Continuous Antisolvent Crystallization of L-Histidine: Impact of Process Parameters and Kinetic Estimation

Continuous crystallization has recently attracted extensive attention in both industry and academia. In this work, a continuous MSMPR (mixed-suspension mixed-product removal) crystallization apparatus was established, and continuous antisolvent crystallization experiments of the L-histidine-water-ethanol system were first conducted. The effects of various process parameters, such as the feed concentration, the stirring rate, and the mean residence time, on the crystal form and volume-based mean crystal size of the product were investigated. Within the explored experimental conditions, changes in the feed concentration or the stirring speed can influence the crystal size but do not affect the crystal form of the product. However, modifying the mean residence time can affect the crystalline form of the product. These findings indicate that it is possible to control the crystal form and volume-based mean size of L-histidine by adjusting the process parameters of continuous MSMPR crystallization. Finally, the continuous crystallization kinetics of form B was studied, and it was found that the growth kinetics of form B was size-dependent, and the MJ3 model was more suitable. The total nucleation and growth kinetics of form B were also fitted in this study. The results will provide some meaningful guidance on the control of polymorph and size in continuous crystallization, which is a topic of great concern in the pharmaceutical industry.