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

CrystEngComm Pub Date: 2012-04-24 DOI: 10.1039/C2CE25299F

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 theophylline–oxalic 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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