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. 2020 Jul 6;12(7):633.
doi: 10.3390/pharmaceutics12070633.

Candesartan Cilexetil In Vitro-In Vivo Correlation: Predictive Dissolution as a Development Tool

Andrés Figueroa-Campos  1   2   3 , Bárbara Sánchez-Dengra  1 , Virginia Merino  2   3 , Arik Dahan  4 , Isabel González-Álvarez  1 , Alfredo García-Arieta  5 , Marta González-Álvarez  1 , Marival Bermejo  1
Affiliations

Candesartan Cilexetil In Vitro-In Vivo Correlation: Predictive Dissolution as a Development Tool

Andrés Figueroa-Campos et al. Pharmaceutics. .

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.

Keywords: BCS; IVIVC; bioequivalence; candesartan cilexetil; predictive in vivo-dissolution.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Average plasma concentrations versus time profiles of in vivo studies after correction/scaling based on the reference product.
Figure 2
Figure 2
Saturation concentrations of candesartan cilexetil products (Reference, Product A and Product B) obtained in water. * indicates that there is a statistically significant difference with reference.
Figure 3
Figure 3
Absorption rates (ka) obtained experimentally for the API candesartan cilexetil and candesartan cilexetil products (Reference, Product A and Product B). * indicates that there is a statistically significant difference between Product B and the other two products.
Figure 4
Figure 4
Disintegration times of candesartan cilexetil products (Reference, Product A and Product B) (n = 6 tablets/product).
Figure 5
Figure 5
Dissolution profiles of the three products of candesartan cilexetil (Reference, Product A and Product B) obtained in different conditions in USP IV apparatus. In the bottom panel, the Y-axis is limited to 25% to allow a better visualization of the results obtained. T20 = Tween 20, fdiss = fraction dissolved.
Figure 6
Figure 6
Absorption and dissolution profiles of the three products of candesartan cilexetil (Reference, Product A and Product B) represented together in the real time scale. The first panel shows the complete profiles and the second one is limited to time equal to 10 h. fa = fraction absorbed, fdiss = fraction dissolved.
Figure 7
Figure 7
Levy plot and the Inverse Release Functions (IRF).
Figure 8
Figure 8
Absorption and dissolution profiles of the three formulations of candesartan cilexetil (Reference, Product A and Product B) after time scaling. The first panel shows the complete profiles and the second one is limited to time equal to 10 h to facilitate viewing the overlapping of the processes. fa = fraction absorbed, fdiss = fraction dissolved.
Figure 9
Figure 9
Linear two-step in vitro-in vivo correlation.
Figure 10
Figure 10
Polynomial two-step in vitro-in vivo correlation. fabs = fraction absorbed, fdiss = fraction dissolved.
Figure 11
Figure 11
Experimental and predicted candesartan plasma profiles for the three studied formulations using the linear two-step IVIVC and the polynomial two-step IVIVC. Cp = plasma concentration.
Figure 12
Figure 12
Experimental and predicted candesartan plasma profiles for the three studied formulations using the tesc one-step IVIVC and the besc and ESC one-step IVIVC. Cp = plasma concentration.
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