Intensified solid-state transformation during anti-solvent cocrystallization in flow

Pharmaceutical cocrystals consist of an active pharmaceutical ingredient and a coformer in a fixed stoichiometric ratio. They can improve the manufacturability and properties of a drug powder. However, the manufacture of cocrystals is often more complicated compared to crystals of an active ingredient due to the possible formation of different solid-state forms. Cocrystallization through anti-solvent addition is a commonly used technique. However, the risk of nucleation of multiple solid-state forms is often high due to the high supersaturation levels achieved during anti-solvent crystallization. Therefore, intensifying a solution-mediated phase transformation is important. In this work, the ability of tubular flow crystallizers to intensify the phase transformation process in the carbamazepine-saccharin cocrystal system is characterized and compared to a conventional stirred tank crystallizer. The influence of the flow rate, tubular crystallizer type, and ratio of residence time in the tube to that in the tank are documented. The phase transformation process is substantially faster with the tubular crystallizers compared to that in a stirred tank crystallizer, which we explain through increased nucleation rates. We show that such intensification can be achieved either by recirculating the slurry through a static mixer or by installing a tubular crystallizer upstream of a stirred tank crystallizer.