Early Drug Development : Bringing a Preclinical Candidate to the Clinic.
- 1st ed.
- 1 online resource (801 pages)
- Methods and Principles in Medicinal Chemistry Series .
- Methods and Principles in Medicinal Chemistry Series .
Cover -- Title Page -- Copyright -- Contents -- Preface -- A Personal Foreword -- Chapter 1 Early Drug Development: Progressing a Candidate Compound to the Clinics -- References -- Part I Drug Substance -- Chapter 2 Early Phase API Process Development Overview -- 2.1 Introduction -- 2.2 API Process Development Overview -- 2.2.1 Early Process Development -- 2.2.2 Early Development Drivers and Constraints -- 2.3 The Transition from Discovery to Development -- 2.4 Process Development Organizational Construct -- 2.4.1 Core Functions -- 2.4.2 Specialized Technology Groups -- 2.4.3 Partner Functions -- 2.5 Process Development Equipment -- 2.5.1 Lab Equipment -- 2.5.2 Scale-up Equipment in the Laboratory -- 2.5.3 cGMP Manufacturing Equipment -- 2.6 Summary -- References -- Chapter 3 The Discovery/Development Transition -- 3.1 Introduction -- 3.2 Discovery-to-development Transition Before 1980 -- 3.2.1 Discovery/Development Handover -- 3.3 Discovery-to-development Transition in the 1980s -- 3.4 Discovery-to-development Transition in the 1990s -- 3.4.1 Development Time -- 3.4.2 The BMS IND Initiative -- 3.4.2.1 Parallel Activities -- 3.4.2.2 Integration -- 3.4.2.3 Optimization -- 3.4.2.4 Teamwork -- 3.4.2.5 Enthusiasm -- 3.5 Present Practice at BMS -- 3.5.1 The Role of Chemical Complexity -- 3.5.2 An Example of Early Prospective Chemical Development -- 3.6 Application in Small Biotechnology Companies Today -- 3.7 Application in CROs -- 3.7.1 Colocation of CMC Activities -- 3.8 Conclusions -- References -- Chapter 4 Active Pharmaceutical Ingredient Cost of Goods: Discovery to Early Development -- 4.1 Introduction -- 4.2 Stages of Research -- 4.3 Synthetic Route Translatability and Scalability: Strategy -- 4.4 Raw Material Considerations -- 4.5 Continual Assessment of Alternative Routes and Technologies, Including Preparative Chromatography. 4.6 Initial CoG Projections -- 4.7 CoG Versus Campaign Time Cycle -- 4.8 Synthetic Route Translatability and Scalability: Tactics -- 4.9 Preparing a CoG Estimate -- 4.10 Ancillary Expenses -- 4.10.1 Analytical Considerations -- 4.10.2 Polymorph Screening and Salt Screening -- 4.10.3 cGMP Surcharges -- 4.10.4 Critique of the Abilities of Process Groups and Drug Discovery Groups to Advance Development of APIs -- 4.11 Long-Term Considerations -- 4.12 Summary -- Acknowledgments -- References -- Chapter 5 New Technologies in Process Development -- 5.1 Introduction -- 5.2 Synthetic Biochemistry -- 5.2.1 Current State Biocatalysis -- 5.2.2 New Single-step Biotransformations -- 5.2.3 Cascade Biotransformations -- 5.2.4 The Future of Synthetic Biochemistry -- 5.3 Chemical Catalysis -- 5.3.1 Considerations for Application on Process Scale -- 5.3.2 Examples of Recent Catalysis Developments Applied in an Industrial Setting -- 5.3.3 The Future of Chemical Catalysis -- 5.4 Continuous Chemistry -- 5.4.1 Single-stage Continuous Processing -- 5.4.2 Fast Reactions with Unstable Intermediates -- 5.4.3 High Temperature and Pressure -- 5.4.4 Mixing of Biphasic Reactions -- 5.4.5 Safety -- 5.4.6 Photochemistry -- 5.4.7 Electrochemistry -- 5.4.8 Multistage Continuous Processing -- 5.4.9 The Future of Continuous Chemistry -- 5.5 Conclusion -- Acknowledgments -- References -- Chapter 6 Vortioxetine and Early Drug Development Considerations at the Interface of R& -- D -- 6.1 Introduction -- 6.2 Synthesis of Vortioxetine -- 6.2.1 Iron-mediated Synthetic Route -- 6.2.2 Mustard Route -- 6.2.3 Palladium-mediated Route -- 6.2.4 Radioligand Synthesis -- 6.3 Metabolites of Vortioxetine -- 6.4 Conclusion -- Abbreviations -- References -- Chapter 7 Development of a Practical Synthesis of 4'-Azido-2' -Methyl-2'-Desoxycytosine and Its Prodrugs as HCV Chemotherapeutic Agents. 7.1 Introduction -- 7.2 New Synthesis of (2'R)-2'-deoxy-2'-C-methyl uridine (10) -- 7.3 Dehydration and Iodoazidation Steps -- 7.4 Functionalization at C-4' -- 7.5 Synthesis of the API -- 7.6 Solid Form Selection -- 7.7 Process Safety -- 7.8 Impurity Strategy -- 7.9 Conclusion -- References -- Part II Drug Product -- Chapter 8 Solubility, Permeability, and Their Interplay -- 8.1 Introduction -- 8.2 Solubility -- 8.2.1 Solubility and Dissolution Rate -- 8.2.2 Log P -- 8.2.3 pH -- 8.2.4 Bile Salts -- 8.2.5 The Particle Size -- 8.2.6 Volume of Fluids -- 8.3 Permeability -- 8.3.1 Passive Diffusion -- 8.3.2 Unstirred Water Layer -- 8.3.3 Membrane Transporters -- 8.3.4 P-Glycoprotein (P-gp) -- 8.3.5 MRP2 -- 8.3.6 PEPT1 -- 8.3.7 OATP -- 8.4 The Solubility-Permeability Interplay -- 8.5 Summary -- List of Abbreviations -- References -- Chapter 9 Solid-State Properties -- 9.1 Introduction -- 9.2 Amorphous and Crystalline States: Basic Concepts -- 9.2.1 Crystalline States: Polymorphs, Hydrates, Solvates, Salts, and Cocrystals -- 9.2.2 Polymorph Screening and the Solid Form Selection Process -- 9.2.2.1 Goal of Form Selection -- 9.2.2.2 Characterization of the Starting Material -- 9.2.2.3 Polymorph Screening Methods -- 9.2.2.4 Assessing the Relative Stability of Multiple Physical Forms -- 9.2.2.5 Form Selection Process -- 9.2.3 Amorphous Solid Dispersions -- 9.2.3.1 Spray Drying -- 9.2.3.2 Hot Melt Extrusion -- 9.2.3.3 Solid Dispersion Workflow -- 9.2.3.4 Dissolution and Stability Issue -- 9.3 Physical Properties of Drug Substance -- 9.3.1 Particle Habit -- 9.3.2 Particle Size -- 9.4 Summary -- List of Abbreviations -- References -- Chapter 10 Salt and Cocrystal Screening -- 10.1 Introduction -- 10.2 Screening -- 10.2.1 Counterions and Coformers -- 10.2.2 Manual Versus Automated Screening -- 10.2.3 Computational Approaches. 10.2.4 Salt and Cocrystal Screening Strategies -- 10.2.5 Polymorph Screen of Salts/Cocrystals -- 10.3 Salt/Cocrystal Selection -- 10.4 Scale-Up -- 10.5 Formulation Considerations -- 10.6 Regulatory Aspects -- 10.7 Case Studies -- 10.7.1 Indinavir: Early Salt Form Change -- 10.7.2 Atorvastatin: Crystalline Form Change in Late Development -- 10.8 Summary -- List of Abbreviations -- References -- Chapter 11 Particle Size Reduction: From Microsizing to Nanosizing -- 11.1 Strategic Plans and Risk Management of Particle Size -- 11.2 Particle Size Reduction Techniques -- 11.2.1 Top-Down Approaches -- 11.2.2 Bottom-Up Approaches -- 11.3 Particle Size Analysis -- 11.3.1 Regulatory and Quality Considerations -- 11.3.2 Particle Size Techniques -- 11.3.3 Selection of Appropriate Technique or Set of Techniques -- 11.4 Bioavailability and the Desired Particle Size -- 11.4.1 Particle Size and Bioavailability -- 11.4.2 Initial Desired Particle Size -- 11.5 Enabling Formulation Approach by Particle Size Reduction in Early Drug Development -- 11.6 Benefits of Commercial Products Using Nanosized Crystalline Particles -- 11.7 Perspectives in Nanosizing Crystalline Particles -- 11.7.1 Nanoparticles and Targeting Delivery -- 11.7.2 Emerging Nanoparticle Techniques -- 11.8 Conclusions -- References -- Chapter 12 Early Drug Development: From a Drug Candidate to the Clinic -- 12.1 Preclinical Formulation Selection -- 12.1.1 Guiding Principles and Technology Selection for Preclinical Formulation -- 12.1.2 Predicting Preclinical Formulation Performance -- 12.2 Formulation Selection for FiH -- 12.2.1 Extemporaneous Preparation -- 12.2.2 Powder in Capsule (PIC) Formulation -- 12.2.2.1 Clinical Performance of PIC Dosage Forms: A Retrospective Data Analysis of Pfizer NCEs -- 12.2.2.2 Clinical Data Analysis Methodology. 12.2.2.3 Relationship Between Physicochemical Properties and Clinical Performance for PIC Dosage Forms: Results from Clinical Data Analysis -- 12.3 Conclusion -- Acknowledgments -- References -- Chapter 13 A Practical Guide for the Preparation of Drug Nanosuspensions for Preclinical Studies: Including In Vivo Case Studies -- 13.1 Introduction -- 13.2 Selecting the Appropriate Type of Formulation Based on Compound Properties and Type of Study -- 13.2.1 Solutions -- 13.2.1.1 pH Adjustment -- 13.2.1.2 Cosolvents -- 13.2.1.3 Solubilization in Cyclodextrins -- 13.2.1.4 Solubilization in Surfactants -- 13.3 Microsuspensions -- 13.4 Nanosuspensions -- 13.4.1 Amorphous or Crystalline Nanosuspension? -- 13.4.2 Selection of Stabilizers -- 13.4.3 Manufacturing Method Selection -- 13.4.3.1 Low API Concentrations (Up to Approximately 10 mM) -- 13.4.3.2 High API Concentrations (Above 10 mM) -- 13.5 Manufacturing Methods -- 13.5.1 Amorphous Nanoparticles at Low Compound Concentrations: The Precipitation Method -- 13.5.2 Amorphous Nanoparticles at High Compound Concentrations: The Melt Emulsion Method -- 13.5.3 Crystalline Drug Nanoparticles at Low Compound Concentrations: The Ultrasonic Crystallization Method -- 13.5.4 Crystalline Drug Nanoparticles at High Compound Concentrations: The Wet Milling Method -- 13.6 Additional Characterizations and Considerations Before In Vivo Dose Decisions and Administration Route Selection -- 13.6.1 Solubility Measurements -- 13.6.2 Measurements of Dissolution Rate -- 13.6.3 Colloidal Stability -- 13.6.4 Chemical Stability of the Compound -- 13.6.5 Sterilization Before Parenteral Administration -- 13.7 Case Studies -- 13.7.1 Case Study 1: Milled Nanocrystals of a Compound for Toxicological Studies. 13.7.2 Case Study 2: Amorphous Nanosuspensions Selected for Preclinical and Toxicological Studies Due to Improved Exposure Versus Crystalline Suspensions with Different Particle Sizes.