Comparative Analysis of Acyclovir Esters Stability in Solutions: The Influence of the Substituent Structure, Kinetics, and Steric Effects

Abstract

Reversed‐phase high‐performance liquid chromatography has been applied to the determination of acyclovir (ACV) esters such as acetate, isobutyrate, pivalate, ethoxycarbonate, and nicotinate. All analyses were carried out at laboratory temperature using a column LiChrospher RP‐18 (250 × 4 mm, 5 µm) and a proper mobile phase consisting of acetonitrile and phosphate buffer (pH 6 or 6.7) or acetonitrile and potassium dihydrogen phosphate, and acetic acid. The methods were validated by the determination of the following parameters: selectivity, precision, accuracy, and linearity. Kinetic studies on the hydrolysis were investigated in solutions at 310 K over the pH range 0.42–1.38. The pH‐profiles indicated specific acid‐catalyzed and spontaneous water‐catalyzed degradation. The stability of the studied ACV esters were determined not only by steric factors. In the case of ethoxycarbonyl ester of ACV, the hydrolysis was a two‐step reaction.

Comparative analysis of stability of tricyclic analogues of acyclovir in an acidic environment

“…The result of such reaction is the formation of 6-(4-MeOPh)-TACV and carbonic acid. The above-mentioned reaction mechanism is compliant with the mechanism previously described for ACV esters [24]. The 6-(4-MeOPh)-TACV compound created as a product of the hydrolysis of tricyclic esters in the studied conditions is a subject to further decomposition in the follow-up reaction (Scheme 1a).…”

“…The steric factors for the studied substituents were calculated, taking into consideration the k H + value determined for ACV esters. Their values were as follows: [24]. Negative values demonstrate that the above-mentioned substituents decrease the esters hydrolysis rate.…”

“…The studies on decomposition of the analysed compounds in the acidic environment enabled to determine the kinetic parameters of the observed reactions. While comparing the results of the analysis of the ACV stability in analogous conditions [24], it was observed that the rate constant of analogous ACV and 6-(4-MeOPh)-TACV esters (except for nicotinic esters) are similar, and it was stated that the presence of an additional ring in the structure of tricyclic analogues does not have influence on the vulnerability of esters on the hydrolysis under the influence of hydrogen ions as catalytic factors. On the other hand, the spatial structure of substituents in the ester part has a significant influence on the rate of hydrolysis of the studied compounds in the acidic environment.…”