Investigation of the multi-step dehydration reaction of theophylline monohydrate using 2-dimensional powder X-ray diffractometry.
OBJECTIVE
(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 (C(7)H(8)N(4)O(2).H(2)O; M) was recrystallized from aqueous PVP solutions of different concentrations. Dehydration kinetics was studied isothermally, at several temperatures, from 35 to 130 degrees 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 degrees 2theta.


RESULTS
Dehydration of M resulted in either the stable (C(7)H(8)N(4)O(2); 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.
Nunes
Cletus
C
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Mahendrasingam
Arumugam
A
Suryanarayanan
Raj
R
D000465:Algorithms; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003890:Desiccation; D004055:Differential Thermal Analysis; D007700:Kinetics; D017356:Synchrotrons; D013607:Tablets; D013806:Theophylline / Q000737:chemistry*; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D013607:Tablets; D013806:Theophylline