Cholesterol monohydrate dissolution rates and solubilities in aqueous taurocholate, taurochenodeoxycholate, and tauroursodeoxycholate solutions: A comparative study

Abstract A comparative study of the cholesterol monohydrate (ChM) dissolution rates ( J A ) and solubilities (CChMS) has been carried out in aqueous solutions of taurocholate (TC), taurochenodeoxycholate (TCDC), and tauroursodeoxycholate (TUDC) over a wide range of bile salt (BS) concentrations (from 20 to 120 mM) and at three added sodium chloride levels, 0, 0.2, and 0.4 M. After correcting for total sodium ion concentration, the initial dissolution rate and the rate constant (kS) obtained in static disk experiments were found to be bile salt species dependent and varied in the order TCDC > TC ⪢ TUDC at low Na+ and bile salt concentrations. However, at high Na+ and bile salt concentrations, the order changed to TC ⩾ TCDC ⪢ TUDC. Furthermore, the bile salt concentration dependence of J A values was nonlinear and showed a negative curvature for TCDC and TUDC at bile salt concentrations above 40 mM, but was more linear for TC. The CChMS values were also found to be dependent on bile salt species, Na+, and bile salt concentrations. Their ranking and different curvature closely paralleled those of J A values. The CChMS data were analyzed in terms of the solubilization ratio (nChM:nBS) in order to account for the contrasting ChM solubilization behaviors and capacities observed for the three bile salts over the investigated range of Na+ and bile salt concentrations. At saturation, all three bile salts have fewer than one cholesterol per micelle. The much poorer ChM solubilization capacity of TUDC than that of the other bile salts is consistent with the view that the β orientation of its 7-OH group reduces the effective hydrophobicity of the micellar surface and thereby decreases the surface adsorption of cholesterol. It is further suggested that the dependence of ChM solubilization ratio on bile salt concentration and added NaCl may reflect subtle changes in the size and surface structure of the micelles (primary-secondary micelle formation) associated with these variables. The close parallelism between the J A and the CChMS values leads to nearly identical values for the resistance to dissolution (R) at constant Na+ and bile salt concentrations for the three taurine-conjugated bile salts. On the basis of static disk dissolution rate studies made in the presence of benzalkonium chloride (BC) and additional rotating disk experiments, it was concluded that the relative constancy of R comes primarily from the resistance of the crystal-solution interface rather than from the micellar diffusion across the aqueous boundary layer. Regarding the physical nature of the interfacial barrier, the present study reconfirms our previous finding that the electrostatic repulsion between negatively charged micelles and a negatively charged crystal surface plays a key role. However, we do not rule out contributions from other possible nonelectrical mechanisms. The results of the present study strongly support the hypothesis that the rate-determining step in the interfacial kinetics of ChM dissolution in the three taurine-conjugated bile salt solutions involves the collision complex mechanism rather than a free solute mechanism.