For many, a journey into flow chemistry has just begun; therefore, understanding the key aspects of this process is extremely important.
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The transition from traditional batch processes to flow chemistry can be quite daunting, especially when you are a first-timer. Our previous blog explains why flow chemistry is more beneficial in the industry than batch reactions. Before using flow processes for your applications, there are so many different aspects to consider. Whether you want to produce large quantities of APIs (active pharmaceutical ingredients) or are looking to test different catalysts, this blog will be your quick guide to flow chemistry.
The flow process involves reactants continuously traveling through a reactor vessel to form the desired product (Figure 1). In comparison, multi-step reactions require thorough step-by-step transformations of the initial reactants to achieve the final product. After the isolation step, purification is necessary to remove undesired materials that may disrupt further steps. A significant benefit of flow chemistry is that it allows researchers to bypass the isolation step.
In flow processes, pumps are used to flow the reaction liquid into the reactor, and this can be achieved using semi-continuous or continuous pumps. Semi-continuous pumps may need a syringe to be refilled; however, continuous pumps do allow for an indefinite flow of solution [1]
A typical flow setup consists of six zones (Figure 2): reagent delivery, mixing, reactor, quenching, pressure regulation, and collection. Purification and further analysis are often also included when the end product is collected.
Figure 2. A breakdown of the six main components within a basic flow system with a coil reactor. Other stages in the system can include purification and analysis of the final product.
Before you start your flow journey, a number one consideration is the type of reactor that is suitable for your application. These reactor vessels are divided into four main groups: coil, packed bed, chip reactors, and continuous stirred tank reactors [2]. The most used of the three are the packed bed and coil reactors (Figure 3).
Figure 3. Common reactors used in flow chemical process i) coil ii) packed -bed iii) continuous stirred tank reactor (CSTR) iv) continuous flow reactor chip
Coil reactors are mainly used for single-phase chemistry, where the mixing of reagents relies on diffusion rates. Due to the higher cost of chip reactors, coil reactors have become a suitable alternative for synthetic reactions. These reactors tend to be made from fluoropolymers such as PTFE, PFA, and FEP but can also be stainless steel with a range of internal diameters [3].
Packed bed reactors work best for heterogeneous reactions. These reactors are generally tubular and are often stainless steel or Hastelloy to facilitate working at pressure, with a filter frit to ensure particulates do not escape the reactor. Inside the reactor are the catalysts, typically transitional metals, which are coated onto a support material. The support material is then spaced out with some inert packing material, such as glass beads. Fixed bed reactors are highly advantageous for heterogeneous reactions, as the reactants have a greater retention time and thus have a long contact time with the catalyst. Secondly, these reactors achieve a higher effective molarity of catalyst to reagents, decreasing the reaction time.
Mixing is a significant component in flow chemistry; flow conditions allow for enhanced mixing and control of reactant residence time. Mixing is influential in the conversion of reactions in flow chemistry. The two main mixing methods are passive and active mixing. Active mixing involves using an agitator to mix the reactants, which can be seen in continuous stirred tank reactors (CSTRs) [3]. Passive mixing, the main form of mixing in our FlowCAT, utilizes pressure that forces fluids to move through the reactor at a constant rate.
Temperature and pressure play a significant role in flow chemistry. Along with the flow rate of reactants, temperature and pressure are controlled parameters for the desired reactions to occur. With flow chemistry, heat transfer increases due to the larger surface areas compared with batch methods, allowing for better temperature control.
Pressure control is essential for reaction speeds. In liquid/gas reactions, the reactant gas must efficiently dissolve into the liquid reactant. Increasing pressure allows for increased gas solubility, which will increase the reaction speed. Flow reactions are pressurized using back-pressure regulators, usually found towards the end of the flow system. Back-pressure regulators prevent the liquid and gas flow from the reactor unless the process pressure exceeds a specific threshold.
For many, a journey into flow chemistry has just begun; therefore, understanding the key aspects of this process is extremely important.
Flow chemistry can provide excellent solutions to the chemical industry when utilizing the best and most appropriate technologies to meet demands.
This blog has covered some of these critical points, and we hope it can be the guide you need to start your journey.
A conventional way of doing chemistry is batch. The batch reactor is simply a vessel with a volume of microliters to cubic meters filled with chemicals that are subjected to mixing, temperature and pressure. A batch synthesis is repeated many times over to produce more material. Chemistry often starts in 1-100 mL round-bottom flasks (batch reactors) and travels through several steps into scale-up, pilot, and production at 1-10 m3 reactors.
In flow chemistry, we move materials constantly through the vessel. Like in batch, the continuous reactor vessel contains the materials and provides sufficient time for the reaction. The major difference is that we do not have to start and stop the process to produce more. We can scale-up flow processes by using wider reactors, longer reactors, put multiple reactors in parallel, or combine these approaches.
Therefore, one major difference between the batch and flow reactors is that flow processes can be scaled up by running for longer without incurring additional costs such as repeated cleaning, cooling and heating which required in batch. Therefore, a flow process is intrinsically more efficient and has a substantially lower downtime.
Industry experts we surveyed indicate that a “fully utilised batch reactor” is used only about 30% of the time for chemistry in a “good manufacturing practice” (GMP) environment. In the fine and bulk chemicals industries, utilisation may be higher but still intrinsically limited – the rest of the time the reactors are cleaned, heated, cooled… Larger reactors require much longer to heat up or cool down.
Continuous processes, on the other hand, do not require such downtime. It does not mean that any flow process is 100% efficient – depending on the process and industry, the downtime varies. The key is that continuous processing theoretically allows achieving 100% reactor operation and has demonstrated utilisation of above 90% with only annual maintenance and inspection downtime.
Flow chemistry (or continuous flow chemistry) is not novel. All top 300 commodity chemicals by volume are produced in continuous plants. [reference and visual for the fine chemicals book]
At the turn of the millennium however, the term “continuous flow chemistry” attracted increasing attention in fine chemicals and pharmaceuticals – areas dominated almost exclusively by batch manufacturing.
All large-volume processes use continuous due to the discussed efficiency benefits. At a smaller scale (small, we are still talking about 10,000 ton a year), the batch reactors dominate because setting up a continuous process is expensive. Traditionally, establishing a continuous process requires a substantial upfront investment that is not justified when the production scale is small.
Yet, the situation is changing because continuous flow reactors can be multifunctional, scalable and rapidly translated from batch.
Rapid mixing increases reaction rates and may reduce over-reaction (decrease the impurity levels and/or increase the selectivity).
When we have small reaction channels, the main mixing mechanism moves from convection (movement of fluid) to diffusion. Diffusion, however, is extremely slow when applied to macroscopic distances of centimetres. Diffusion alone is irrelevant in batch, that is why we have agitation. In small channels, diffusion mixing is exceptionally quick.
In a continuous reactor with small channels, the whole reaction is mixed in a matter of milli- and micro-seconds.
Reaction conditions in batch are severely constrained by the possible conditions. A majority of batch reactors have a narrow process conditions window they could operate in. For example, a batch typical reactor has a rated (maximum) pressure of below 5 bar, and temperature – below 150 oC.
Not surprisingly, most batch chemistries take place at the temperature range of -20 – 150 oC, and a pressure below 5 bar. These conditions do not mean that the chemistry is optimal, or even the costs are minimised.
Another problem of going beyond the traditional process conditions is safety. A large-scale process requires a detailed Hazard and operability (HAZOP) study. It takes time money and more “adventurous” process conditions may require a lot of consideration, mitigation… A financial gain in the product costs may not be justified by the upfront safety costs, development delays and the corresponding uncertainty.
Smaller continuous reactors provide faster heat transfer and could withstand much higher pressure (20-200 bar). The plot shows that a tin foil of 0.5mm stainless could withstand 100 bar pressure in a reactor 2mm outer diameter, while a 10 cm diameter for the same pressure requires almost 1 cm of metal wall.
There are high-pressure batch reactors but they are often bespoke units with large capital cost implications. A smaller continuous reactor may produce as much as batch, but it may require simpler safety assessment and contain much harsher process conditions due to its smaller volume. A reaction that requires hours in batch could be performed at a higher temperature in flow within minutes.
Flow chemistry can bring significant benefits. The reactions could be performed faster, safer, with rapid scalability and higher quality. There are 3 main drivers to use flow chemistry:
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The case of safety does not imply that batch production is not safe. The continuous processes are simply much more intrinsically safer. Lower risks mean less capital into safety measures and a broader scope for chemistry to reduce the number of steps and maximise the yield.
Flow processes are usually considered intrinsically safer because of a dramatically lower reactor volume in flow reactors compared to batch. 1 mg of an explosive azide is far less hazardous than 1 gram.
In batch chemistries, a hazardous intermediate is obtained first and then reacted. Depending on the reactor volume, this means a hazardous inventory of kilograms to tons – a major hazard. This does not mean that once a year a batch reactor explodes; such hazardous batch processes are not run at all regardless of any benefits the hazardous chemistry could bring.
Microreactors with their small volume do eliminate bulky agitators and accelerate heat and mass transfer. As such, the specific reaction rates could be significantly increased per unit of reactor volume. There are strong cases where a factor of 1,000X improvement could be realised in continuous flow.
At a smaller scale – laboratory and kilo-plant – the continuous synthesis brings the possibility to develop a process and run them for several days or weeks to obtain the required quantities. While the pumps and basic process control work, people do not have to operate (as in batch) – the continuous processes reactors saving on additional scale-up R&D.
Rapid heat and mass transfer in continuous processes bring much more precise process control. As a result, the possibilities of a reaction runaway and the corresponding side-reactions are greatly reduced. With less by-products, precise and consistent reaction timing, the amounts of impurities go down.
Most importantly, such an increased product quality is significantly more consistent over time because continuous processes could accommodate minor process disturbances better. A minor momentary excess of one of the components may result in a local hot spot, but this energy will be dissipated quickly due to excellent micro-mixing and thermal performance of continuous processes.
Batch processes are still the main way of producing chemicals. Not every process is worth converting into flow, not every process will benefit. The major advantages of batch processes include:
Low-cost multipurpose plants. Batch reactors are versatile – a vast majority of chemistry could be performed in batch. A single investment into a plant could produce almost any material.
Availability. Batch plants of any scale are readily available and are mostly inter-exchangeable. You could contract a laboratory study in a 50 mL reactor, or a production in 10 m³ reactor – the reactor technology or availability will unlikely be your limiting factor.
Predictability. Batch processes are known for centuries. Process chemists know what to expect, know possible problems, and how to solve them. Problems do occur, but these are not out-of-the-blue hurdles but mostly minor process deviations.
Scalability. Process chemists know how to scale up a batch process following a well-trodden path of laboratory, pilot, and manufacturing stages. Each stage helps to reduce uncertainties and improve the procedures. Yet, the path is known and success is almost inevitable.
Making efficient high-energy chemistries feasible. Rapid heat and mass transfer is crucial in opening chemistries that are impossible in batch. Lithiation is one such example requiring cryogenics in batch (-80 C) to maintain reaction rates and avoid thermal runaway that ruins the product quality by favouring side-reactions.
Reaction telescoping. Not all processes are optimal under the same conditions. Stitt notes that “the advantages of multifunctionality are rapidly lost if design or operation is not proximate to the optimal requirements for the various integrated co-processes” [Stitt]. Yet, there are plenty of examples where optimal parameters for one process are very broad. For example, quenching could open new reaction possibilities. You could handle hazardous reaction intermediates and obtain kilograms and tonnes with only grams of hazardous compounds that are constantly produced and used up.
Maximising efficiency. “If the campaigns are short, cleaning can be the biggest «product» in a multi-purpose plant, Rolf Dach (Boehringer-Ingelheim)”[fine chemicals]. In larger batch campaigns, changeover times could be lower – only 50%. This means that you pay for 100% time and premises, but use the reactor to obtain products only 50% time; often only 30%. Flow reactors minimise or eliminate changeover, so the benefits of flow increase dramatically with production scale.
The advantages of batch and flow are often mutually exclusive. Flow reactors are available in multiple types; they do limited tasks exceptionally well, but a multipurpose flow plant becomes very expensive due to purchasing lots of specialised equipment.
There is no general way to combine all the benefits, but we could combine the majority of benefits. And the core is as old as batch – a continuously stirred tank reactor (also sometimes called semi-batch) – a system where the reactants are constantly added and the products withdrawn.
They are multipurpose, predictable in behaviour and scale-up. A series of stirred tanks enables efficient telescoping and maximises efficiency. Small stirred tanks also have high heat and mass transfer rates. However, many stirred tanks in series are required to control residence time well. If you have a selective process, you may need 50 or 100 effective stirred tanks to ensure materials spend precisely the required time in a reactor. A series of many stirred tanks is cumbersome, expensive and complex.
Are series of stirred tanks solution to all problems?
No, series of stirred tanks is not an ultimate solution. There are plenty of cases where batch or a microreactor is the best tool. Batch is greatly beneficial in slow processes which could not be intensified. An intrinsically slow process does not benefit much from elimination of the (infrequent) start-stop routine.
Conventional microreactors also have strong merits – exceptionally fast chemistries do greatly benefit. Some chemistries are simply impossible otherwise – see flash chemistry. These processes require fractions of a second time; they could be scaled up to kilos in a single microreactor. Yet, there is a substantial area in between where continuous flow chemistry may bring benefits.
(infographic? – reaction time. Too fast – flow; too slow – batch; middle – flow/batch/cstr)
Faster, cheaper, and safer chemistry with series of stirred tanks
Our novel SABRe system contains 10+ stirred tanks in series in a single package – a single pressure vessel with shaft and magnetic drive, and without numerous leak-prone connections.
Yet, with excellent control of reactions and residence time. Hydrodynamics of batch processes all apply – you may reasonably predict the behaviour and scale-up the approach. You do need to do piloting, but you have high confidence upfront being able to use known engineering correlations to heat and mass transfer. Rapid telescoping is possible by adding several reaction components to open new chemistry.
There are several classical papers that provide in-depth analysis of continuous flow chemistry from various angles:
(1) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. , 117 (18), –. https://doi.org/10./acs.chemrev.7b.
(2) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Chemistry in Microstructured Reactors. Angew. Chemie Int. Ed. , 43 (4), 406–446. https://doi.org/10./anie..
(3) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry. ChemSusChem. , pp 746–789. https://doi.org/10./cssc..
(4) Jensen, K. F. Flow Chemistry—Microreaction Technology Comes of Age. AlChe , 63 (3), 858–869. https://doi.org/10./aic..
(5) Dong, Z.; Wen, Z.; Zhao, F.; Kuhn, S.; Noël, T. Scale-up of Micro- and Milli-Reactors: An Overview of Strategies, Design Principles and Applications. Chem. Eng. Sci. X , 10, . https://doi.org/10./j.cesx...
(6) Irfan, M.; Glasnov, T. N.; Kappe, C. O. Heterogeneous Catalytic Hydrogenation Reactions in Continuous-Flow Reactors. ChemSusChem , 4 (3), 300–316. https://doi.org/10./cssc..
(7) Newman, S. G.; Jensen, K. F. The Role of Flow in Green Chemistry and Engineering. Green Chem. , 15 (6), –. https://doi.org/10./c3gcb.