Stability and kinetics of hydrolysis of metronidazole monosuccinate in aqueous solution and in plasma

The kinetics of hydrolysis of metronidazole monosuccinate in aqueous solution at pH 1.5–10 and 60°C has been investigated. The decomposition was monitored by a high-performance liquid chromatographic method capable of determining the monosuccinate ester and the parent metronidazole simultaneously. At any given pH the reactions displayed strict first-order kinetics and were subject to specific acid-base catalysis; no general acid-base catalytic effect by various buffer substances was observed. Maximal stability was observed at pH 3–6, where the degradation rate was independent of pH indicating that intramolecular catalysis by the terminal carboxylate ion on the ester group is not involved in the hydrolysis reactions in this pH range. The lack of intramolecular catalysis is suggested to be due to the poor leaving ability of the strongly basic metronidazole alkoxide ion.The rates of conversion of the ester to metronidazole at 37°C in 80% human plasma and in 0.05 M phosphate buffer pH 7.40, respectively, were found to be nearly identical, $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$~ 580 h, revealing that the degradation in plasma proceeds in the absence of enzymatic catalysis.