Preformulation Basics for Drug Development

Preformulation: A Foundation for Dosage Form Development

• Preformulation investigations are designed to collect data, especially on physicochemical properties of drug substances, excipients, and packaging materials, to develop stable and bioavailable dosage forms for mass production.

Preformulation Parameters

• Physical Characteristics:
  • Organoleptic Properties: Describing the drug substance based on color, odor, and taste. Examples: White, pungent, acidic; off-white, fruity, bitter; yellow, odorless, sweet.
  • Bulk Characteristics:
    • Solid state characteristics (e.g., particle size, shape, suspendability, uniform distribution)
    • Flow properties (e.g., free-flowing, cohesive)
    • Crystallinity (e.g., crystalline, amorphous structure).
    • Density
    • Substance under atmosphere/humidity (e.g., deliquescent, efflorescent, hygroscopic)
• Chemical Characteristics:
  • Solubility Analysis:
    • Partition coefficient
    • Solubilization
    • Dissolution
  • Stability Analysis: Assessing drug-excipient compatibility.
    • Hydrolysis: Breakdown by water.
    • Oxidation: Reaction with oxygen.
    • Photolysis: Degradation by light.
    • Racemization: Conversion between isomers.
    • Polymerization: Formation of polymers.

Stability Analysis

• Why Stability Studies: To understand how environmental factors (temperature, humidity, light) impact drug product quality over time and to recommend storage conditions and shelf life.
• Types of Changes in Physical, Chemical, and Microbial aspects
  • Physical Changes: Alterations in appearance, clarity, color, crystal modification, and particle size.
  • Chemical Changes: Increased breakdown and reduced drug concentration.
  • Microbial Changes: Increase in microbial load or contamination.
• Stability Studies: Performed on drug substances (unformulated drug substance/API) and drug products (the dosage form in the final immediate packaging).

ICH Guidelines

• ICH stands for International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
• ICH guidelines are important for regulatory compliance for forced degradation studies.
• Different conditions for forced degradation studies:
  • Hydrolytic (acidic & basic conditions)
  • Oxidative (Hydrogen peroxide)
  • Thermal (Dry heat exposure)
  • Photolytic (UV radiation exposure)

Analytical Testing Methods for Pharmaceuticals

• Physical Testing Methods: Melting point, boiling point, color change.
• Methods Interacting with Electromagnetic Radiation: UV/Visible spectroscopy, infrared spectroscopy, X-ray spectroscopy, flame emission and atomic absorption spectroscopy, mass spectrometry.
• Separation Techniques: Chromatography (e.g., HPLC, GC, column, thin-layer, and paper chromatography)
• Immunoassay Methods: Radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA).

Drug-Excipient Compatibility Studies

• Excipients are pharmacologically inert substances that can undergo chemical or physical interactions with drug substances. Important in formulation.
• Various mechanisms of drug-excipient interactions:
  • Physical interactions
  • Chemical interactions (hydrolysis, oxidation, photolysis, racemization, polymerization)
  • Physiological/biopharmaceuitcal interactions

Chromatography

• Used to separate mixtures into their components using a mobile phase and a stationary phase, based on differences in interactions between molecules and stationary / mobile phase.
• Types of chromatography include HPLC (High-performance liquid chromatography), GC (Gas chromatography), column chromatography, thin-layer chromatography, and paper chromatography.
• Principle: Different interactions between the components of a mixture and the stationary and mobile phase.