Continuous crystallization - Contribution to the implementation of the Pasteurian resolution of racemic Ibuprofen in a Couette-Taylor crystallizer

Overview & Synopsis

The main objective of the work described in the present manuscript was to implement the chiral resolution of racemic Ibuprofen (rac-Ibu) by diastereomeric salt formation with S-αMethylBenzylAmine (S-αMBA) in a continuous crystallizer called Couette-Taylor (CT) crystallizerFirstly, the system to resolve was investigated, which led to the revision of the phase diagram between the two diastereomers since a partial solid solution enriched in S-Ibu-S-αMBA was evidenced. The crystals of ss-S-Ibu-S-αMBA exhibit a surprising fibrous aspect, favoring the formation of biphasic fluid inclusions. Investigations on these particles served the formulation of hypotheses around their fibrous nature, and the development of a procedure to limit the occurrence of fluid inclusions.After a careful design of the continuous set-up, Couette-Taylor experiments were performed through two different designs of experiments (DoE). The continuous mode resulted in lower yield than batch mode, but this can largely be counterbalanced by the outstanding improvement of the productivity of at least 1.5 times, and up to 30 times. Also, the transfer from batch to continuous mode seems to ensure the access to high diastereomeric excesses, in a repeatable manner.Unfortunately, encrustation issues were encountered during the continuous experiments. The causes and potential solutions were extensively discussed leading to the proposition of an original continuous CT set-up.