Mechanistic Study of Cholesterol Monohydrate Dissolution in Aqueous Bile Salt-Lecithin Systems.

Abstract

The interfacially controlled dissolution of cholesterol monohydrate in simulated bile solutions was studied. It was found that in almost all of the situations the rates of dissolution in ursodeoxycholate (UDC) containing solutions were much slower than in chenodeoxycholate (CDC) or cholate (C) containing solutions. During dissolution in bile salt-lecithin solution, a phase transition from the micellar phase to a mesomorphic liquid crystalline phase was found using polarizing microscopy in the UDC containing solutions but not in the CDC or C solutions in physiological bile salt-lecithin concentration ranges. In the presence of actual cholesterol gallstones, the formation of mesophase was also found in the UDC medium, in mixed bile salt-lecithin solutions and in reconstituted UDC enriched human duodenal bile. The formation and subsequent dispersion of the mesophase formed in vivo may contribute to the total dissolution/disintegration of solid phase cholesterol and affect mass transfer significantly beyond the micellar phase saturation limit. The simple micelle-mixed micelle equilibria and how this is related to the dissolution rate of cholesterol monohydrate in bile acid-lecithin solutions were investigated for the taurocholate (TC)-lecithin system. The TC and lecithin concentrations were determined using a two-chamber dialysis cell or a dialysis bag apparatus. The bile salt-lecithin ratios for the mixed micelles were calculated over wide ranges of bile salt and lecithin concentrations. These data were then used in the analysis of the dissolution rate data. Clearly, the analysis revealed that, for the TC-L system, the simple TC micelle was the important rate-limiting species in cholesterol dissolution. A similar analysis of the tauroursodeoxycholate (TUDC)-lecithin system was not possible because of very long equilibration times in the dialysis experiments. On the basis of the dissolution rate data alone, however, it is believed that either (a) mixed micelles are significantly important in the dissolution kinetics for this system or (b) lecithin adsorption on the cholesterol crystal surface may enhance the rate of cholesterol dissolution in TUDC-lecithin systems. The main results of this research, viz., mesophase formation in UDC containing medium during the cholesterol dissolution and the analysis of dissolution kinetics based on roles played by each micellar species, are believed to be useful in future mechanistic studies of cholesterol dissolution in bile solutions.