Kinetics of hydrolysis of indomethacin and indomethacin ester prodrugs in aqueous solution.

The kinetics of hydrolysis of indomethacin and a glycolamide ester of the drug was studied to assess the possibility of designing a water-soluble and solution-stable prodrug of indomethacin suitable for parenteral or ocular administration. The pH-rate profiles for these compounds were obtained at 60 degrees C and were accounted for by specific acid and base catalytic reactions as well as by a water-catalyzed hydrolysis. From temperature-accelerated studies, pH-rate profiles at 25 degrees C were predicted. Indomethacin and its ester showed maximal stability at pH 4.9 and 4.7, respectively, the shelf lives at these pH values and 25 degrees C being 2.0 years for indomethacin but only 43 days for the ester. The ester degrades both at its ester group and at the indole amide group of the indomethacin moiety, and shows a very pronounced water-catalyzed hydrolysis which accounts for the limited stability. It is concluded that the design of an indomethacin ester prodrug with a stability allowing formulation of a ready-to-use aqueous solution may be difficult.