The hydrolysis of azidoprofen esters: A model for a soft anti-inflammatory drug for topical application

Abstract

A series of ester prodrugs of azidoprofen was investigated for susceptibility towards in vitro enzymatic and chemical hydrolysis. In each case, the parent acid was regenerated with the rate and extent of the process being dependent on the nature of the ester moiety. All esters, with the exception of the glycolamide derivative, exhibited much greater lability towards enzyme-mediated hydrolysis compared to chemical decomposition. In particular, the tetrahydropyranylmethyl ester showed the largest difference in sensitivity towards these two processes. This specificity is an important requirement in prodrug design and indicates the capacity to undergo rapid metabolic activation while exhibiting stability under conditions encountered during formulation and storage. The ability of skin to activate these prodrugs was demonstrated by hydrolysis of the methyl ester of azidoprofen on incubation with a hairless mouse skin homogenate. In addition, when enzymatic hydrolysis was monitored in aqueous alcoholic systems competitive hydrolysis and enzyme-mediated transesterification were observed. The rate of both processes increased with a longer chain ester and transesterification was the predominant reaction. Eventually, the new ester also underwent enzyme-mediated hydrolysis to yield azidoprofen.