Ultrasonic Irradiation and Seeding To Prevent Metastable Liquid–Liquid Phase Separation and Intensify Crystallization

During the crystallization of complex pharmaceutical molecules, a liquid–liquid phase (LLP) separation phenomenon may occur that could hinder crystallization processes and adversely affect the crystal quality and process robustness. In this study, the LLP separation behavior of a vanillin and water mixture was investigated using a hot-stage microscope and a cooling crystallization process. Thermodynamic stability of phases and the crystallization phase diagram including the metastable zone width, nucleation, and LLP separation were developed. The impact of ultrasound and seeding on LLP separation was investigated and used to optimize the crystallization process. Our results show that the LLP separation may exist in both the stable and metastable zones of the crystallization phase diagram. Ultrasound can effectively promote nucleation, narrow the metastable zone of LLP separation, and inhibit LLP separation within the concentration range of 3.8–4.8 g/100 g water. Moreover, ultrasonic crystallization was optimized to produce small, uniformly sized crystals in a reproducible manner, whereas seeding crystallization was able to grow larger crystals without obvious agglomeration. In the case of a vanillin aqueous solution, both the ultrasonic induced and seeding crystallization strategies were able to prevent LLP separation and improve process performance. These results would be of significant use in the crystallization of other pharmaceutical molecules in which LLP separation occurs.