Can Ultrasound Replace Seeding in Flow Reactive Crystallization of an Aromatic Amine?

Continuous crystallization has gained substantial interest due to its high product reproducibility, high labor efficiency, and low capital and production costs. Continuous seeding is preferable and often even required in the application of pharmaceuticals, which presents a bottleneck in continuous crystallization. This work proposes to apply ultrasound for continuous in situ seeding in the continuous reactive crystallization of an aromatic amine. Flow crystallization experiments with both ultrasound and conventionally prepared seeds were conducted. It was found that sonication initiated nucleation and continuously produced crystals in a stable manner. The nucleation rate could be controlled by adjusting the sonication power, highlighting the advantages of the sonicated seed generation strategy. Experiments under different flow conditions demonstrated that a higher flow rate combined with an appropriate sonication power was favorable for robust particle quality, reduced likelihood of clogging, and better reproducibility. Compared with the conventional addition of seed crystals, sonication-induced crystallization achieved higher yields and produced products with a narrow and unimodal size distribution. All sonicated experiments exhibited high robustness, indicating the feasibility and reliability of this method as a replacement for conventional seeding techniques in the continuous reactive crystallization of the studied compound. In summary, using ultrasound for continuous in situ seeding of the aromatic amine offers unique advantages in process robustness and product quality control, providing a promising strategy for continuous crystallization of similar systems.