A BCS-Based Biowaiver Approach Using Biphasic Dissolution Test

Abstract

Biowaivers based on the Biopharmaceutics Classification System (BCS) class can be used to establish therapeutic equivalence based on dissolution tests, which can be used as a surrogate to determine if two pharmaceutical equivalent products are interchangeable (i.e., bioequivalent). The objective of the present study was to use a biphasic dissolution system to replicate a study in which the authors followed compendial methods to examine the in vitro performance of widely used drug products. Furthermore, since biphasic dissolution studies are mainly applied to poorly soluble drugs, the present study was conducted to broaden its application to highly soluble drugs. The approach taken in this manuscript was to have scientific insight and mechanistic understanding rather than a strict regulatory application. In the initial study, none of the tested metronidazole products were (in vitro) equivalent to the comparator pharmaceutical product (CPP) or to other manufacturers. We hypothesized that whereas in vitro equivalence was not achieved in compendial methods, the partitioning profile to the organic phase in the biphasic system could signal in vitro equivalence between the tested drug products and CPP. In the aqueous phase of the biphasic system, the tested metronidazole products followed a similar pattern as obtained in the compendial buffer; however, this was not the case for the organic phase partition profiles. All the tested products had a good correlation to the CPP, which could indicate in vitro equivalence between these products. This could potentially allow for a biowaiver application. Hence, the application of biphasic dissolution to highly soluble drugs might be beneficial to estimate the product’s in vivo behavior. Further clinical studies would be needed to confirm these findings to guarantee their interchangeability.