Pharmaceutical Preformulation
Book addresses problems and solutions of formulation and preformulation with which I have concerned myself for 34 years. When I was employed in the pharmaceutical industry I worked at functions, in the 1960's, which were the precursors of preformulation, and my early publications dealt with such matters. In the following decades advances have been made in methodology and the realm of preformulation has grown. Theory and the way in which problems are viewed have also undergone change. The text deals with the pharmaceutical aspects of preformulation, not the synthetic nor the analytical aspects. It takes its vantage point at the point in time when the pharmaceutical preformulator first obtains a sample of the drug substance, and it explores the physical, chemical and technological aspects that are needed for a full exploration of the potential advantages and disadvantages of the drug substance. It is only through the understanding of underlying principles that adequate exploration can be carried out.
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
- 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
- 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
- pH and pK
- Definition of pH
- Obtaining pK
- 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
- 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
- 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
- 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
- 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
- Drug Substance Considerations
- Salt Selection
- Purifacation by Perticipation
- Purity Assessment by Means of Phase Solubility
- Differential Scanning Calorimetry (DSC)
- Eutectic Diagrams
- Preformulation Tasks
- 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
- Principles of Dissolution
- The Noyes-Whitney Equation
- The Dissolution Rate "Constant"
- Particulate Dissolution
- Multiparticulates
- Equivalent "Diameters"
- Preformulation Tasks
- Micromeritics
- Microscopy
- Geometric Surface Areas
- Sieve Analysis
- Surface Areas
- Preformulation Tasks
- 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
- 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
- Compatibility Testing
- Compatibility Test for Solid Dosage Forms
- Hydrates
- Dissolution Compatibility
- Vapor Pressure
- Aqueous Solution Compatibility
- Non-Aqueous Liquids
- Preformulation Task
- 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
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