Degradation kinetics of metronidazole and its mutual prodrug with ciprofloxacin: a calorimetric analysis

Abstract

Calorimetric technique has aroused considerable interest as a versatile tool in pharmaceutical industry and academia to provide useful information about thermodynamic and kinetic aspects of drug molecules. The present paper utilizes this technique to monitor the hydrolytic degradation of metronidazole and its prodrug with ciprofloxacin, i.e. 2-(2-methyl-5-nitroimidazol-1-yl)ethyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylate. The synthesis of the present mutual prodrug was envisaged to combine the antiprotozoal and anaerobic antibacterial effects of metronidazole with antibacterial effects of ciprofloxacin. Heat flux microcalorimeter was used to determine the rate of heat evolved during the degradation of the drug and prodrug as a function of concentration, pH and temperature. In terms of enthalpy of hydrolysis the response is exothermic both for drug and prodrug. However, the absolute value of the enthalpy of reaction (ΔrH0) is low for the prodrug. The degradation followed pseudo first order kinetics, showed marked stability at pH 3-7 followed by accelerated hydrolysis at higher pH, characteristic of general acid-base catalysis. The catalytic rate constant for hydrogen ion (kH) and hydroxyl ion (kOH) were found to be 0.413 and 526.1 M^-1h^-1, respectively, at 318.15 K. The hydrolysis of the prodrug was found to be approximately 50-60 times faster than that of the drug. This may be attributed to the fact that hydrolysis of ester group in prodrug is assisted by keto group on the ciprofloxacin. However, there is no effect of protonation of nitrogen in piperazine ring in ciprofloxacin on the hydrolysis due to the distance from the ester moiety.

Keywords: Calorimetry, stability studies, degradation kinetics, ciprofloxacin, metronidazole.

International Journal of Biological and Chemical Sciences Vol. 1 (3) 2007: pp.197-210