Pure theophylline-benzoic acid cocrystal was prepared via slurry and cooling crystallization in solution to overcome the disadvantages of existing preparation methods. The target cocrystal was characterized by powder X-ray diffraction (PXRD), thermalgravimetric analysis (TGA), differential scanning calorimetry (DSC) and Raman spectroscopy. The slurry and cooling cocrystallization process in solution was monitored via on-line Raman spectroscopy. The results obtained from on-line Raman monitoring can exhibit the transformation process from raw materials (theophylline and benzoic acid) to cocrystal and show the cocrystal formation rate. Comparing each transformation process under different conditions in slurry crystallization, we found that suspension density of raw materials and temperature both have an impact on the theophylline-benzoic acid cocrystal formation rate. It could be concluded that the cocrystal formation rate increased with the increase of suspension density of raw materials. Further under the same suspension density, higher temperature will accelerate theophylline-benzoic acid cocrystal formation. Meanwhile, various data from the cocrystallization process in cooling crystallization, including nucleation time, nucleation temperature and suitable cooling ending point can be gained from results of on-line Raman monitoring.
