Development of a Biorelevant Dissolution Test Using Bicarbonate Buffer and Apex Vessel to Predict Clinical Bioequivalence

Abstract

Bioequivalence (BE) studies are essential for confirming therapeutic equivalence. However, current compendial dissolution tests do not necessarily provide a reliable prediction of clinical BE. We aimed to develop a biorelevant dissolution test that predicts clinical bioequivalence (BE). Three enteric-coated pellets of esomeprazole magnesium trihydrate (ECP-ESO), either clinically BE or non-BE (NBE), were evaluated. Dissolution tests were performed using the paddle method (pH 6.5 or 6.8, 25–100 rpm, 500 mL, 37°C). Biorelevant bicarbonate buffer (BCB) was used as a simulated intestinal fluid, with a floating lid applied to prevent CO₂ escape and maintain pH. Hydrodynamics that suppresses artifact cone formation (coning) were produced using an apex vessel (Apex-V). These biorelevant conditions were compared with the compendial phosphate buffer (PPB) and the round-bottom vessel (RB-V). RB-V is considered less biorelevant as it causes coning at the vessel bottom. When PPB and RB-V were used, BE and NBE formulations could not be distinguished. Substitution of RB-V with Apex-V eliminated coning but lacked discriminative power. This outcome was also observed with BCB and RB-V. Combining both BCB and Apex-V successfully differentiated between BE and NBE formulations, consistent with the clinical BE results. Dissolution testing using biorelevant BCB and Apex-V predicted the clinical BE/NBE of ECP-ESOs. The floating lid method enabled the practical use of BCB, while Apex-V prevented coning. This simple, yet biorelevant, dissolution test could help to predict clinical BE in formulation development.