by J. T. Carstensen

This book addresses problems and solutions of formulation and preformulation.The text deals with the pharmaceutical aspects of preformulation, not the synthetic nor the analytical aspects.

Pharmaceutical Preformulation will be of most interest to industrial and academic formulators, preformulators, universities, government, and patent litigators.

Contents

1. The Innovator Company
   • Patent Considerations
   • Biological Equivalence and the Principle of (Patent) Equivalence
   • Pharmaceutical Preformulation
   • Molecular Investigation in Later Phases
   • Macroscopic Property Determination in Later Phases
   • Statistics and Optimization of Protocols
   • Computer Programs
   • Analytical Techniques
2. Solubility
   • Aqueous Solubility of Non-Ionized Drugs
   • Solubility Determinations by RH-Relations
   • Solubility in mixed solvents
   • Solubility of Drug Substances which Ionize in Solution
   • Ionic Strength
   • Solubility Determinations when Adequate Supplies of Drug Substance are Available
   • Solubility of Poorly Stable Compounds
   • Effect of Surfactants
   • Mixed Solvent Systems as a Formulation Aid in Solubilization
   • Partition Coefficients
   • Dielectric Constant and Solubility Parameters
   • Solubility and pH
   • Curved Van't Hoff Plots
   • Preformulation Tasks in the Area of Solubility
3. pH and pK
   • Definition of pH
   • Obtaining pKa with small Amounts of Drug
   • Approximate Relation between pKa and pK(c)
   • Spectrophotometric Determination of pK
   • Solubility of a Weak Electrolyte as a Function of pH
   • Partition Coefficients of Weak Electrolytes
   • Preformulation Tasks
4. Surface Tension and Critical Micelle Concentration
   • Instrument Properties
   • Surface Tension
   • Critical Micelle Concentration
   • Effect of Temperature on CMC-Values
   • Effect of Counter Ion on Surface Tension
   • Effect of Temperature on Surface Tension
   • General Impact of Amphiphilic
5. Solution Kinetics
   • Preliminary Task
   • Reaction Order
   • Fractional Lives
   • Temperature Effects
   • Effect of Reaction Mechanisms
   • Calorimetric Methods
   • pH Profiles and Buffer Effect
   • Oxidation
   • Kinetic Salt Effect
   • Amphiphilic Drugs
   • Optimization
   • Preformulation Check Sheet
6. Suspensions
   • Solubility
   • Rationale for Suspensions
   • Taste
   • Stability
   • Viscosity
   • Settling of Suspensions
   • Sedimentation Kinetics
   • Density Matching
   • Particle Growth
   • Rheograms
   • Yield Diameter of Suspensions
   • Protective Colloids
   • Adsorption Isotherms
   • Coascervates
   • Surfactants
   • Preservation and Surface Adsorption
   • Dissolution of Suspensions
   • Content Uniformity
   • Pre-NDA and Pre-ANDA Testing
   • Initial Specifications
   • Test Post-NDA and Post-ANDA
   • Production Problems
7. Crystalline Solids
   • Crystal Systems
   • Drug Purification
   • Crystal Habit
   • Vapor Pressure of Solids
   • Solubility Measurements
   • Polymorphism by Solubility Measurements
   • Metastable Solutions
   • Differential Scanning Calorimetry (DSC)
   • Preformulation Tasks
8. Drug Substance Considerations
   • Salt Selection
   • Purifacation by Perticipation
   • Purity Assessment by Means of Phase Solubility
   • Differential Scanning Calorimetry (DSC)
   • Eutectic Diagrams
   • Preformulation Tasks
9. Moisture Isotherms
   • Water Adsorption
   • Classifacation of Solids in Regards to Moisture
   • Critical Moisture Content(RH*)
   • Moisture Uptake below the Critical RH
   • Automated Equipment
   • Isotherms of "Soluble" Compounds
   • Hydrates
   • Hygroscopicity
   • Solubilities from Moisture Isotherms
   • Preformulation Tasks
   • Nomenclature
10. Principles of Dissolution
    • The Noyes-Whitney Equation
    • The Dissolution Rate "Constant"
    • Particulate Dissolution
    • Multiparticulates
    • Equivalent "Diameters"
    • Preformulation Tasks
11. Micromeritics
    • Microscopy
    • Geometric Surface Areas
    • Sieve Analysis
    • Surface Areas
    • Preformulation Tasks
12. Shape Factors
    • Geometric Surface Area and Rugosity
    • Microscopically Determined shape Factors
    • The Ridgeway-Rupp Experiments
    • Shape Factors in General
    • Dimensional Microscopic Shape Factors
    • Fractal Geometry
    • Fractal Analysis and Pharmaceutical Parameters
    • Preformulation Tasks
13. Physical Testing
    • Pharmaceutical Equipment for Solid Dosage Forms
    • Hard Shell Capsules
    • Dissolution of Capsules
    • Routine Task with Hard Shell Capsules
    • Soft Shell Capsules
    • Tablets
    • Mechanical Testing of Solid Dosage Forms
    • Disintegration Test
    • Tablets-Dissolution
    • Physical Compatibility
    • Some Routine Tests
    • Weight and Content Uniformity
    • Apparent Density of Mixtures
    • Cohesion-Repose Angles
    • Sieve Analysis
    • Effects of Polymorphism
    • Preformulation Tasks
14. Compatibility Testing
    • Compatibility Test for Solid Dosage Forms
    • Hydrates
    • Dissolution Compatibility
    • Vapor Pressure
    • Aqueous Solution Compatibility
    • Non-Aqueous Liquids
    • Preformulation Task
15. Dissolution Test Design
    • In vitro Dissolution of Solid Dosage Forms
    • Blood Level Equations
    • In vivo Dissolution
    • Calculating the Correlating in vitro Curve
    • Calculating the Correlating in vitro Curve
    • One Point Methods and Deconvolution
    • Symbols

Index

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