(121b) Novel Integration of Continuous Crystallization Platforms for Control of Crystal Size Distribution and Polymorphic Form

Continuous crystallization has been in the focus of pharmaceutical industry as an appealing method to obtain drug substances of consistent critical quality attributes (CQAs), which meet strict regulatory guidelines. Traditionally, continuous crystallization is done in mixed suspension mixed product removal (MSMPR) crystallizers, but one main disadvantage of MSMPR crystallizers is the broad crystal size distribution (CSD) generated due to broad residence time distribution (RTD).¹ On the other hand, the new emerging continuous oscillatory baffled crystallizers (COBCs) offer plug-flow conditions with narrow RTD properties to generate product with narrow CSD.² Unlike traditional plug flow crystallizers that use high volumetric flow rate to achieve plug flow conditions, the COBCs use an oscillating piston to generate turbulent mixing within its concentric baffles without a high volumetric flow rate. However, a main disadvantage of COBCs is fouling and encrustation due to nucleation on the crystallizer walls which can lead to clogging and process failure.³ To remedy fouling and prolong the operating time of the COBC, seeding is a common methodology to not only reduce the supersaturation in the system for nucleation but also provide polymorphic form control. Although seeding is very common method in the pharmaceutical industry, seeding for continuous crystallization has proven to be challenging, especially in the case of the COBC. Consistent manual preparation of seeds is labor intensive and economically infeasible, and, furthermore, any fluctuations of seed quality can impact startup dynamics.⁴ In addition, seeds can be washed away after a few residence times, which no longer provide the benefits of seeding.

In this work, a novel integration of the MSMPR crystallizer with a COBC demonstrated in-situ seed generation capabilities while demonstrating CSD and polymorphic control in continuous combined cooling antisolvent crystallization (CCAC). Firstly, the 3D solubility surfaces of the metastable and stable form were generated to provide an operating regime for the continuous CCAC. It was discovered that the continuous generation of the metastable form required higher concentration of solvent than that of the stable form. Secondly, the MSMPR crystallizer was integrated into the COBC as a separate temperature zone to generate seeds via primary nucleation. The seeds generated were then fed into the COBC without pump transfer to allow for further growth. While compared to a single stage MSMPR crystallizer, the integrated system showed little signs of fouling and encrustation while generating product of uniform CSD. While both platforms are capable of polymorphic control using a temperature switch, the integrated system was able to maintain the narrower CSD while compared to the MSMPR, which makes this combined system a novel next generation continuous crystallization platform for systems with polymorphism and seeding requirements.

References:

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(4) Wood, B.; Girard, K. P.; Polster, C. S.; Croker, D. M. Progress to Date in the Design and Operation of Continuous Crystallization Processes for Pharmaceutical Applications. Org. Process Res. Dev. 2019, 23, 122–144. https://doi.org/10.1021/acs.oprd.8b00319.