IN VITRO DISSOLUTION METHODOLOGY AND ESTIMATED
CONSEQUENCES OF BIOWAIVER EXTENSION FOR IMMEDIATE
RELEASE SOLID ORAL DOSAGE FORMS WITH METFORMIN
HYDROCHLORIDE
MONICA ARDELEAN 1, SILVIA MARIA STOICESCU 2*, ANA ANDREEA STĂNESCU 1,3, DUMITRU LUPULIASA 1,3, DIANA MARIANA STĂNICIOIU 3, FLAVIAN ȘTEFAN RĂDULESCU 3,4, DALIA SIMONA MIRON 3,5
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
1Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, 6 Traian Vuia Street, 020956
2Department of Obstetrics and Gynaecology, “Polizu” Clinical Hospital, Faculty of Medicine, 38-52 Gh. Polizu Street
3Center for Drug Sciences (CedS), Faculty of Pharmacy, 6 Traian Vuia Street, 020956
4Department of Drug Industry and Pharmaceutical Biotechnologies, Faculty of Pharmacy, 6 Traian Vuia Street, 020956
5Department of Pharmaceutical Physics and Informatics, Faculty of Pharmacy, 6 Traian Vuia Street, 020956
*corresponding author: stoicescusilvia@yahoo.com
Download Full Article

Abstract:
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 GastroPlusTM 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.

Top