Cyclodextrin-catalyzed deacetylation of spironolactone is pH and cyclodextrin dependent

The complexation of spironolactone (SP) with cyclodextrins (CDs) and the effect of pH on the CD catalyzed deacetylation of SP was studied in the presence of beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), sulfobutylether-beta-cyclodextrin ([SBE](7m)-beta-CD), gamma-cyclodextrin (gamma-CD), and sulfobutylether gamma-cyclodextrin (SBE-gamma-CD). The complexation of SP with beta-CD and the mechanism of deacetylation was confirmed using NMR. The complexation of SP with CDs was determined by means of the phase-solubility method at pH 2, in which chemical degradation was minimal. The phase-solubility diagrams were classified as A(L)-type and the apparent stability constants (K(1:1)) for 1 : 1 inclusion complex were calculated to be 9939 M(-1), 10,976 M(-1), 15,816 M(-1), 4792 M(-1) and 4118 M(-1) for beta-CD, HP-beta-CD, (SBE)(7m)-beta-CD, gamma-CD, and SBE-gamma-CD, respectively. The effect of pH on the degradation rate of SP was studied in the presence and absence of 4.4 mM CD solutions at pH 4, 5, 6, 7, and 8 (25 degrees C). The stability studies showed that CD-catalyzed degradation of SP can be decreased by lowering the pH. The pH-rate profiles of SP degradation with different CDs gave slopes of 1.0. Because no buffer catalysis was observed, the reaction appears to be specific-base catalyzed. The catalytic activity of CDs was as follows: SBE-gamma-CD < (SBE)(7m)-beta-CD < HP-beta-CD approximately gamma-CD < beta-CD. NMR studies confirmed that SP forms an inclusion complex with beta-CD and complexation occurs by means of the secondary face. The NMR studies also showed that during the deacetylation of SP, the secondary hydroxyl groups of beta-CD at the 2- and 3-position were acetylated. The decrease of catalytic activity of CDs at low pH values and the CDs differing ability to catalyze the degradation of SP correlated qualitatively with the ionization state of the CD hydroxyl groups, which were lower in SBE-CDs. The site of binding differences and the number of hydroxyl groups present probably also contribute to the differences.