Innovative Dosage Forms Design and Development at Early Stage

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 Introduction 1

1.1.1 Background 1

1.1.2 Types of Polymorphism 2

1.1.3 Thermodynamic-Based Classification of Polymorphism 4

1.1.4 Concomitant Polymorphism 6

1.1.5 Debatable Polymorphism Cases 7

1.2 Polymorphism Impact on Drug/Excipient Properties 9

1.2.1 Physicochemical Properties 10

1.2.2 Mechanical Properties 11

1.2.3 Impact of Polymorphism on In Vivo Performance 13

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation 22

1.3.1 Process-induced Transformation Types 23

1.3.1.1 Grinding-induced Transitions 23

1.4 Conclusion 37

References 38

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

2.1 Introduction 50

2.2 Quality by Testing (QbT) and Quality by Design (QbD) 50

2.3 Linking the Formulation to the Clinical Phase 52

2.4 Defining the Formulation Strategy 55

2.5 Nanosuspensions 58

2.5.1 Description 58

2.5.2 Method of Manufacturing 59

2.5.3 Characterization of Nanosuspensions 63

2.6 Solid Dispersion 64

2.6.1 Description 65

2.6.2 Method of Manufacturing 66

2.6.3 Characterization 68

2.7 Lipid-Based Drug Delivery Systems 69

2.7.1 Description 70

2.7.2 Method of Manufacture 71

2.7.3 Characterization 75

2.7.4 Role of API Property on Lipid-Based DDS 76

2.8 Micellar System 76

2.8.1 Description 76

2.8.2 Formulation Development and Optimization 80

2.8.3 Characterization 81

2.9 Mesoporous Silica Particles 81

2.9.1 Description 82

2.9.2 Method of Manufacturing and Characterization 83

2.9.3 Case Study on the in Vivo Efficacy of Mesoporous Silica Particles 84

2.10 Conclusion 84

References 85

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

3.1 Introduction 91

3.2 Reactive Impurities in the Excipients and Their Impact on Drug Stability 92

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility 93

3.3.1 Physical Interactions 93

3.3.2 Chemical Interactions 94

3.3.3 Oxidative Degradation 94

3.3.4 Peroxides 95

3.3.5 Transition Metal Impurities 96

3.3.6 Condensation Reactions 99

3.3.7 Aldehyde Impurities 99

3.3.8 Reducing Sugars 102

3.3.9 Organic Acids 103

3.3.10 Hydrolytic Degradation 105

3.4 Risk Assessment for API Incompatibilities and Mitigation Strategies 107

3.5 Assessment of Incompatibilities of API with Excipients 108

3.6 Design and Selection of Drug Substance 109

3.7 Formulation Strategies to Circumvent API Degradation 110

3.8 Inhibition of Oxidative Degradation 110

3.8.1 Initiation Inhibitors 111

3.8.2 Propagation Inhibitors 111

3.8.3 Selection of Antioxidant 112

3.9 Super-Refined Excipients 113

3.9.1 Polyethylene Glycols (PEG) 114

3.9.2 Polysorbates 114

3.9.3 Fatty Acids 115

3.10 Packaging and Storage 115

3.11 Concluding Remarks 116

References 116

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

4.1 Introduction 120

4.2 Significance of Various Properties of NCEs in Early Drug Discovery 122

4.2.1 Solubility 123

4.2.2 Permeability 124

4.2.3 Stability 125

4.3 Formulation Strategies to Improve Properties of NCEs 125

4.3.1 pH Modification 127

4.3.2 Cosolvents 127

4.3.3 Cyclodextrins 128

4.3.4 Surfactants 128

4.3.5 Suspensions and Nanosuspensions 129

4.3.6 Emulsions and Microemulsions 130

4.3.7 Solid Dispersions 130

4.3.8 Liposomes 131

4.4 Preclinical Formulation Assessment of Oral, Parenteral, and Topical Dosage Forms 131

4.4.1 Oral Formulations 131

4.4.2 Parenteral Formulations 134

4.4.3 Topical Formulations 135

4.4.4 Excipients 138

4.4.5 Characterization and Stability of Preclinical Formulations 140

4.4.6 Formulation Selection for Pharmacokinetic Studies 141

4.4.7 Formulation Selection for Pharmacodynamic Studies 142

4.4.8 Formulation Development for Toxicity Studies 142

4.5 Case Studies 143

4.5.1 Case 1: Use of Surfactant to Prevent Precipitation of API in Cosolvent-Based Formulations 143

4.5.2 Case 2: Topical Gel Microemulsion Formulation of Lipophilic Drug WHI-07 144

4.5.3 Case 3: Salt Approach to Improve the Bioavailability of the Poorly Soluble Drug 144

4.5.4 Case 4: Use of SMEDDS Dosage Form to Improve Bioavailability 145

4.5.5 Case 5: Micronized Suspension of Poorly Soluble Lead Compounds Using Wet Milling Technique 145

4.5.6 Case 6: Polymer Addition in Cyclodextrin-Based Formulations and pH Adjustment 146

4.5.7 Case 7: Cyclodextrin Complexation to Improve Topical Delivery of a Poorly Soluble Compound 146

4.5.8 Case 8: Use of Solublizers and Their Effect on PK of Preclinical Lead Candidates 147

4.5.9 Case 9: Self-nanoemulsifying Drug Delivery Systems (SNEDDS) to Improve Solubility and Bioavailability 147

4.6 Conclusion and Future Perspectives 148

References 148

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

5.1 The Understanding of “Regulatory” 156

5.2 Formulation Design 157

5.3 An Extended Timescale 158

5.4 Solubility Data 158

5.5 Impact of Solubility and Dissolution Rate on Formulation Design 162

5.6 Single and Multicomponent Systems 163

5.6.1 Introduction 163

5.6.2 Scientific Point of View 164

5.6.3 Fate and Pathway of a Compound During Development 166

5.6.4 Regulatory Point of View 167

5.7 Analytical Techniques for the Characterization of the Solid State 168

5.7.1 Scientific Literature 168

5.7.2 Pharmacopeias 169

5.8 Control of Solid-state Constitution 171

5.8.1 The Process – from Synthesis to Patient 171

5.8.2 Change of Properties and Constitution 173

5.8.3 Need for Control of Solid-State Properties During the Process and Supply Chain 173

5.9 Regulatory Consideration of Solid Compounds 174

5.9.1 Definitions for Solid Compounds 174

5.9.2 Common Technical Document (CTD) – M4Q 175

5.9.3 Guideline on the Chemistry of Active Substances 178

5.9.4 Guideline on Quality of Transdermal Patches 180

5.9.5 Quality Guidelines 181

5.9.6 EMA – Consideration and Perspective 188

5.9.7 FDA – Consideration and Perspective 190

5.9.8 Similarities and Differences Between the Regulative Systems in the EU and United States 197

5.10 Conclusions and Recommendations 198

Disclaimer 198

References 198

6 Insight into Innovative Applications of Parenteral Formulations 209
Clara Fernandes

6.1 Introduction 209

6.2 Factors Affecting Development of Sustained-/Controlled-Release Formulations 209

6.3 Overview of Sustained and Controlled Release Parenteral Formulations 213

6.3.1 Suspension Based Formulations 213

6.3.2 Particulate System Based Formulations 215

6.4 Case Studies 219

6.4.1 Nanosuspension Formulation of Paclitaxel – Abraxane^® 219

6.4.2 PLGA Depot Based Formulation of Triptorelin – Trelstar^® 219

6.4.3 Microemulsion Formulation of Propofol 220

6.4.4 Inorganic Metal Nanoparticle Based Formulation for Parenteral Applications 220

6.4.5 Polymeric Formulation of Glatiramer 221

6.5 Conclusion 222

6.6 Future Prospects 222

References 222

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

7.1 Introduction 227

7.2 Definition of Pharmacokinetics 229

7.2.1 ADME Parameters 229

7.2.2 Pharmacokinetic Parameters 231

7.2.3 PK Studies During Drug Development 236

7.3 Case Studies 241

7.3.1 Case Study 1 241

7.3.2 Case Study 2 241

7.3.3 Case Study 3 242

7.3.4 Case Study 4 243

7.4 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 Introduction 246

8.2 Microneedles 247

8.2.1 Delivery Using Solid Microneedles: Skin Pretreatment 248

8.2.2 Delivery Using Coated Microneedles 252

Challenges Related to the Formulation of Coated Microneedles – A Case Study 252

8.2.3 Delivery Using Dissolvable Microneedles 254

8.2.4 Delivery Using Hollow Microneedles 255

8.2.5 Delivery of Vaccines 257

8.2.6 Modalities of Microneedle Use 259

8.2.7 Perspectives in Microneedle-Mediated Transdermal Delivery 259

8.3 Laser-Assisted Ablation: Skin Pretreatment 260

8.3.1 Laser–Skin Interaction 261

8.3.2 Formulation Aspects 262

8.3.3 Perspective 263

8.4 Iontophoresis 263

8.4.1 Clinical Benefits of Iontophoresis in Transdermal/Topical Delivery 264

8.4.2 Selection of Drug Candidates 265

8.4.3 Iontophoretic Device Formulation Characteristics: Compositions and Challenges 265

8.4.4 Earlier Approved Commercial Devices 266

8.4.5 Smart Ionto System Features 268

8.4.6 Perspectives 269

References 269

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

9.1 Introduction 282

9.1.1 Limitations of the Amorphous Form 285

9.1.2 Stabilization of the Amorphous Form 285

9.1.3 Solid Dispersion 285

9.1.4 Factors Affecting Solubility of API in the Form of Solid Dispersions 287

9.1.5 Limitations 289

9.1.6 Co-Amorphous 289

9.2 Screening Techniques for Amorphization 290

9.2.1 Amorphization: Solution-Based Techniques 291

9.2.2 Amorphization: Solid-State Techniques 294

9.3 Characterization of Amorphous Materials 298

9.3.1 X-Ray Powder Diffraction (XRPD) 299

9.3.2 Thermal Methods 302

9.3.3 Perfusion/Solution Calorimetry 307

9.3.4 Density Measurements 310

9.3.5 Sorption Technique: Dynamic Vapor Sorption (DVS) 310

9.3.6 Vibrational Spectroscopy 312

9.4 Summary 321

9.5 Future Prospects 322

References 323

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

10.1 Introduction 331

10.2 Ocular Anatomy and Physiology 332

10.3 Ocular Routes of Administration 336

10.4 Drug Discovery in Ophthalmology 337

10.4.1 Repositioning of Existing Drugs from Other Disease Area 337

10.4.2 Optimization of Compound Class to Enhance Selectivity, Tolerance Profile, and Efficacy 338

10.4.3 Specific Development 339

10.5 Topical Drug Administration 340

10.5.1 Ocular Bioavailability 340

10.5.2 Drug Design 340

10.5.3 Prodrugs 342

10.5.4 Physiological Factors 343

10.5.5 Formulation and Drug Delivery Systems 344

10.5.6 Patient Compliance Through Packaging 354

10.6 Posterior Segment Delivery 356

10.6.1 In Situ Depot 357

10.6.2 Prodrugs 357

10.6.3 Intraocular Implants/Microparticles 358

10.7 Conclusion 360

References 361

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

11.1 Introduction 368

11.2 General Considerations 369

11.3 Undesired Side Effects of Excipients 370

11.4 Novel Excipients 371

11.4.1 Regulatory Requirements 372

11.5 Rationale in Selecting an Excipient 375

11.5.1 Data Sources 376

11.5.2 Strategies to Determine “Estimated Safe Excipient Doses” 378

11.5.3 Special Considerations for Oral Use 381

11.5.4 Special Considerations for Intravenous Use 381

11.5.5 Special Considerations for Topical Use 385

11.6 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 Introduction 392

12.1.1 Use of Proteins for Different Therapeutic Indications 392

12.1.2 Importance of Physicochemical Properties on Preformulation and Formulation Development of Protein Therapeutics 394

12.1.3 Stability Constraints and Formulation Challenges 395

12.1.4 Current Market Status and Opportunities of Therapeutic Proteins 396

12.1.5 Current Technologies for Protein Formulation Development 398

12.1.6 Current Approaches in Oral Delivery of Proteins for Enhanced GIT Absorption 400

12.2 Types of Proteins Used in Therapeutic Indications 400

12.3 Important Physicochemical Properties of Proteins for Formulation Development 402

12.4 Existing Route of Administrations of Protein Formulations 404

12.5 Developmental Aspects of Oral Protein Formulations 405

12.5.1 Resource Requirements for Manufacturing of Protein-Based Formulations 406

12.5.2 Stability Concerns of Proteins in the Gastrointestinal Tract (GIT) 407

12.5.3 Physical Barriers to Delivering Proteins and Peptides 407

12.5.4 Formulation Strategies for the Oral Delivery of Proteins and Peptides 409

12.5.5 Modification of the Physicochemical Properties 411

12.5.6 Use of Particulate Formulations 412

12.5.7 Colon-Targeted Delivery Systems for Proteins and Peptides 416

12.5.8 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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