Sustainable and Robust Closed-Loop Enzymatic Platform for Continuous/Semi-continuous Synthesis of Ursodeoxycholic Acid

Biocatalysis in continuous flow systems is an appealing strategy for efficient and environmentally sustainable manufacturing of value-added compounds. Here, a robust, productive, and sustainable closed-loop packed bed reactor system was developed for continuous asymmetric reduction of 7-oxo-lithocholic acid to ursodeoxycholic acid (UDCA). UDCA is a clinically valuable active pharmaceutical ingredient for treatment of hepatobiliary-related diseases. In this packed bed reactor, a conversion of 92% was achieved at a residence time of only 5 min, which represented an extremely high space-time yield of 1040 g UDCA L –1 d –1 . Furthermore, the reactor exhibited excellent operational stability, maintaining a steady conversion above 95% after 31 days of continuous operation with a residence time of 10 min. By recovering and recycling the used reaction buffer containing the expensive cofactor (NAD + ), the environment factor of this bioprocess was greatly reduced from 293 to 77, and the cost for UDCA biosynthesis decreased by approximately 21%. This closed-loop enzymatic system improves the potential for application of environmentally benign and cost-effective operation modes for bioprocesses that require expensive cofactors.