Kinetics and Factors Affecting Stability of Methylprednisolone in Aqueous Formulation

An investigation was made of the factors affecting the rate of degradation of methylprednisolone solubilized by polysorbate 80 in an aqueous formulation containing polar additives and a sequestering agent as a function of temperature at pH 4.6 and 5.1. The presence of polar additives decreased the apparent solubility of methylprednisolone in one formulation at pH 4.6 and 25°. However, since methylprednisolone was in solution, but not within the polyoxyethylene exterior of the polysorbate 80 micelles, it degraded at a faster rate. By selecting the proper concentration of polysorbate 80 and adjusting to the same pH of 4.6 in another formulation, the autoxidative degradation rate of the primary alcoholic group at C-21 was reduced to approximately half even in the presence of oxygen. The increase in stability was also evident from the increase of the apparent activation energy from 18.2 to 23.1 kcal./mole. The mechanism of solubilization and stabilization based on hydrogen bonding and inclusion into the polyoxyethylene exterior of the polysorbate 80 micelles is proposed.