Hydrolysis of Lincomycin-2-phosphate and Clindamycin-2-Phosphate

Abstract

The aqueous stabilities of lincomycin-2-phosphate and its 7-deoxy-7(S)-chloro analog, clindamycin-2-phosphate, were studied at a variety of temperatures and pH values. The predominant degradative routes of lincomycin-2-phosphate in the pH range 1-10 are thioglycoside and phosphate ester hydrolysis, and pH-rate studies show that it is most stable at pH 6-10. Clindamycin-2-phosphate degrades by three major routes from pH 1 to 10 with phosphate ester and thioglycoside hydrolysis predominating at pH less than 6 and scission of 7(S)-Cl to form the 7(R)-OH analog predominating at pH greater than 6. The rate of 7(S)-Cl to 7(R)-OH conversion was obtained using gas chromatography to measure the disappearance of clindamycin in reaction mixtures prepared under identical conditions as clindamycin-2-phosphate reaction mixtures. Rates of phosphate ester hydrolysis of the two compounds were measured by spectrophotometric determination of the amount of inorganic phosphate formed in reaction mixtures as a function of time. Apparent first-order rate constants of phosphate ester hydrolysis as well as activation energies (32.1 kcal./mole for lincomy-cin-2-phosphate and 32.9 kcal./mole for clindamycin-2-phosphate) agree favorably. The rate of lincomycin-2-phosphate hydrolysis in a formulated pediatric syrup at room temperature agrees favorably with extrapolated rates from high temperature hydrolysis in simple solutions.