Continuous crystallization of α-form L-glutamic acid in an MSMPR-Tubular crystallizer system.

Graphical abstract In this paper, a continuous crystallizer system is proposed to ensure tight control over the crystalline product size distribution and polymorphic identity of pharmaceuticals. A continuous supply of seeds of metastable α-form L-glutamic acid was prepared online in a mixed suspension mixed product removal (MSMPR) crystallizer. Operational conditions were deduced to fine-tune the continuous production of seeds with a desired size ranging from 5.0 to 15.0 µm and number density ranging from 500 to 1500 counts detected by the FBRM probe. At the outlet of the MSMPR crystallizer, the suspension with fine-tuned continuous supply of seeds was transferred to a series of three coiled tubular crystallizers for further growth. Finally, the metastable α-form crystals of L-glutamic acid with a uniform mean size of 130 µm were successfully prepared. Highlights • A continuous crystallizer system is proposed for the continuous production of active pharmaceutical ingredients. • The proposed system consists of an MSMPR and several tubular crystallizers in series. • The proposed system separates the nucleation and growth processes. • The product crystals of L-glutamic acid have the desirable polymorphic form and size. Abstract Continuous crystallization of active pharmaceutical ingredients is of prime significance. A continuous mixed suspension mixed product removal (MSMPR)-tubular crystallizer geometry is designed and optimized to produce the metastable α-form crystals of L-glutamic acid with uniform mean size of 130 µm. The MSMPR is used to produce well-tuned seed crystals that undergo further growth in a series of tubular crystallizers. The effects of the initial supersaturation, stirring speed, nucleation temperature and residence time were optimized in the MSMPR crystallizer to tune the supply of continuous seeds by using the principal component analysis and in-situ particle tracking measurement. The continuous seeds of the desired metastable polymorphic form with specific size ranging from 5.0 to 15.0 µm and number density ranging from 500 to 1500 counts, were transferred to a series of three coiled tubular crystallizers for further growth. In addition, the cooling strategy in the tubular crystallizers was utilized to further optimize the quality of the final crystal product. The crystal size distribution (CSD) in the MSMPR-tubular crystallizer system was compared with a single MSMPR with the same residence time and found to be superior. Finally, a potential scale up strategy of the MSMPR-tubular crystallizer system was proposed for further study. [ABSTRACT FROM AUTHOR]