Dosage Form Design Considerations

Volume I
 
 
Elsevier (Verlag)
  • 1. Auflage
  • |
  • erschienen am 28. Juli 2018
  • |
  • 820 Seiten
 
E-Book | ePUB mit Adobe-DRM | Systemvoraussetzungen
E-Book | PDF mit Adobe-DRM | Systemvoraussetzungen
978-0-12-814424-4 (ISBN)
 

Dosage Form Design Parameters, Volume I, 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 Considerations
  • Copyright Page
  • Dedication
  • Contents
  • List of Contributors
  • About the Editor
  • 1 Preformulation in Drug Research and Pharmaceutical Product Development
  • 1.1 Introduction
  • 1.1.1 An Overview of Formulation Life Cycle and Management
  • 1.1.2 Need of Preformulation: First Stage of Formulation Development
  • 1.1.3 Major Hurdles Impeding Successful Product Development
  • 1.1.4 Role of Preformulation During Product Development
  • 1.2 Parameters of preformulation studies
  • 1.2.1 Solubility
  • 1.2.2 The Permeability of the Drug
  • 1.2.3 Bulk Characterization: Physical, Analytical, and Physicochemical
  • 1.2.4 Inherent Properties: pH, pKa, Log P, Log D, and Intrinsic Dissolution
  • 1.2.5 Stability: The Solution, Solid State, & ICH Photostability
  • 1.2.6 Drug-Excipient Compatibility
  • 1.2.7 Particle Size and Distribution
  • 1.2.8 Thermal Properties
  • 1.2.9 Hygroscopicity
  • 1.2.10 Bulk Properties
  • 1.2.11 Mechanical Properties and Compatibility
  • 1.2.12 Crystallinity and Polymorphism
  • 1.3 Role of preformulation in drug discovery
  • 1.3.1 Material Properties in Lead Selection, High Throughput Preformulation Studies
  • 1.3.2 "Drugability" of New Chemical Entities
  • 1.3.3 Tools to Assist in Lead Selection
  • 1.4 Role of preformulation in drug development
  • 1.4.1 Identification of Challenges During Formulation Development: Pre-Assumptions
  • 1.4.2 The Dosage Form Specific Studies
  • 1.5 Preformulation studies of proteins and peptides
  • 1.6 Preformulation in vaccine development: Critical views
  • 1.7 Preformulation studies of packaging components
  • 1.8 Preformulation in 21st century: technological advancements
  • 1.8.1 Computerization and Aid of Software in the Preformulation Studies
  • 1.8.2 Artificial Neural Network Tool Used in the Factorial Design: An Optimization Approach
  • 1.9 Case studies on preformulation of dosage forms
  • 1.10 Pharmacokinetics and preformulation: Point to note
  • 1.11 Rules and regulations in preformulation studies: Role of regulatory bodies
  • 1.12 Future remarks and conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 2 Physicochemical Aspects to Be Considered in Pharmaceutical Product Development
  • 2.1 Introduction
  • 2.2 Physical Characteristics of Solid Substances Used in Pharmaceutical Product Development
  • 2.2.1 Crystalline Solid-State Substances
  • 2.2.1.1 Polymorphism
  • 2.2.1.2 Hydrates
  • 2.2.1.3 Solvates
  • 2.2.1.4 Cocrystals
  • 2.2.2 Amorphous Solids
  • 2.2.3 Particle Size
  • 2.2.4 Wettability
  • 2.2.5 Hygroscopicity
  • 2.3 Chemical Characteristics to be Considered in Pharmaceutical Product Development
  • 2.3.1 Degradation Reactions of Drugs
  • 2.3.1.1 Hydrolysis
  • 2.3.1.2 Dehydration
  • 2.3.1.3 Oxidation
  • 2.3.1.4 Photochemical Degradation
  • 2.3.1.5 Isomerization
  • 2.3.1.6 Polymerization
  • 2.3.1.7 Other Reactions
  • 2.4 Solubility Aspects in Pharmaceutical Products Development
  • 2.4.1 Aqueous Solubility
  • 2.4.1.1 Effect of pH
  • 2.4.1.2 Cosolvent Effect
  • 2.4.1.3 Solubilizing Agents
  • 2.4.1.4 Particle Size Reduction
  • 2.4.1.5 Molecular Modifications
  • 2.5 Conclusion
  • Acknowledgement
  • Abbreviations
  • References
  • Further Reading
  • 3 Role of Physicochemical Parameters on Drug Absorption and Their Implications in Pharmaceutical Product Development
  • 3.1 Introduction
  • 3.2 Drug Absorption Process: Basic Ideology and Illustrations
  • 3.2.1 Passive Diffusion
  • 3.2.2 Facilitated Passive Diffusion
  • 3.2.3 Active Transport
  • 3.2.3.1 Primary Active Transport
  • 3.2.3.2 Secondary Active Transport
  • 3.2.4 Endocytosis
  • 3.2.4.1 Pinocytosis (Cell Drinking or Uptake of Fluid Solute)
  • 3.2.4.2 Phagocytosis (Cell Eating or Uptake of Solid Stuff Through Adsorption)
  • 3.3 Barriers in Drug Absorption: Obstacle in Product Development
  • 3.3.1 Barriers of Gastro-Intestinal Tract
  • 3.3.1.1 Barriers of Mouth
  • 3.3.1.2 Barriers of Stomach
  • 3.3.1.3 Barriers of Intestine
  • 3.3.1.4 Barriers of Liver
  • 3.3.1.5 Barriers of Kidneys
  • 3.3.2 Bloodstream Barriers
  • 3.3.3 Blood Tissue Barrier
  • 3.3.4 Blood-Brain Barrier (BBB)
  • 3.4 Physicochemical Parameters and Their Effect on Drug Absorption
  • 3.4.1 Chemical Nature of Drug
  • 3.4.1.1 Effect of Solubility
  • 3.4.1.1.1 Estimation of Solubility
  • 3.4.1.1.2 Influence of Solubility on Drug Absorption
  • 3.4.1.1.3 Modification of solubility
  • 3.4.1.2 Effect of Permeability
  • 3.4.1.2.1 Permeability Versus Fraction Absorbed
  • 3.4.1.2.2 Solubility-Permeability Interplay From the Binding System
  • 3.4.1.2.3 Solubility-Permeability Interplay From the Nonbinding System
  • 3.4.1.3 Effect of pH
  • 3.4.1.3.1 pH-Partition Theory
  • 3.4.1.3.2 pH of Gastrointestinal Tract (GIT) & Plasma Fluid
  • 3.4.1.3.3 Calculation of Buffering Capacity
  • 3.4.1.4 Concept and Effect of pKa and Partition Coefficient
  • 3.4.1.4.1 pH-pKa Relationship With Proportion Unionized
  • 3.4.1.4.2 Effect of pKa on Drug Distribution Between Stomach and Blood
  • 3.4.1.4.3 Measurement of pKa
  • 3.4.1.4.4 Measurement of logP
  • 3.4.1.4.5 Apparent Versus True Partition Coefficient (log P0 Versus log P)
  • 3.4.2 Effect of Particles Size & Effective Surface Area
  • 3.4.3 Effect of Dissolution Rate
  • 3.4.3.1 Diffusion Gradient or Concentration Gradient
  • 3.4.3.2 Noyes-Whitney Equation
  • 3.4.3.3 Effect of Salt Form on Dissolution Rate
  • 3.4.3.4 Sink Condition
  • 3.4.3.5 Factors Affecting Drug Dissolution
  • 3.4.4 Effect of Drug Form
  • 3.4.4.1 Prodrugs and Its Implications
  • 3.4.4.2 Complex Form
  • 3.4.4.3 Clathrate Forms
  • 3.4.5 Solvates & Hydrates
  • 3.4.6 Ionization State
  • 3.5 Drug Absorption Through GIT: Role of Saturation Solubility
  • 3.5.1 Polymorphism
  • 3.5.1.1 Methods of Polymorph Preparation
  • 3.5.1.2 Role of Polymorphism in Drug Absorption
  • 3.5.1.3 Amorphism
  • 3.5.2 Surfactant Based Solubilization
  • 3.5.3 Complexation
  • 3.5.3.1 Pi (p) Donor or Pi (p) Acceptor Complexes
  • 3.5.3.2 Cyclodextrin
  • 3.6 Relationship Between Structure of Drug and Their Physicochemical Properties/Biological Properties
  • 3.7 Conclusions
  • Abbreviations
  • References
  • Further Reading
  • 4 Physiologic Factors Related to Drug Absorption
  • 4.1 Introduction
  • 4.1.1 Events Involved in Drug Absorption
  • 4.1.1.1 Physiology of Membrane
  • 4.1.2 Pathways of Drug Absorption
  • 4.1.2.1 Passive Diffusion
  • 4.1.2.1.1 Passive Transport: Simple Diffusion
  • 4.1.2.1.2 Passive Transport: Facilitated Diffusion
  • 4.1.2.2 Active Diffusion
  • 4.1.2.2.1 Transport Against a Concentration Gradient
  • 4.1.2.3 Facilitated Drug Absorption
  • 4.1.2.3.1 Endocytosis
  • Classification of Endocytosis
  • Pinocytosis (Cell Drinking)
  • Phagocytosis (Cell Eating)
  • Receptor-Mediated Endocytosis or Clathrin-Mediated Endocytosis
  • 4.2 Barriers to Drug Absorption
  • 4.2.1 Mucus Thickness
  • 4.2.2 Mucus Clearance
  • 4.2.3 Unstirred Water Layer (The Steric Barrier)
  • 4.2.4 Peristalsis (The Dynamic Barrier)
  • 4.2.5 Nonmucosal Barrier to Drug Absorption
  • 4.2.5.1 Skin as Barrier
  • 4.2.5.2 Nail as Barrier
  • 4.2.6 Drug Transporters as Determinants for Drug Absorption
  • 4.2.6.1 ATP-Binding Cassette (ABC) Transporters
  • 4.2.6.1.1 ATP-Binding Cassette (ABC) Transporters Such as P-Glycoprotein (p-gp)
  • 4.2.6.1.2 ATP-Binding Cassette (ABC) Transporters Such as Multidrug Resistance-Associated Proteins (MRPs)
  • 4.2.6.1.3 ATP-Binding Cassette (ABC) Transporters Such as Breast Cancer Resistance Protein (BCRP)
  • 4.2.7 Metabolism as Barrier to Drug Absorption
  • 4.2.7.1 Gut Luminal Enzymes
  • 4.2.7.2 Gut Wall Metabolism by Cytochrome P450
  • 4.2.7.3 Metabolism in Skin
  • 4.2.7.4 Microbial Metabolism
  • 4.2.8 Lymphatic Absorption
  • 4.2.9 Indirect Factors Affecting Physiological Factors of Drug Absorption
  • 4.2.9.1 Food Habit
  • 4.2.9.2 Age and Gender
  • 4.2.9.3 Diseased Conditions
  • 4.2.9.4 Gastric Emptying and Motility
  • 4.2.9.5 Gastrointestinal pH
  • 4.2.9.6 Blood Flow Through GIT
  • 4.2.9.7 Gastrointestinal Contents (Type and the Amount of Food Material)
  • 4.3 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 5 Physicochemical, Pharmaceutical, and Biological Considerations in GIT Absorption of Drugs
  • 5.1 Introduction
  • 5.2 Mechanism of Gastrointestinal Absorption of Drugs
  • 5.3 Barriers in GI Absorption of Drugs: An Overview
  • 5.4 Various Physicochemical Factors Affecting Gastrointestinal Absorption of Drugs
  • 5.4.1 Chemical Nature
  • 5.4.2 Drug Solubility and Dissolution Rate
  • 5.4.3 Particles Size and Effective Surface Area
  • 5.4.4 Polymorphism and Amorphism
  • 5.4.5 Solvates and Hydrates
  • 5.4.6 Salt Form of Drug
  • 5.4.7 Ionization State
  • 5.4.8 Drug pKa, Lipophilicity, and GI pH
  • 5.4.9 pH Partition Hypothesis
  • 5.4.10 Drug Stability
  • 5.5 Pharmaceutical Factors
  • 5.5.1 Disintegration Time
  • 5.5.2 Dissolution Rate
  • 5.5.3 Manufacturing Variables
  • 5.5.3.1 Method of Granulation
  • 5.5.3.2 Compression Force
  • 5.5.4 Nature and Type of Dosage Form
  • 5.5.5 Pharmaceutical Ingredients
  • 5.5.6 Product Age and Storage Conditions
  • 5.6 Biological Factors
  • 5.6.1 Membrane Physiology
  • 5.6.1.1 Nature of Cell Membrane
  • 5.6.1.2 Transport Processes
  • 5.6.2 Gastrointestinal Physiology
  • 5.6.2.1 Gastric Emptying Time
  • 5.6.2.2 Gastrointestinal pH
  • 5.6.2.3 Surface Area of GIT
  • 5.6.2.4 Gastrointestinal Motility and Intestinal Transit Time
  • 5.6.2.5 Gastrointestinal Contents
  • 5.6.2.6 Effect of Food
  • 5.6.2.7 Effect of Fluid
  • 5.6.2.8 Effect of Other Normal GI Contents
  • 5.6.2.9 Drug Stability in GIT
  • 5.6.2.10 Effect of Presystemic Metabolism
  • 5.6.2.10.1 Luminal Enzymes
  • 5.6.2.10.2 Gut Wall Enzymes
  • 5.6.2.10.3 Bacterial Enzymes
  • 5.6.2.10.4 Hepatic Enzymes
  • 5.6.3 Age
  • 5.6.4 Gender
  • 5.6.5 Disease state
  • 5.6.6 Presence of other drugs
  • 5.7 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • 6 Influence of Drug Properties and Routes of Drug Administration on the Design of Controlled Release System
  • 6.1 Introduction
  • 6.1.1 Objective of Sustained and Controlled Release Formulations
  • 6.1.2 Advantages of Sustained and Controlled Release Dosage Forms
  • 6.1.3 Limitations of Sustained and Controlled Release Dosage Form
  • 6.1.4 Current Market Share of Controlled Release Pharmaceutical Formulations
  • 6.2 Rationale for the Design of Controlled Release System
  • 6.3 Factors Influencing the Design of Controlled Release System
  • 6.4 Physiochemical Properties of a Drug Influencing Design of Controlled Release System
  • 6.4.1 Molecular Weight and Diffusivity
  • 6.4.2 Aqueous Solubility
  • 6.4.3 pH and pKa
  • 6.4.4 Partition Coefficient
  • 6.4.5 Permeability
  • 6.4.6 Mechanism and Site of Absorption
  • 6.4.7 Drug Stability
  • 6.4.8 Ionization
  • 6.5 Pharmacokinetic Factors Influencing the Design of Controlled Release System
  • 6.5.1 Absorption
  • 6.5.2 Distribution
  • 6.5.3 Metabolism
  • 6.5.4 Elimination Half-Life
  • 6.5.5 Duration of Action
  • 6.5.6 Drug-Protein Binding
  • 6.5.7 First-Pass Metabolism
  • 6.6 Pharmacodynamic Factors Influencing the Design of Controlled Release System
  • 6.6.1 Drug Dose
  • 6.6.2 Frequency of Dosing
  • 6.6.3 Margin of Safety
  • 6.6.4 Role of Disease State
  • 6.6.5 Side Effects
  • 6.6.6 Disease Condition and the Patient Condition
  • 6.7 Patient Compliance
  • 6.8 Controlled Release From Different Formulations: Importance of Route and Effect of Varying Properties
  • 6.8.1 Oral Controlled Release Drug Delivery Systems
  • 6.8.2 Buccal/Sublingual Controlled Release Drug Delivery Systems
  • 6.8.3 Parenteral Controlled Release Drug Delivery Systems
  • 6.8.3.1 Intravenous Controlled Release Drug Delivery Systems
  • 6.8.3.2 Intraarterial Controlled Release Drug Delivery Systems
  • 6.8.3.3 Intramuscular Controlled Release Drug Delivery Systems
  • 6.8.3.4 Subcutaneous Controlled Release Drug Delivery Systems
  • 6.8.4 Transdermal Controlled Release Drug Delivery Systems
  • 6.8.5 Ocular Controlled Release Drug Delivery Systems
  • 6.8.6 Nasal Controlled Release Drug Delivery Systems
  • 6.8.7 Pulmonary Controlled Release Drug Delivery Systems
  • 6.8.8 Rectal Controlled Release Drug Delivery Systems
  • 6.8.9 Vaginal Controlled Release Drug Delivery Systems
  • 6.8.10 Intrauterine Controlled Release Drug Delivery Systems
  • 6.9 Drug Targeting Using Controlled Release System
  • 6.10 Current Developments in Controlled Release Formulations
  • 6.11 Patented Controlled Release Drug Delivery Systems
  • 6.12 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 7 Stability and Degradation Studies for Drug and Drug Product
  • 7.1 Introduction
  • 7.1.1 Significance of Stability Studies
  • 7.1.2 Methods for Stability Study
  • 7.1.2.1 Real-Time Stability Testing
  • 7.1.2.2 Accelerated Stability Testing
  • 7.1.2.3 Retained Sample Stability Testing
  • 7.1.2.4 Cyclic Temperature Stress Testing
  • 7.2 Stability Studies of Drug and Drug Product
  • 7.2.1 Steps Involved and Practical Considerations During Development of Stability-Testing Protocol
  • 7.2.1.1 Steps of Stability Studies
  • 7.2.1.2 Practical Considerations During Development of Stability-Testing Protocol
  • 7.2.1.2.1 Batches
  • 7.2.1.2.2 Containers and closures
  • 7.2.1.2.3 Orientation of storage of containers
  • 7.2.2 Stability Testing Equipment
  • 7.3 Degradation Studies of Drug and Drug Products
  • 7.3.1 Chemical Degradation
  • 7.3.1.1 Hydrolysis
  • 7.3.1.2 Oxidation
  • 7.3.1.3 Drug-Excipient and Drug-Drug Interactions
  • 7.3.2 Physical Stability of Drug Substances
  • 7.3.2.1 Crystallization of Amorphous Drugs
  • 7.3.3 Photodegradation
  • 7.4 Evaluation of Stability Data to Determine Retest Period/Shelf-Life Determination
  • 7.5 Regulatory Aspects and Requirements for a Stability Testing Program
  • 7.5.1 Regulatory Status of Stability Testing Program
  • 7.5.2 Requirements for a Stability Testing Program
  • 7.6 Stability Testing of Biotechnological Product
  • 7.6.1 Stability Tests for Biologic or Biological Products
  • 7.7 Stability Testing of Phytopharmaceuticals
  • 7.7.1 Requirements of Stability Testing of Herbal Products
  • 7.7.2 Protocol: Stability Testing of Phytopharmaceuticals/Herbal Products
  • 7.7.2.1 Selection of Batches
  • 7.7.2.2 Container Closure System
  • 7.7.2.3 Stress Testing
  • 7.7.2.4 Specification
  • 7.7.2.5 Frequency of Stability Testing
  • 7.8 Stability Indicating Assay Method (SIAMs): Current Update
  • 7.8.1 Regulatory Status of Stability-Indicating Assays
  • 7.8.2 Current Updates in Regulation of Stability Indicating Assay
  • 7.8.3 Development of Stability Indicating Assay Method (SIAM)
  • 7.8.3.1 Step 1: Critical Study of the API Structure to Assess the Particular Degradation Pathway
  • 7.8.3.2 Step 2: Collection of Information on Physicochemical Properties of API
  • 7.8.3.3 Step 3: Forced Degradation Studies
  • 7.8.3.4 Step 4: Preliminary Separation Studies on Stressed Sample
  • 7.8.3.5 Step 5: Method Development and Optimization
  • 7.8.3.6 Step 6: Identification and Characterization of Decomposition Products, and Preparation of Standards
  • 7.8.3.7 Step 7: Validation of Stability Indicating Assay Method
  • 7.9 Reduced Stability-Testing Plans
  • 7.9.1 Bracketing and Matrixing Design
  • 7.9.2 Bracketing
  • 7.9.2.1 Factors Related to Design
  • 7.9.2.2 Strength
  • 7.9.2.3 Sizes of Container Closure and Fills
  • 7.9.2.4 Design Instance
  • 7.9.3 Matrixing
  • 7.9.3.1 Design Influences
  • 7.9.3.2 Design Examples
  • 7.10 Conclusion
  • Acknowledgment
  • References
  • Further Reading
  • 8 First-Pass Metabolism Considerations in Pharmaceutical Product Development
  • 8.1 Introduction
  • 8.2 Role of Liver and Small Intestine in First-Pass Metabolism
  • 8.2.1 Physiological and Biochemical Factors Affecting Intestinal Metabolism
  • 8.2.1.1 Mucosal Blood Flow
  • 8.2.1.2 Drug-Metabolizing Enzymes in the Small Intestine
  • 8.2.1.3 Cytochromes P-450
  • 8.2.2 Hepatic and Intestinal Enzyme Induction
  • 8.2.2.1 Cytochromes P-450
  • 8.2.2.2 UDP Glucosyltransferases and Sulfotransferases
  • 8.2.2.3 p-Glycoprotein
  • 8.2.3 Effect of Hepatic Blood Supply on First-Pass Metabolism
  • 8.2.4 Effect of Plasma Protein Binding on First-Pass Metabolism
  • 8.2.5 Effect of Gastrointestinal Motility on First-Pass Metabolism
  • 8.2.6 Effect of Dose-Dependent First-Pass Metabolism
  • 8.2.7 Effect of Genetic Polymorphism on First-Pass Metabolism
  • 8.2.8 Route of Administration and First-Pass Metabolism
  • 8.2.8.1 Oral Administration
  • 8.2.8.2 Transdermal Delivery
  • 8.2.8.3 Ocular Drug Delivery
  • 8.2.8.4 Subcutaneous and Intramuscular Administration
  • 8.2.8.5 Inhalation and Buccal Administration
  • 8.2.8.6 Rectal Administration
  • 8.3 First-Pass Metabolism Considerations in Prodrug Development
  • 8.4 Perspectives on First-Pass Metabolism Considerations in Pharmaceutical Product Development
  • 8.5 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 9 Dissolution Profile Consideration in Pharmaceutical Product Development
  • 9.1 Introduction: Drug Dissolution Concept
  • 9.2 Theories of Dissolution
  • 9.2.1 Diffusion Layer Model
  • 9.2.2 Interfacial Barrier Model
  • 9.2.3 The Danckwerts Model
  • 9.3 Factors Affecting Dissolution Rate (In Vitro)
  • 9.3.1 Drug-Related Factors
  • 9.3.1.1 Solubility
  • 9.3.1.2 Drug Ionization: pH Effects, Salt Form of Drug
  • 9.3.1.3 Particle Size
  • 9.3.1.4 Solid State Characteristics
  • 9.3.1.4.1 Polymorphism
  • 9.3.1.4.2 Crystalline/Amorphous Form
  • 9.3.1.4.3 Solvate Formation
  • 9.3.1.4.4 Complexation
  • 9.3.2 Drug Product Formulation Related Factors
  • 9.3.3 Manufacturing/Processing Related Factors
  • 9.3.3.1 Methods Involve in Manufacturing
  • 9.3.3.2 Compression Force
  • 9.3.3.3 Moisture Content
  • 9.3.3.4 Machine
  • 9.3.4 Dissolution Testing Conditions Related Factors
  • 9.3.4.1 Dissolution Apparatus
  • 9.3.4.1.1 Agitation
  • 9.3.4.1.2 Vibration
  • 9.3.4.1.3 Flow Pattern Nonuniformities
  • 9.3.4.1.4 Eccentricity of Agitating (Stirring) Element
  • 9.3.4.1.5 Sampling Probe Position and Filter
  • 9.3.4.2 Dissolution Test Parameters
  • 9.4 Physiological Factors Affecting In Vivo Drug Dissolution Rate
  • 9.4.1 Composition of GI Fluid
  • 9.4.2 pH
  • 9.4.3 Buffer Capacity
  • 9.4.4 Osmolality
  • 9.4.5 Surface Tension
  • 9.4.6 Viscosity
  • 9.4.7 Temperature
  • 9.4.8 Volume
  • 9.4.9 Hydrodynamics
  • 9.4.10 Gastric-Emptying Rate and Forces
  • 9.4.11 Concomitant Use of Antisecretory Therapy
  • 9.5 Dissolution Testing
  • 9.5.1 Approaches for Dissolution Test Method Design
  • 9.5.2 Design of Dissolution Method
  • 9.5.2.1 Choice of Dissolution Equipment
  • 9.5.2.2 Selection of Agitation Rate
  • 9.5.2.3 Dissolution Medium
  • 9.5.2.4 Analytical Methods Associated With the Dissolutions
  • 9.5.2.5 Automation
  • 9.5.2.6 Data Simulation
  • 9.6 Dissolution Profile: Analysis and Comparison
  • 9.6.1 Dissolution Profile
  • 9.6.2 Analysis of Cumulative Dissolution Profiles
  • 9.7 In vitro-In vivo Correlation (IVIVC)
  • 9.7.1 Definition
  • 9.7.2 Significance and Purpose of IVIVC
  • 9.7.3 Levels of IVIVC Correlation
  • 9.7.3.1 Level A Correlation
  • 9.7.3.2 Level B Correlation: The Statistical Moment Theory
  • 9.7.3.3 Level C Correlation
  • 9.7.3.4 Multiple Level C Correlations
  • 9.7.3.5 Level D Correlation
  • 9.7.4 Applications of IVIVC
  • 9.7.4.1 Application in Drug Delivery System
  • 9.7.4.2 Pharmaceutical Product Development
  • 9.8 Biopharmaceutical Classification System (BCS) and Biopharmaceutical Drug Disposition Classification System (BDDCS)
  • 9.8.1 BCS Classes and Parameters
  • 9.8.2 Biopharmaceutical Drug Disposition Classification System (BDDCS)
  • 9.9 Role of Dissolution Testing in Pharmaceutical Product Development
  • 9.9.1 Pharmaceutical Product Development Phases
  • 9.9.1.1 Drug Product Approval
  • 9.9.2 Determining Drug Developability at Preformulation Stage
  • 9.9.3 Simulation of Food Effects
  • 9.9.4 Determination of the Impact of Concomitant Use of Other Substances With Drug Product
  • 9.9.5 Dissolution as a Key Feature for Biopharmaceutical Approach in QbD
  • 9.9.6 Prediction of In Vivo Dissolution: Biorelevant Dissolution Testing
  • 9.9.6.1 Need of Bio-Relevant Dissolution Testing
  • 9.9.6.2 Development of Relevant Dissolution Test
  • 9.9.6.3 Biorelevant Dissolution Apparatus
  • 9.9.6.3.1 Fed Stomach Model
  • 9.9.6.3.2 Artificial Stomach Duodenal Model
  • 9.9.6.3.3 Dynamic Gastric Model (DGM)
  • 9.9.6.3.4 TNO Gastro-Intestinal Model (TIM)
  • 9.9.6.3.5 Gastric Digestion Model (GDM)
  • 9.9.6.4 Limitations of Biorelevant Dissolution Testing
  • 9.9.7 Biowaiver Application: Role of BCS, IVIVC, and Similarity-Dissimilarity Factor
  • 9.9.7.1 Definition and Purpose of Biowaiver
  • 9.9.7.2 Criteria for Biowaiver Recommended by USFDA BCS Guidance on Biowaivers
  • 9.9.7.2.1 Additional Criteria for Biowaiver Application
  • 9.9.7.2.2 Exceptions
  • 9.9.7.3 Biowaiver Extension Potential
  • 9.9.7.4 Data Required for Requesting Biowaiver
  • 9.9.8 Prognosis of Drug Disposition
  • 9.9.9 Identification of Critical Manufacturing Variables (CMVs)
  • 9.9.10 Surrogate of Bioequivalence Study at Postapproval Changes of Drug Product (SUPAC)
  • 9.9.11 Quality Control Tool
  • 9.9.12 Determination of Product Storage Stability
  • 9.9.13 Investigation of Drug Release Mechanisms
  • 9.10 Dissolution Mechanism: Role of Density Functional Theory (DFT)
  • 9.10.1 Basics of Density Functional Theory
  • 9.10.2 DFT Application to Predict Dissolution Mechanisms
  • 9.11 Dissolution Controlled Drug Delivery Systems
  • 9.11.1 Dissolution of Solid Particles
  • 9.11.2 Dissolution of Coated Systems
  • 9.11.3 Dissolution of Matrix Systems
  • 9.11.4 Examples of Dissolution Controlled Drug Delivery Systems
  • 9.12 Conclusion and Prospects
  • Acknowledgments
  • Abbreviations
  • References
  • 10 Drug Disposition Considerations in Pharmaceutical Product
  • 10.1 Introduction
  • 10.1.1 General Principles of Drug Disposition
  • 10.1.2 Routes of Administration
  • 10.1.2.1 Oral Route
  • 10.1.2.2 Intravenous Route
  • 10.1.2.3 Subcutaneous Route
  • 10.1.2.4 Topical/Local Route of Administration
  • 10.2 Factors Affecting the Interplay of Drug Disposition
  • 10.2.1 Factors Affecting the Absorption
  • 10.2.1.1 Physicochemical Properties of a Drug
  • 10.2.1.2 Physiological Properties Affecting Drug Absorption
  • 10.2.1.3 Pharmaceutical/Dosage Form Related Factors Affecting Absorption
  • 10.2.2 Factors Affecting the Metabolism
  • 10.2.2.1 Species
  • 10.2.2.2 Age
  • 10.2.2.3 Sex
  • 10.2.2.4 Pathological Status/Diseased State
  • 10.2.2.5 Hormonal Control of Drug Metabolism
  • 10.2.2.6 Environmental Factors
  • 10.2.3 Factors Affecting Distribution
  • 10.2.3.1 Cell Membrane Composition
  • 10.2.3.2 Molecular Weight of Drug
  • 10.2.4 Factors Affecting Excretion
  • 10.2.4.1 Enterohepatic Circulation
  • 10.3 Role of ADME in Product Development
  • 10.3.1 Role of Absorption in Product Development
  • 10.3.2 Role of Distribution in Product Development
  • 10.3.3 Role of Metabolism in Product Development
  • 10.3.4 Role of Excretion in Product Development
  • 10.4 Biopharmaceutics Classification System
  • 10.4.1 Different Classes of BCS
  • 10.4.1.1 Class I (High Solubility, High Permeability)
  • 10.4.1.2 Class II (High Permeability, Low Solubility)
  • 10.4.1.3 Class III Drugs (Low Permeability, High Solubility)
  • 10.4.1.4 Class IV (Low Solubility, Low Permeability)
  • 10.4.2 Applications of BCS in Biowaiver of Drugs
  • 10.5 Various Factors Affecting Drug Disposition
  • 10.5.1 Effects of Enzymes
  • 10.5.2 Drug-Drug Interaction
  • 10.5.3 Herb-Drug Interactions
  • 10.5.3.1 Pharmacokinetic Interactions
  • 10.5.3.2 Pharmacodynamic Interactions
  • 10.5.4 Food-Drug Interactions
  • 10.5.5 Polypharmacy
  • 10.5.6 Genetic and Environmental Factors
  • 10.5.7 Drug Dose Frequency
  • 10.6 Transporters in Drug Disposition
  • 10.7 Experimental Models for Drug Disposition Investigations During Product Development
  • 10.7.1 In Vitro Metabolic Models
  • 10.7.1.1 Expressed Enzymes
  • 10.7.1.2 Subcellular Fraction
  • 10.7.2 In Vitro Transporter Models
  • 10.7.2.1 Immortalized Cell Lines
  • 10.7.2.2 Transfected Cell Lines
  • 10.7.2.3 Hepatocytes
  • 10.7.2.4 Membrane Vesicles
  • 10.7.3 In Situ Ex Vivo Models
  • 10.7.3.1 In Situ Models (Perfusion)
  • 10.7.3.2 Ex Vivo Models for Induction and Toxicity Studies
  • 10.8 Effect of Disease State on Drug Disposition
  • 10.8.1 Effect of Cardiovascular Diseases
  • 10.8.2 Effect of Gastrointestinal Diseases
  • 10.8.3 Effect of Liver Diseases
  • 10.8.4 Effect of Kidney Diseases
  • 10.9 Conclusion
  • Acknowledgment
  • References
  • 11 Protein and Tissue Binding: Implication on Pharmacokinetic Parameters
  • 11.1 Introduction
  • 11.2 Binding Kinetics
  • 11.2.1 Graphical Plots Used to Determine Binding Constants
  • 11.3 Overview of Plasma Proteins
  • 11.3.1 Albumin
  • 11.3.2 Alpha-1-Acid Glycoprotein
  • 11.3.3 Lipoproteins
  • 11.4 Tissue Binding
  • 11.5 Plasma and Tissue Protein Binding Implications on Pharmacokinetics Parameters
  • 11.5.1 Bioavailability
  • 11.5.2 Volume of Distribution
  • 11.5.3 Hepatic Clearance
  • 11.5.3.1 Restrictive and Nonrestrictive Clearance
  • 11.5.4 Renal Clearance
  • 11.5.5 Half-Life
  • 11.5.6 Drug Plasma Concentration-Time Profile
  • 11.6 Factors Influencing Protein Binding
  • 11.6.1 Physiologic Factors Influencing Protein Binding
  • 11.6.2 Pathologic Factors Influencing Protein Binding
  • 11.6.3 Drug-Induced Changes in Protein Binding
  • 11.7 Plasma Protein Binding Determination Methods
  • 11.7.1 Equilibrium Dialysis Method
  • 11.7.2 Ultrafiltration Method
  • 11.7.3 Ultracentrifugation Method
  • 11.7.4 Important Considerations When Using In Vitro Methods
  • 11.7.5 In Vivo Methods
  • 11.7.6 In Silico Methods
  • 11.8 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 12 Preformulation Studies of Drug Substances, Protein, and Peptides: Role in Drug Discovery and Pharmaceutical Product Deve...
  • 12.1 Introduction
  • 12.2 Preformulation Studies: Vital Concepts
  • 12.3 Preformulation: Drug Substances
  • 12.3.1 Physical Factors
  • 12.3.1.1 Organoleptic Properties
  • 12.3.1.2 Bulk Characteristics
  • 12.3.1.2.1 Crystalline and Polymorphism
  • 12.3.1.2.2 Hygroscopicity
  • 12.3.1.2.3 Particle Size and Shape
  • 12.3.1.2.4 Densities
  • 12.3.1.2.5 Flow Properties
  • 12.3.1.2.6 Compressibility
  • 12.3.1.3 Solubility Analysis
  • 12.3.1.3.1 Ionization Constant (pKa)
  • 12.3.1.3.2 Partition Coefficient
  • 12.3.1.3.3 Solubilization
  • 12.3.1.3.4 Dissolution
  • 12.3.1.4 Stability Analysis
  • 12.3.1.4.1 Stability Study in Toxicological Formulation
  • 12.3.1.4.2 Solution-State Stability
  • 12.3.1.4.3 Solid-State Stability
  • 12.3.1.4.4 Drug-Excipients Compatibility
  • 12.3.2 Biopharmaceutical Factors
  • 12.4 Preformulation: Proteins and Peptides
  • 12.4.1 Types and Structural Considerations
  • 12.4.1.1 Classification of Therapeutic Proteins
  • 12.4.2 Factors Influencing Preformulation Studies
  • 12.4.2.1 Effect of Molecular Size
  • 12.4.2.2 Factors Influencing Solubility Profile and Partition Coefficient
  • 12.4.2.3 Complexity in Structural Conformation
  • 12.4.2.4 Effect of Electrostatic Charges in Membrane Permeability
  • 12.4.2.5 Biopharmaceutical Aspects
  • 12.5 Role of Preformulation Studies in Drug Discovery and Pharmaceutical Product Development: Drug Substances
  • 12.5.1 Need for Drug Discovery
  • 12.5.2 Stages in Drug Discovery Process
  • 12.5.2.1 Strategic Research
  • 12.5.2.2 Exploratory Research
  • 12.5.2.3 Candidate Drug Selection
  • 12.5.2.4 Exploratory Development
  • 12.5.2.5 Full Development
  • 12.5.3 Preformulation as an Aid in Early Product Development
  • 12.6 Role of Preformulation Studies in Drug Discovery and Pharmaceutical Product Development: Proteins and Peptides
  • 12.6.1 Prodrug Approach
  • 12.6.2 Degradation Pathways Indicating Instability of Proteins and Peptides
  • 12.6.2.1 Physical Stability of Proteins and Peptides
  • 12.6.2.1.1 Physical Degradation Pathways
  • 12.6.2.1.1.1 Formation of Stable Misfolded Species
  • 12.6.2.1.1.2 Aggregation or Precipitation of Misfolded Species
  • 12.6.2.1.1.3 Surface-Induced Structural Changes/Aggregation
  • 12.6.2.2 Chemical Stability of Proteins and Peptides
  • 12.6.2.2.1 Deamidation
  • 12.6.2.2.2 Oxidation
  • 12.6.2.2.3 Reduction
  • 12.6.2.2.4 Hydrolysis
  • 12.6.2.2.5 Racemization
  • 12.6.2.2.6 ß-Elimination
  • 12.6.3 Influence of Preformulation on the Delivery of Protein and Peptides
  • 12.6.3.1 Formulation Design Considerations
  • 12.6.3.2 Delivery Routes for Proteins and Peptides
  • 12.6.3.2.1 Oral Route
  • 12.6.3.2.2 Nasal Route
  • 12.6.3.2.3 Pulmonary Route
  • 12.6.3.2.4 Buccal Route
  • 12.6.3.2.5 Transdermal Route
  • 12.6.3.2.6 Ocular Route
  • 12.6.3.2.7 Rectal Route
  • 12.6.3.2.8 Vaginal Route
  • 12.6.4 Factors Causing Problems in Protein Delivery
  • 12.6.4.1 Biochemical and Biological Factors
  • 12.6.4.2 Selection of Targeting Ligands
  • 12.6.4.3 Uptake of Protein Drugs
  • 12.7 Conclusion
  • Abbreviations
  • References
  • 13 Role of Salt Selection in Drug Discovery and Development
  • 13.1 Introduction
  • 13.1.1 Fundamentals of Salt Preparation
  • 13.1.2 Merits and Demerits of Pharmaceutical Salts
  • 13.1.3 Rationale of the Pharmaceutical Salt Preparation
  • 13.2 Selection of the API and counterions for Pharmaceutical salt Preparations
  • 13.2.1 Salt Selection Strategy
  • 13.2.2 pKa Rule for Salt Formation
  • 13.2.3 Ionic Factors
  • 13.2.4 Biopharmaceutical Factors
  • 13.2.5 Biological Factors
  • 13.2.6 Dosage Form and Routes of Administration
  • 13.2.7 Choice of Organic Solvent
  • 13.2.8 Decision Tree for Salt Selection
  • 13.3 Characterization of the Pharmaceutical Salt
  • 13.3.1 Structure Confirmation
  • 13.3.2 Assessment of the Physicochemical Properties
  • 13.3.3 Physical Properties
  • 13.3.4 Assessment of the Process Impurities
  • 13.3.5 Stability and Preformulation Assessments
  • 13.3.6 Large-Scale Methods
  • 13.3.7 Method Optimization and Large-Scale Production
  • 13.3.7.1 Solvent Selection
  • 13.3.7.2 Control of the Crystallization
  • 13.3.7.3 Filtration and Drying
  • 13.4 Regulatory Requirements
  • 13.4.1 Patenting Prospective
  • 13.4.2 Safety and Efficacy
  • 13.4.2.1 ADME and Bioavailability
  • 13.4.2.2 Some Specific Examples and Case in Hands
  • 13.5 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 14 Drug Complexation: Implications in Drug Solubilization and Oral Bioavailability Enhancement
  • 14.1 Introduction: Complexation in Pharmaceutical Products
  • 14.1.1 Types of Complexation
  • 14.1.1.1 Coordination Complexes
  • 14.1.1.2 Molecular Complexes
  • 14.1.1.3 Metal Ion Coordinate Complexes
  • 14.1.1.4 Inclusion Complexes
  • 14.1.2 Application of Complexation
  • 14.2 Fundamental Methods of Formation of Drug Complexes
  • 14.2.1 Physical Blending Method
  • 14.2.2 Kneading Method
  • 14.2.3 Coprecipitation Technique
  • 14.2.4 Solution/Solvent Evaporation Method
  • 14.2.5 Neutralization Precipitation Method
  • 14.2.6 Milling/Cogrinding Technique
  • 14.2.7 Atomization/Spray Drying Technique
  • 14.2.8 Lyophilization/Freeze Drying Technique
  • 14.2.9 Microwave Irradiation Method
  • 14.2.10 Supercritical Antisolvent Technique
  • 14.2.11 Extrusion
  • 14.3 Characterization of Drug Complexation
  • 14.3.1 Determination of Guest Content
  • 14.3.2 Thermo-Analytical Methods
  • 14.3.3 Infrared Spectroscopy
  • 14.3.4 X-ray Powder Diffraction
  • 14.3.5 Scanning Electron Microscopy
  • 14.3.6 Diffusion NMR Studies
  • 14.4 Factors Influencing Complex Formation
  • 14.4.1 Influence of Temperature on Complex Formation
  • 14.4.2 Influence of Chemical Modification on Complex Formation
  • 14.4.3 Influence of Enzymatic Modification on Complex Formation
  • 14.4.4 Effect of Coacervate on Complex Formation
  • 14.5 Effect of Complexation on Drug Solubility and Bioavailability
  • 14.6 Thermodynamics and Kinetics of Complex Formation
  • 14.7 Protein Complex Formation: Role in Oncology
  • 14.8 Application of Complexation in Drug Delivery
  • 14.8.1 Metal Ion Complex in Cancer
  • 14.8.1.1 Platinum-Based Analogs
  • 14.8.1.2 Platinum(IV) Complexes and Anticancer Activity
  • 14.8.1.3 Ruthenium and Copper Complexes in Cancer Therapy
  • 14.8.1.4 Gold and Silver Complexes in Cancer Therapy
  • 14.8.2 Cyclodextrin in Drug Delivery System
  • 14.8.3 Polyelectrolyte Complexation in Drug Delivery
  • 14.9 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • 15 Solubility and Solubilization Approaches in Pharmaceutical Product Development
  • 15.1 Understanding the Concept of Solubility
  • 15.1.1 Phenomenon of Solubilization
  • 15.1.1.1 Importance of Solubility and Solubilization in Product Development
  • 15.1.1.2 Process of Solubilization
  • 15.1.1.3 Solvent-Solute Interactions
  • 15.1.2 Solubility of Electrolytes, Weak Electrolytes, and Nonelectrolytes
  • 15.1.3 Types of Solubility
  • 15.1.3.1 Based on pH
  • 15.1.3.1.1 Unbuffered Solubility
  • 15.1.3.1.2 Buffered Solubility
  • 15.1.3.1.3 Intrinsic Solubility
  • 15.1.3.2 Based on Experimental Setup
  • 15.1.3.2.1 Kinetic (or Nonthermodynamic) Solubility
  • 15.1.3.2.2 Equilibrium (or Thermodynamic) Solubility
  • 15.1.3.3 Based on Solid Structure
  • 15.1.3.3.1 Crystalline Solubility
  • 15.1.3.3.2 Amorphous solubility
  • 15.1.4 Factors Influencing Drug Solubility
  • 15.1.4.1 Crystal Habit
  • 15.1.4.2 pH
  • 15.1.4.3 Particle Size
  • 15.1.5 Solute-Solvent Interaction
  • 15.2 Relationship Between Solubility and Biopharmaceutical Classification Systems (BCS)
  • 15.3 Approaches to Modulate Drug Solubility
  • 15.3.1 pH Modification
  • 15.3.2 Crystal Structure Manipulation
  • 15.3.2.1 Polymorphs
  • 15.3.2.1.1 Pseudopolymorphs
  • 15.3.2.2 Salt Formation
  • 15.3.2.3 Cocrystal
  • 15.3.3 Prodrug Strategies
  • 15.3.4 Crystal Structure Disruption (Amorphization)
  • 15.3.5 Size Reduction
  • 15.3.5.1 Micronization
  • 15.3.5.2 Nanonization
  • 15.4 Excipient-Based Solubilization
  • 15.4.1 Cosolvency
  • 15.4.1.1 Hydrotopes
  • 15.4.2 Cyclodextrin
  • 15.4.3 Ionic Liquids
  • 15.5 Conclusion
  • Acknowledgments
  • Abbreviations
  • References
  • 16 Rheology and Its Implications on Performance of Liquid Dosage Forms
  • 16.1 Understanding the Basic Concepts of Rheology
  • 16.1.1 Shear Viscosity, Its Dimensions, and Units
  • 16.1.2 Pharmaceutical Systems Based on Rheological Behavior
  • 16.1.2.1 Newtonian Systems
  • 16.1.2.2 Non-Newtonian Systems
  • 16.1.2.2.1 Time-Independent Non-Newtonian Flow
  • 16.1.2.2.2 Time-Dependent Non-Newtonian Flow
  • 16.1.3 Deformation of Liquids and Deformation Forces
  • 16.1.4 Viscoelasticity
  • 16.1.5 Determination of Molar Weight by Viscosity
  • 16.2 Rheology of Pharmaceutical Dosage Forms
  • 16.2.1 Rheology of Suspensions
  • 16.2.2 Rheology of Emulsions
  • 16.2.3 Rheology of Nano-Based Systems
  • 16.2.3.1 Lipid-Based Nanoformulations
  • 16.2.3.2 Surfactant-Based Nanoformulations
  • 16.2.3.3 Polymer-Based Nanoformulations
  • 16.2.3.4 Lipid-Polymer-Based Nanoformulations
  • 16.3 Pharmaceutical Considerations
  • 16.3.1 Influence of Physical Variables
  • 16.3.1.1 Shear Rate
  • 16.3.1.2 Temperature
  • 16.3.1.3 Formulation Components
  • 16.3.1.4 Aeration
  • 16.3.1.5 Light
  • 16.3.1.6 Sterilization
  • 16.3.2 Influence of Chemical Variables
  • 16.3.2.1 pH
  • 16.3.2.2 Polymer-Related Factors
  • 16.3.2.3 Presence of Impurities, Ions, and Electrolytes
  • 16.3.2.4 Addition of Additives such as Sequestering Agents, Buffers, Surfactants, etc
  • 16.3.3 Rheology Modifiers, Thickeners, and Gels
  • 16.4 Rheological Instruments for Fluids and Their Limitations
  • 16.4.1 Measurement of Rheological Parameters
  • 16.5 Rotational-Type Rheometer
  • 16.6 Broad-Gap Concentric Cylinder Viscometer
  • 16.7 Cone and Plate Viscometer
  • 16.8 Parallel-Plate Viscometer
  • 16.9 Tube-Type Rheometers
  • 16.10 Dilation Rheology
  • 16.11 Applications of Rheology
  • 16.11.1 Materials Science
  • 16.11.1.1 Polymer Engineering
  • 16.11.1.2 Biopolymers
  • 16.11.2 In Geophysics
  • 16.11.3 Physiology
  • 16.11.4 Food Rheology
  • 16.11.5 Concrete Rheology
  • 16.11.6 Filled Polymer Rheology
  • 16.11.7 Pharmaceuticals
  • 16.12 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • 17 Micromeritics in Pharmaceutical Product Development
  • 17.1 Introduction
  • 17.2 Particle Size
  • 17.2.1 Effects Particle Size
  • 17.2.1.1 Effect of Particle Size on Dissolution
  • 17.2.1.2 Effect of Particle Size on Manufacturing Processing Parameters
  • 17.2.2 Particle Size Distribution
  • 17.2.2.1 Types of Particle Size Distribution
  • 17.2.2.1.1 Number Weighted Distributions
  • 17.2.2.1.2 Volume Weighted Distributions
  • 17.2.2.1.3 Intensity Weighted Distributions
  • 17.2.2.2 Particle Size Distribution Analysis of Data by Statistics
  • 17.3 Methods to Determine Particle Size Distribution
  • 17.3.1 Microscopy
  • 17.3.1.1 Optical Microscopy
  • 17.3.1.2 Electron Microscopy
  • 17.3.1.2.1 Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM)
  • 17.3.2 Sieving Method
  • 17.3.2.1 Air-Jet Sieving
  • 17.3.2.2 Sedimentation Method
  • 17.3.2.2.1 Andreasen Pipette
  • 17.3.3 Dynamic Light Scattering
  • 17.3.4 Electronic Scanning Zone (Coulter Counter)
  • 17.3.5 Cascade Impactor
  • 17.3.6 Laser Diffraction
  • 17.3.7 Elutriation
  • 17.3.8 Acoustic Spectroscopy
  • 17.4 Significance of Micrometrics in Product Development: Tablet and Capsule
  • 17.4.1 Content Uniformity
  • 17.4.2 Flow Properties
  • 17.4.3 Particle Arrangement and Compaction
  • 17.4.4 Weight Variation
  • 17.4.5 Segregation
  • 17.4.6 Hardness
  • 17.4.7 Compressibility and Compatibility or Tablet Strength
  • 17.5 Powders
  • 17.5.1 Flow Properties
  • 17.5.1.1 Angle of Repose
  • 17.5.1.2 Bulk and Tapped Density
  • 17.6 Suspensions
  • 17.7 Emulsions
  • 17.8 Novel Drug Delivery Systems
  • 17.9 Relation Between Crystallization and Micromeritics of Drug Substances
  • 17.10 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 18 Four Stages of Pharmaceutical Product Development: Preformulation, Prototype Development and Scale-Up, Biological Aspect...
  • 18.1 Introduction
  • 18.2 Preformulation Aspects in Pharmaceutical Product Development
  • 18.2.1 The Sphere of Preformulation Studies
  • 18.2.2 Major Disciplines of Preformulation Studies
  • 18.2.2.1 Bulk Characterization
  • 18.2.2.2 Solubility Analysis
  • 18.2.2.3 Stability Analysis
  • 18.3 Prototype Development
  • 18.3.1 Considerations to Ideate/Conceptualize a Product
  • 18.3.1.1 API Chemistry and Preformulation
  • 18.3.1.2 Biological Considerations (Preclinical and Clinical Activity) w.r.t. Safety and Efficacy
  • 18.3.1.3 Intellectual Property
  • 18.3.2 Experimental Design and Product Optimization
  • 18.3.2.1 Parenteral Dosage Forms
  • 18.3.2.2 Oral Solid Dosage Forms
  • 18.3.2.3 Topical/Dermal/Transdermal Dosage Forms
  • 18.3.2.4 Inhalational Formulations
  • 18.3.2.5 Nasal Solutions/Suspensions
  • 18.3.2.6 Ophthalmic Formulations
  • 18.4 Biological Aspects in Pharmaceutical Product Development
  • 18.4.1 The Preclinical Tenure and Strategies
  • 18.4.1.1 In Vitro Screenings and Importance
  • 18.4.1.2 In Silico Models and Simulation Predictions
  • 18.4.1.3 The Use of Animal Models
  • 18.4.2 The Clinical Cycle Development
  • 18.4.2.1 Safety and Efficacy
  • 18.4.2.2 Different Phases
  • 18.4.2.3 Regulatory Requirements Comparing Different Countries
  • 18.4.3 Emerging Trends
  • 18.4.3.1 Pharmacovigilance
  • 18.4.3.2 Pharmacogenomics and Its Clinical Applications
  • 18.4.3.3 Drug Repositioning and Repurposing
  • 18.4.3.4 Use of Cell Lines and Cultures of Human Origin
  • 18.5 Commercialization Aspects in Pharmaceutical Products Development
  • 18.5.1 Patents, Exclusivity, and Evergreening Strategies
  • 18.5.1.1 Patent Listing With Different World Body
  • 18.5.1.2 Evergreening Strategies
  • 18.5.2 The Product Life Cycle
  • 18.5.2.1 Management of Product Life Cycle
  • 18.5.2.2 Brands and Generics
  • 18.5.2.3 Competitive Advantage
  • 18.5.3 Commercialization Realities
  • 18.5.3.1 Problems and Litigations Around Patents
  • 18.5.3.2 Maintaining a Viable Product and Business
  • 18.5.3.3 Access to Medicine
  • 18.5.3.4 Environmental Challenges
  • 18.5.4 Factors Affecting Commercialization
  • 18.6 Conclusion
  • Abbreviations
  • References
  • Further Reading
  • 19 Scale-Up Studies in Pharmaceutical Products Development
  • 19.1 Introduction
  • 19.2 Solid Dosage Forms
  • 19.2.1 Scale-Up in Dry Blending, Mixing, and Granulation
  • 19.2.2 Common Mixing Guidance
  • 19.2.2.1 Describing Mixing Phenomenon
  • 19.2.2.2 Issues Related to Mixing
  • 19.2.2.3 Process Parameters
  • 19.2.2.4 Scale-Up Approaches
  • 19.2.3 Granulation and Drying
  • 19.2.3.1 Continuous Models
  • 19.2.4 Compaction and Tableting
  • 19.2.4.1 Roller Compactor: Use From Pilot to Scale-Up
  • 19.3 Parenteral Dosage Forms
  • 19.3.1 Mixing and Agitation
  • 19.4 Semisolid Dosage Forms
  • 19.4.1 Material Transfer Rate
  • 19.4.2 Mixing
  • 19.4.3 Heating and Cooling Rates
  • 19.4.4 Viscous and Non-Newtonian Liquids
  • 19.5 Scale-Up of Nanoformulations: Case Studies
  • 19.6 Quality by Design (QbD) for Scale-Up
  • 19.7 Problems Encountered During Scale-Up
  • 19.8 Conclusions
  • Acknowledgments
  • References
  • Further Reading
  • 20 Manipulation of Physiological Processes for Pharmaceutical Product Development
  • 20.1 Introduction
  • 20.2 Various Physiological Factors Affecting Product Development
  • 20.2.1 Route of Administration
  • 20.2.2 Environmental pH
  • 20.2.3 Gastric Emptying
  • 20.2.4 Small and Large Bowel Transit Time
  • 20.2.5 Active Transport and Efflux
  • 20.2.6 Gut Wall Metabolism
  • 20.2.7 First-Pass Excretion
  • 20.2.8 Liver Metabolism
  • 20.2.9 Carrier-Mediated Transport
  • 20.2.10 Enhanced Permeation and Retention (EPR) Effect
  • 20.2.11 Mucosal Layer and Bioadhesion
  • 20.2.11.1 Mucus Membrane
  • 20.2.11.2 Bioadhesion
  • 20.2.12 Blood Supply - Sublingual
  • 20.2.13 Skin Permeation
  • 20.2.14 Macrophage Uptake and Spleen/Lymph Node Targeting
  • 20.2.14.1 Macrophages
  • 20.2.14.2 Spleen/Lymph Node Targeting
  • 20.3 Modeling Procedures for Transport, Metabolism, and Efflux of Drug
  • 20.3.1 Gastrointestinal Drug Absorption Model and Elimination Model
  • 20.3.2 Liver Metabolism Model
  • 20.3.3 Intestinal Metabolism Model
  • 20.3.4 Efflux and Transport Model
  • 20.3.5 Pharmacokinetics Modeling
  • 20.3.6 Numerical Integration of the Model
  • 20.4 Bioavailability: The Ultimate Goal to Achieve
  • 20.5 Role of Computer in Physiological Process Manipulations
  • 20.6 Conclusion
  • Acknowledgments
  • References
  • 21 Impact of Pharmaceutical Product Quality on Clinical Efficacy
  • 21.1 Introduction
  • 21.2 Risk Assessment and Management of Medicine
  • 21.2.1 Product Quality Defects
  • 21.2.1.1 Critical Quality Defects or Class I Recall
  • 21.2.1.2 Major Quality Defects or Class II Recall
  • 21.2.1.3 Minor Quality Defects or Class III Recall
  • 21.2.2 Medication Errors
  • 21.2.2.1 Classification of Medication Errors
  • 21.2.3 Known Side Effects
  • 21.3 Elements of Pharmaceutical Development
  • 21.3.1 Quality Target Product Profile
  • 21.3.2 Critical Quality Attributes
  • 21.3.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs
  • 21.3.4 Design Space and Control Strategy
  • 21.4 Factors Affecting Drug Product Performance
  • 21.4.1 Physicochemical Properties of Drug Substance
  • 21.4.1.1 Chemical Factors
  • 21.4.1.2 Molecular Size and Diffusivity
  • 21.4.1.3 Aqueous Solubility and Dissolution Rate
  • 21.4.1.4 Amorphous and Crystalline Form
  • 21.4.1.5 Particle Size and Effective Surface Area
  • 21.4.1.6 Polymorphism and Amorphism
  • 21.4.1.7 Partition Coefficient
  • 21.4.1.8 pKa-Ionization Constant
  • 21.4.1.9 Solvates/Hydrates
  • 21.4.2 Differences in Manufacturing Processes
  • 21.4.2.1 Initial Planning Stage
  • 21.4.2.2 Product Development Phase
  • 21.4.2.3 Prototype Production/Evaluation
  • 21.4.2.4 Commercial Prototype Production Planning
  • 21.4.2.5 Commercial Prototype Production/Evaluation
  • 21.4.2.6 Commercial Production
  • 21.4.2.7 Inspection, Shipment, and Delivery
  • 21.4.3 Differences in Excipients, Excipient Selection, and Quality Control
  • 21.5 Drug Product Quality and Drug Product Performance
  • 21.6 Scale-Up and Postapproval Changes
  • 21.6.1 FDA Level of Changes
  • 21.6.2 Assessment of the Effects of the Changes
  • 21.6.3 Critical Manufacturing Variables
  • 21.6.4 Bulk Active Postapproval Changes
  • 21.7 Postmarketing Surveillance
  • 21.8 Conclusion
  • Acknowledgment
  • Abbreviations
  • References
  • Further Reading
  • 22 Formulation Additives Used in Pharmaceutical Products: Emphasis on Regulatory Perspectives and GRAS
  • 22.1 Introduction: Background of Additives
  • 22.2 Role of Additives in Pharmaceutical Formulation
  • 22.3 Classification and Sources of Formulation Additives
  • 22.3.1 Additives Based on Their Origin
  • 22.3.2 Classification of Additives Based on Their Functions
  • 22.3.3 Classification of Additives Based on Their Therapeutic Values
  • 22.4 Processing of Additives as per Good Manufacturing Practice
  • 22.4.1 Processing
  • 22.4.2 Production Records
  • 22.4.3 Training of Employees
  • 22.4.4 Control of Raw Materials
  • 22.4.5 Preventing Contamination
  • 22.4.6 Qualification of Manufacturing Equipment
  • 22.4.7 Process Validation
  • 22.4.8 Cleaning Validation
  • 22.4.9 Process Monitoring and Control
  • 22.4.10 Sampling and Testing
  • 22.4.11 Packaging and Labeling
  • 22.4.12 Quality Release
  • 22.4.13 Storage
  • 22.5 Additives Interaction in Pharmaceutical Products
  • 22.6 Formulation Additives for Designing of Solid Dosage Forms
  • 22.6.1 Additives in Spray-Dried Powders
  • 22.6.2 Additives in Controlled Release Solid Dosage Forms
  • 22.7 Formulation Additives for Designing of Semisolid Dosage Forms
  • 22.8 Formulation Additives for Designing of Liquid Dosage Forms
  • 22.9 Current Guidelines for Pharmaceutical Additives (FDA, EU, Japan)
  • 22.10 Regulatory Aspects of Additives Approval
  • 22.10.1 Current Regulatory Status of New Additives
  • 22.10.2 The IPEC Procedure
  • 22.10.3 Additive Master Files and Other Filings
  • 22.10.4 Recommended Strategies to Support Marketing of New Additives in Drug Products
  • 22.10.4.1 Safety Pharmacology
  • 22.10.4.2 Potential Additives Intended for Short-Term Use
  • 22.10.4.3 Potential Additives Intended for Intermediate Use
  • 22.10.4.4 Potential Additives Intended for Long-Term Use
  • 22.10.4.5 Potential Additives for Use in Pulmonary, Injectable, or Topical Products
  • 22.11 Regulatory Perspectives of Formulation Additives
  • 22.11.1 IPEC Perspectives
  • 22.11.2 Regulatory Perspectives: GRAS, IIG
  • 22.11.2.1 Generally Recognized As Safe Food Status
  • 22.12 WHO Perspectives
  • 22.12.1 Documentation
  • 22.13 Study of Different Types of Additives
  • 22.13.1 Antioxidant
  • 22.13.1.1 Synthetic Antioxidants
  • 22.13.1.2 Butylated Hydroxyanisole and Butylated Hydroxytoluene
  • 22.13.1.3 Gallates
  • 22.13.1.4 Natural Antioxidants
  • 22.13.1.5 Tocopherols and Tocotrienols
  • 22.13.1.6 Ascorbic Acid
  • 22.13.2 Preservatives
  • 22.13.3 Colors
  • 22.13.3.1 Classification
  • 22.13.4 Flavoring Agents
  • 22.13.5 Emulsifying Agent
  • 22.13.6 Suspending Agent
  • 22.14 Functional and Coprocessed Additives
  • 22.14.1 Approaches for Development of Coprocessed Additives
  • 22.14.2 Properties and Advantages of the Coprocessed Additives
  • 22.14.2.1 Alteration in Physicomechanical Traits
  • 22.15 Classification of Pharmaceutical Diluents
  • 22.15.1 Organic Diluents
  • 22.15.2 Inorganic Diluents
  • 22.15.3 Coprocessed Diluents
  • 22.16 Pharmaceutical Solvents
  • 22.16.1 Inorganic Solvents
  • 22.16.2 Organic Solvent
  • 22.17 Evaluation and Quality Testing of Pharmaceutical Additives
  • 22.17.1 Additive Specifications
  • 22.17.2 Additive Stability
  • 22.17.3 Receipt, Sampling, Testing, and Approval of Raw Materials
  • 22.17.4 Packaging and Labeling Control
  • 22.17.5 Analytical Procedures
  • 22.18 Current Developments in Additive Science
  • 22.19 International Patented Additives
  • 22.19.1 Sustained Release Excipient and Tablet Formulation (US5128143 A)
  • 22.19.2 Cross-Linked Cellulose as Some Tablet Excipients (US5989589 A)
  • 22.19.3 Low-Melting Moldable Pharmaceutical Excipient and Dosage Forms Prepared Therewith (US5004601 A)
  • 22.19.4 Pharmaceutical Excipient Having Improved Compressibility (US5585115 A)
  • 22.19.5 Trehalose as Stabilizer and Tableting Excipients (US4762857 A)
  • 22.19.6 Coprocessed Tablet Excipient Composition Its Preparation and Use (US20130177649 A1)
  • 22.19.7 Chemical Additives to Make Polymeric Materials Biodegradable (US8513329 B2)
  • 22.19.8 Coprocessed Microcrystalline Cellulose and Sugar Alcohol as an Excipient for Tablet Formulations (US 8932629 B2)
  • 22.20 FDA GRAS Additives
  • 22.20.1 Substances That Are Generally Recognized as Safe
  • 22.20.2 Examples of GRAS Additives
  • 22.21 Conclusion
  • Abbreviations
  • References
  • Further Reading
  • Index
  • Back Cover

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