Biopharmaceutical relevance of the comparison of dissolution profiles: proposal of a combined approach

Abstract

The aim of the present study was to analyze comparatively the performance of the main methods proposed for the comparison of percent dissolved vs. time curves, and to propose a more biorrelevant combined-approach for the comparison of dissolution profiles of multisource drug products. In vitro dissolution tests of four brands of Oxcarbazepine (OxCBZ) tablets were performed, and the resulting profiles were compared by model independent, model dependent and ANOVA-based statistical methods. After a careful analysis of the results, some methods were chosen and applied to the comparison of dissolution profiles of four brands of Carbamazepine (CBZ) tablets and two brands of Phenytoin (PHT) capsules. Finally, these in vitro results were qualitatively correlated with the corresponding in vivo results previously obtained with the same CBZ and PHT products assayed in healthy volunteers. The analysis of the dissolution data obtained with OxCBZ tablets allowed discarding the ANOVA-based statistical methods since in all cases they were over-discriminating from a biopharmaceutical point of view. When the remaining comparison methods were applied to in vitro profiles of CBZ and PHT products and the results correlated with in vivo data, the most suitable methods for the biopharmaceutical comparison of in vitro dissolution profiles proved to be the model independent ones, and among them the best correlations were found for the f2 similarity factor along with a measure of the dissolution extent (e.g., area under the curve). This combined approach gives a robust and informative result, with the most biopharmaceutical relevance.