Complexation of 6-ACYL-O-β-Cyclodextrin derivatives with steroids - effects of chain length and substitution degree

Abstract

This study was designed to test a hypothesis that the esterification of the primary 6-hydroxyl groups on β-cyclodextrin (β-CD) may disrupt its crystallinity, thereby enhancing its aqueous solubility and increasing its ability to solubilize water-insoluble compounds. 6-acyl-o-β-CD derivatives with different chain length and substitution degree were synthesized by esterifying the primary hydroxyl groups at 6-position of β-CD with various acyl chlorides. X-ray diffraction patterns confirmed the existence of 6-acyl-o-β-CD derivatives as amorphous solid. Effects of chain length and substitution degree of the acyl groups on 6-acyl-o-β-CD/steroid complexation and solubilization were investigated with the phase solubility method. The results indicated that the solubilities of 6-acyl-o-β-CD derivatives were significantly higher than that of β-CD itself, which resulted in an increase in their ability to solubilize poorly water-soluble drugs such as steroids. The addition of side chains to β-CD did not change the stoichiometric ratio (2:1) of β-CD/steroid complexes. The increase in chain length can enhance the association of 6-acyl-o-β-CDs with steroids as it was evidenced from the apparent stability constants. A solubility study utilizing different combinations of 6-acyl-o-β-CDs, α-CD and 2,6- dimethyl-o-β-CD suggested a competitive complexation process among the family of acyl-β-CD derivatives. A non-competitive steroid complexation between 6-acyl-o-β-CDs and α-CD and between 6-acyl-o-β-CDs and 2,6-dimethyl-o-β-CD was observed.