Kinetics of azathioprine degradation in aqueous solution

Abstract

The kinetics of decomposition of azathioprine to 6-mercaptopurine was studied as a model reaction to assess the suitability of thioether derivatives as potential prodrugs for compounds containing thiol functionality. The rates of decomposition yielding 6-mercaptopurine and 1-methyl-4-nitro-5-hydroxyimidazole in stoichiometric amounts were determined at 73° C over the pH range of 1–13 at an ionic strength of 0.5. The pH-rate profile was accounted for by the specific acid- and base-catalyzed reactions and also by assuming spontaneous or water-catalyzed decomposition of both undissociated and dissociated azathioprine. Maximum stability occurred at pH 5.5–6.5 in which region water was the principal catalyst in the decomposition pathway. Various buffer substances were found to exhibit general acid and base catalysis of the degradation. The effects of temperature and ionic strength on the reaction rates were also evaluated. The principal mode of azathioprine degradation may be the cleavage of the carbon sulfur bond by direct nucleophilic attack of the water molecule or the hydroxide ion on the carbon atom at the 5-position of the methyl-nitro-imidazole ring.