Bioequivalence Dissolution Test Criteria for Formulation Development of High Solubility-Low Permeability Drugs

Area of Science:

• Pharmaceutical Sciences
• Drug Development
• Biopharmaceutics

Background:

• The biopharmaceutics classification system (BCS) biowaiver scheme suggests 85% drug dissolution within 15 minutes (T85% < 15 min) for BCS Class III drugs.
• Previous studies indicated potential for relaxing this dissolution criterion for practical formulation development.
• High solubility-low permeability drugs (BCS Class III) have membrane permeation as the rate-limiting step for absorption.

Purpose of the Study:

• To establish experimental and theoretical foundations for bioequivalence (BE) dissolution test criteria in formulating high solubility-low permeability drugs.
• To evaluate the existing biowaiver criteria for BCS Class III drugs.
• To determine a relaxed dissolution rate range for bioequivalent famotidine formulations.

Main Methods:

• Evaluated dissolution profiles of 14 clinically confirmed bioequivalent famotidine formulations using compendial dissolution tests at pH 1.2 and 6.8.
• Simulated plasma concentration-time profiles using dissolution data.
• Conducted virtual simulations to estimate the range of dissolution rates for bioequivalence.

Main Results:

• Observed famotidine dissolution rates (T85%) ranged from 10 to 60 minutes at pH 6.8.
• Virtual simulations indicated that famotidine formulations can be bioequivalent with T85% < 99 minutes.
• Dissolution rate differences have a limited impact on bioequivalence for BCS Class III drugs due to permeation rate-limiting absorption.

Conclusions:

• The current 15-minute dissolution criterion for BCS Class III drugs may be overly stringent.
• A relaxed dissolution criterion (T85% < 99 min) is proposed for famotidine formulations.
• Findings support a broader application of the biowaiver approach for BCS Class III drug formulation development.