Abstract
The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f2 similarity factor. 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 vivo behavior of the products of candesartan cilexetil employed the USP IV apparatus and a three-step pH buffer change, from 1.2 to 4.5 and 6.8, with 0.2% of Tween 20. This new model was able to predict the in vivo differences in dissolution and it could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.
Highlights
An in vitro–in vivo correlation (IVIVC) can be defined as a mathematical relationship between an in vitro characteristic of the drug Product And an in vivo characteristic of the same drug product
We have recently showed how it is possible to combine data from separate Bioequivalence studies to construct an IVIVC by normalizing the data sets with the reference plasma levels ratios in the different studies [13,14]
An in vitro dissolution test that is able to predict the in vivo behavior of two IR generic products of candesartan cilexetil has been developed based on an IVIVC
Summary
An in vitro–in vivo correlation (IVIVC) can be defined as a mathematical relationship between an in vitro characteristic of the drug Product And an in vivo characteristic of the same drug product. While a drug product is developed, IVIVCs are useful tools as they serve to predict in vivo behavior and, can be used to guide formulation development. This avoids in vivo failures and, if adequately validated, they can be used to obtain a biowaiver based on the in vitro dissolution tests [1]. A recent study reported a so-called in vitro–in vivo correlation for candesartan cilexetil products, but the dissolution results were not reported and both formulations demonstrated bioequivalence [4].
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