PRODRUGS AS DRUG DELIVERY SYSTEMS .27. CHEMICAL-STABILITY AND BIOAVAILABILITY OF A WATER-SOLUBLE PRODRUG OF METRONIDAZOLE FOR PARENTERAL ADMINISTRATION

The hydrochloride salt of the N,N-dimethylglycine ester of metronidazole was previously identified as a prodrug candidate as a parenteral delivery form of metronidazole [an antibacterial agent]. In this study, the bioavailability of metronidazole from the ester after i.v. administration was evaluated in beagle dogs and the kinetics of degradation of the ester in aqueous solution was examined. The ester is rapidly and completely converted to metronidazole after i.v. injection of a 13% w/v [wt/vol] aqueous solution and the metabolism and elimination pattern of the parent drug remain similar to that following administration of metronidazole per se. The kinetics of degradation was studied in aqueous solution over the pH range 1-10. The ester hydrolyzed quantitatively to metronidazole with maximum stability at pH < 4. It would not be suitably stable for formulation as a ready-to-use solution but its stability at pH .apprx. 4.5 (corresponding to the pH of 5-20% w/v solutions) is compatible with its use as a formulation to be reconstituted as a solution within several h prior to use.