Continuous crystallization of levamisole hydrochloride in a segmented flow crystallizer

Continuous crystallization is a promising and widely used method for obtaining drug crystals with controlled morphology and crystal size distribution (CSD). Levamisole hydrochloride (LH) is an important broad-spectrum, highly effective, low-toxic nematode repellent which is available as single-drug preparation and also in combinative therapies. However, the production of uniform LH crystals under flexible operation is still a challenge for chemical engineers. In this contribution, a crystallization process for the production of LH crystals with narrow CSD and improved crystal properties in a continuous segmented flow crystallizer has been proposed. Specifically, at the inlet of the reactor tube, the hot LH methanol solution and anti-solvent solution were mixed through a Y-type connector in the plug flow while cooling down in the nucleation zone to generate the supersaturation. After that, the liquid flow was cut by air to form the stable liquid slugs in which the crystals grew under strong recirculation. Effects of feed concentration, aspect ratio, residence time in nucleation zone, and tube material on the growth rate and CSD have been investigated. Using this coupling crystallization method, LH with a crystal size of 80–130 µm has been successfully prepared at a residence time of less than 15 min