Kinetics of the acid-catalyzed hydrolysis of acyclovir and an ester prodrug in aqueous solution.

Abstract

The kinetics of hydrolysis of acyclovir was studied in 0.01-0.5 M hydrochloric acid solutions (pH 0.5-2.2) at 80 degrees C. The hydrolytic cleavage of the 9-C-N bond in acyclovir to give guanine was found to proceed almost quantitatively (greater than 90%) as evidenced by HPLC analysis. The rate of hydrolysis was subject to apparent specific acid catalysis, the specific hydrogen ion catalytic rate constant being 4.9 x 10(-2) M-1 min-1 at 80 degrees C and mu = 0.5. The possible significance of acid-catalyzed hydrolysis for the stability of acyclovir during its transit through the stomach after peroral administration was found to be negligible. A novel 4-(morpholinomethyl)benzoate ester prodrug of acyclovir was found to be three times more stable in acidic solutions than acyclovir itself despite the ester group being an additional site of degradation. The dominating degradation reaction of the ester was found to be cleavage of the 9-C-N bond. The higher stability of the ester was ascribed to the greater electron-withdrawing effect of the ester group relative to the hydroxyl group which decreases the tendency of the 9-C-N bond to be ruptured by an A-1 mechanism.