drug Discovery

chemical libraries. One such rule is “Lipinski’s rule of five” [14]. The rule has set the various required properties for a molecule to be termed as “drug-like.” These include the following: (a) (b) (c) (d)

Molecular weight ≥ 500, log P ≥ 5, H-bond donor ≥5, H-bond acceptors ≥10.

Physicochemical properties are critical in lead selection as they affect the overall performance of the compound of interest. Preformulation studies are critical in determining key physicochemical properties of drugs in the early stages. Before presenting the formulations for in vivo studies, it is essential to evaluate drug physicochemical properties as medicinal chemists generally favor a structure with high potency rather than one with better physicochemical properties. This early evaluation can provide sufficient data to the chemist so that he/she can incorporate any required changes in structural optimization. The major hurdle at this stage is the availability of only smaller quantities of the NCEs to the preformulation scientist. Special approaches need to be employed by the formulation scientist to ensure that the maximum preformulation data can be generated with the minimal consumption of the compound. This preformulation data should be generated readily so that the medicinal chemist can proceed with the lead candidate selection [15]. Some of the laboratories employed advanced means to increase the output in a short time with a drug consumption of less than 25 mg [16]. In developmental studies, it is critical that the physical form of the drug is not changed as it may mislead the overall result. Preformulation scientists should take care that the NCE is well characterized for its solid-state properties prior to formulation development. Hence, it is always advised that each batch of the NCE received be characterized through differential scanning calorimetry (DSC) and X-ray powder diffraction to ensure that the identical form (crystalline/amorphous) of the drug is being used for further studies as the solid-state properties significantly impact the in vivo exposure of the drug candidate. 4.2.1

Solubility

Solubility is the property shown by solid, liquid, and gas substances (solutes) to dissolve in a solid, liquid, or gaseous solvent. Dissolution of a solute in a solvent depends on both physical and chemical properties of a solute and solvent and also on the pressure, temperature, and pH. Solubility is defined to express polarity of a substance in general. It is given utmost importance in the huge number of scientific disciplines and practical applications. Solubility is the most important of all the drug properties in the early stage of development. It is the single factor that governs the progress of the development process of an NCE. The majority of the NCEs have poor aqueous solubility, and this has resulted in multiple problems for scientists to develop NCEs into clinical/commercial drug candidates besides increasing developmental and manufacturing costs [17, 18]. Solubility data along with permeability profiles of molecules have been utilized to classify the various drugs, and this classification

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system is called the “Biopharmaceutics Classification System” (BCS). The BCS categorizes drugs into four classes. Of all the classes, class I compounds are ideal for product development. The role of the formulation scientist is to emulate the properties of class I compounds to class II, III, and IV compounds [19]. Solubility studies are usually carried out in aqueous solutions and buffers like hydrochloric acid buffer pH 1.2, acetate buffer pH 4.5, phosphate buffer pH 6.8, and phosphate buffer pH 7.4. Furthermore, the solubility is also determined in the fasted-state simulated intestinal fluid (FaSSIF) and fed-state simulated intestinal fluid (FeSSIF). If the calculated solubility is less than 1% w/v in aqueous solutions and buffers, further solubility studies in pharmaceutical excipients and vehicles are recommended [20]. In the discovery phase, kinetic solubility is preferred over equilibrium solubility for rapid characterization of lead molecules as it consumes smaller quantities of the NCEs but often misguides lead selection [21]. Yalkowsky and Valvani proposed an equation to predict solubility from the octanol/water partition coefficient and melting point of the drug [22]. This can be helpful in initial screening of molecules. The equation is log [S] = −0.01(Tm − 25) − log P + 0.5

(4.1)

Here, S denotes solubility, T m denotes the melting point of the compound, and P represents the octanol/water partition coefficient. Good solubility is always indicative of better product performance. However, the majority of the compounds possess poor solubility. This is a major concern for pharmaceutical scientists as the solubility of the drug must be maintained for effective delivery. Various strategies have been introduced to improve the solubility of these drugs, which is disused in the later sections. 4.2.2

Permeability

Permeability means allowing passing through, and it can be for liquids or gases. Permeability across the biological membrane is a key factor for absorption, distribution, metabolism, and excretion of drugs. Permeability can be affected by structural features of drugs and the efflux mechanism of the membrane. Permeability is the next important property of a molecule to be continued for further developmental studies. Initially, the permeability of the NCEs is assessed by determining permeability through the Caco-2 monolayer [23]. Caco-2 comprises heterogeneous human epithelial colorectal adenocarcinoma cells with distinct features like P-glycoprotein (P-gp) efflux transporters, microvilli, various enzymes, and tight junctions like the intestine, and hence it is easy to translate the permeability from this in vitro study to in vivo conditions. Also, this method is suitable to assess both active and passive transport. The advantage of this method is that numerous compounds can be screened with reproducibility within a short time. Apart from permeability determination, the Caco-2 permeation study can also evaluate the improvement in permeation of drugs actively transported through a membrane, or drugs that are substrates to efflux transporters, or drugs that are metabolized extensively by enterocytic enzymes. Similarly, parallel artificial membrane permeability assay (PAMPA) can be used to evaluate the passive absorption of drugs [24].

4.3 Formulation Strategies to Improve Properties of NCEs

4.2.3

Stability

Chemical stability was the frequently neglected parameter of formulation development in previous decades, but it is gaining more importance in recent days. Instability/degradation may differ depending on the source of the stress. It may be due to pH change, hydrolysis, oxidation, light, temperature, etc. It is essential to investigate the degradation patterns of the NCEs during the discovery phase itself to prevent discrepancies in further developmental stages. Degradation at extreme pH is often common with many drugs, and this is often observed in drugs which are intended for oral delivery. Hydrolysis is the other common means by which the majority of the drugs undergo degradation and it is due to the presence of the labile groups in the structure [25]. Metabolic stability is also another major concern apart from the chemical stability of the drug. Many NCEs failed due to inadequate metabolism and PK parameters. This led to early metabolic screening of the NCEs through in vitro assays. The availability of hepatocytes, human liver fraction, and other advanced models paved the way for high-throughput metabolic studies. This offers two advantages; first, it includes early identification metabolites so that the compound’s structure can be easily optimized, and second, the use of the human enzymes, hepatocytes, and liver fractions provides meaningful results that represent in vivo conditions [26, 27]. Generally, short-term stability studies for preclinical formulations are performed in the interest of time. The chemical stability data of 24–48 hours is sufficient for solutions (in-use stability for preclinical dosing). For suspensions and lipid-based formulations, physical and chemical stability needs to be investigated. For chronic toxicity studies, where the formulation needs to be administered for a longer duration, the chemical stability needs to be ensured for that specific period of time. For a solution formulation, parameters that need to be evaluated include turbidity, risk of precipitation, discoloration, etc. Similarly, for suspensions, microscopic observation, particle size and distribution, and homogeneity need to be evaluated for stability. Complex formulations such as lipid-based formulations need extensive studies to evaluate stability. These include observation for phase separation, particle size, caking, lumping, decoloration, etc. Furthermore, standard guidelines should be followed while preparing preclinical formulations, such as fresh preparation prior to dosing, storage of formulation in the tightly closed container under cold conditions to avoid exposure to light and protections against oxidation, solid-state transitions [28–31].

4.3 Formulation Strategies to Improve Properties of NCEs In the drug discovery process, solubility is of paramount importance. For simple molecules, methods such as pH adjustment, use of cosolvents and surfactants, or formation of a complex can be used to improve solubility. In case of complex molecules (difficult to develop), enabled technologies such as nanosuspensions, lipid-based drug delivery systems, or solid dispersions can be used. Figure 4.1

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Suspensions

Cosolvent

Micronization

PEG, PG, DMA, transcutol

Surfactants

Aqueous surfactants (Tweens)

Figure 4.1 Preclinical formulation options to improve solubility.

Nanoforms

Nanoparticles (