Special Issue

Pharmaceutical Research

, Volume 23, Issue 10, pp 2393-2404

First online:

Investigation of the Multi-Step Dehydration Reaction of Theophylline Monohydrate Using 2-Dimensional Powder X-ray Diffractometry

  • Cletus NunesAffiliated withDepartment of Pharmaceutics, University of MinnesotaPharmaceutics R&D, Bristol Myers Squibb Company
  • , Arumugam MahendrasingamAffiliated withDepartment of Physics, Keele University
  • , Raj SuryanarayananAffiliated withDepartment of Pharmaceutics, University of Minnesota Email author 

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(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.


Theophylline monohydrate (C7H8N4O2·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.


Dehydration of M resulted in either the stable (C7H8N4O2; 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 (MA*; MA 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 MA transition, resulting in an increased build-up of A* in the product. The inhibitory effect of PVP on MA transition was more pronounced at lower dehydration temperatures, and was proportional to the concentration of PVP.


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.

Key words

anhydrate dehydration metastable polymorph synchrotron theophylline monohydrate two-dimensional X-ray diffraction