Evaluation of Hydroxyethyl Esters of Mefenamic Acid and Diclofenac as Prodrugs

Hydroxyethyl esters of diclofenac and mefenamic acid were prepared with the aim of obtaining enzymatically labile prodrugs, and their stability was evaluated in aqueous buffer solutions of pH 7.4, 1 N HCl, and also in human plasma. The hydrolytic degradation of diclofenac ester in aqueous buffer solutions was slow, as shown by t1/2 values greater than 22 hr, while rapid enzymatic hydrolysis occurred in the plasma (t1/2 = 1.12 hr). However, the mefenamic acid ester showed a relatively higher stability in buffer solutions (t1/2 greater than 38 hr at pH 10) as well as in the plasma (t1/2 = 7.28 hr) compared with the diclofenac ester. Therefore, the mefenamic acid ester would not be considered suitable as a prodrug.