Effect of natural aging conditions on in vitro dissolution stability of metformin tablets

VARILLAS, M. A.; BREVEDAN, M. I. V.; STARKLOFF, W. J.; CALDUBEHERE, S. O.; FERNANDEZ BAND, B. S.; GONZALEZ VIDAL, N. L.

Rosario

Congreso; 2° Reunión Internacional de Ciencias Farmacéuticas RICiFa; 2012

Universidad Nacional de Rosario - Universidad Nacional de Córdoba

INTRODUCTION: For some solid oral dosage forms, in vitro dissolution profile similarity can be used to establish equivalence of the test product with the reference product. Such studies are called "Biowaivers" and comprise in vitro dissolution profile evaluation in three media: pH 1.2, 4.5 and 6.8. During aging, absence of dissolution changes suggests that bioavailability could remain intact. Cheng et al. state that if a pharmaceutical form dissolves quickly, the bioavailability of the active ingredient will not be affected by dissolution and, in this case, there is the possibility of extending biowaivers to Class III, on the basis of the in vitro dissolution profile. Metformin is a class III drug in the Biopharmaceutics Classification System, widely used as an oral anti-hyperglycemic agent. Our research attempted to evaluate the influence of natural aging conditions on in vitro dissolution and biowaiver assessment of different metformin formulations available in the Argentine market, during one year of storage. MATERIALS AND METHODS: Fourteen samples (A - N) of metformin tablets (500mg) were purchased from pharmacies in Bahía Blanca city. The formulations contained the same amount of active pharmaceutical ingredient, but different types or amounts of excipients. All dissolution studies were performed using USP Apparatus 1 (Erweka DT60) at 100 rpm, under sink conditions in 900 mL of USP buffer solutions (hydrochloric acid buffer at pH 1.2, acetate buffer at pH 4.5, and phosphate buffer at pH 6.8) at 37 ± 0.5 ºC. Twelve tablets from each sample were analyzed in each condition. Samples (5 mL) were withdrawn at 5, 10, 15, 20, 30, 45, and 60 minutes with replacement of fresh medium, filtered through 0.45 µm membrane filters, and suitably diluted. Drug concentration was determined spectrophotometrically (Varian Cary 50Conc) at 233 nm. The formulations were stored for twelve months under ICH natural conditions (25°C/60% R.H.). Analysis of variance (ANOVA) was used to evaluate dissolution stability, in terms of Dissolution Efficiency (DE). RESULTS: Dissolution profiles of all formulations differed from at pH 1.2 and 4.5, both at time zero and after one year of storage. At pH 6.8 formulations D, F, G, J and K did not differ from the reference product, at time zero. However, after aging, samples D and G were similar to the reference. After storage, statistically significant differences were recorded for dissolution profiles of formulations D, J and L (at pH 1.2). Nevertheless, no significant changes were recorded for samples K and L (at pH 4.5), and for samples B, D, I, L and N (at pH 6.8), after twelve months aging. DISCUSSION / CONCLUSIONS: The dissolution stability and biowaiver assessment of evaluated metformin formulations are clearly affected by storage, given the statistically significant differences found in comparison of the dissolution profiles. ACKNOWLEDGMENTS: This work was supported by funds from Universidad Nacional del Sur, Argentina (PGI 24/B175).