Steep improvement in dissolution profile of ezetimibe through co-inclusion in urea

Abstract

The main objective of the present study was to simultaneously improve the dissolution profile and content uniformity of ezetimibe (EZ), a low dose poorly soluble drug, through co-inclusion in urea. EZ, a new category of cholesterol absorption inhibitor used in the treatment of primary hypercholesterolemia and sitosterolemia, reveals extremely poor solubility in water and dissolution rate limited absorption resulting in its low bioavailability. In the current study, EZ—a highly substituted potent compound which is normally non-complexing guest (NNCG) was successfully incorporated in urea lattice in the presence of readily complexing guest (RCG). The modified Zimmerschied calorimetric method was used for the estimation of the minimum amount of RCG required per unit weight of drug for co-inclusion in urea. Ezetimibe urea co-inclusion complexes (EZUCIC) containing varying proportions of RCG and NNCG were prepared and subjected to thermal analysis using DSC. The formation of EZUCIC was confirmed by FTIR, DSC, XRD and 1H-NMR studies. The thermal data was subjected to the regression studies to study the effect of the relative molar fraction of RCG on the heat of decomposition of EZUCIC. Study exhibited improved content uniformity of EZ in EZUCIC. In vitro dissolution rate studies exhibited steep improvement in the dissolution profile of EZ, a BCS class II drug. The dissolution data was subjected to various release kinetic models. Steep improvement in the dissolution profile offer urea co-inclusion technique a promising alternative for formulation of poorly soluble potent drug candidates into immediate release products with improved content uniformity.