Theophylline–citric acid co-crystals easily induced by DSC–FTIR microspectroscopy or different storage conditions

Abstract

A simultaneous differential scanning calorimetry–Fourier transform infrared (DSC–FTIR) microspectroscopy was used to quickly investigate the co-crystal formulation between anhydrous theophylline (TP) and anhydrous citric acid (CA) in a one-step procedure. The raw materials of TP and CA, as well as the intact TP–CA co-crystal prepared by slow solvent evaporation were also respectively examined by this approach. The result indicates that the TP–CA co-crystal formulation was easily induced using this DSC–FTIR technique. The thermal-dependent changes in three-dimensional FTIR spectral contour profiles were started from 165 °C to induce the co-crystal formation of TP–CA, which was prior to the endothermic peak at 173 °C found in the conventional DSC curve. Beyond 165 °C, several new IR absorption peaks at 3515, 3124, 1730, 1710, 1677, 1648, 1552 and 1265 cm−1 corresponding to unique IR spectral peaks of intact TP–CA co-crystal were observed. The DSC–FTIR microspectroscopic results also evidenced the dimer–monomer transition of CA, but there were no markedly changes for TP or intact TP–CA co-crystal before its fusion. This strongly implies that the DSC–FTIR technique giving spectroscopic and thermodynamic information could simultaneously induce and identify the TP–CA co-crystal formation and phase transition of samples. Different storage conditions affecting the stability of both physical mixture and ground mixture of TP–CA were also determined. The physical mixture of TP–CA after storing at 55 °C/75% RH condition for one day was fast transformed to TP–CA co-crystal, indicating that TP–CA co-crystal was easily induced under accelerated storage condition. While the co-crystal formed from TP–CA ground mixture was stable in both 25 °C/75% RH and 55 °C/75% RH conditions.