Flow Biocatalysis: A Challenging Alternative for the Synthesis of APIs and Natural Compounds

Abstract

Biocatalysts represent an efficient, highly selective and greener alternative to metal catalysts in both industry and academia. In the last two decades, the interest in biocatalytic transformations has increased due to an urgent need for more sustainable industrial processes that comply with the principles of green chemistry. Thanks to the recent advances in biotechnologies, protein engineering and the Nobel prize awarded concept of direct enzymatic evolution, the synthetic enzymatic toolbox has expanded significantly. In particular, the implementation of biocatalysts in continuous flow systems has attracted much attention, especially from industry. The advantages of flow chemistry enable biosynthesis to overcome well-known limitations of “classic” enzymatic catalysis, such as time-consuming work-ups and enzyme inhibition, as well as difficult scale-up and process intensifications. Moreover, continuous flow biocatalysis provides access to practical, economical and more sustainable synthetic pathways, an important aspect for the future of pharmaceutical companies if they want to compete in the market while complying with European Medicines Agency (EMA), Food and Drug Administration (FDA) and green chemistry requirements. This review focuses on the most recent advances in the use of flow biocatalysis for the synthesis of active pharmaceutical ingredients (APIs), pharmaceuticals and natural products, and the advantages and limitations are discussed.

Immobilisation and flow chemistry: tools for implementing biocatalysis

“…This comparison should be made at the same level of conversion since the product formation in batch and flow follow different kinetics. 2 Specific rate (SR). This parameter enables one to establish the rate of an enzyme under given conditions and comparison of different set ups.…”

“…In recent years the utilisation of enzymes has facilitated the design of more environmentally friendly batch processes that fulfil 10 out of the 12 green chemistry principles. 1,2 However, mass transfer limitation, the generation of significant amounts of waste and handling of large volumes of toxic reagents are still problems that have to be overcome. Flow chemistry solves most of these challenges.…”

Applications of Ionic Liquids in Whole-Cell and Isolated Enzyme Biocatalysis

“…Flow biocatalysis is an emerging technology for sustainable chemical manufacturing. The use of flow can lead to significant process intensification due to high energy and mass transfer [ 106 , 107 , 108 , 109 ]. Lozano and Reetz pioneered the introduction of ionic liquids in flow biocatalysis [ 110 , 111 , 112 , 113 , 114 , 115 ].…”

Continuous process technology for glucoside production from sucrose using a whole cell-derived solid catalyst of sucrose phosphorylase

“…It builds on the idea of continuous bioprocessing, especially in the upstream part of the process, and involves process intensification and integration as key guiding principles (Tamborini et al 2018;De Santis et al 2020). Continuous bioprocessing with enzymes for chemical synthesis can be viewed as realization of the trendsetting idea of "flow bio-catalysis" in industrial applications (Buchholz et al 2012;Thompson et al 2019;Santi et al 2021). Biotransformation performed continuously promotes the tight interconnection of the upstream and downstream parts of the production process for optimum overall output of product (Liese et al 2006;Tamborini et al 2018).…”