 Users may download and print one copy of any publication from the public portal for the purpose of private study or research.  You may not further distribute the material or use it for any profit-making activity or commercial gain  You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Enzyme catalyzed reactions are rapidly becoming an invaluable tool for the synthesis of many active pharmaceutical ingredients. These reactions are commonly performed in batch, but continuous biocatalysis is gaining interest in industry because it would allow seamless integration of chemical and enzymatic reaction steps. However, because this is an emerging field, little attention has been paid towards the suitability of different reactor types for continuous biocatalytic reactions. Two types of continuous flow reactor are possible: continuous stirred tank and continuous plug-flow. These reactor types differ in a number of ways, but in this contribution, we focus on residence time distribution and how enzyme kinetics are affected by the unique mass balance of each reactor. For the first time, we present a tool to facilitate reactor selection for continuous biocatalytic production of pharmaceuticals. From this analysis, it was found that plug-flow reactors should generally be the system of choice. However, there are particular cases where they may need to be coupled with a continuous stirred tank reactor or replaced entirely by a series of continuous stirred tank reactors, which can approximate plug-flow behavior. This systematic approach should accelerate the implementation of biocatalysis for continuous pharmaceutical production.Catalysts 2019, 9, 262 2 of 17 counterparts) and thereby the use of flow technology is hard to justify. In reality, the arguments for flow technology are perhaps a little different for enzymes and, in this brief review, we will discuss the issue of reactor selection, in order to capitalize upon the benefits of both flow technology and biocatalysis. Downstream unit operations are not included in this discussion. Figure 1 shows schematic diagrams of the three ideal reactor types, namely the batch stirred tank reactor (BSTR), the continuous stirred tank reactor (CSTR) and the continuous plug-flow reactor (CPFR). The characteristics of these reactors have been described in extensive detail elsewhere [18] and will therefore be only briefly summarized here. Reactor TypesCatalysts 2019, 9, x FOR PEER REVIEW 2 of 17 (compared to their chemical counterparts) and thereby the use of flow technology is hard to justify. In reality, the arguments for flow technology are perhaps a little different for enzymes and, in this brief review, we will discuss the issue of reactor selection, in order to capitalize upon the benefits of both flow technology and biocatalysis. Downstream unit operations are not included in this discussion. Reactor Types

The rate of oxygen transfer from the gas phase to the liquid phase is a critical process parameter for biocatalytic oxidations due to the poor water solubility of molecular oxygen and the low oxygen affinity of many of the relevant enzymes, such as oxidases. In gas–liquid systems, mechanical mixing can be used to increase the interfacial area available for mass transfer and thereby increase the volumetric mass transfer coefficient (k L a). As such, the operation of these reactions in a continuous stirred tank reactor (CSTR) may allow for better performance in a readily scalable way. Even so, achieving a high substrate conversion in a single reactor would require operation at high pressure, to improve the solubility of oxygen, as well as a high enzyme concentration. An alternative and more cost-effective means of improving the substrate conversion might be to operate a series of multiple CSTRs. As such, the oxidation of glucose to gluconic acid by glucose oxidase, coupled with catalase, was modeled in a series of identical well-mixed reactors. It was found that achieving full conversion would require an impractical number of reactors at atmospheric pressure. However, the overall conversion of the reaction could be doubled by simply using two CSTRs in series. Subsequently, experiments were carried out to validate this, and the results showed that the overall conversion was in fact tripled. This likely resulted from a higher k L a in the second reactor, which was potentially caused by the change in the media composition from the first reactor.