Effects of a citrate buffer system on the solid-state chemical stability of lyophilized quinapril preparations.

Abstract

The objective of this study was to examine the effect of a citric acid-citrate buffer system on the chemical instability of lyophilized amorphous samples of quinapril hydrochloride (QHCI). Molecular dispersions of QHCI and citric acid were prepared by colyophilization from their corresponding aqueous solutions with a molar ratio of QHCI to citric acid from 1:1 to 6:1 and solution pH from 2.49 to 3.05. Solid samples were subjected to a temperature of 80 degrees C and were analyzed for degradation using high-performance liquid chromatography. The glass transition temperature, Tg, of all samples was measured by differential scanning calorimetry. Samples were first examined by varying the Tg and maintaining the initial solution pH constant. At pH 2.49 the rate of reaction was found to be less dependent on the sample Tg, whereas at pH > or = 2.75 the rate decreased with an increase in Tg. In a second set of experiments at a constant Tg of approximately 70 degrees C, the reaction rate increased as the pH increased. The overall solid-state chemical reactivity of amorphous quinapril depends on the relative amount of QHCI and Q+-, the zwitterionic form of quinapril. At high proportions of Q+- (higher pH values) the reaction rate seems to be strongly influenced by the Tg of the mixture, and hence the molecular mobility, whereas at higher proportions of QHCI (lower pH) the reaction rate is less sensitive to Tg, presumably because of different mechanistic rate determining steps for the two sets of conditions.