Continuous chiral resolution of racemic Ibuprofen by diastereomeric salt formation in a Couette-Taylor crystallizer

Abstract

S-Ibuprofen has been proved to be more efficient than racemic Ibuprofen, one the best sell drugs over the world. Thus, there is a strong interest in implementing chiral resolution of racemic Ibuprofen in the continuous mode.Chiral resolution by diastereomeric salt formation of racemic Ibuprofen has been successfully implemented in a Couette-Taylor (CT) crystallizer. Among the seven parameters identified as impacting, a screening has been performed on the four factors expected to have the strongest influence: temperature gradient in the CT crystallizer, rotation speed, residence time and target temperature within the crystallizer.Thanks to the rationalization of the study through a design of experiments approach, only 14 distinct experiments were performed to identify the influence of these factors on global productivity/yield, diastereomeric excess and diastereomeric productivity/yield, and to find a first operating point.If the obtained yields were unsurprisingly low, global productivity and diastereomeric productivity are increased by 16 and 8 times respectively, in comparison with batch mode. Also, continuous mode gives an easy access to a higher diastereomeric excess, in a repeatable manner.Surprisingly, under the selected process conditions, the steady state does not seem to be reached before 14–15 residence times, which is longer than expected from previous results.