Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies (II) Methods to evaluate the microcalorimetric response

Abstract

In this study, a well-known reaction, the hydrolysis of acetylsalicylic acid in aqueous solutions between pH 1.9 and 7.5 at 40.0 and 50.0°C, has been investigated by a microcalorimetric technique. The heat flow produced from the reaction was monitored as a function of time, and the degradation rate constant was then calculated from the slope. The precision was evaluated by repeated measurements at 40.0 and 50.0°C, respectively. The obtained rate constant-pH profile had the same general appearance as has been reported earlier for other temperatures. At 40.0°C and in the pH region of maximum stability the value of the rate constant showed low precision, because of a small heat flow change. As alternatives, the heat flow-time curves were evaluated by other methods to characterize stability. The heat flow value for a defined time (2, 4, and 12 h) and the quantity of heat evolved during a defined time interval (2–4, 1–7, and 0–11.5 h) were used. These pH profiles had the same shape, position of the minimum and plateau, as the rate constant-pH profile, except for heat flow at 12 h at 50.0°C. The two alternatives, the heat flow at 4 h and the quantity of heat at 2–4 h, also gave improved precision and the experimental time was shortened. Thermodynamic data for the transition state were calculated for two pH values. The resulting data were found to agree with the literature. The entropy of activation has a negative value, which indicates that the activated complex has a more organized structure than do the reactants.