Beta-Cyclodextrin/Steroid Complexation: Effect of Steroid Structure on Association Equilibria

Abstract

Molecular associations of beta-cyclodextrin (beta-CyD) with four steroids (cortisone, hydrocortisone, progesterone, and testosterone) have been studied using phase-solubility and spectroscopic techniques. Phase solubility diagrams could be categorized as B type. The complexes are formed at the stoichiometric ratios of 1:2 (drug:beta-CyD). A mathematical model has been proposed to calculate the apparent stability constants. The results suggest that the inclusion of a steroid molecule into the first beta-CyD cavity is thermodynamically more favorable over the association of 1:1 complex with the second beta-CyD molecule except for cortisone, which exhibits anomalous behavior. A mechanism of complexation has been proposed based on the apparent stability constants and chemical structures of the steroids and beta-CyD. It suggests that complexation is first brought about by inclusion of the five-member cyclopentane ring of the steroid molecule into the first beta-CyD cavity. The 1:1 complex subsequently binds with the second beta-CyD to form the 1:2 complex. The association constants of steroid/beta-CyD complexes are of the following order: progesterone > cortisone > testosterone > hydrocortisone. The order of aqueous solubilities of the complexes is hydrocortisone > cortisone > testosterone > progesterone.