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

Abstract

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 (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.

• Authors: Cletus Nunes, Arumugam Mahendrasingam, Raj Suryanarayanan
• Journal: Pharmaceutical research (Pharm Res) Vol. 23 Issue 10 Pg. 2393-404 (Oct 2006) ISSN: 0724-8741 [Print] United States
• PMID: 16947081 (Publication Type: Journal Article)

Chemical References

• Tablets
• Theophylline

Topics

• Algorithms
• Calorimetry, Differential Scanning
• Chemistry, Pharmaceutical
• Desiccation
• Differential Thermal Analysis
• Kinetics
• Synchrotrons
• Tablets
• Theophylline (chemistry)
• Thermogravimetry
• X-Ray Diffraction