Investigation of the multi-step dehydration reaction of theophylline monohydrate using 2-dimensional powder X-ray diffractometry

Purpose. (i) To study the dehydration kinetics of theophylline monohydrate using 2-dimensional (2D) powder X-ray diffractometry (XRD), and (ii) to investigate the effect of polyvinylpyrrolidone (PVP) on the dehydration pathway and kinetics. Methods. Theophylline monohydrate (C₇H ₈N₄O₂•H₂O; M) was recrystallized from aqueous PVP solutions of different concentrations. Dehydration kinetics was studied isothermally, at several temperatures, from 35 to 130°C. The experimental set-up comprised of a high intensity X-ray source (synchrotron radiation or 8 kW rotating anode), a heating chamber, and a 2D area detector. Diffraction patterns were collected continuously, with a time resolution ranging from 40 ms to 30 s, over the angular range of 3 to 27°2θ. Results. Dehydration of M resulted in either the stable (C ₇H₈N₄O₂; A), or the metastable anhydrate (A*), with the latter having a tendency to transform to A. The XRD technique allowed simultaneous quantification of M, A*and A during the dehydration reaction. The rate constants for individual reaction steps (M→A*; M→A and A*→A) were determined by fitting the data to solid-state reaction models. In presence of PVP, there was a decrease in the magnitude of the rate constant associated with the M→A transition, resulting in an increased build-up of A*in the product. The inhibitory effect of PVP on M→A transition was more pronounced at lower dehydration temperatures, and was proportional to the concentration of PVP. Conclusions. Two dimensional powder X-ray diffractometry, using a high intensity source, is a powerful technique to study kinetics of rapid solid-state reactions. The inhibitory effect of excipients can have profound effect on phases formed during pharmaceutical processing.