Dosage Form Design Parameters

Volume II
 
 
Elsevier (Verlag)
  • 1. Auflage
  • |
  • erschienen am 25. Juli 2018
  • |
  • 810 Seiten
 
E-Book | ePUB mit Adobe-DRM | Systemvoraussetzungen
E-Book | PDF mit Adobe-DRM | Systemvoraussetzungen
978-0-12-814422-0 (ISBN)
 

Dosage Form Design Parameters, Volume II, examines the history and current state of the field within the pharmaceutical sciences, presenting key developments. Content includes drug development issues, the scale up of formulations, regulatory issues, intellectual property, solid state properties and polymorphism. Written by experts in the field, this volume in the Advances in Pharmaceutical Product Development and Research series deepens our understanding of dosage form design parameters. Chapters delve into a particular aspect of this fundamental field, covering principles, methodologies and the technologies employed by pharmaceutical scientists. In addition, the book contains a comprehensive examination suitable for researchers and advanced students working in pharmaceuticals, cosmetics, biotechnology and related industries.

  • Examines the history and recent developments in drug dosage forms for pharmaceutical sciences
  • Focuses on physicochemical aspects, prefomulation solid state properties and polymorphism
  • Contains extensive references for further discovery and learning that are appropriate for advanced undergraduates, graduate students and those interested in drug dosage design
weitere Ausgaben werden ermittelt
  • Front Cover
  • Dosage Form Design Parameters
  • Copyright Page
  • Dedication
  • Contents
  • List of Contributors
  • About the Editor
  • 1 Levels of Solid State Properties: Role of Different Levels During Pharmaceutical Product Development
  • 1.1 Introduction
  • 1.2 Solids and its Forms
  • 1.2.1 Amorphous
  • 1.2.2 Polymorphs
  • 1.2.2.1 Solvates/Hydrates
  • 1.2.2.2 Salts/Cocrystals
  • 1.3 Levels of SSP
  • 1.3.1 Molecular Level
  • 1.3.2 Particle Level
  • 1.3.3 Bulk Level
  • 1.4 Solid State Thermodynamics
  • 1.5 Bioavailability of Solids
  • 1.6 Polymorphism and its Types
  • 1.6.1 Enantiotropy and Monotropy
  • 1.6.1.1 Density Rule
  • 1.6.1.2 Infrared Rule
  • 1.7 Formulation Methods of Polymorphs
  • 1.7.1 Solvent Evaporation Method
  • 1.7.2 Slow Cooling Approach
  • 1.7.3 Solvent Diffusion Technique
  • 1.7.4 Vapor Diffusion Method
  • 1.7.5 Sublimation
  • 1.8 Characterization of Polymorphs
  • 1.9 Evaluation Technique
  • 1.9.1 Dissolution
  • 1.9.2 The Temperature-Dependent Solubility of Polymorphs: van't Hoff Plot
  • 1.9.3 Biological Studies
  • 1.10 Importance of SSP in Pharmaceutical Product Development
  • 1.10.1 Importance of Particle Size
  • 1.10.1.1 Biopharmaceutical Aspect of Particle Size
  • 1.11 Conclusion
  • Acknowledgments
  • References
  • Further Reading
  • 2 Polymorphism and its Implications in Pharmaceutical Product Development
  • 2.1 Introduction
  • 2.1.1 Solids
  • 2.1.2 Industrial Perspectives
  • 2.2 Potential Solid Polymorphic Forms
  • 2.2.1 Crystal
  • 2.2.2 Crystal Solvates or Hydrates
  • 2.2.3 Crystal Desolvated Solvates (Dehydrated Hydrates)
  • 2.2.4 Amorphous
  • 2.3 Formation of Polymorphs: Theoretical Considerations
  • 2.3.1 Ostwald's Rule of Stages
  • 2.3.2 Cross-Nucleation
  • 2.3.3 Heterogeneous Two-Dimensional Nucleation: Chemotaxy, Ledge-Directed Epitaxial Growth, and Two-Dimensional Lattice Mat...
  • 2.3.4 Additive-Induced Polymorph Selection
  • 2.4 Effect of Polymorphism on Different Drug Properties
  • 2.4.1 Physical and Thermodynamic Properties
  • 2.4.1.1 Morphology
  • 2.4.1.2 Density and Refractive Index
  • 2.4.1.3 Wettability
  • 2.4.1.4 Melting Point
  • 2.4.1.5 Solubility
  • 2.4.1.6 Thermal Stability
  • 2.4.2 Kinetic Properties
  • 2.4.2.1 Dissolution
  • 2.4.2.2 Kinetics of Solid-State Reaction
  • 2.4.2.3 Stability
  • 2.4.3 Surface Properties
  • 2.4.3.1 Surface Free Energy
  • 2.4.3.2 Crystal Habit
  • 2.4.3.3 Surface Area
  • 2.4.3.4 Particle Size Distribution
  • 2.4.4 Mechanical Properties
  • 2.4.4.1 Compressibility and Hardness
  • 2.4.5 Chemical Properties
  • 2.4.5.1 Reactivity
  • 2.5 Techniques of Polymorph Preparation
  • 2.5.1 Solvent Evaporation Technique
  • 2.5.2 Slow Cooling Technique
  • 2.5.3 Solvent Diffusion Technique
  • 2.5.4 Vapor Diffusion Technique
  • 2.5.5 Vacuum Sublimation Technique
  • 2.5.6 Crystallization in the Presence of Tailor-Made Additives
  • 2.6 Characterization Techniques of Polymorphs
  • 2.6.1 Differential Scanning Calorimetry
  • 2.6.2 Thermogravimetric Analysis
  • 2.6.3 Infrared (FT-IR) Spectroscopy
  • 2.6.4 Raman Spectroscopy
  • 2.6.5 Powder X-Ray Diffraction
  • 2.6.6 Single-Crystal XRD
  • 2.6.7 Solid-State NMR (SSNMR)
  • 2.6.8 Terahertz Spectroscopy
  • 2.6.9 Optical and Electron Microscopy
  • 2.6.10 Incoherent Inelastic Neutron Scattering
  • 2.7 Evaluation of Polymorphs
  • 2.7.1 Solubility of Polymorphs: Van't Hoff Plot
  • 2.7.2 Dissolution Study
  • 2.8 Polymorphism in Drug Products: Challenges for the Pharmaceutical Industry
  • 2.9 Regulatory Considerations
  • 2.10 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 3 Basics of Crystallization Process Applied in Drug Exploration
  • 3.1 Introduction
  • 3.2 Crystallization: Basic Concepts and Mechanisms in Crystallization
  • 3.2.1 Crystal Lattice-Building Block Arrangements and Symmetries
  • 3.2.2 Crystal Habit, Morphology, and Generation of Different Crystal Habits
  • 3.2.3 Primary Mechanism and Types of Nucleation
  • 3.2.4 Crystallization Process and Mier's Supersaturation Theory
  • 3.2.4.1 Mier's Supersaturation Process
  • 3.2.5 Metastable Zone and Induction of Nucleation
  • 3.2.6 Ostwald Law of Stages in Crystal Formation
  • 3.2.7 Ideal and Real Crystals Growth
  • 3.2.7.1 Birth and Spread Model of Crystal Growth via 2D Nucleation
  • 3.2.7.2 Real Crystals Growth
  • 3.3 Energetics of Crystallization
  • 3.4 Experimental Protocols for Polymorph Screening
  • 3.5 Crystallization Techniques
  • 3.5.1 Sublimation
  • 3.5.2 Precipitation
  • 3.5.3 Crystallization from a Single Solvent
  • 3.5.4 Evaporation Technique (From a Binary Mixture of Solvents)
  • 3.5.5 Vapor Diffusion
  • 3.5.6 Thermal Treatment
  • 3.5.7 Melt Crystallization
  • 3.5.8 Crystalline Solvates-Thermal Desolvation
  • 3.5.9 Growth in the Presence of Additives
  • 3.5.10 Grinding
  • 3.5.11 Lyophilization
  • 3.5.12 Laser-Induced Crystallization
  • 3.5.13 Capillary Crystallization
  • 3.5.14 Sonocrystallization
  • 3.5.15 Crystallization by Ionic Liquids
  • 3.5.16 Crystallization in Supercritical Liquids
  • 3.6 Crystallization-Agglomeration Control
  • 3.7 Crystallization-Application in Drug Research
  • 3.7.1 Preparation of API-Control of Crystal Properties
  • 3.7.1.1 Selection of Process Variables
  • 3.7.1.2 Cocrystal Formation
  • 3.7.1.3 Process Analytical Technology and Process Control
  • 3.7.2 Novel Crystalline Pharmaceuticals for Pulmonic Target-Chiral Isomers Separation by Crystallization
  • 3.7.3 Crystallization of Chiral Isomers Separation
  • 3.8 Conclusions
  • Acknowledgments
  • Abbreviations
  • References
  • 4 Role of Amorphous State in Drug Delivery
  • 4.1 Introduction: Basic Concepts of Amorphous State of Solid
  • 4.1.1 Properties of Amorphous Solids
  • 4.1.2 Concept of Glass Transition Temperature (Tg)
  • 4.1.2.1 Thermodynamic Necessity for Tg
  • 4.1.2.2 The Kinetic Point of View of Tg
  • 4.1.2.3 Factors Affecting Tg Value
  • 4.1.3 Molecular Mobility
  • 4.1.3.1 Global Mobility
  • 4.1.3.2 Local Mobility
  • 4.1.4 Fragility of Amorphous Materials
  • 4.1.4.1 Strong Glass Formers
  • 4.1.4.2 Fragile Glass Formers
  • 4.1.4.3 Prediction of Fragility
  • 4.1.5 Physical and Chemical Stability of the Amorphous Forms
  • 4.1.5.1 Physical Stability
  • 4.1.5.1.1 The Relationship Between the Physical Stability and Tg
  • 4.1.5.2 Chemical Stability
  • 4.1.5.2.1 Enhanced Rate of Degradation
  • 4.1.5.2.2 Changes in Mechanism and Kinetics of Degradation Reaction
  • 4.1.5.3 Shelf Life Prediction of Amorphous Pharmaceutical Preparations
  • 4.1.6 Glass Forming Ability of Pharmaceutical Substances
  • 4.2 Significance of Amorphous State in Pharmaceutical Formulation
  • 4.2.1 Solubility Enhancement of Active Pharmaceutical Ingredients
  • 4.2.1.1 Spring Parachute Effect During Solubility Studies
  • 4.2.2 Functionality Enhancement of Pharmaceutical Excipients
  • 4.2.2.1 Tablet Compression
  • 4.2.2.2 Polymeric Tablet Coating
  • 4.3 Techniques for Stabilization of Amorphous Forms in Pharmaceutical Formulation
  • 4.3.1 Storage at Temperatures Lower Than Tg
  • 4.3.2 Vitrification-Based Stabilization: Antiplasticization Approach
  • 4.3.2.1 Application of Gordon-Taylor Equation to Binary Amorphous Mixtures
  • 4.3.2.1.1 Indication of the Ideality of Mixing of Two Components
  • 4.3.2.1.2 Assessment of the Effect of Different Levels of a Second Material on Tg of Another
  • 4.3.2.1.3 Evaluation of the Degree of Intermolecular Interaction of Individual Components and Between the Drug and the Poly...
  • 4.3.3 Drug-Carrier/Polymer Interaction
  • 4.3.4 Nano-Confinement in the Nanopores of Mesoporous Inorganic Silicates
  • 4.4 Amorphous Solid Dispersions
  • 4.4.1 Mechanisms of Dissolution Enhancement
  • 4.4.2 Carriers used in Amorphous Solid Dispersions
  • 4.4.2.1 Polymeric Carriers
  • 4.4.2.2 Inorganic Mesoporous Carriers
  • 4.4.3 Preparation of Amorphous Solid Dispersions
  • 4.4.3.1 Solvent-Based Methods
  • 4.4.3.1.1 Vacuum Solvent Evaporation
  • 4.4.3.1.2 Spray Drying and Spray Drying-Related Methods
  • 4.4.3.1.3 Freeze Drying and Freeze Drying-Related Methods
  • 4.4.3.1.4 Addition of Antisolvent
  • 4.4.3.1.5 Electrospray Technique
  • 4.4.3.1.6 Supercritical Fluid-Based Methods
  • 4.4.3.2 Solvent Free Methods
  • 4.4.3.2.1 Vapor Condensation
  • 4.4.3.2.2 Mechanical Destruction of a Crystalline Mass
  • 4.4.3.2.3 Rapid Cooling (Quenching) of a Melt
  • 4.4.3.2.3.1 Fusion Method
  • 4.4.3.2.3.2 Hot Melt Extrusion
  • 4.4.3.3 Innovative Methods: Combined Solvent Evaporation/Spray Drying-Melt Extrusion
  • 4.5 Structure Characterization and Quantification of the Amorphous Content in Pharmaceutical Systems
  • 4.5.1 Thermal Analysis
  • 4.5.1.1 Differential Scanning Calorimetry and Related Techniques
  • 4.5.1.2 Isothermal Microcalorimetry
  • 4.5.2 Spectroscopic Techniques
  • 4.5.2.1 X-Ray Powder Diffraction and Related Techniques
  • 4.5.2.2 Vibrational Spectroscopy Techniques
  • 4.5.2.3 Solid State Nuclear Magnetic Resonance (NMR)
  • 4.5.3 Microscopic Techniques
  • 4.5.3.1 Microthermal Analysis
  • 4.5.4 Vapor Sorption
  • 4.5.5 Gas/Liquid Displacement Pycnometry
  • 4.5.6 Viscosity/Viscoelastic Characterization
  • 4.5.7 Phosphorescent/Fluorescent Molecular Probes
  • 4.6 Case Studies
  • 4.6.1 The Classic Case of Novobiocin
  • 4.6.2 The Novel Case of Kaletra
  • 4.6.3 Insulin Preparations
  • 4.7 Conclusion and Future Perspective
  • Abbreviations
  • References
  • 5 Particulate Level Properties and its Implications on Product Performance and Processing
  • 5.1 Introduction
  • 5.2 Mechanism of Particle-Particle Interactions
  • 5.2.1 Mechanisms that Restrict Particle Movement
  • 5.2.1.1 Friction
  • 5.2.1.2 Mechanical Interlocking
  • 5.2.1.3 Interparticulate Forces of Cohesion
  • 5.2.1.4 Liquid Bridging
  • 5.2.2 Mechanisms that Promote Particle Movement
  • 5.2.2.1 Gravity
  • 5.3 Levels of Solid State Particles
  • 5.3.1 Molecular Level
  • 5.3.2 Particle Level
  • 5.3.3 Bulk Level
  • 5.4 Particle Properties
  • 5.4.1 Particle Shape
  • 5.4.2 Particle Size
  • 5.4.3 Particle Surface Area
  • 5.4.4 Particle Mechanical Properties
  • 5.4.5 Properties of Charged Particles
  • 5.4.6 Microstructure of Particles
  • 5.5 Pharmaceutical Particle Technologies
  • 5.5.1 Particle Technologies to Improve Drugs Solubility
  • 5.5.1.1 Mechanical Micronization or Nanosization
  • 5.5.1.1.1 Jet Milling
  • 5.5.1.1.2 Ball Milling
  • 5.5.1.1.3 High-Pressure Homogenization (HPH)
  • 5.5.1.2 Engineered Particle Size Control
  • 5.5.1.2.1 Cryogenic Spray Process
  • 5.5.1.2.2 Supercritical Fluid Technology
  • 5.5.1.3 Crystallization Engineering
  • 5.5.2 Improving Drugs Bioavailability by Particle Technologies
  • 5.5.2.1 Solid Self-Emulsifying Drug Delivery Systems
  • 5.5.2.2 Complexation with Cyclodextrins
  • 5.5.2.3 Polymeric Micelles and Solubilization of Drugs
  • 5.5.2.4 Freeze-Dried Liposomes
  • 5.5.2.5 Solid Lipid Nanoparticles (SLNs)
  • 5.6 Characterization of Properties of Particles and its Impact on Product Manufacturing and Performance
  • 5.6.1 Characterization of Physical Properties of Particles
  • 5.6.1.1 Sampling and Sample Preparation for Particle Characterization
  • 5.6.1.1.1 Origins of Problems in the Characterization of Particles
  • 5.6.1.1.2 Sampling from Particulate Systems
  • 5.6.1.1.3 Sample Preparation
  • 5.6.1.2 Particle Size Analysis
  • 5.6.1.2.1 Equivalent Diameters
  • 5.6.1.2.2 Particle Size Distribution
  • 5.6.1.2.3 State-of-the-Art Instruments for Particle Sizing
  • 5.6.1.3 Particle's Shape and Structure Characterization
  • 5.6.1.3.1 Shape and Shape Description
  • 5.6.1.3.2 Surface Morphology and Structure
  • 5.6.1.3.3 Application to Density Determination
  • 5.6.1.4 Suspension Rheology
  • 5.6.1.4.1 Particle Structuring in Suspensions
  • 5.6.1.4.2 Measurement of Suspension Rheology
  • 5.6.1.5 Bulk Flow of Powders
  • 5.6.1.5.1 Cohesive and Free-Flowing Powders
  • 5.6.1.5.2 Segregation and Structure
  • 5.6.1.5.3 Application of Powder Flow to Process Design
  • 5.6.2 Characterization of Mechanical Properties of Particles
  • 5.6.2.1 Mechanical Properties of Powders
  • 5.6.2.1.1 Characterization of Deformation and Breakage of Particles
  • 5.6.2.1.2 Characterization by Nano-Indentation
  • 5.6.2.1.3 Particle Breakage Under Brittle and Semibrittle Failure Modes
  • 5.6.2.1.4 Impact and Side Crushing of Single Particles
  • 5.6.2.1.5 Bulk Compression and Crushing
  • 5.6.2.2 Bulk Characterization of Powders
  • 5.6.2.2.1 Shear Cells and Powder Rheometry
  • 5.6.2.2.2 Frictional Properties
  • 5.6.2.2.3 Consolidation and Unconfined Yield Stress
  • 5.6.2.3 Electrostatics in Powder Systems
  • 5.6.2.3.1 Fundamentals of Tribo-Electrification of Powders
  • 5.6.2.3.2 Measurements of Tribo-Electrification of Powders
  • 5.6.2.3.3 Industrial Applications of Electrostatics in Powder Systems
  • 5.6.3 Characterization of Chemical Properties of Particles
  • 5.6.3.1 Adhesion of Particles
  • 5.6.3.1.1 Principles of Particle's Adhesion
  • 5.6.3.1.2 Measurement Techniques
  • 5.6.3.1.3 State-of-the-Art in the Field
  • 5.6.3.2 Solubility and Dissolution of Particles
  • 5.6.3.3 Tableting and Compaction of Powders
  • 5.6.3.3.1 Fundamentals of Tableting and Compaction of Powders
  • 5.6.3.3.2 Industrial Use of Tableting and Compaction
  • 5.6.3.4 Determination of Powder Surface Energy and Surface Chemistry
  • 5.7 Processing Parameters: Formulation of Tablets
  • 5.8 Evaluation and Control of Drug Performance and Processing
  • 5.9 Practical Implications of Particle Size
  • 5.9.1 Formulation and Process Understanding Including Risk Analysis
  • 5.9.2 API Biopharmaceutics
  • 5.9.3 API Process Effects
  • 5.9.4 Pharmaceutical Product Process Effects
  • 5.9.5 Change Control and Validation
  • 5.9.6 Manual Processes
  • 5.9.7 Raw Material Supply
  • 5.9.8 Analytical Data
  • 5.9.9 Controlled Manufacturing and Testing
  • 5.10 Effects of Particulate Properties on Various Pharmaceutical Products' Characteristics
  • 5.10.1 Powders Flowability and Tabletability
  • 5.10.2 Semisolid Spreadability of Pharmaceutical Pastes
  • 5.10.3 Dry Powder Inhalers
  • 5.10.4 Color, Hydration and Rheological Properties of Excipients
  • 5.10.5 Thermal Conductivity and Mechanical Properties
  • 5.10.6 Impact of Particulate Properties on a Particle Granulation Model
  • 5.11 Effects of Polymorphism on the Particle and Compaction Properties
  • 5.12 Regulatory Guidelines
  • 5.12.1 Biopharmaceutics Classification System
  • 5.12.2 Code of Federal Regulations Decision Tree
  • 5.13 Conclusions
  • Abbreviations
  • References
  • Further Reading
  • 6 Bulk Level Properties and its Role in Formulation Development and Processing
  • 6.1 Introduction
  • 6.1.1 Pharmaceutical "Powder"
  • 6.1.2 Material in Bulk
  • 6.1.3 Material at Nano-Scale
  • 6.2 Properties of Pharmaceutical Bulk Material: Role in Product Development
  • 6.2.1 Solid-State Properties
  • 6.2.1.1 Molecular Level of Solid State
  • 6.2.1.2 Particle Level of Solid State
  • 6.2.1.3 Bulk Level of Solid State
  • 6.2.1.4 Significance of Solid State Properties
  • 6.2.2 Shape
  • 6.2.3 Particle Size
  • 6.2.4 Surface Area
  • 6.2.5 Surface Roughness
  • 6.2.6 Surface Energetics
  • 6.2.7 Crystallinity
  • 6.2.8 Polymorphism
  • 6.2.9 Hygroscopicity
  • 6.2.10 Melting Point
  • 6.2.11 Flow Properties
  • 6.2.11.1 Moisture Content
  • 6.2.11.2 Temperature
  • 6.2.11.3 Particle Size
  • 6.2.11.4 Time of Storage at Rest
  • 6.2.12 Compressibility and Compactibility
  • 6.3 Insight into Interparticle Interaction: Mechanism and Modeling Approaches
  • 6.3.1 Interparticle Force of Particulate Solids
  • 6.3.2 Van der Waals Force
  • 6.3.3 Electrostatic Forces
  • 6.3.4 Capillary Force
  • 6.4 Role of Bulk level Properties in Formulation Development: Industrial Perspective
  • 6.4.1 Material Processing Conditions: Moisture and Temperature
  • 6.4.1.1 Tablet Coating
  • 6.4.2 Particle Formulation Methods to Modulate Particle Properties and Interparticle Interaction
  • 6.4.2.1 Crystallization
  • 6.4.2.2 Spray Drying
  • 6.4.2.3 Milling
  • 6.4.2.4 Blending
  • 6.4.3 Particle Interaction with Processing Equipment Surface
  • 6.4.4 Effect of Bulk Properties on Individual Unit Operation
  • 6.5 Computational Efforts: Modeling and Simulation of Pharmaceutical Powder Properties
  • 6.6 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 7 Concepts of Hypothesis Testing and Types of Errors
  • 7.1 Introduction
  • 7.1.1 Brief History of Hypothesis
  • 7.1.2 Salient Features of Hypothesis
  • 7.2 Formulation Importance and Function of Hypothesis
  • 7.2.1 Formulation of Research Hypothesis
  • 7.2.2 Importance of Hypothesis in Research
  • 7.2.3 Functions of Hypothesis
  • 7.3 Types of Hypothesis
  • 7.3.1 Simple Hypothesis
  • 7.3.2 Complex Hypothesis
  • 7.3.3 Empirical Hypothesis
  • 7.3.4 Null Hypothesis
  • 7.3.5 Alternative Hypothesis
  • 7.3.6 Logical Hypothesis
  • 7.3.7 Statistical Hypothesis
  • 7.4 Nature of Hypothesis
  • 7.4.1 Question Form
  • 7.4.2 Declarative Hypothesis
  • 7.4.3 Directional Hypothesis
  • 7.4.4 Nondirectional Hypothesis
  • 7.5 Sources of Hypothesis
  • 7.5.1 Personal Experience
  • 7.5.2 Imagination
  • 7.5.3 Observation
  • 7.6 Developing the Hypotheses
  • 7.6.1 Condition for Testing Hypothesis
  • 7.6.2 Principles of Evaluating Hypothesis
  • 7.7 Types of Errors
  • 7.7.1 Type I Error
  • 7.7.2 Type II Error
  • 7.7.3 Placebo Effect
  • 7.7.4 Hawthorne Effect
  • 7.7.5 Rating Effect
  • 7.7.6 John Henry Effect
  • 7.7.7 Estimators
  • 7.7.7.1 Point Estimation
  • 7.7.7.2 Interval Estimation
  • 7.8 Bias in Pharmaceutical Perspective
  • 7.8.1 Cognitive Bias
  • 7.9 Sample Size and Power
  • 7.10 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • Further Reading
  • 8 Experimental Design and Analysis of Variance
  • 8.1 Introduction
  • 8.2 Levels of Evidence in Research Design
  • 8.2.1 First Level of Research Design (Collective, 2003)
  • 8.2.2 Second Level of Research Design (Cobb et al., 2003)
  • 8.2.3 Third Level of Design (Ritchie et al., 2003)
  • 8.2.4 Fourth Level of Design (Morgan and Harmon, 2001)
  • 8.3 Importance of Research Design
  • 8.4 Types and Objectives of Research
  • 8.4.1 Exploratory Research
  • 8.4.2 Descriptive Research
  • 8.4.3 Causal Research
  • 8.5 Characteristics of a Good Experimental Design
  • 8.6 Types of DOE and Associated Case Studies
  • 8.6.1 One Factor Designs
  • 8.6.2 Factorial Designs
  • 8.6.2.1 General Full Factorial Designs
  • 8.6.2.2 Two-Level Full Factorial Designs
  • 8.6.3 Plackett-Burman Designs
  • 8.6.4 Taguchi's Orthogonal Arrays
  • 8.6.5 Response Surface Method (RSM) Designs
  • 8.6.6 Evolutionary Operations (EVOPs)
  • 8.6.7 Mixture Designs
  • 8.6.8 Completely Randomized, Randomized Blocks Design
  • 8.6.9 Quality by Design
  • 8.7 Selection Criteria for Suitable DOE: An Insight for Refreshers
  • 8.8 Comparative Objective
  • 8.9 Screening Objective
  • 8.9.1 Response Surface (Method) Objective
  • 8.10 Optimizing Responses When Factors are Proportions of a Mixture Objective
  • 8.11 Optimal Fitting of a Regression Model Objective
  • 8.12 Specialized application of DOE in different area of pharmaceuticals
  • 8.12.1 Experimental Design for Toxicologists
  • 8.12.2 Experimental Design in Alcohol Administration Research
  • 8.12.3 Experimental Design in Pharmacokinetics of Proteins and Peptides
  • 8.12.4 Screening Study
  • 8.12.5 Optimization Study
  • 8.13 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • Further Reading
  • 9 Basic Concept and Application of Sampling Procedures
  • 9.1 Sampling of Pharmaceutical Products: General Considerations
  • 9.2 Fundamental to Sampling
  • 9.3 Classes and Types of Pharmaceutical Products
  • 9.3.1 Starting Materials for Use in the Manufacture of Finished Pharmaceutical Products
  • 9.3.2 Intermediates in the Manufacturing Process and Bulk Pharmaceuticals Products
  • 9.3.3 Pharmaceutical Products (In-Process)
  • 9.3.4 Primary and Secondary Packaging Materials
  • 9.3.5 Finished Products
  • 9.4 Design Requirements for Sampling
  • 9.5 Responsibilities for Sampling
  • 9.6 Sampling Process
  • 9.6.1 Preparation of Sampling
  • 9.6.2 Sampling Operation and Precautions
  • 9.6.3 Storage and Retention
  • 9.7 Regulatory Considerations in Sampling
  • 9.7.1 USFDA Requirements
  • 9.7.1.1 Starting Material
  • 9.7.1.2 Packaging Material
  • 9.7.2 WHO Requirements
  • 9.7.2.1 Purpose of Sampling
  • 9.7.2.2 Regulatory Consideration
  • 9.7.2.3 Sampling Plans for Starting Materials, Packaging Materials, and Finished Products
  • 9.7.2.3.1 The n Plan
  • 9.7.2.3.2 The p Plan
  • 9.7.2.3.3 The r Plan
  • 9.8 Sampling in Pharmaceutical Formulations
  • 9.8.1 Sampling of Pharmaceutical in Process Powders Blend and Finish Products
  • 9.9 Correlation of In-Process Stratified Sampling with Powder Mix and Finished Product
  • 9.9.1 Evaluation of Powder Mixed Uniformity Based on Following Procedure
  • 9.9.2 Correlation of Powder Mix Uniformity with Stratified In-Process Dosage Unit Data
  • 9.9.3 Correlation of Stratified In-Process Samples with the Finished Product
  • 9.9.4 Exhibit/Validation Batch Powder Mix Homogeneity
  • 9.9.5 Verification of Manufacturing Criteria
  • 9.9.6 In-Process Dosage Unit Sampling and Analysis
  • 9.9.6.1 Standard Criteria Method (SCM)
  • 9.9.6.1.1 Stage 1 Test
  • 9.9.6.1.2 Stage 2 Test
  • 9.9.6.2 Marginal Criteria Method (MCM)
  • 9.9.6.3 Switching to Standard Test Method from Marginal Test Method
  • 9.10 Error in Sampling
  • 9.10.1 Chance
  • 9.10.2 Sampling Bias
  • 9.10.3 Another Kind of Errors
  • 9.10.4 Human Error
  • 9.10.5 Population-Specific Errors
  • 9.10.6 Sample Frame Error
  • 9.11 Sampling for Long-Term Profitability: Industrial Perspective
  • 9.12 Conclusion
  • Acknowledgments
  • References
  • Further Reading
  • 10 Statistical Techniques in Pharmaceutical Product Development
  • 10.1 Introduction to Biostatistics
  • 10.2 Objective and Significance of Statistical Analysis
  • 10.3 Statistical Procedures
  • 10.3.1 Nonclinical Trials
  • 10.3.2 Clinical Trials
  • 10.4 Taguchi Methodology as a Statistical Tool for Biotechnological Applications
  • 10.5 Statistical Analysis: Regulatory Considerations
  • 10.5.1 FDA Perspective
  • 10.5.2 ICH Guidelines
  • 10.5.2.1 Quality Guidelines
  • 10.5.2.2 Safety Guidelines
  • 10.5.2.3 Efficacy Guidelines
  • 10.5.2.4 Multidisciplinary Guidelines
  • 10.6 Factors Responsible for a High Phase III Failure Rate
  • 10.7 Role of Statistics in Quality Improvement of Pharmaceuticals
  • 10.8 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 11 Drug-Excipient Interaction and Incompatibilities
  • 11.1 Introduction to Pharmaceutical Interaction
  • 11.1.1 Drug-Drug Interactions
  • 11.1.2 Role of Excipients in Pharmaceutical Formulations
  • 11.1.3 Drug-Excipient Interactions
  • 11.2 Modes of Drug Decomposition/Degradation
  • 11.2.1 Hydrolysis
  • 11.2.2 Oxidation
  • 11.2.3 Isomerization
  • 11.2.4 Photolysis
  • 11.2.5 Polymerization
  • 11.3 Mechanism of Drug-Excipient Interaction
  • 11.3.1 Physical Drug-Excipient Interaction
  • 11.3.2 Chemical Drug-Excipient-Interaction
  • 11.3.3 Therapeutic/Physiological Interaction
  • 11.4 Potential Effects of Drug-Excipient Interactions: Recent Case Studies
  • 11.4.1 Favorable Interactions: Add in Clinical Benefits
  • 11.4.2 Unfavorable Interactions: Leading to Product Degradation
  • 11.5 Incompatibilities in Pharmaceutical Formulations: Role of Drug-Excipient Interaction
  • 11.5.1 Direct Reactions Between Drug and Excipient
  • 11.5.2 Drug Degradations Enhanced by Excipients
  • 11.6 Analytical Techniques to Detect Drug-Excipient Interaction
  • 11.6.1 Thermal Methods of Analysis
  • 11.6.1.1 Differential Scanning Calorimetry
  • 11.6.1.2 Differential Thermal Analysis
  • 11.6.1.3 Thermogravimetric Analysis
  • 11.6.1.4 Isothermal Microcalorimetry
  • 11.6.1.5 Hot Stage Microscopy (HSM)
  • 11.6.2 Spectroscopic Technique
  • 11.6.2.1 Vibrational Spectroscopy
  • 11.6.2.2 Powder X-Ray Diffraction
  • 11.6.2.3 Solid-State Nuclear Magnetic Resonance Spectroscopy
  • 11.6.3 Chromatography
  • 11.6.3.1 Thin-Layer Chromatography or High-Performance TLC (HPTLC)
  • 11.6.3.2 High-Performance Liquid Chromatography
  • 11.6.4 Microscopical Technique
  • 11.6.4.1 Scanning Electron Microscopy
  • 11.6.5 Accelerated Stability Study
  • 11.7 Regulatory Implications
  • 11.8 Conclusions
  • Acknowledgements
  • Abbreviations
  • References
  • 12 Documentation Protocol in Product Development Including Clinical Records
  • 12.1 Introduction to Pharmaceutical Documentation
  • 12.2 Pharmaceutical Development
  • 12.2.1 Components of the Drug Product
  • 12.2.1.1 Drug Substance
  • 12.2.1.2 Excipients
  • 12.2.2 Drug Product
  • 12.2.2.1 Formulation Development
  • 12.2.2.2 Overages
  • 12.2.2.3 Physicochemical and Biological Properties
  • 12.2.3 Manufacturing Process Development
  • 12.2.4 Container Closure System
  • 12.2.5 Microbiological Attributes
  • 12.2.6 Compatibility
  • 12.3 Annex to Pharmaceutical Development
  • 12.3.1 Quality Target Product Profile (QTPP)
  • 12.3.2 Critical Quality Attributes (CQAs)
  • 12.3.3 Linking Material Attributes and Process Parameters to CQAs-Risk Assessment
  • 12.3.4 Design Space
  • 12.3.4.1 Selection of Variables
  • 12.3.4.2 Defining and Describing a Design Space in a Submission
  • 12.3.4.3 Unit Operation Design Space(s)
  • 12.3.4.4 Relationship of Design Space to Scale and Equipment
  • 12.3.4.5 Design Space Versus Proven Acceptable Ranges
  • 12.3.4.6 Design Space and Edge of Failure
  • 12.3.5 Control Strategy
  • 12.3.6 Product Life Cycle Management and Continual Improvement
  • 12.4 Submission of Pharmaceutical Development and related Information in Common Technical Document Format (CTD)
  • 12.4.1 Quality Risk Management and Product and Process Development
  • 12.4.2 Design Space
  • 12.4.3 Control Strategy
  • 12.4.4 Drug Substance-Related Information
  • 12.5 Clinical Trial Protocol
  • 12.5.1 General Information
  • 12.5.2 Background Information
  • 12.5.3 Trial Objectives and Purpose
  • 12.5.4 Trial Design
  • 12.5.5 Selection and Withdrawal of Subjects
  • 12.5.6 Treatment of Subjects
  • 12.5.7 Assessment of Efficacy
  • 12.5.8 Assessment of Safety
  • 12.5.9 Statistics
  • 12.5.10 Direct Access to Source Data/Documents
  • 12.5.11 Quality Control and Quality Assurance
  • 12.5.12 Ethics
  • 12.5.13 Data Handling and Record Keeping
  • 12.5.14 Financing and Insurance
  • 12.5.15 Publication Policy
  • 12.5.16 Supplements
  • 12.6 Essential Documents for the Conduct of a Clinical Trial
  • 12.6.1 The List of the Essential Documents Required Before Commencement of Clinical Trial Studies
  • 12.6.1.1 Investigators Brochure
  • 12.6.1.2 Signed Protocol and Amendments, If Any, and Sample Case Report Form
  • 12.6.1.3 Information Given to Trial Subject
  • 12.6.1.4 Financial Aspects of the Trial
  • 12.6.1.5 Insurance Statement (Where Required)
  • 12.6.1.6 Signed Agreements Between Involved Parties
  • 12.6.1.7 Dated, Documented Approval/Favorable Opinion of Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
  • 12.6.1.8 IRB/IEC Composition
  • 12.6.1.9 Regulatory Authority Authorization/Approval/ Notification of Protocol
  • 12.6.1.10 Curriculum Vitae and/or Other Relevant Documents Evidencing Qualifications of Investigator(s) and Subinvestigator(s)
  • 12.6.1.11 Normal Value(s)/Range(s) for Medical/Laboratory/Technical Procedure(s) and/or Test(s) Included in the Protocol
  • 12.6.1.12 Medical/Laboratory/Technical Procedures/Tests
  • 12.6.1.13 Sample of Label(s) Attached to Investigational Product Container(s)
  • 12.6.1.14 Instructions for Handling of Investigational Product(s) and Trial-Related Materials
  • 12.6.1.15 Shipping Records for Investigational Product(s) and Trial-Related Materials
  • 12.6.1.16 Certificate(s) of Analysis of Investigational Product(s) Shipped
  • 12.6.1.17 Decoding Procedures for Blinded Trials
  • 12.6.1.18 Master Randomization List
  • 12.6.1.19 Pretrial Monitoring Report
  • 12.6.1.20 Trial Initiation Monitoring Report
  • 12.6.2 The List of the Essential Documents Required During the Clinical Trial Studies
  • 12.6.2.1 Investigator's Brochure Updates
  • 12.6.2.2 Any Revision
  • 12.6.2.3 Dated, Documented Approval/Favorable Opinion of IRB/IEC
  • 12.6.2.4 Regulatory Authority(ies) Authorizations/Approvals/Notifications Where Required
  • 12.6.2.5 Curriculum Vitae for New Investigator(s) and/or Subinvestigator(s)
  • 12.6.2.6 Updates to Normal Value(s)/Range(s) for Medical/Laboratory/Technical Procedure(s)/Test(s) Included in the Protocol
  • 12.6.2.7 Updates of Medical/Laboratory/Technical Procedures/Tests
  • 12.6.2.8 Documentation of Investigational Product(s) and Trial-Related Materials Shipment
  • 12.6.2.9 Certificate(s) of Analysis for New Batches of Investigational Products
  • 12.6.2.10 Monitoring Visit Reports
  • 12.6.2.11 Relevant Communications Other Than Site Visits
  • 12.6.2.12 Signed Informed Consent Forms
  • 12.6.2.13 Source Documents
  • 12.6.2.14 Signed, Dated and Completed CRF
  • 12.6.2.15 Documentation of CRF Corrections
  • 12.6.2.16 Notification by Originating Investigator to Sponsor of Serious Adverse Events and Related Reports
  • 12.6.2.17 Notification by Sponsor and/or Investigator, Where Applicable, to Regulatory Authority(ies) and IRB(s)/IEC(s) of ...
  • 12.6.2.18 Notification by Sponsor to Investigators of Safety Information
  • 12.6.2.19 Interim or Annual Reports to IRB/IEC and Authority(ies)
  • 12.6.2.20 Subject Screening Log
  • 12.6.2.21 Subject Identification Code List
  • 12.6.2.22 Subject Enrollment Log
  • 12.6.2.23 Investigational Products Accountability at the Site
  • 12.6.2.24 Signature Sheet
  • 12.6.2.25 Record of Retained Body Fluids/Tissue Samples (If Any)
  • 12.6.3 Documents Required After the Completion of the Trial
  • 12.6.3.1 Investigational Product(s) Accountability at Site
  • 12.6.3.2 Documentation of Investigational Product Destruction
  • 12.6.3.3 Completed Subject Identification Code List
  • 12.6.3.4 Audit Certificate (If Available)
  • 12.6.3.5 Final Trial Close-Out Monitoring Report
  • 12.6.3.6 Treatment Allocation and Decoding Documentation
  • 12.6.3.7 Final Report by Investigator to IRB/IEC Where Required, and Where Applicable, to the Regulatory Authorities
  • 12.6.3.8 Clinical Study Report
  • 12.7 Pharmaceutical Documentation and Records: Harmonized GMP Requirements
  • 12.8 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • Further Reading
  • 13 Correlation Between In Vitro and In Vivo Screens: Special Emphasis on High Throughput Screening and High Throughput Phar...
  • 13.1 Introduction
  • 13.2 General Principles of Screening
  • 13.3 Correlations Between Various Animal Models and Human Situations
  • 13.4 Animal Ethics
  • 13.5 Drug Pharmacokinetics-In Vitro Drug Release and its Bioavailability
  • 13.6 Biopharmaceutics Classification System for Drugs
  • 13.7 In Vitro-In Vivo Correlation
  • 13.7.1 Levels of IVIVC
  • 13.7.2 Applications of IVIVC
  • 13.7.3 Need and Importance of IVIVC
  • 13.8 Principles in Establishment of IVIVC
  • 13.8.1 Dissolution Rate Versus Absorption Rate
  • 13.8.2 Percent of Drug Dissolved Versus Percent of Drug Absorbed
  • 13.8.3 Maximum Plasma Concentration Versus Percent of Drug Dissolved In Vitro
  • 13.9 Advancement in IVIVC Studies: Novel Technologies
  • 13.9.1 ACAT Model (Advanced Compartmental Absorption and Transit)
  • 13.9.1.1 Gastroplasty
  • 13.9.1.2 The Simcyp Simulator
  • 13.9.2 CaCo-2 Monolayer Diffusion Studies
  • 13.9.2.1 Simultaneous Evaluation of Dissolution and Permeation
  • 13.9.2.2 Continuous Dissolution/Caco-2 System in a Closed Form
  • 13.9.2.3 Open Dissolution/Caco-2 Systems
  • 13.9.2.4 Continuous Dissolution/Caco-2 System
  • 13.9.3 Use of Biorelevant Media
  • 13.9.3.1 Simulated Gastric Fluid (SGF)
  • 13.9.3.2 Water
  • 13.9.3.3 Simulated Intestinal Fluid
  • 13.9.4 High Content Analysis of Hepatic Stellate Cells
  • 13.9.5 Use of Low-Efflux MDCKII Cells
  • 13.9.6 Microsomal Stability Assay
  • 13.10 Correlation Between In Vitro and In Vivo Screens: Special Emphasis on Cell-Based Assays
  • 13.10.1 Biochemical Assay
  • 13.10.2 Receptor/Radioligand and Binding Assay
  • 13.10.3 High-Throughput Screening (HTS)
  • 13.11 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • Further Reading
  • 14 Sterilization of Pharmaceuticals: Technology, Equipment, and Validation
  • 14.1 Introduction to Sterilization
  • 14.1.1 History
  • 14.1.2 Sterility, Sterilization, and Disinfection
  • 14.1.3 Objectives of Sterilization
  • 14.1.4 Importance of Sterilization: Pharmaceutical Perspective
  • 14.1.5 A Quick Overview of General Procedures for Sterilization
  • 14.1.6 Items to be Sterilized
  • 14.2 Factors Affecting Sterilization
  • 14.2.1 The Population of Microorganisms and Spatial Arrangements of Microorganisms
  • 14.2.2 Microorganisms Intrinsic Resistance
  • 14.2.3 Physical and Chemical Factors
  • 14.2.4 Storage Condition
  • 14.3 Risk Assessment, Sterility Assurance Level (SAL), and Cleanroom Concept: Industrial Perspective
  • 14.3.1 Risk Assessment
  • 14.3.2 Sterility Assurance Level
  • 14.3.3 Cleanrooms in Pharmaceutical Production
  • 14.4 Sterility Testing Techniques
  • 14.4.1 Microbial Destruction Kinetics
  • 14.4.1.1 D Value
  • 14.4.1.2 Z Value
  • 14.4.1.3 F Value
  • 14.4.2 Sterility Testing Techniques
  • 14.4.2.1 Membrane Filtration
  • 14.4.2.2 Direct Inoculation
  • 14.4.3 Incubation and Examination of Sterility Tests
  • 14.4.3.1 Interpretation of the Test Results
  • 14.4.4 Culture Medium
  • 14.4.4.1 Method of Preparation of TM
  • 14.4.4.2 Method of Preparation of Soybean-Casein Digest Medium or TSB
  • 14.4.5 Sterility Test Method Validation
  • 14.4.6 Rapid Microbiological Methods
  • 14.5 Sterilization: Methods and Mechanism
  • 14.5.1 Method of Sterilization
  • 14.5.1.1 Heat Sterilization
  • 14.5.1.2 Radiation Sterilization
  • 14.5.1.3 Filtration Sterilization
  • 14.5.1.4 Chemical Sterilization
  • 14.5.2 Mechanism of Sterilization
  • 14.5.2.1 Moist Heat Sterilization
  • 14.5.2.2 Dry-Heat Sterilization
  • 14.5.2.3 Radiation Sterilization
  • 14.5.2.4 Filtration Method
  • 14.5.2.5 Chemical Sterilization
  • 14.6 Choosing a Correct Sterilization Process
  • 14.7 Bioburden Monitoring Program
  • 14.8 Sterilization Indicators
  • 14.8.1 Physical Indicators
  • 14.8.1.1 Bubble Point Pressure Test
  • 14.8.2 Chemical Indicators
  • 14.8.3 BIs
  • 14.8.3.1 Types of BI
  • 14.8.3.2 Characteristics of BIs
  • 14.8.3.3 Use of BIs
  • 14.9 Validation of Sterilization Process and Equipment
  • 14.9.1 Steam Sterilization
  • 14.9.1.1 Validation Process in Steam Sterilization
  • 14.9.1.2 Bowie-Dick Test for Steam Penetration
  • 14.9.1.3 Heat Distribution and Penetration Studies
  • 14.9.1.3.1 Empty Chamber Heat Distribution Studies
  • 14.9.1.3.2 Loaded Chamber Heat Distribution and Penetration Studies
  • 14.9.1.4 Biochallenge Test
  • 14.9.1.5 Estimation of F0 Values
  • 14.9.2 Gaseous Sterilization
  • 14.9.2.1 Validation Process in Gaseous Sterilization
  • 14.9.3 Dry-Heat Sterilization
  • 14.9.3.1 Validation Process in Dry-Heat Sterilization
  • 14.9.4 Filtration Sterilization and its Validation
  • 14.10 Technological Development of Sterilization: Newer Perspectives
  • 14.10.1 Terminal Sterilization
  • 14.10.2 Radiation Sterilization
  • 14.10.3 Synergetic Processes
  • 14.10.3.1 Psoralens and UVA (PUVA)
  • 14.10.3.2 Microwaves and Bactericide
  • 14.10.3.3 Low-Temperature Steam and Formaldehyde
  • 14.10.4 Supercritical Carbon Dioxide Sterilization
  • 14.10.5 Chemical Processes
  • 14.10.5.1 Peracetic Acid
  • 14.10.5.2 Hydrogen Peroxide
  • 14.10.6 Physicochemical Process
  • 14.10.6.1 Plasma
  • 14.10.6.2 Steam
  • 14.10.7 Physical Process
  • 14.10.7.1 Pulsed-Light Systems
  • 14.10.7.2 Microwaves
  • 14.11 Sterilization-in-Place (SIP) Technology and Validation
  • 14.12 Importance of Relative Humidity and Temperatures in Manufacturing of Dry Powders
  • 14.13 Effect of Sterilization on Excipients
  • 14.14 Effect of Sterilization on Packing Material
  • 14.15 Sterilization of Biotechnology Products
  • 14.16 Sterilization of Nanoformulations
  • 14.17 The Benefits of Terminal Sterilization of APIs and Pharmaceutical Fillers
  • 14.18 Conclusion
  • Acknowledgements
  • Abbreviations
  • References
  • Further Reading
  • 15 Package Development of Pharmaceutical Products: Aspects of Packaging Materials Used for Pharmaceutical Products
  • 15.1 Introduction
  • 15.1.1 Why Packaging?
  • 15.1.2 Ideal Characteristics of Packaging Material
  • 15.1.3 General Terminology
  • 15.1.4 Category of Packaging Container
  • 15.1.4.1 Primary Packaging Container
  • 15.1.4.2 Secondary Packaging Container
  • 15.1.4.3 Tertiary Packaging Container
  • 15.1.5 Types of Packaging Materials
  • 15.1.5.1 Plastic Containers
  • 15.1.5.2 Glass Containers
  • 15.1.5.2.1 Highly Resistant Borosilicate (Type I Glass)
  • 15.1.5.2.2 Moderately Resistant Soda Lime Glass (Type II Glass)
  • 15.1.5.2.3 Highly Resistant Soda Lime Glass (Type III Glass)
  • 15.1.5.2.4 General Purpose Soda Lime Glass (Type IV Glass)
  • 15.1.5.3 Metal Containers
  • 15.1.5.4 Closures Used with Packaging Containers
  • 15.2 Formulation Aspect
  • 15.2.1 Formulation Specific Requirement of Packaging Material
  • 15.2.1.1 Compatibility
  • 15.2.1.2 Integrity
  • 15.2.1.3 Toxicity
  • 15.2.1.4 Leachable
  • 15.2.1.4.1 Determination of All Possible Extractables From the Packaging Material Without the Formulation
  • 15.2.1.4.2 Leachables Profiling in Formulation
  • 15.2.1.5 Dose Delivery
  • 15.2.1.6 Administration Feasibility
  • 15.2.1.7 Durability
  • 15.2.2 Formulation Stability
  • 15.2.2.1 Stability Issues Due to Packaging Material
  • 15.2.2.2 Stability Prediction During Formulation Development
  • 15.2.3 Screening of Packaging Materials for Formulations
  • 15.2.4 Testing for Evaluation of Packaging Materials
  • 15.2.4.1 Physical
  • 15.2.4.2 Identification
  • 15.2.4.3 Dimension/Measurement
  • 15.2.4.4 Volume in Container
  • 15.2.4.5 Deliverable Dose/Volume
  • 15.2.4.6 Extractable, Leachable, Delamination
  • 15.3 Regulatory Aspect
  • 15.3.1 Purpose of Regulations in Packaging Materials of Drug Products
  • 15.3.1.1 Safety
  • 15.3.1.2 Quality
  • 15.3.2 Regulation for Food Packaging Products and Materials
  • 15.3.2.1 European Union (EU)
  • 15.3.2.2 United States
  • 15.3.2.3 China
  • 15.3.2.4 Japan
  • 15.4 Environment Aspects
  • 15.4.1 Type of Packaging Material Waste
  • 15.4.1.1 Plastic
  • 15.4.1.2 Paper
  • 15.4.1.3 Glass
  • 15.4.1.4 Metals
  • 15.4.2 Root Causes for Waste Generation of Packaging Materials
  • 15.4.2.1 Improper Utilization
  • 15.4.2.2 Improper handling
  • 15.4.2.3 Oversized Packaging
  • 15.4.2.4 Multiple Packaging
  • 15.4.3 Impact on Environment
  • 15.4.3.1 Pollution
  • 15.4.3.2 Resource Consumption
  • 15.4.3.3 Energy Consumption
  • 15.4.3.4 Contamination
  • 15.5 Conclusion
  • Abbreviations
  • References
  • 16 Package Types for Different Dosage Forms
  • 16.1 Introduction
  • 16.2 Requirements of Packaging: Characteristics of Ideal Packaging Material
  • 16.3 Type of Packaging
  • 16.3.1 Primary Packaging
  • 16.3.2 Secondary Packaging
  • 16.3.3 Tertiary Packaging
  • 16.4 Packaging Technology
  • 16.4.1 Aseptic Filling and Sealing Equipment
  • 16.4.2 Bottle Filling and Capping Equipment
  • 16.4.3 Blister Packaging Technology
  • 16.4.4 Sachet Packaging Technology
  • 16.5 Packaging Materials
  • 16.5.1 Selection of Packaging Material
  • 16.5.2 Types of Packaging Material
  • 16.5.2.1 Glass Containers
  • 16.5.2.2 Metal
  • 16.5.2.3 Plastic
  • 16.5.2.4 Rubber
  • 16.5.2.5 Paper/Cardboard
  • 16.5.2.6 Mixed Material Packaging
  • 16.6 Influence of Packaging Compounds on Dosage Form Stability
  • 16.7 Pharmaceutical Packages
  • 16.7.1 Well-Closed Container
  • 16.7.2 Airtight Container
  • 16.7.3 Hermetically Sealed Container
  • 16.7.4 Light Resistant Container
  • 16.7.5 Single-Dose Container
  • 16.7.6 Multidose Container
  • 16.7.7 Aerosol Container
  • 16.7.8 Polyethylene Bottles
  • 16.7.9 Dropping Nozzles
  • 16.7.10 Collapsible Tubes
  • 16.7.11 Ampoules
  • 16.8 Tamper-Resistant Packaging
  • 16.8.1 Blister Package
  • 16.8.2 Strip Package
  • 16.8.3 Shrink Seals and Bands
  • 16.8.4 Foils, Paper, or Plastic Pouches
  • 16.8.5 Bottle Seals
  • 16.8.6 Tape Seals
  • 16.8.7 Breakable Caps
  • 16.9 Closure and Closure Liners
  • 16.9.1 Roll-On Closure
  • 16.9.2 Lug Cap
  • 16.9.3 Threaded Screw Cap
  • 16.9.4 Pilfer-Proof Closure
  • 16.10 Evaluation of Packaging Materials
  • 16.10.1 Test for Hydrolytic Resistance
  • 16.10.1.1 Crushed Glass Test
  • 16.10.1.2 Whole Container Test
  • 16.10.2 Metal Containers for Eye Ointments
  • 16.10.3 Plastic Containers
  • 16.10.3.1 Leakage Test
  • 16.10.3.2 Collapsibility Test
  • 16.10.3.3 Transparency Test
  • 16.10.3.4 Water Vapor Permeability Test
  • 16.10.4 Other Tests
  • 16.10.5 Test Standards
  • 16.11 Preformulation Screening of Package Components, Regulatory Perspectives
  • 16.12 Coding in Pharmaceutical Packaging
  • 16.13 Current trends in Pharmaceutical Packaging
  • 16.13.1 Blow-Fill-Seal Technology
  • 16.13.2 Prefilled Syringes
  • 16.13.3 Safety Ampoule Breaker
  • 16.13.4 Prefilled Vials
  • 16.13.5 Eco-friendly Packaging
  • 16.13.6 Ecoslide-RX
  • 16.14 Innovation in Packaging Material
  • 16.14.1 Tamper-Evident Stickers
  • 16.14.2 Holographic Materials
  • 16.14.3 Radiofrequency Identification (RFID)
  • 16.14.4 Child Resistance Packaging
  • 16.14.5 Color Shifting Security Films and Inks
  • 16.15 Speediness in Packaging Innovations Results in Reduction of Cost and Time
  • 16.16 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 17 Food and Drug Laws Affecting Pharmaceutical Product Design, Development, and Commercial Manufacturing
  • 17.1 Introduction: Background
  • 17.2 Function of Regulatory Agencies
  • 17.2.1 Chemistry, Manufacturing, and Control (CMC)
  • 17.2.2 Policy and Regulatory Intelligence Team
  • 17.2.3 Advertising Team
  • 17.2.4 Regulatory Submissions Team
  • 17.2.5 Product Labeling Team
  • 17.3 Global Regulatory Bodies: Similarity and Differences
  • 17.3.1 Analysis of Pharmerging (Emerging Countries of Pharmaceutical Industry) Countries
  • 17.4 Historical Evolution of Regulation for Development of Pharmaceutical Product
  • 17.5 Process Flow of Product Design, Development, and Commercial Manufacturing
  • 17.5.1 Drug Discovery
  • 17.5.2 Nonclinical Development
  • 17.5.3 Clinical Development
  • 17.5.4 Phases of Clinical Trials
  • 17.6 Approval Process
  • 17.6.1 Investigational New Drug Application
  • 17.6.2 New Drug Application
  • 17.7 Generic Drug Development
  • 17.8 Regular Commercial Manufacturing
  • 17.9 Regulatory Obligation and Guidance
  • 17.9.1 Different Health Agency Recommendation to Different Health Authorities
  • 17.9.2 Obligations in Clinical Trial From USFDA Prospective
  • 17.9.3 Obligations to Marketing Authorization as per EMEA and Other Health Authorities
  • 17.10 Time and Economical Prospective of Drug Development
  • 17.11 Risk Versus Benefit Aspect for Industry
  • 17.12 Faith of Patient and Doctors
  • 17.12.1 Investment Benefits Aspects for Industry
  • 17.12.1.1 Set Product Line and Future Directions
  • 17.12.1.2 Enhance the Quality of a Product
  • 17.12.1.3 Healthy Competition
  • 17.13 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • Further Reading
  • 18 Guiding Principles for Human and Animal Research During Pharmaceutical Product Development
  • 18.1 Introduction to Pharmaceutical Product Development (PPD)
  • 18.2 Type of Evaluations Required During PPD
  • 18.2.1 In Vitro Studies
  • 18.2.2 In Vivo Studies
  • 18.3 Animal Requirements for Developing a Pharmaceutical Product
  • 18.4 Animal Procurement and Transportation
  • 18.5 Animal Models in Biomedical Research
  • 18.6 Factors Influencing the Selection of Animals in an Experiment
  • 18.7 Adaptation and Acclimatization of Animals
  • 18.8 Animal Housing and Bedding
  • 18.9 Commonly Used Laboratory Animals
  • 18.9.1 Rats
  • 18.9.1.1 Wistar Rats
  • 18.9.1.2 Long Evans Rats
  • 18.9.1.3 Sprague Dawley Rats
  • 18.9.1.4 Spontaneously Hypertensive Rats
  • 18.9.1.5 Wistar Kyoto Rats
  • 18.9.2 Mice
  • 18.9.2.1 BALB/c Mouse
  • 18.9.2.2 C57BL/6 Mouse
  • 18.9.2.3 Knockout Mouse
  • 18.9.3 Dog
  • 18.9.4 Cats
  • 18.9.5 Guinea Pigs
  • 18.10 Ethics in Animal Research: A Brief Overview
  • 18.11 Types of Design in Animal Research
  • 18.11.1 Principle of 3R (Reduction, Refinement, Replacement)
  • 18.11.2 Important Steps in Experimental Designs
  • 18.12 Critical Factors to be Considered While Undertaking Research on Animals
  • 18.12.1 Quarantine, Separation, as well as Stabilization
  • 18.12.2 Atmospheric Conditions
  • 18.12.3 Food Supply
  • 18.12.4 Precaution During Anesthetizing an Animal
  • 18.12.4.1 Local Anesthetics
  • 18.12.4.2 General Anaesthetics
  • 18.12.4.3 Sedatives and Analgesics
  • 18.12.5 Animal Handling
  • 18.12.6 Caging and Housing Facility to the Animals
  • 18.12.7 Record Keeping
  • 18.12.8 Checklist of an Animal Study Protocol
  • 18.13 Authorities for Approval of Animal Study Protocol: International Perspective
  • 18.13.1 Europe
  • 18.13.2 Japan
  • 18.13.3 United States
  • 18.13.4 Canada
  • 18.13.5 Australia
  • 18.13.6 New Zealand
  • 18.13.7 India
  • 18.14 Role of Power Analysis in Animal Research
  • 18.14.1 Signal
  • 18.14.2 Noise
  • 18.14.3 Signal-to-Noise Ratio
  • 18.14.4 The Other Variables
  • 18.14.4.1 Alternative Hypothesis
  • 18.14.4.2 The Significance Level
  • 18.14.4.3 The Power
  • 18.14.4.4 The Sample Size
  • 18.15 Design Considerations for the Studies in Human
  • 18.15.1 Difference Between Research on Animals and Research on Humans
  • 18.15.2 Stages of Clinical Trial
  • 18.15.2.1 Phase I Study
  • 18.15.2.2 Phase II Study
  • 18.15.2.3 Phase III Study
  • 18.15.2.4 Phase IV Study
  • 18.15.3 Guideline for Volunteers Selection
  • 18.15.4 Dose Selection
  • 18.15.5 Dosage Form and Route of Administration
  • 18.15.6 Host Susceptibility and Response
  • 18.15.7 History of the Disease or Disease Condition
  • 18.15.7.1 Time of Onset
  • 18.15.7.2 Time Course of Progression
  • 18.15.7.3 Manifestations
  • 18.15.8 Cautions During Human Clinical Trials
  • 18.15.9 Patient Consent and Confidentiality
  • 18.16 Research on Animals and Humans: In Vaccines Development
  • 18.17 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 19 Applications of Computers in Pharmaceutical Product Formulation
  • 19.1 Introduction
  • 19.2 Basic Concepts and Methodology of Expert Systems
  • 19.2.1 Applications of Expert Systems in Pharmaceutical Formulations
  • 19.2.1.1 Tablet Formulations
  • 19.2.1.1.1 The Cadila System
  • 19.2.1.1.2 The Zeneca System
  • 19.2.1.1.3 The Expert-Tab System
  • 19.2.1.1.4 The SeDeM Expert System
  • 19.2.1.2 Capsule Formulations
  • 19.2.1.2.1 The Sanofi System
  • 19.2.1.2.2 The Capsugel System
  • 19.2.1.3 Other Applications
  • 19.2.2 Advantages and Pitfalls of Expert Systems
  • 19.3 Neural Computation in Pharmaceutical Product Formulation
  • 19.3.1 Basic Concepts and Methodology of Neural Computation
  • 19.3.1.1 Composition and Architecture of ANN
  • 19.3.1.2 Training of ANN
  • 19.3.1.3 Uses of ANN
  • 19.3.2 Applications of Neural Computation in Formulation
  • 19.3.2.1 Solid Dosage Formulation
  • 19.3.2.2 Liquid Dosage Formulation
  • 19.3.2.3 Other Formulations
  • 19.3.3 Advantages and Pitfalls of Neural Computation
  • 19.4 Computer Simulation in Pharmaceutical Formulations
  • 19.4.1 Applications of Computer Simulation in Pharmaceutical Formulations
  • 19.4.2 Advantages and Pitfalls of Computer-Aided Simulation
  • 19.5 Overview of Computers Applications in the Drug Discovery and Development Process
  • 19.5.1 Lead Compound Generation
  • 19.5.1.1 Structure-Based Drug Design
  • 19.5.1.1.1 Molecular Docking Studies
  • 19.5.1.1.2 Molecular Dynamics (MD) Simulation Studies
  • 19.5.1.2 Ligand-Based Drug Design
  • 19.5.2 Prediction (In Silico) of Pharmacokinetic Properties of Compounds
  • 19.6 Summary
  • Abbreviations
  • References
  • Further Reading
  • 20 Patents and Other Intellectual Property Rights in Drug Delivery
  • 20.1 Introduction
  • 20.2 Intellectual Property Rights (IPRs)
  • 20.2.1 Types of IPRs
  • 20.2.2 Relevance of IPRs to the Pharmaceutical Sector
  • 20.3 Patents: Glimpse on Methodology
  • 20.3.1 Conditions for Patentability
  • 20.3.1.1 Novelty
  • 20.3.1.2 Nonobviousness
  • 20.3.1.3 Industrial Application/Utility
  • 20.3.2 Patent Rights and Infringement
  • 20.3.3 Nonpatentable Inventions
  • 20.3.4 Patent Licensing
  • 20.3.5 Compulsory Licensing
  • 20.3.6 Patent Linkage and Data Exclusivity
  • 20.3.7 Strategies of Obtaining Patent and Other IPRs
  • 20.3.8 Patent Law in India and Other Major Pharmaceutical Markets
  • 20.4 Patents in Drug Delivery: A Survey
  • 20.5 Trademarks: General Considerations
  • 20.5.1 Process for Registration of Trademark
  • 20.5.2 Importance of Trademarks for Pharmaceutical Products
  • 20.5.2.1 Trademarks Reduce Chances of Medication Errors Among Health Professionals
  • 20.5.2.2 Trademarks Enable Consumers to Select the Right Medications
  • 20.5.2.3 Trademarks Enable Manufacturers for Market Analysis of Efficacy and Safety of Their Products
  • 20.5.2.4 Trademark Identification Facilitates in Customs Enforcement to Stop Trafficking of Pharmaceuticals
  • 20.6 Copyrights: An Overview
  • 20.7 Recent Changes in IPR Laws in India Impacting Pharmaceutical Industry
  • 20.8 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • Further Reading
  • 21 Computer-Aided Prediction of Pharmacokinetic (ADMET) Properties
  • 21.1 Introduction
  • 21.2 Overview of the Development of ADMET Prediction Models
  • 21.2.1 Descriptors
  • 21.2.2 Datasets
  • 21.2.3 Statistical Methods
  • 21.2.4 Model Validation
  • 21.3 In Silico Prediction of Physicochemical and Pharmacokinetic Properties
  • 21.3.1 In Silico Prediction of Physicochemical Properties
  • 21.3.1.1 Lipophilicity
  • 21.3.1.2 Hydrogen Bonding
  • 21.3.1.3 Solubility
  • 21.3.1.4 Permeability
  • 21.3.2 In Silico Prediction of Drug Absorption
  • 21.3.3 In Silico Prediction of Intestinal Permeation
  • 21.3.4 In Silico Prediction of Drug Distribution
  • 21.3.4.1 In Silico Prediction of PPB
  • 21.3.5 In Silico Prediction of Drug Metabolism
  • 21.3.6 In Silico Prediction of Drug Excretion
  • 21.3.7 In Silico Prediction of Toxicity Profile
  • 21.3.8 In Silico Prediction of Biological Activity Spectra
  • 21.3.9 In Silico Prediction of Active Transport of Drug
  • 21.3.9.1 P-glycoprotein (P-gp)
  • 21.3.9.2 Breast Cancer Resistance Protein (BCRP)
  • 21.3.9.3 Nucleoside Transporters
  • 21.3.9.4 Human Peptide Transporter (hPEPT1)
  • 21.3.9.5 Human Apical Sodium-Dependent Bile Acid Transporter (hASBT)
  • 21.3.9.6 Organic Cation Transporters (OCTs)
  • 21.3.9.7 Organic Anion Transporting Polypeptides (OATPs)
  • 21.3.9.8 BBB-Choline Transporter
  • 21.4 Commercial Sources for ADMET Prediction: Light on Recent Tools
  • 21.5 Challenges and Future Perspectives of In Silico ADMET Prediction
  • 21.6 Conclusions
  • Abbreviations
  • References
  • Further Reading
  • 22 Ethics and Legal Protection of Uses of Computer Applications in Pharmaceutical Research
  • 22.1 Computers in Pharmaceutical Research: Legal Perspective
  • 22.2 Philosophy of Ethical Use of Computer Applications in Pharmaceutical Research
  • 22.3 Codes of Conduct Pertinent to the Use of Computer Applications in Pharmaceutical Research
  • 22.4 Intellectual Property Rights Relevant to Computer Applications in Pharmaceutical Research
  • 22.5 Patents Applicable to Computer Application
  • 22.5.1 Patents on Algorithms of Computer Applications
  • 22.5.2 Patents on Human Interfaces
  • 22.5.3 Patents on Machine-Machine Interfaces
  • 22.5.4 Patents on Data Structures
  • 22.6 Ethical Issues: Privacy, Liability, Ownership, and Power
  • 22.6.1 Privacy
  • 22.6.2 Liability
  • 22.6.3 Ownership
  • 22.6.4 Power
  • 22.7 Copyrights Applicable to Computer Applications
  • 22.8 Protection of Databases
  • 22.9 Conclusion
  • Abbreviations
  • References
  • Further Reading
  • Index
  • Back Cover

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