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• Cover
• Title Page
• Copyright
• Dedication
• Preface
• Contents
• 1 Interpretive Tools
• Introduction
• Data Analysis Tools
• Dimensional Analysis
• Measurement and Data Types
• Significant Figures
• Calculations with Significant Figures
• Error and Describing Variability
• Determinate Errors
• Indeterminate Errors
• Descriptive Statistics
• Central Tendency: Mean, Median, Mode
• Variability: Measures of Dispersion
• Hypothesis Testing: Z-Statistic and Student’s T-Statistic
• Error Types (I, II)
• Visualizing Data
• Using Two Points to Determine a Line
• Linear Regression Analysis
• Distribution Functions
• Visual Presentation of Data
• References
• Recommended Readings
• 2 States of Matter
• Introduction
• Repulsive and Attractive Forces
• van der Waals Forces (Keesom Forces, Debye Forces, London Dispersion Forces)
• Ion-Induced Dipole Forces
• Dipole–Dipole Forces
• Hydrogen Bonds
• Ion–Dipole Forces
• Ion–Ion Interactions
• Bond Energies
• States of Matter
• The Gaseous State
• The Liquid State
• Vapor Pressure of Liquids
• Solids and the Crystalline State
• The Liquid Crystalline State
• The Supercritical Fluid State
• Thermal Analysis
• Differential Scanning Calorimetry
• Differential Thermal Analysis
• Thermogravimetric and Thermomechanical Analyses
• Karl Fischer Method
• Vapor Sorption/Desorption Analysis
• Phase Equilibria and the Phase Rule
• The Phase Rule
• Systems Containing One Component
• Condensed Systems
• Two-Component Systems Containing Liquid Phases
• Two-Component Systems Containing Solid and Liquid Phases: Eutectic Mixtures
• Solid Dispersions
• Phase Equilibria in Three-Component Systems
• Rules Relating to Triangular Diagrams
• Ternary Systems with One Pair of Partially Miscible Liquids
• Effect of Temperature
• Ternary Systems with Two or Three Pairs of Partially Miscible Liquids
• References and Notes
• Recommended Readings
• 3 Thermodynamics
• Introduction
• The Zeroth Law of Thermodynamics
• The First Law of Thermodynamics
• Isothermal and Adiabatic Processes
• Work of Expansion Against a Constant Pressure
• Reversible Processes
• Maximum Work
• Changes of State at Constant Volume
• Ideal Gases and the First Law
• Changes of State at Constant Pressure
• Thermochemistry
• Heat of Formation
• Hess’s Law and Heat of Combustion
• Heats of Reaction from Bond Energies
• Additional Applications of Thermochemistry
• The Second Law of Thermodynamics
• The Efficiency of a Heat Engine
• Entropy
• Entropy and Disorder
• The Third Law of Thermodynamics
• Free Energy Functions and Applications
• Maximum Net Work
• Criteria of Equilibrium and Spontaneity
• Pressure and Temperature Coefficients of Free Energy
• Fugacity
• Open Systems
• Chemical Potential
• Equilibrium in a Heterogeneous System
• Clausius–Clapeyron Equation
• Activities: Activity Coefficients
• Gibbs–Helmholtz Equation
• Standard Free Energy and the Equilibrium Constant
• The van’t Hoff Equation
• References
• Recommended Readings
• 4 Physical Properties of Drug Molecules
• Introduction
• Additive and Constitutive Properties
• Electromagnetic Radiation
• Atomic and Molecular Spectra
• Ultraviolet and Visible Spectrophotometry
• Fluorescence and Phosphorescence
• Dielectric Constant and Induced Polarization
• Permanent Dipole Moment of Polar Molecules
• Infrared Spectroscopy
• Near-Infrared Spectroscopy
• Electron Paramagnetic and Nuclear Magnetic Resonance Spectroscopy
• Refractive Index and Molar Refraction
• Optical Rotation
• Optical Rotatory Dispersion
• Circular Dichroism
• Electron and Neutron Scattering and Emission Spectroscopy
• References and Notes
• Recommended Readings
• 5 Molecular Dispersions
• Introduction
• Physical Properties of Substances
• Types of Solutions
• Concentration Expressions
• Molarity and Normality
• Molality
• Mole Fraction
• Percentage Expressions
• Calculations Involving Concentration Expressions
• Equivalent Weights
• Nonelectrolyte Solutions
• Escaping Tendency
• Ideal Solutions and Raoult’s Law
• Aerosols and Raoult’s Law
• Real Solutions
• Henry’s Law
• Distillation of Binary Mixtures
• Colligative Properties
• Lowering of the Vapor Pressure
• Elevation of the Boiling Point
• Depression of the Freezing Point
• Osmotic Pressure
• Measurement of Osmotic Pressure
• van’t Hoff and Morse Equations for Osmotic Pressure
• Thermodynamics of Osmotic Pressure and Vapor Pressure Lowering
• Molecular Weight Determination
• Choice of Colligative Properties
• Electrolyte Solutions
• Properties of Solutions of Electrolytes
• Electrolytic Conductance
• Theory of Electrolytic Dissociation
• Theory of Strong Electrolytes
• Coefficients for Expressing Colligative Properties
• Solid Solutions
• Solid Solution or Solid Dispersion?
• Classifying Solid Solutions
• Cocrystals
• References and Notes
• Recommended Readings
• 6 Ionic Equilibria
• Introduction
• Brønsted–Lowry Theory
• Lewis Electronic Theory
• Acid–Base Equilibria
• Ionization of Weak Acids
• Ionization of Weak Bases
• The Ionization of Water
• Relationship Between Ka and Kb
• Ionization of Polyprotic Electrolytes
• Ampholytes
• Sørensen’s pH
• Conversion of Hydronium Ion Concentration to pH
• Conversion of pH to Hydronium Ion Concentration
• pK and pOH
• Species Concentration as a Function of pH
• Calculation of pH
• Proton Balance Equations
• Solutions of Strong Acids and Bases
• Conjugate Acid–Base Pairs
• Solutions Containing Only a Weak Acid
• Solutions Containing Only a Weak Base
• Solutions Containing a Single Conjugate Acid–Base Pair
• Two Conjugate Acid–Base Pairs
• Solutions Containing Only a Diprotic Acid
• Solutions Containing Only an Ampholyte
• Solutions Containing Only a Diacidic Base
• Two Independent Acid–Base Pairs
• Solutions Containing Two Weak Acids
• Solutions Containing a Salt of a Weak Acid and a Weak Base
• Solutions Containing a Weak Acid and a Weak Base
• Acidity Constants
• Effect of Ionic Strength on Acidity Constants
• References and Notes
• Recommended Readings
• 7 Buffered and Isotonic Solutions
• Introduction
• The Buffer Equation
• Common Ion Effect and the Buffer Equation for a Weak Acid and Its Salt
• The Buffer Equation for a Weak Base and Its Salt
• Activity Coefficients and the Buffer Equation
• Some Factors Influencing the pH of Buffer Solutions
• Drugs as Buffers
• pH Indicators
• Buffer Capacity
• Approximate Calculation of Buffer Capacity
• A More Exact Equation for Buffer Capacity
• The Influence of Concentration on Buffer Capacity
• Maximum Buffer Capacity
• Neutralization Curves and Buffer Capacity
• Buffers in Pharmaceutical and Biologic Systems
• In Vivo Biologic Buffer Systems
• Urine
• Pharmaceutical Buffers
• General Procedures for Preparing Pharmaceutical Buffer Solutions
• Influence of Buffer Capacity and pH on Tissue Irritation
• Stability versus Optimum Therapeutic Response
• pH and Solubility
• Buffered Isotonic Solutions
• Measurement of Tonicity
• Calculating Tonicity Using Liso Values
• Methods of Adjusting Tonicity and pH
• Class I Methods
• Class II Methods
• References and Notes
• Recommended Reading
• 8 Solubility and Distribution Phenomena
• General Principles
• Introduction
• Solubility Expressions
• Solvent–Solute Interactions
• Polar Solvents
• Nonpolar Solvents
• Semipolar Solvents
• Solubility of Liquids in Liquids
• Complete Miscibility
• Partial Miscibility
• Three-Component Systems
• Solubility of Solids in Liquids
• Calculating the Solubility of Weak Electrolytes as Influenced by pH
• The Influence of Solvents on the Solubility of Drugs
• Combined Effect of pH and Solvents
• Influence of Complexation in Multicomponent Systems
• Influence of Other Factors on the Solubility of Solids
• Determining Thermodynamic and “Kinetic” Solubility
• The Phase Rule and Solubility
• Some Limitations of Thermodynamic Solubility
• Measuring Solubility
• High-Throughput Solubility Measurements
• Estimating Drug Solubility in the Gastrointestinal Tract
• Computational Approaches
• Distribution of Solutes between Immiscible Solvents
• Effect of Ionic Dissociation and Molecular Association on Partitioning
• Extraction
• Solubility and Partition Coefficients
• References and Notes
• Recommended Readings
• 9 Complexation and Protein Binding
• Introduction
• Metal Complexes
• Inorganic Complexes
• Chelates
• Organic Molecular Complexes
• Drug Complexes
• Polymer Complexes
• Inclusion Compounds
• Channel Lattice Type
• Layer Type
• Clathrates
• Monomolecular Inclusion Compounds: Cyclodextrins
• Molecular Sieves
• Methods of Analysis
• Method of Continuous Variation
• pH Titration Method
• Distribution Method
• Solubility Method
• Spectroscopy and Change Transfer Complexation
• Other Methods
• Protein Binding
• Binding Equilibria
• Equilibrium Dialysis and Ultrafiltration
• Dynamic Dialysis
• Hydrophobic Interaction
• Self-Association
• Factors Affecting Complexation and Protein Binding
• References and Notes
• Recommended Readings
• 10 Interfacial Phenomena
• Introduction
• Liquid Interfaces
• Surface and Interfacial Tensions
• Surface Free Energy
• Pressure Differences Across Curved Interfaces
• Measurement of Surface and Interfacial Tensions
• Adsorption at Liquid Interfaces
• Surface-Active Agents
• Systems of Hydrophile–Lipophile Classification
• Types of Monolayers at Liquid Surfaces
• Soluble Monolayers and the Gibbs Adsorption Equation
• Insoluble Monolayers and the Film Balance
• Adsorption at Solid Interfaces
• The Solid–Gas Interface
• The Solid–Liquid Interface
• Activated Charcoal
• Contact Angle and Wetting
• Applications of Surface-Active Agents
• Foams and Antifoaming Agents
• Electric Properties of Interfaces
• The Electric Double Layer
• Nernst and Zeta Potentials
• Effect of Electrolytes
• References and Notes
• Recommended Reading
• 11 Rheology
• Introduction
• Newtonian Systems
• Newton’s Law of Flow
• Kinematic Viscosity
• Temperature Dependence and the Theory of Viscosity
• Non-Newtonian Systems
• Plastic Flow
• Pseudoplastic Flow
• Dilatant Flow
• Thixotropy
• Measurement of Thixotropy
• Bulges and Spurs
• Negative Thixotropy
• Thixotropy in Formulation
• Determination of Rheologic Properties
• Choice of Viscometer
• Capillary Viscometer
• Falling-Sphere (Ball) Viscometer
• Cup-and-Bob Viscometer
• Cone-and-Plate Viscometer
• Viscoelasticity
• Psychorheology
• Applications to Pharmacy
• References
• Recommended Readings
• 12 Diffusion
• Introduction
• Steady-State Diffusion
• Fick’s First Law of Diffusion
• Fick’s Second Law
• Steady State
• Diffusion Through Membranes
• Steady Diffusion Across a Thin Film and Diffusional Resistance
• Boundary Layers
• Permeability
• Diffusion Driving Forces
• Systems With Multiple Diffusional Components
• Multilayer Diffusion
• Lag Time
• Membrane and Diffusion Layer Control
• Lag Time Under Diffusion-Layer Control
• Various Apparatus and Methods for Assessing Drug Diffusion
• Diffusion in Biologic Systems
• Gastrointestinal Absorption of Drugs
• Effect of pH
• pH-Partition Hypothesis
• Modification of the pH-Partition Principle
• Percutaneous Absorption
• Buccal Absorption
• Uterine Diffusion
• Elementary Drug Release
• Zero-Order Drug Release
• Drugs in Polymer Matrices
• Release from Granular Matrices: Porosity and Tortuosity
• Soluble Drugs in Topical Vehicles and Matrices
• Osmotic Drug Release
• Dialysis
• References
• Recommended Readings
• 13 Disintegration, Dissolution, and Drug Release
• Introduction
• Terminology
• The Basics
• Disintegration
• Dissolution
• Drug Release
• Mechanisms of Dissolution and Drug Release
• Noyes–Whitney Equation
• Hixson–Crowell Cube-Root Law
• Drug Release
• Dissolution and Release From Oral Drug Products
• Dissolution Methods and Apparatus
• Disintegration Versus Dissolution; Scientific and Regulatory Requirements
• Intrinsic Dissolution
• Research and Development Relevant Dissolution Methods
• Artificial Stomach-Duodenum
• Gastrointestinal Simulator
• TNO Intestinal Model System
• Rotating Membrane Method for Nanocarriers
• Vibrating Tube Sensor
• Biphasic Dissolution
• Dissolution Media
• Quality Control, Physiologically Relevant and Clinically Relevant Dissolution Media
• Bicarbonate Buffer
• Dissolution Tests in Phosphate Buffer Versus Bicarbonate Buffer
• Biopharmaceutics Classification System (BCS)
• Dose, Dissolution, and Absorption Numbers
• Regulatory Sciences
• References and Notes
• 14 Chemical Kinetics and Stability
• Introduction
• Fundamentals and Concentration Effects
• Rates, Order, and Molecularity of Reactions
• Rate Constants, Half-Life, Shelf Life, and Apparent or Pseudo-Order
• Temperature Effects
• Collision Theory
• Classical Collision Theory of Reaction Rates
• Q10 Calculations
• Shelf-Life Calculations
• Other Factors—A Molecular Viewpoint
• Transition-State Theory
• Medium Effects: Solvent, Ionic Strength, Dielectric Constant
• Catalysis: Specific and General Acid–Base Catalysis and pH Effects
• Stability of Pharmaceuticals
• Decomposition and Stabilization of Medicinal Agents
• Nucleophilic Mechanisms
• Oxidative Degradation
• Photodegradation
• Accelerated Stability and Stress Testing
• Containers and Closures
• Biotechnology Products
• Solid-State Stability
• References and Notes
• Recommended Readings
• 15 Biopharmaceutics and Pharmacokinetics
• Introduction
• Terminology
• Bioavailability
• Pharmacogenetics
• Membrane Permeability
• Pharmacokinetics
• Pharmacodynamics
• Introductory Pharmacokinetics
• ADME—Absorption, Distribution, Metabolism, and Excretion
• Compartmental Models in Pharmacokinetics
• Gastrointestinal Absorption
• Causes of Low Bioavailability
• Biopharmaceutics Classification System
• Predictive Models of Pharmacokinetics
• Molecular and Cellular Biopharmaceutics
• Introduction
• Drug Transporters, Cells, and Transport Pathways
• Drug Metabolism
• Organ-Level Biopharmaceutics
• Gastrointestinal Tract
• Brain–Barrier Systems
• Kidney
• Liver
• References and Notes
• Recommended Readings
• 16 Pharmaceutical Biotechnology
• Introduction
• Types of Biotechnology-Derived Products
• Peptides and Proteins
• Currently Available Recombinant Protein-Based Pharmaceuticals
• Vaccines
• Nucleic Acids
• Discovery of Biotech Drugs
• Cloning
• Purification of Macromolecular Therapeutics
• Characterization
• Biology-Based Assays (Bioassays)
• Immunoassays
• Electrophoresis
• High-Performance Liquid Chromatography
• Ultraviolet/Visible Spectroscopy
• Fluorescence
• Circular Dichroism
• Vibrational Spectroscopy
• Light Scattering, Hydrodynamic, and Calorimetric Techniques
• Analysis of Macromolecular Dynamics
• Preformulation
• Physical Degradation
• Chemical Degradation
• Deamidation Reactions
• Asp-Mediated Backbone Hydrolysis
• N,O-Acyl Migration in Ser or Thr Residues
• β- and α-Elimination Reactions
• Oxidative Reactions (Met, His, Trp)
• Other Reactions
• Formulation
• Drying of Biopharmaceuticals
• Formulation of Vaccines
• Next-Generation Approaches in Pharmaceutical Biotechnologies
• Rapid Advances in Protein Drug Discovery
• Fusion Proteins in Precision Medicine
• Cell-Based Therapeutics
• References and Notes
• Recommended Reading
• 17 Pharmaceutical Polymers
• Introduction
• History of Polymers
• Polymers in General
• Polymer Synthesis
• Addition Polymerization
• Condensation Polymerization
• Polymerization Methods
• Homogeneous Polymerization
• Dispersion Polymerization
• Copolymers and Polymer Blends
• Interpenetrating Polymer Networks
• Topology and Isomerism
• Thermoplastic and Thermoset Polymers
• Polymer Properties
• Crystalline and Amorphous Polymers
• Thermal Transitions
• Glass Transition Temperature
• Plasticized Polymers
• Molecular Weight
• Mechanical Properties
• Viscoelastic Properties
• Molecular Weight and Polymer Properties
• Variety of Polymers
• Rubbers
• Plastics
• Fibers
• Adhesives and Coatings
• Polymers as Rheology Modifiers
• Hydrogels
• Chemical Gels
• Physical Gels
• Polymers for Pharmaceutical Applications
• Cellulose-Based Polymers
• Hydrocolloids
• Polymers in Drug Delivery
• Introduction
• Synthetic Polymers
• Biodegradable Polymers
• Ion-Exchange Resins
• Recent Applications of Polymers in Pharmaceutical Sciences
• References and Notes
• Recommended Readings
• 18 Pharmaceutical Compounding
• Introduction
• Physical Characteristics
• Hydrates and Solvates
• Calculations
• Packaging, Storage, and Weighing
• Hygroscopic, Deliquescent, and Efflorescent Powders
• Water and Solvent Content of Powders
• Organic Salts
• Organic Esters
• Labeling of Official Monographs
• Inorganic Salts
• Incompatibilities
• Solubility of Inorganic Salts
• Potency-Designated Ingredients
• Complex Organic Molecules
• Stabilization
• Preparation
• Physicochemical Considerations
• Packaging
• Storage/Labeling
• Stability
• Manufactured Products
• Manufactured Products as Source of Active Drugs
• Out-of-Specification Compounding Resulting from Using Manufactured Products
• Appearance and Palatability
• Flavoring Pharmaceuticals
• Sweetening Pharmaceuticals
• Coloring Pharmaceuticals
• Preservatives
• Biopharmaceutics Classification System (BCS)
• Compounding Considerations for Class 1 Drugs
• Compounding Considerations for BCS Class 2 Drugs
• Compounding Considerations for BCS Class 3 Drugs
• Compounding Considerations for BCS Class 4 Drugs
• References
• 19 Pharmaceutical Micromeritics
• Introduction
• Introduction to Pharmaceutical Particles
• Particle Properties
• Particle Size
• Shape Parameters
• Surface Properties
• Mechanical Properties
• Charge Properties
• Particle Sizing Techniques
• Orthogonal Measurements
• Imaging Analysis
• Dynamic Light Scattering
• Laser Diffraction
• Sedimentation
• Sieving
• Methods for Determining Surface Area
• Determining Particle Size and Particle Size Distribution—Controversies or Misunderstandings?
• References and Notes
• 20 Coarse Dispersions
• Introduction
• Fundamental Properties of Disperse Systems
• Suspensions
• Physical Stability of Suspensions
• Formulation of Suspensions
• Wetting of Particles
• Controlled Flocculation
• Flocculation in Structured Vehicles
• Rheologic Considerations
• Preparation of Suspensions
• Emulsions
• Theories of Emulsification
• Emulsion Types
• Rheologic Properties of Emulsions
• Evaluation of Stability
• Semisolids
• Classification of Pharmaceutical Semisolids
• References and Notes
• Recommended Readings
• 21 Colloidal Dispersions and Nanomeritics
• Introduction
• Colloids
• Size and Shape of Colloidal Particles
• Types of Colloidal Systems
• Optical Properties of Colloids
• Kinetic Properties of Colloids
• Electrical Properties of Colloids
• Pharmaceutical Applications of Colloids
• Solubilization
• Colloidal Drug Delivery Systems
• Nanomeritics
• Introduction
• Orthogonality
• Low-Resolution Techniques
• High-Resolution Techniques
• EUNCL/NCI-NCL Multiple Orthogonal Measurements Approach for Measuring PSD
• References and Notes
• Recommended Readings
• 22 Pharmaceutical Excipients
• Introduction
• Excipient Function, Quality, and Safety
• What Is an Excipient?
• Excipient Functional Categories
• Excipients Can Have Multiple Functions in Pharmaceutical Preparations
• Excipient Quality and Regulation
• Novel Excipients
• Adverse Reactions to Excipients
• Oral Solid Dosage Forms
• Critical Attributes of Excipients Used in Oral Solid Dosage Forms
• Diluent
• Binder
• Disintegrant
• Lubricant
• Glidants and Anticaking Agents
• Wetting and Solubilizing Agents
• Coating Agents
• Other Excipients
• Considerations for Other Dosage Forms
• References and Notes
• Recommended Readings
• 23 Oral Solid Dosage Forms
• Introduction
• Excipient functionalities
• Quality by Design
• Preformulation Characterization
• Physical Properties
• Mechanical Properties
• Chemical Properties
• Biologic Properties
• Formulation Development
• Drug Release from Oral Dosage Forms
• Powders
• Capsules
• Tablets
• Manufacturing
• Regulated Environment
• Manufacturing Routes (Advantages and Disadvantages)
• Processing Modes (Batch, End-to-End Continuous, Segmented Continuous, Hybrid)
• Unit Operations and Processing Steps
• Failure Modes in the Process
• Special Situations in Formulation Development
• Poorly Soluble APIs
• Poorly Flowing, Electrostatic Ingredients
• Dosage Form Testing
• Uniformity of Dosage
• Tablet Hardness
• Friability
• Disintegration
• Dissolution
• Stability
• References and Notes
• 24 Drug Delivery Systems
• Introduction
• Advanced Drug Delivery Systems: Definition and Economic Opportunities
• Patient-Centric Drug Product Design
• Controlled Drug Delivery
• Controlled Drug Release Profiles
• Mechanisms of Controlled Drug Release
• Advanced DDS by Main Routes of Administration
• Gastrointestinal (Oral, Per Os)
• Parenteral
• Sublingual and Buccal
• Pulmonary (Inhalation)
• Nebulizers
• Pressurized Metered-Dose Inhalers
• Dry Powder Inhalers
• Pulmonary Delivery of Proteins
• Nasal
• Ocular
• Vaginal
• Transdermal
• Central Nervous System
• Targeted Drug Delivery
• Passive Targeting Mechanisms
• Active Targeting Mechanisms
• Prodrugs and Conjugates Single-Molecule Delivery Approaches
• Nanoscale Drug Delivery Carriers—Molecular Assembly Approaches
• Liposomes and Other Vesicles
• Micelles
• Polymersomes and Dendrimers
• Polymeric and Lipid Particles
• Nanocrystals
• Delivery of Nucleic Acid Therapeutics
• Nucleic Acid Therapeutics
• Gene Delivery and Therapy
• Delivery of Nucleic Acids and Genes
• Cell-Based Therapy and Beyond
• Terminology
• References and Notes
• Recommended Readings
• Index