The Dynamic Study of Cocrystal Formation between Anhydrous and Monohydrate Theophylline with Sodium Saccharine Dihydrate by FTIR

Anhydrous theophylline and sodium saccharin have been reported can form cocrystals with many compounds as well as anhydrous theophylline and saccharin base co-crystal, but co-crystallization between teophylline monohydrate (TM) and sodium saccharin dihydrate (NSD) and its co-crystallization dynamics has not been reported yet. Usually the dynamics of the co-crystal formation was studied using PXRD and DSC. In this research FTIR instrument was tried to used. TM, TA, NSD, and the physical mixture of TM-NSD and TA-NSD were characterized by Karl Fischer titration, polarized microscopy, electrothermal, differential thermal analysis (DTA), powder X-ray diffraction (PXRD), and fourier-transform infrared spectroscopy (FTIR). To investigate the co-crystallization dynamics, a serie of physical mixtures of TM-NSD and TA-NSD were ball milled to induce co-crystal formation, in a serie of speeds and were sampled periodically along 60 minutes milling. Then these milled mixtures was analyzed by FTIR, confirmed by DTA and PXRD. Thermal contact method and phase diagram from electrothermal data early indicated the formation of co-crystals either on TM-NSD or TA-NSD. DTA thermograms of both mixture indicated the melting point of co-crystals at 121oC, then the diffractograms showed a new similar crystal phase from TM-NSD and TA-NSD after milling, differ from their physical mixtures. FTIR analysis showed the spectra N-H streching shift of 3124.12 cm-1 (TM-NSD) and 3127.97 cm-1(TA-NSD) to 3131.83 cm-1 after ball milling; that occured faster with the increasing of speed. TM or TA can produces a similar co-crystal after milling with NSD, proved that there are no effect of their hydrate on theophylline-saccharin co-crystallization. Then, FTIR was proved can be used to study the dynamics these co-crystals formation and showed that TM-NSD needs more energy than TA-NSD to release theophylline hydrate.