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Applications, Benefits and Challenges of Flow Chemistry

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Applications, Benefits and Challenges of Flow Chemistry flow chemistry Krist V. Gernaey Applications, benefits and challenges of flow chemistry ALEKSANDAR MITIC, SØREN HEINTZ, ROLF H. RINGBORG, VIJAyA BODLA, JOHN M WOODLEy, KRIST V. GERNAEy* *Corresponding author 1. Technical University of Denmark (DTU), Department of Chemical and Biochemical Engineering, Søltofts Plads, Building 229, 2800 Kgs. Lyngby, Denmark KEyWORDS MICRO-CHEMICAL PROCESSING IN ORGANIC SyNTHESIS Flow chemistry; Organic Synthesis; Biocatalysis; Process Organic synthesis can be performed in continuous mode by Analytical Technology (PAT); Microreactor Technology. using mini- and micro-structured flow devices. Small scale continuous flow technology has many potential advantages, such as: rapid heat and mass transfer, increased safety, easy ABSTRACT scale-up/scale-out, fast process characterization, potential for real-time release, operation with unstable reaction Organic synthesis (incorporating both chemo-catalysis species, and so on (9, 10). Due to such advantages and biocatalysis) is essential for the production of a wide integration of these small scale devices in plant architectures range of small-molecule pharmaceuticals. However, has become more common in the last two decades (11). It is traditional production processes are mainly based on important to note here that not all chemical reactions are batch and semi-batch operating modes, which have suited to such small-scale equipment. For example, disadvantages from an economic, environmental according to Roberge et al. (12), chemical reactions with a and manufacturing perspective. A potential solution 4 half-life higher than 10 min should preferably be operated in to resolve these issues is to use flow chemistry in such batch manufacturing mode. However, it has been processes, preferably with applications of micro- and demonstrated that some of these reactions too could be mini-sized equipment. In addition, Process Analytical drastically accelerated by downsizing the equipment to a Technology (PAT) may be implemented in a very micro-scale level (13). Furthermore, chemical reactions with efficient way in such equipment due to the high degree very reactive substrates, such as Grignard exchange of automation and process controllability that can be reactions and reactions with chloride, bromide and amine achieved in small scale continuous equipment. species are all very suitable for flow chemistry applications. These reactions, with typical half-lives below 1 s, can therefore be completed in the mixing zone alone (12, 14, 15). Finally, chemical reactions with half-lives from 1 s up INTRODUCTION to 10 min could also benefit from the micro-scale devices (16). Better control of heat flow and temperature ontinuous production is often cited as both eco- are the main advantages of operating such reactions friendly and economic, mainly due to the higher at micro-scale (12). C energy efficiency and reduced consumption of The kinetics of biocatalytic processes (mixed order, resources that can be achieved in comparison with traditional obeying Michelis-Menten) will always be best exploited in batch production (1-4). Furthermore, continuous production a batch or continuous plug flow mode, especially for fulfills very well the requirements defined by the regulatory reactions requiring a high conversion. For this reason, bodies, such as the Food and Drug Administration (FDA). More continuously stirred tank reactors are rarely used for particularly, the FDA has clearly indicated that it favors such biocatalytic reactions in industry. However, at reasonable processes – including on-line measurement and control – with concentrations for industrial implementation most the publication of the Process Analytical Technology (PAT) biocatalytic reactions are limited by substrate inhibition, guidance in 2004 (5). PAT defines the key Initiative of cGMP (6) meaning that a fed-batch system becomes favorable. and is incorporated into the International Conference on Often the product too is inhibitory which is most normally Harmonization (ICH) Q8 guidance (7). The Initiative has shown dealt with, by in-situ product removal (ISPR) (1, 3, 17-19). many advantages in modern organic synthesis and Such a combination of ‘feed and bleed’ combined with biotechnology, and has consequently been applied in other the mixed order kinetics, characteristic of an enzyme industry sectors, such as food, chemical and life sciences (8). catalyzed reaction, implies that a batch with feed and The objective of this manuscript is to briefly review applications ISPR, or alternatively a plug flow with multiple feed and of flow chemistry in modern organic synthesis. Furthermore, the product removal points down the column, would be focus will be on emphasizing the benefits of such processes attractive. Hence, we believe that flow chemistry also can and additionally on identifying the remaining challenges for be attractive to biocatalysis. Performing synthesis at further improvement. micro-scale is even more attractive when one considers Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 flow chemistry the small amounts of material (both substrates and products) available at an early stage of biocatalytic process development. Operating in plug flow enables the effective testing of immobilized enzyme formats as well, and simplifies integration with the neighboring chemical operations (20). Besides the limiting effects of inhibitions at industrially relevant process conditions, there are also situations where the reaction equilibrium of the biocatalytic processes is unfavorable. In those situations it is necessary to use different methodologies to shift the equilibrium towards the Figure 1. Simplified scheme of the Lab-on-a-chip system with implemented PAT requirements. Blue solid desired products. For line – main flow; blue dashed line – process signal obtained by in-line process monitoring; black dashed example in-Situ co-Product line – on-line process monitoring and resulting process signal; green solid line – data from a process Removal (IScPR) is a potential analyzer to data analysis section intended to establish process control and automation of the pumps for solution enabling higher yields the reactor section; yellow solid lines – data from a process analyzer to data analysis section intended and productivities (21, 22). to establish process control and automation of the pumps for the separation section; red solid line – The benefits of flow systems separation agent and waste material flow. have been reported to some extent in the scientific literature, for both simple and more membrane separator (Figure 2) showed great efficiency for complex systems. One example of relatively simple biocatalytic separating two immiscible liquids (28). However, it requires systems is using lipase (EC. 3.1.1.3). The enzyme is particularly long-term tests at industrial scale before such membrane robust in non-natural environments, e.g. high concentrations, separators will be accepted by industry. While waiting for the organic solvents, etc. (3, 23, 24). An example of more complex results of such trials, development of separators without biocatalytic systems is the use of ω-transaminase (ω-TA – EC. membranes is preferred (29). Furthermore, effective separation 5 2.6.1.1) to transfer an amine to a prochiral ketone. Transaminase of two miscible liquids has been achieved by applying micro- based biocatalytic processes typically experience severe evaporation principles (30), as well. substrate and product inhibition, along with unfavorable Solid particles form a major issue in meso- and especially in reaction equilibrium depending on the choice of amine donor micro-scaled equipment. One successful approach for (21, 25). In preliminary work Bodla et al. (26) showed improved handling solids is to use acoustic irradiation, which is often productivity in micro-scale systems compared to conventional applied in modern organic synthesis with the main purpose to batch methods for such a reaction. avoid bridging inside the channels. Another phenomenon called constriction could also cause potential problems in small scale flow devices, and it is usually avoided by using different INTEGRATION OF MICROREACTORS IN THE PLANT fluid velocities, or more precisely by applying periodical flushing ARCHITECTURE actions. Assuming constant concentrations of starting materials or formed particles present inside micro-channels, the extent of Even though they are only suited for micro-chemical processing, such constriction phenomena could be predicted. Indeed, miniaturized total analysis systems (µ-TAS) or lab-on-a-chip assuming constant inflow conditions, quantification of the systems are receiving increasing attention in the process constriction rates is possible on the basis of simple industries. This approach integrates all analytical steps on the measurements of pressure drops along the microchannels (31). same platform (27), and could thereby successfully avoid For biocatalytic applications it will often be a necessity to operate unnecessary storage of intermediate products. In this way, faster these systems in the presence of solids, e.g. as a consequence of manufacturing of a desired compound could be obtained, as the biocatalyst formulation (see below), or in some cases due to well as circumventing significant losses in processes with very reaction species with low solubilities (21, 24). Operating biocatalytic reactive substrates and intermediates. A simplified process flow processes in these miniaturized modules can therefore, for many
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