A genuine clotrimazole γ-cyclodextrin inclusion complex-isolation, antimycotic activity, toxicity and an unusual dissolution rate

Abstract

A crystalline clotrimazole γ-cyclodextrin inclusion complex, molar ratio 1:1.0, was isolated from phosphate buffer 0.05 M, pH 7.1. Due to the low water solubility of the inclusion complex, the clotrimazole dissolution rate from the complex was very low. However, application of a new method to disclose supersaturation phenomena showed that the complex gave rise to a profound clotrimazole supersaturation during the dissolution rate test. Probably, the clotrimazole supersaturation was the reason why the inclusion complex had higher antimycotic activity than both clotrimazole and a physical mixture of clotrimazole and γ-cyclodextrin, molar ratio 1:1.0. In addition, the inclusion complex was the most toxic on human erythrocytes and on non-differentiated monolayers of epithelial like human TR146 cells. On the other hand, no difference in the toxicity of the inclusion complex, the physical mixture and clotrimazole was observable when robust multilayers of differentiated TR146 cells were exposed to the compounds.