THE SYNTHESIS, HYDROLYSIS KINETICS AND LIPOPHILICITY OF O-ACYL ESTERSOF PROPRANOLOL

The stability-of a series of O-acyl eaters of propranolol, prepared as potential prodrugs, is investigated over the pH range 2.2-9.0 at 37 d egrees C. All compounds were hydrolyzed to yield propranolol. In solut ions of pH greater than or equal to 7, an alternative degradation rout e must be taken into consideration, namely a rearrangement reaction to the N-acyl analogue. The relative importance of the hydrolysis and in tramolecular aminolysis reactions depends on both the pH of the soluti on and the steric properties of the acyl moiety of the eaters. The rel ationship between the Charton steric parameter (v) and the rate of hyd rolysis is investigated. From Arrhenius-type plots, the activation ene rgy (E(a)) and frequency factor (A) were obtained and on the basis of these data, the shelf-lives of the esters were determined at both 10 d egrees C and 25 degrees C. Air the eaters were more lipophilic than pr opranolol in terms of octanol-buffer partition coefficients.