Automated Determination of Oxygen‐Dependent Enzyme Kinetics in a Tube‐in‐Tube Flow Reactor

Ringborg, Rolf Hoffmeyer; Pedersen, Asbjørn Toftgaard; Woodley, John M.

doi:10.1002/cctc.201700811

Cited by 45 publications

(32 citation statements)

References 33 publications

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“…The tool allowed perfect control of dissolved oxygen concentrations, which by pressurizing the system enabled up to 25‐fold higher values than achievable by using air under atmospheric conditions. The system can be used also for other enzymes using gaseous substrates, such as hydrogenases (using H 2 ), formate dehydrogenases (using CO 2 ), or methane monooxygenases (using CH 4 ) …”

Section: Microfluidics For High‐throughput Process Parameters Estimationmentioning

confidence: 99%

The Promises and the Challenges of Biotransformations in Microflow

Žnidaršič–Plazl

2019

Biotechnology Journal

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The challenges of transition toward the postpetroleum world shed light on the biocatalysis as the most sustainable way for the valorization of biobased raw materials. However, its industrial exploitation strongly relies on integration with innovative technologies such as microscale processing. Microflow devices remarkably accelerate biocatalyst screening and engineering, as well as evaluation of process parameters, and intensify biocatalytic processes in multiphase systems. The inherent feature of microfluidic devices to operate in a continuous mode brings additional interest for their use in chemoenzymatic cascade systems and in connection with the downstream processing units. Further steps toward automation and analytics integration, as well as computer‐assisted process development, will significantly affect the industrial implementation of biocatalysis and fulfill the promises of the bioeconomy. This review provides an overview of recent examples on implementation of microfluidic devices into various stages of biocatalytic process development comprising ultrahigh‐throughput biocatalyst screening, highly efficient biocatalytic process design including specific immobilization techniques for long‐term biocatalyst use, integration with other (bio)chemical steps, and/or downstream processing.

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Section: Microfluidics For High‐throughput Process Parameters Estimationmentioning

confidence: 99%

The Promises and the Challenges of Biotransformations in Microflow

Žnidaršič–Plazl

2019

Biotechnology Journal

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“…k L a values of up to 30 min −1 were reported for segmented gasliquid flow in microchannels (Kashid et al, 2011). A falling-film microreactor operated in continuous countercurrent gas-liquid flow showed a k L a of 450 min −1 (Bolivar, Krämer, Ungerböck, Mayr, & Nidetzky, 2016 (Chapman, Cosgrove, Turner, Kapur, & Blacker, 2018;Jones, McClean, Housden, Gasparini, & Archer, 2012;Karande et al, 2016;Ringborg, Toftgaard Pedersen, & Woodley, 2017;Toftgaard Pedersen et al, 2017;Tomaszewski, Lloyd, Warr, Buehler, & Schmid, 2014;van Schie et al, 2018). Only to mention, complex interdependence of the residence time, the mass transport (dependent on mass flows) and the product formation (dependent on gas hold-up) renders reaction optimization in segmented gas-liquid flow a rather difficult task.…”

Section: Introductionmentioning

confidence: 98%

Process intensification for O₂‐dependent enzymatic transformations in continuous single‐phase pressurized flow

Bolívar

Mannsberger

Thomsen

et al. 2019

Biotech & Bioengineering

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Oxidative O 2 ‐dependent biotransformations are promising for chemical synthesis, but their development to an efficiency required in fine chemical manufacturing has proven difficult. General problem for process engineering of these systems is that thermodynamic and kinetic limitations on supplying O 2 to the enzymatic reaction combine to create a complex bottleneck on conversion efficiency. We show here that continuous‐flow microreactor technology offers a comprehensive solution. It does so by expanding the process window to the medium pressure range (here, ≤34 bar) and thus enables biotransformations to be conducted in a single liquid phase at boosted concentrations of the dissolved O 2 (here, up to 43 mM). We take reactions of glucose oxidase and d ‐amino acid oxidase as exemplary cases to demonstrate that the pressurized microreactor presents a powerful engineering tool uniquely apt to overcome restrictions inherent to the individual O 2 ‐dependent transformation considered. Using soluble enzymes in liquid flow, we show reaction rate enhancement (up to six‐fold) due to the effect of elevated O 2 concentrations on the oxidase kinetics. When additional catalase was used to recycle dissolved O 2 from the H 2 O 2 released in the oxidase reaction, product formation was doubled compared to the O 2 supplied, in the absence of transfer from a gas phase. A packed‐bed reactor containing oxidase and catalase coimmobilized on porous beads was implemented to demonstrate catalyst recyclability and operational stability during continuous high‐pressure conversion. Product concentrations of up to 80 mM were obtained at low residence times (1–4 min). Up to 360 reactor cycles were performed at constant product release and near‐theoretical utilization of the O 2 supplied. Therefore, we show that the pressurized microreactor is practical embodiment of a general reaction‐engineering concept for process intensification in enzymatic conversions requiring O 2 as the cosubstrate.

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“…Indeed, this special issue is testament to the interest in this field. There are already some superb examples of flow biocatalysis both in the area of enzyme characterization and property measurements [14,15], as well as development and production [16,17]. Nevertheless, an often-cited challenge is that biocatalytic reactions in general are rather slow (compared to their chemical 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).…”

Section: Introductionmentioning

confidence: 99%

Reactor Selection for Effective Continuous Biocatalytic Production of Pharmaceuticals

Lindeque

Woodley

2019

Catalysts

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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

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Automated Determination of Oxygen‐Dependent Enzyme Kinetics in a Tube‐in‐Tube Flow Reactor

Cited by 45 publications

References 33 publications

The Promises and the Challenges of Biotransformations in Microflow

The Promises and the Challenges of Biotransformations in Microflow

Process intensification for O₂‐dependent enzymatic transformations in continuous single‐phase pressurized flow

Reactor Selection for Effective Continuous Biocatalytic Production of Pharmaceuticals

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Automated Determination of Oxygen‐Dependent Enzyme Kinetics in a Tube‐in‐Tube Flow Reactor

Cited by 45 publications

References 33 publications

The Promises and the Challenges of Biotransformations in Microflow

The Promises and the Challenges of Biotransformations in Microflow

Process intensification for O2‐dependent enzymatic transformations in continuous single‐phase pressurized flow

Reactor Selection for Effective Continuous Biocatalytic Production of Pharmaceuticals

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Product

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Process intensification for O₂‐dependent enzymatic transformations in continuous single‐phase pressurized flow