(262e) Continuous-Flow Synthesis of Antibiotics and Diastereoisomers in Modular Multi-Phase Microfluidic Devices

Key players in the pharmaceutical industry invest in developing versatile mini plants for continuous manufacturing of active pharmaceutical ingredients. Process intensification coupled with savings on space, energy, reactants, and harmony with the principles of green chemistry are appreciated. In this contribution, we will report on our recent efforts to develop microfluidic devices for the continuous-flow synthesis and separation of valuable chemical and pharmaceutical products.

We have constructed microfluidic devices of several types that allow for the enzyme synthesis of diastereoisomers (L-phenyl serine) and antibiotics and their precursors (cephalexin and 6-aminopenicillanic acid – 6-APA). The microdevices operate in continuous regimes and employ two-phase flows of different types: (i) slug flow, (ii) co-current parallel flow, and (iii) counter-current parallel flow stabilized by a thin semipermeable membrane. Enzymes are used in soluble forms in one of the phases. Reactants are typically introduced in the other phase. Instead of aqueous-organic systems, we employ aqueous two-phase systems (ATPS) with high contents of water soluble polyethylene glycols (PEG) and phosphate salts providing a buffer capacity of the reaction system.

We showed that cephalexin can be continuously synthesized in an integrated slug-flow microfluidic reactor-separator. Free enzyme is highly utilized in a closed loop. The other phase serves for the introduction of reactants and at the same time for the cephalexin extraction. The developed microfluidic platform also integrates a microdialysis unit for the withdrawal of phenylglycine – the side product causing clogging of the system. The microdevice can operate for at least 5 h and the operational time seems to be limited only by the wash-out of the enzyme. Our microfluidic platform represents a possible way for the transfer of enzyme-based processes from batch to continuous flow arrangements.

Vobecka et.al., Chemical Engineering Journal 396, AN. 125236, 2020.