In vitro dissolution testing to assess pharmaceutical equivalence of selected amoxicillin products available in sri lanka: A post-marketing study

Abstract

Guidance documents on biowaivers and published literature, including the biowaiver monograph on amoxicillin, recommend conducting biopharmaceutics classification system (BCS)-based in vitro dissolution studies as a surrogate for in vivo bioequivalence (BE) studies for solid oral amoxicillin products. Until now, comparative in vitro dissolution studies have not been used in regulatory submissions in Sri Lanka. This post-marketing study was conducted to compare dissolution profiles of three registered amoxicillin products. In vitro dissolution testing was conducted according to the WHO guideline for biowaiver studies. We compared three generic solid oral amoxicillin products of 500 mg (generic A, B, and C) available in Sri Lanka with the innovator product. Dissolution samples were quantified using a validated high-performance liquid chromatography (HPLC) method with ultraviolet (UV) absorption at 229 nm. The results showed that all products complied with pharmacopoeial specifications, but variation of dissolution data greater than 20% was noted at the 10-min time point, and 10% variation was noted at later time points with product A at pH 4.5 and product C at pH 4.5 and 6.8. Therefore, both conventional similarity factor (f2) and model-independent multivariate confidence region procedures (bootstrap approach) were used to compare the dissolution profiles. Only generic A met dissolution study criteria at all three pH conditions. Generic B failed to meet dissolution study criteria at pH 4.5, and generic C, with highly variable dissolution data, met the dissolution criteria at pH 4 using bootstrap f2 and failed to meet dissolution criteria at pH 6.8. This study highlights the need for careful consideration of an appropriate mathematical model or models for comparing dissolution profiles, especially when the coefficient of variation (CV) warrants application of two models for different pH conditions. The international guidelines on BCS-based dissolution studies do not provide adequate guidance on these issues.