IN VITRO DISSOLUTION METHODOLOGY AND ESTIMATED CONSEQUENCES OF BIOWAIVER EXTENSION FOR IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS WITH METFORMIN HYDROCHLORIDE

The in vitro dissolution methodologies are frequently used as quality control tools for the assessment of solid oral dosage forms. The current bioequivalence guidance issued by the European Medicine Agency indicates that biowaiver extension for high solubility and low permeability drugs can be granted based on a very rapid in vitro release profile (more than 85% of the label claimed content in 15 minutes or less). The paper presents the results of dissolution testing for four commercially available immediate-release solid dosage forms containing 500 mg metformin hydrochloride. The in vitro evaluation was performed according to compendial monograph and by implementing non-compendial devices (Palmieri baskets, Peak vessels). The most discriminative profiles were further used for the estimation of the absorption processes, based on build-in GastroPlus (TM) models, considering the permeability and the pharmacokinetic characteristics of metformin. Theoretical, the in vivo exposure patterns were generated for 85% fraction released in 15 and 30 minutes and considered as reference in the evaluation of bioequivalence. Despite the in vitro difference in the release rate, presumably related to formulation variables, the estimated pharmacokinetic profiles were similar in terms of rate and extent of absorption. It can be assumed that, in the absence of factors interfering with the gastro-intestinal volume of fluid, transit times or active transporters, compliance with compendial standards could be used as a basis of biowaiver granting for metformin hydrochloride.