(713g) A Novel Preparative Method and Solid-State Characterization of the Theophylline-Benzoic Acid Co-Crystal

Co-crystals are molecular complexes that contain two or more components together and can be prepared through many methods, such as slow evaporation, cooling crystallization, slurry conversion crystallization, mechanochemical synthesis and so on. Furthermore, mechanochemical synthesis includes neat grinding and solvent-assisted grinding. The theophyllineâ??benzoic acid co-crystal have be reported to be prepared via slow evaporation and neat grinding. But each method has its disadvantage in the process of preparing co-crystals. It takes a long time to get the product by slow evaporation and it is too difficult to make a large amount of co-crystals through neat grinding. In our study, we succeed in synthesizing the theophyllineâ??benzoic acid co-crystal via slurry conversion crystallization in acetonitrile to solve these problems. The solid phase of the theophyllineâ??benzoic acid co-crystal is characterized by powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR), Differential scanning calorimetry (DSC), Raman spectroscopy and Scanning electron microscopy(SEM). The DSC curve of the co-crystal presents melt point of co-crystals. The hydrogen bond in the structure can be confirmed via FTIR and Raman spectrum. The result of SEM could show the difference of morphology between the co-crystal and the initial substance.

In the course of preparing the theophyllineâ??benzoic acid co-crystal through slurry conversion crystallization, the initial conditions are changed and the purity of products which got with different conditions draws our attention. We find that sometimes the final product is a mixture of our target co-crystal and one raw material. A explanation for this observation is that because the benzoic acid solubility in acetonitrile is much higher than that of theophylline (Form â?¡, the stable form), the co-crystal dissolves in that incongruently. The region in the phase diagram where the co-crystal is the only solid stable phase is evidently shifted toward the benzoic acid side and is also narrow. To solve the problem, the pure solvent could be replaced by the binary mixed solvent. We measure the solubility of theophylline and benzoic acid in water/ methanol mixture at 298K and prepare the much purer co-crystal in methanol/water mixture by slurry conversion crystallization. In methanol/water mixture the theophyllineâ??benzoic acid co-crystal can dissolve congruently.

To investigate the process of mechanochemical synthesis to prepare co-crystals, a solvent-assisted grinding approach is used to synthesize the title compound. The products are compared with that of neat grinding. The result indicates that the reaction rate is faster and the product of higher crystallinity can be got via solvent-assisted grinding. In conclusion, solvent is conductive to promoting the mechanochemical synthesis of our target co-crystal. Through changing the grinding time, the amount of solvent, the kind of solvent, the effect of every factors in the mechanochemical method can be got with comparing the powder X-ray diffraction data of the co-crystal product in different condition and it has some reference value for preparation of the co-crystal.