Influence of premicellar and micellar association on the reactivity of methylprednisolone 21-hemiesters in aqueous solution

Article abstract of 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 → 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.