In Vitro Dissolution as a Tool for Formulation Selection: Telmisartan Two-Step IVIVC

Abstract

The purpose of this investigation was todevelop an exploratory two-step level A IVIVC for threetelmisartan oral immediate release formulations, the referenceproduct Micardis, and two generic formulations (X1 and X2).Correlation was validated with a third test formulation, Y1.Experimental solubility and permeability data were obtained toconfirm that telmisartan is a class II compound under theBiopharmaceutic Classification System. Bioequivalence (BE)studies plasma profiles were combined using a previouslypublished reference scaling procedure. X2 demonstrated invivo BE, while X1 and Y1 failed to show BE due to the lowerboundary of the 90% confidence interval for Cmax being outsidethe acceptance limits. Average plasma profiles were deconvo-luted by the Loo-Riegelman method to obtain the oral fractions absorbed (fa ). Fractions dissolved (fdiss ) were obtained in severalconditions in USP II and USP IV apparatus, and later, the results were compared in order to find the most biopredictive model,calculating the f 2 similarity factor. The apparatus and conditions showing the same rank order than in vivo data were selected forfurther refinement of conditions. A Levy plot was constructed to estimate the time scaling factor and to make both processes,dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivobehavior of the different formulations of telmisartan employed the USP IV dissolution apparatus and a dissolution environmentwith a flow rate of 8 mL/min and a three-step pH change, from 1.2 to 4.5 and 6.8, with a 0.05% of Tween 80. Thus, theseconditions gave rise to a biopredictive dissolution test. This new model is able to predict the formulation differences indissolution that were previously observed in vivo, which could be used as a risk-analysis tool for formulation selection in futurebioequivalence trials.