The Effect of Chain Length on the Stabilization Due to Self-Association of Steroid 21-Hemiesters
Johnson, Kevin C.
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Many drugs, such as aspirin, contain ester functional groups and are derivatives of carboxylic acids. Garrett and others have studied the esterification of 21-hydroxysteroids with dicarboxylic acids as a method to develop injectables. Garrett foresaw the importance of developing hemiesters of steroids that combine the desirable properties of adequate solubility, stability, and biological activity. Methylprednisolone is a biologically active steroid used in the treatment of acute hypersensitivity and dermatologic conditions. Methyl prednisolone, however,is virtually insoluble in water and unsuitable for injection. For this reason, methylprednisolone 21-hemisuccinate II was developed as an ionizable pro-moiety to aid in the solubilization of the steroid. Shortly after injection, esterases in the body cleave the ester linkage to give free methylprednisolone which can then perform its biological function. The results from this study show that increasing the chain length of the hemiester is a successful way to increase the aqueous stability of these compounds. Relative to the hemisuccinate, only about a 5-fold decrease in the rate of hydrolysis was observed in the case of the hemioctanedioate as compared to a 200 fold decrease in the case of the hemidodecanedioate.