Innovative enzymatic (R,S)-flurbiprofen resolution in continuous flow reactor with lyophilized cells of Aspergillus oryzae

In our previous work dry mycelia of Aspergillus oryzae, displaying high enantioselectivity towards (R)-flurbiprofen, have been efficiently used in pure organic solvent for the resolution of (R,S)-flurbiprofen through esterification.[1] The use of the lyophilized mycelia facilitated the separation process so that in one step the two enantiomers of flurbiprofen, which are both valuable for pharmaceutical applications,[2] were easily separated. Reaction was performed and optimized in “usual” batch system. New possibilities of process-improvement using the advantages - in terms of processing flexibility, easy scaling factors, heat and mass transfer, reduced substrate and product inhibition phenomena[3] - of a flow chemical approach have been investigated. A column reactor, packed with lyophilized cells of Aspergillus oryzae, was continuously flushed with a solution of (R,S)-flurbiprofen and ethanol. After optimization of the reaction parameters (solvent, temperature, reactor configuration, flow rate) we were able, using the same amount of cells, to increase reaction rate of about 12 times (2 h compared to 24 h in the batch reaction) maintaining the same degree of molar conversion and enantiomeric purity of product. Moreover the cells could be repetitively used for several days, thus allowing for an easy scale up of the process. Future development and optimization of the continuous process for the potential industrial application will also be discussed.