Anderson B D, Conradi R A, Johnson K
J Pharm Sci. 1983 Apr;72(4):448-54. doi: 10.1002/jps.2600720431.
Self-association of drug molecules at formulation concentrations can have a major impact on formulation properties. In this study a homologous series of methylprednisolone 21-hemiesters were found to undergo self-association in aqueous solution. The effect of aggregate formation on the solution degradation of these compounds was examined. To determine the nature and extent of association of these steroidal esters, partition coefficients between butyronitrile and aqueous buffer (pH 8.5) were measured as a function of ester concentration. The partitioning data were found to be consistent with dimer formation at low concentration followed by true micelle formation at higher concentration. Chain length increases favored micelle formation, but appeared to have little effect on dimerization. The first-order rate constants for ester hydrolysis and 21 leads to 17 acyl migration in aqueous buffer (pH 8.5) were also found to be dependent on ester concentration. The kinetic data are consistent with a model which assumes stabilization by both dimer and micelle formation, the limiting factor at high concentration being the reactivity of the ester in the micelles. The degree of stabilization due to self-association was found to increase with chain length.
药物分子在制剂浓度下的自缔合会对制剂性质产生重大影响。在本研究中，发现一系列甲基泼尼松龙21 - 半酯在水溶液中会发生自缔合。研究了聚集体形成对这些化合物溶液降解的影响。为了确定这些甾体酯缔合的性质和程度，测量了丁腈与水性缓冲液（pH 8.5）之间的分配系数作为酯浓度的函数。发现分配数据与低浓度下形成二聚体，随后在较高浓度下形成真正的胶束一致。链长增加有利于胶束形成，但对二聚化似乎影响不大。还发现酯水解和21→17酰基迁移在水性缓冲液（pH 8.5）中的一级速率常数取决于酯浓度。动力学数据与一个模型一致，该模型假定通过二聚体和胶束形成实现稳定，高浓度下的限制因素是酯在胶束中的反应性。发现由于自缔合导致的稳定程度随链长增加而增加。
