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Issue 14, 2012
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The theophylline–oxalic acid co-crystal system: solid phases, thermodynamics and crystallisation

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Abstract

The solid phases in the theophylline–oxalic acid co-crystal system have been investigated by thermal analysis techniques, X-ray diffraction analysis (XRD) and solubility measurements. The work includes the 2 : 1 co-crystal of theophylline and oxalic acid, polymorphs of theophylline, the theophylline monohydrate and solid oxalic acid. The DSC curve of the co-crystal presents two endothermic peaks, one at about 230 °C where the oxalic acid in the co-crystal decomposes and carbon dioxide is liberated, and another one at 279 °C where the remaining theophylline melts. At equilibrium with the solid co-crystal, the theophylline concentration is only 60% of the corresponding value for the pure solid theophylline. Using the solubility data, the standard Gibbs free energy of formation of the co-crystal from the pure solid phases is estimated to be approximately −6.0 kJ mole−1. In a chloroform/methanol mixture (4 : 1 v : v) the commercial form of pure theophylline (Form II) has been observed to transform into a more stable non-solvated form (Form I). The data suggest that the polymorphs are enantiotropically related with an approximate transition temperature of 70 °C. The 2 : 1 theophyllineoxalic acid co-crystal can be successfully produced by cooling crystallisation in chloroform/methanol mixture (4 : 1 v : v) and by slurry conversion crystallisation also in more benign solvents.

Graphical abstract: The theophylline–oxalic acid co-crystal system: solid phases, thermodynamics and crystallisation

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Article information


Submitted
01 Mar 2012
Accepted
23 Apr 2012
First published
24 Apr 2012

CrystEngComm, 2012,14, 4644-4655
Article type
Paper

The theophyllineoxalic acid co-crystal system: solid phases, thermodynamics and crystallisation

S. Zhang and Å. C. Rasmuson, CrystEngComm, 2012, 14, 4644 DOI: 10.1039/C2CE25299F

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