Macromolecular prodrugs IV. Kinetics of hydrolysis of metronidazole monosuccinate dextran ester conjugates in aqueous solution and in plasma — sequential release of metronidazole from the conjugates at physiological pH

Abstract

The kinetics of hydrolysis of metronidazole monosuccinate dextran ester conjugates in aqueous solution over the pH range 6.61–7.80 (37°C) has been investigated. As demonstrated by HPLC the degradation of the dextran conjugates proceeds through parallel formation of metronidazole and metronidazole monosuccinate, respectively. The regeneration rates of the latter compounds followed first-order kinetics. The pH dependence of the various rate constants showed almost parallel straight line portions with slopes varying from 0.93 to 0.95, indicating that the hydrolysis reactions were subject to specific base catalysis. A 5-fold increase in the hydrolysis rate of the metronidazole-spacer arm ester bond compared to the stability of metronidazole monosuccinate, per se, was observed. Similarly, the carbohydrate succinic acid ester linkage showed greater susceptibility to undergo degradation at neutral pH in proportion to corresponding aliphatic ester derivatives, suggesting participation of intramolecular catalysis in the hydrolysis of the conjugate ester bonds by the neighbouring carbohydrate hydroxy groups. Almost identical stability of the conjugates was observed after incubation in 0.05 M phosphate buffer pH 7.40 and in 80% human plasma ( t 1 2 ~ 32 h at 37° C) revealing that the hydrolysis in plasma proceeds without enzymatic catalysis.