PMID: 7086647Apr 1, 1982

Metronidazole phosphate--a water-soluble prodrug for parenteral solutions of metronidazole

Journal of Pharmaceutical Sciences
M J ChoD J Houser

Abstract

To develop a parenteral solution of relatively water-insoluble metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), its phosphate ester was synthesized via two routes. One route utilized 2-cyanoethyl phosphate and the other utilized pyrophosphoryl tetrachloride. The first method used dicyclohexylcarbodiimide as a coupling agent and the cyanoethyl group was removed under mild alkaline conditions. The second method was a one-step procedure in which free acid of metronidazole phosphate was isolated as a crystalline solid. The solubility of metronidazole in various solvents was determined at 25 degrees. From the pH-dependence of its aqueous solubility, the pKa of the conjugate acid of metronidazole was estimated to be 2.62, which agreed well with the pKa values of other nitroimidazoles. Metronidazole phosphate behaved as a zwitterionic compound in an acidic medium with a minimum solubility at pH 2.0. At pH 7, its solubility was approximately 50 times that of metronidazole. The phosphate ester was so soluble at pH higher than 7 that it was difficult to measure the solubility accurately. In human serum, the hydrolysis of metronidazole phosphate followed zero-order kinetics at an initial concentration of 0.25 mg/ml or higher, pres...Continue Reading

References

Apr 5, 1975·Lancet·B Ursing, C Kamme
Jul 10, 1976·Lancet·J E HaleG Smith
Mar 1, 1975·Clinical Obstetrics and Gynecology·W M McCormack
Feb 1, 1975·Journal of Pharmaceutical Sciences·A A Sinkula, S H Yalkowsky
Sep 1, 1975·Journal of Pharmaceutical Sciences·W F Beyer, D D Gleason
Dec 1, 1969·Journal of Pharmaceutical Sciences·W MorozowichE L Rowe

Citations

May 6, 2003·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Juha JuntunenT Järvinen
Jul 26, 2005·Il Farmaco·Cinzia BersaniFrancesco Maria Veronese
Sep 1, 1984·Journal of Dental Research·G GolombM N Sela
Jan 10, 2002·Journal of Pharmaceutical Sciences·Patrick Poulin, Frank-Peter Theil
Sep 1, 1986·Drug Intelligence & Clinical Pharmacy·G G Raymond, J L Born
Apr 1, 2014·Journal of Biomaterials Applications·Meenakshi PathakAllan G A Coombes

Related Concepts

Hydrolysis
Parenteral Infusion
Bayer 5360
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