Purpose. The object of this investigation was to demonstrate the utility of X-ray powder diffractometry (XRD) to study the kinetics of a complex pharmaceutical solid-state reaction wherein the reactant, product and intermediate phases were all simultaneously quantified. Methods. Aminophylline monohydrate (I) decomposed to anhydrous theophylline (III) either directly or through an intermediate (anhydrous aminophylline, II). The reaction kinetics were studied isothermally at several temperatures ranging from 65 to 100°C. By measuring the intensities of the XRD peaks unique to I, II and III, it was possible to simultaneously quantify the 3 phases during the entire reaction. Results. Assuming that all the reaction steps follow first-order kinetics, the three equations describing the concentrations of I, II and III as a function of time, were derived. By fitting the experimental data to these equations, it was possible to obtain the rate constants for the three reaction steps. The rate constants were obtained at different temperatures and were used to draw Arrhenius type plots from which the activation energies were determined. At lower temperatures (<80°C), the concentration of the intermediate phase, i.e., II, was low throughout the reaction while at higher temperatures (>90°C), there was rapid formation and accumulation of II during the early stages of the reaction. These differences could be attributed to the fact that k1 (I → II) had a more pronounced temperature dependence than k2 (I → III) and k3 (II → II). The XRD results were confirmed with isothermal thermogravimetry. Conclusions. Variable temperature XRD is a powerful tool to probe reaction kinetics in crystalline pharmaceuticals since it permits simultaneous quantification of multiple solid phases.
- X-ray powder diffractometry