Alkaline hydrolysis of methyl, ethyl and n-propyl 4-hydroxybenzoate esters in the liquid and frozen states

Abstract

The alkaline hydrolysis of the methyl, ethyl and n-propyl esters of 4-hydroxybenzoic acid was studied in the liquid and frozen states in sodium hydroxide solutions. The temperature range was −26 to 60°C. Significant acceleration of the reaction rate was evident in the frozen state compared with rates found at liquid state temperatures. The maximum reaction rate in the frozen state occurred in the temperature range −12 to −10°C. Methyl 4-hydroxybenzoate showed more than a 20-fold increased rate constant from 7.17 × 10−6 s−1 at 30°C to 1.53 × 10−4 s−1 at −9°C in a 1.00 × 10−2 M solution of sodium hydroxide. Rate constants in the liquid and frozen states followed pseudo first-order kinetics over 2–4 half-lives of reaction. Data were fitted to a theoretical model describing the reaction rate in the frozen state as dependent upon the increased concentration of solutes in liquid vesicles in the frozen state and the predicted reduction in the reaction rate constant with temperature decrease. Although the data exhibited similar trends to that predicted by the model, there was frequently a 50% difference in the rates observed compared with those predicted. This study has clearly demonstrated that there is a significantly increased rate of hydrolysis of these esters in the frozen state. This is a further indication that it cannot be assumed that drugs stored in solution will necessarily be stabilized, or their stability enhanced, on freezing. Storage under refrigeration conditions (4–8°C) results in enhanced shelf-lives compared with deep-freeze storage at −20°C under the conditions of this study.