Cocrystal Preparation via the Cooling Sonocrystallization Process: Case Study of the p-Toluenesulfonamide/4,4′-bipyridine 2:1 Cocrystal

Cooling sonocrystallization was investigated as a control strategy for cocrystallization, using the 2:1 cocrystal of the anticancer agent p-toluenesulfonamide with 4,4′-bipyridine as a structurally well-characterized model system. The influence of the sonication intensity and the probe diameter on the nucleation behavior, cocrystal recovery, particle size, and crystal habit was then examined. Ethanol was identified as the most suitable crystallization medium according to a preliminary solubility study. Each cooling run was then carried out by lowering the temperature linearly from 50 to 10 °C over 2 h. Compared with spontaneous nucleation at 22.8 °C, sonication raised the nucleation temperature to as high as 40.4 °C, indicating the efficient narrowing of the metastable zone width. In addition, applying sonication reduced the mean size of the recrystallized cocrystal from 168.2 μm under spontaneous nucleation to values as small as 68.6 μm. The nucleation temperature could therefore be raised by up to 17.6 °C, and the mean particle size could be tuned across the 68.6–87.7 μm range by adjusting the sonication intensity and the probe diameter alone. Powder X-ray diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry identified all sonocrystallized products as the 2:1 cocrystal. Ultrasound also changed the product from irregular rods to small rectangular prisms with a narrow size distribution. In dissolution tests, the sonocrystallized cocrystal released PTS considerably faster than a physical mixture of the two components.