Cai X, Grant D J, Wiedmann T S
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455-0343, USA.
J Pharm Sci. 1997 Mar;86(3):372-7. doi: 10.1021/js9602148.
Bile salt mixed micelles play an important role in the emulsification, solubilization, and absorption of cholesterol, fats, and lipid-soluble vitamins. Studies have also revealed the importance of wetting and solubilization of drugs by the bile salts; however, the capacity and specificity of bile salt simple and mixed micelles for solubilization are still undefined. Thus, in this study the aqueous solubility and the extent of solubilization in bile salt micellar solutions of a series of steroids were determined. The melting point and enthalpy of fusion were measured to determine the ideal mole fraction solubility of each steroid. From the ideal mole fraction solubility and the observed solubility of each steroid, the activity coefficient of each steroid in solution was calculated with respect to the supercooled pure liquid as the standard state. In aqueous solution, the activity coefficients decreased with increasing number of hydroxyl groups on the steroids. This trend also occurred in the bile salt solutions, although the values of the activity coefficients were smaller by about three orders of magnitude. The stereochemical position of the hydroxyl groups influenced the rank order of the activity coefficients in the aqueous and micellar solutions. Incorporation of a fluoro or methyl group resulted in an increase in the activity coefficient, whereas aromatization of the A ring of the steroid frame markedly decreased the activity coefficient. The results for the aqueous solubility are consistent with the expected interaction of the functional groups with the polar environment. The relatively small activity coefficients observed with the micellar solutions result from the nonpolar environment of the aggregates. However, the similarity of the relationship between the activity coefficient and the number of hydroxyl groups in the aqueous and micellar solutions indicates the importance of polar interactions for solubilization. These results may provide new insight into the solubilization of steroids by bile salt micellar solutions and may provide a basis for predicting solubilization of other compounds by bile salt aggregates.
胆汁盐混合微团在胆固醇、脂肪及脂溶性维生素的乳化、增溶和吸收过程中发挥着重要作用。研究还揭示了胆汁盐对药物的润湿和增溶作用的重要性；然而，胆汁盐单微团和混合微团的增溶能力及特异性仍不明确。因此，在本研究中测定了一系列甾体化合物在胆汁盐微团溶液中的水溶性及增溶程度。测量了熔点和熔化焓以确定每种甾体化合物的理想摩尔分数溶解度。根据每种甾体化合物的理想摩尔分数溶解度和观察到的溶解度，以过冷纯液体为标准态计算了溶液中每种甾体化合物的活度系数。在水溶液中，活度系数随甾体化合物上羟基数量的增加而降低。在胆汁盐溶液中也出现了这种趋势，尽管活度系数的值小了约三个数量级。羟基的立体化学位置影响了水溶液和微团溶液中活度系数的排序。引入氟或甲基会导致活度系数增加，而甾体骨架A环的芳构化则会显著降低活度系数。水溶性的结果与官能团与极性环境的预期相互作用一致。在微团溶液中观察到的相对较小的活度系数是由聚集体的非极性环境导致的。然而，水溶液和微团溶液中活度系数与羟基数量之间关系的相似性表明极性相互作用对增溶的重要性。这些结果可能为胆汁盐微团溶液对甾体化合物的增溶作用提供新的见解，并可能为预测胆汁盐聚集体对其他化合物的增溶作用提供依据。
