Continuous flow: a transformative technology

By Professor Rodrigo de Souza, Laboratory of Biocatalysis and Organic Synthesis at the Chemistry Institute of the Federal University of Rio de Janeiro - 24/10/2018

Syrris - Rodrigo de Souza 310518.jpg
Interest in continuous flow chemistry has grown considerably in recent years, due to the benefits it offers over batch processes. In this article, Professor Rodrigo de Souza, Laboratory of Biocatalysis and Organic Synthesis at the Chemistry Institute of the Federal University of Rio de Janeiro, explains how the commercial availability of benchtop continuous flow instruments has driven widespread adoption of the technique for organic synthesis, biocatalysis, drug encapsulation and polymerization, tackling some of the challenges of batch chemistry to streamline processes and improve efficiency.  
The simplicity of batch processes has made them the standard production technique in modern industrial applications, from research and development to manufacturing. They generally involve loading reagents into a single container – often a round bottom flask or jacketed reactor vessel – and leaving the reaction to go to completion, followed by a work-up to extract the product. In contrast, reagents in a flow chemistry regime are continuously pumped through a milli- or microreactor, and the product is seamlessly collected without interrupting the production process.

Continuous flow reactors can take a variety of forms, including microfluidic glass chips, tubes and packed columns. Microfluidic chips with precisely etched channels – typically only micrometers in diameter – enable rapid mixing, while tube reactors offer longer residence times and are generally used for scale-up. Microfluidic chips and tube reactors are primarily used for homogeneous reactions, whereas packed bed columns support heterogeneous reactions, allowing a liquid to pass over an immobilized solid, such as a catalyst.  

Small volumes, big benefits
The small volumes of milli- or microreactors are responsible for many of the benefits of continuous flow chemistry, offering more precise control of reaction parameters. For example, the much greater surface area-to-volume ratio of these reactors enables more efficient heat transfer, and therefore better temperature control. The microreactors are also easy to pressurize safely, allowing solvents to be superheated to achieve faster reaction rates than could be safely attained under batch conditions. The small diameter of microreactors means that mixing is diffusion limited, and usually takes place under laminar flow conditions, leading to fast and highly reproducible mixing. This precise control of temperature, pressure, mixing and flow rates – combined with automated, in-line analysis – makes it easy to conduct multiple experiments in a short space of time, screening various reaction parameters to optimize conditions. Simply flushing the system with a solvent after each run prepares it for the next reaction, and the short reaction times make the screening process much faster than an equivalent batch approach.
Another advantage offered by continuous flow chemistry is in the transition from lab-scale to industrial manufacturing. Scaling up a batch process can be problematic, because of either safety concerns or impracticality. Polymerization reactions, for example, are often exothermic, and carrying out batch polymerizations on a manufacturing scale represents a significant risk that needs to be mitigated. In contrast, increasing production of an exothermic continuous flow chemistry process can be achieved in one of two ways, either by increasing flow rates and the reactor size while ensuring that the process temperature is maintained and controlled (scale-up), or by running multiple microreactors in parallel (scale-out).
One of the most obvious applications of flow chemistry is in transferring existing batch processes to continuous flow. This can be particularly useful for synthetic pathways involving sequential steps. With careful thought and consideration, many of these cascade syntheses can be redesigned for continuous flow, eliminating multiple work-ups and isolation of intermediates. In one instance, a four-day, seven-step batch synthesis of oxomaritidine – involving the isolation of intermediates and purification steps, such as distillation, crystallization and chromatography – has been converted into a single continuous flow reaction offering significant time savings.1

Making light work of multi-step biocatalytic syntheses
Streamlining these processes is particularly important in biocatalysis. This area is expanding rapidly to meet the increasing demand for biological ‘green’ alternatives to chemical catalysis as part of the drive towards a more sustainable future. Many multi-step reactions involve an initial chemical step, followed by a biocatalysis step, and then a final chemical step. It’s almost impossible to run these steps in a single batch reactor, due to the incompatibility of the chemical catalyst and the biocatalyst. However, when running these cascade reactions in continuous flow, the various stages can be compartmentalized in different environments, enabling a separate and smooth transition between steps.
Continuous flow systems for biocatalysis tend to give rise to faster reaction times without a loss of selectivity. A typical set-up immobilizes an enzyme or calcium alginate-encapsulated cells in a packed bed column and circulates reagents through the system. The amount of biocatalyst that can be used in a batch process is often dependent on the concentration and final volume of the reaction, while under continuous flow conditions, reagents and solvents can be passed through a packed bed column without limitation, maximizing exposure to the biocatalyst. For example, a 24-hour batch process for lipase-catalyzed fructose esterification was transferred to continuous flow and achieved conversion rates between 87 and 93% with residence times under half an hour.2 Batch processes, unlike continuous flow reactions, typically require agitation to enable the reagents to mix thoroughly, and mechanical stirrers can often damage the biocatalyst surface, leading to a loss of catalytic activity. In one particular instance, a transition to continuous flow offered over a two-fold increase in the lifetime of the biocatalyst – increasing the lifetime from 13 to 30 cycles – offering a more cost-effective use of the biocatalyst.3 Many continuous flow regimes also offer greater yields and higher productivity than equivalent batch processes. For example, productivity of an optimized fructose ester synthesis catalyzed by lipase Cal B was increased from 66.8 to 88.1 g/h/g of lipase by switching from batch to flow.4
Straightforward screening
Improving yield and overall productivity are key aims of any industrial process, and the manufacture of polystyrene is a good example of this. The entry of lower cost packaging materials into the market has driven research into more efficient production methods with higher monomer to polymer conversion rates. Styrene polymerization is typically achieved by mixing the styrene monomer with an initiator – such as benzoyl peroxide – that decomposes to form radicals that attack the styrene double bond and kickstart the polymerization process. However, as with many reactions, there are a number of variables to consider when optimizing production efficiency, often requiring a compromise between the various desirable outcomes of high conversion rates, good productivity and narrow molecular weight distributions.
Syrris - Asia Transparent Background.jpg
Traditionally, batch emulsion, solution or suspension polymerization have been the preferred methods for manufacturing polystyrene. However, more recently, scientists have begun to investigate continuous flow techniques. One publication highlighted the potential of a continuous flow reaction using an Asia system (by Syrris; pictured). Using a fluoropolymer tube reactor with an internal diameter of 0.5mm and a total volume of 4ml, a range of parameters were screened – including temperature, concentration, residence time and initiator mass – to optimize the process.5 The screening experiments demonstrated that, in general, aggressive reaction parameters – high temperatures, high monomer concentration and reduced solvent – led to increasing conversion rates up to a maximum of 66.8%, achieved with a residence time of 80 minutes. This represents a significant improvement compared with batch processes, which often have conversion rates of 45% or lower, or require much longer reaction times – often a four- or five-fold increase – to achieve a comparable conversion rate.6 In addition, increasing the incidence time of reaction and initial mass of initiator naturally led to increased conversion. Even under continuous flow conditions, polymerization is often a compromise between multiple variables that sometimes work in a non-complementary manner; achieving a narrower molecular weight distribution, for example, may be at the cost of shorter polymer chains or a decrease in conversion. However, the excellent parameter control and the simplicity of optimizing reaction conditions make the continued pursuit of improved efficiency through continuous flow polymerization a worthwhile endeavour.
Improving control
Continuous flow chemistry has also been readily adopted on all scales by the pharmaceutical industry, particularly in the in area of drug discovery and development. Excellent control of small volumes has enabled the technique to make significant inroads into nanoparticle-based drug delivery. Encapsulating an active pharmaceutical ingredient (API) in a carrier particle offers a number of advantages over conventional formulations, protecting it from degradation and overcoming solubility issues. However, controlling the average size of these nanoparticles, and their size distribution, is paramount to their cellular uptake and drug release profiles.
The variability in uptake and release associated with polydispersity has created a demand for improved process control, and so researchers have turned their attention to continuous flow chemistry using microfluidic systems. Traditionally, drug encapsulation in nanoparticles has relied on a three-stage batch process: dissolution of a hydrophobic polymer and API in a water-miscible solvent, mixing this organic phase with a surfactant-containing aqueous solution, then precipitation of the polymer. This process offers users large volumes of material in a short period of time, as well as being straightforward to execute, either by one-pot pouring or dropwise addition of the organic phase.
The simplicity, however, is overshadowed by a significant drawback – it is almost impossible to scale up a batch process with perfectly reproducible mixing. Even a trivial parameter, such as the distance between a magnetic stirrer and the point of injection of the organic phase, can have a profound effect on the dispersity and average particle size. As with previous examples, the shift towards continuous flow production in microfluidics devices offers a much higher level of control, with mixing taking place in microfluidic channels with a fixed size and geometry. In a flow-focusing, cross-shaped microfluidic chip, for example, the organic phase passes through a central channel and concentrates in the middle region, where water is added laterally via the two remaining perpendicular and counter-flowing channels. These restraints enable reproducible mixing, producing homogeneous particles with a considerably narrower distribution than most equivalent batch processes.7 The particle diameter is also strongly dependent on the aqueous-to-organic ratio and flow rate, which can be altered to achieve the desired particle size.
The benefits of this improved control extend beyond simply the efficacy of drug delivery, offering a number of upstream advantages. During research and development, it is more straightforward to rationalize biological results when working with homogeneous particles, and it is easier to transfer the process to a good laboratory practice or good manufacturing practice environment, which is a necessary step for clinical translation of encapsulated drug products.
The future
The examples from biocatalysis, polymerization and nanoprecipitation demonstrate that improved control lies at the heart of the adoption of continuous flow technology, sometimes enabling processes that are simply not possible using a traditional batch chemistry approach. In addition, the availability of automated modular systems – such as the Asia system from Syrris – is helping chemists to quickly and easily develop continuous flow regimes, without having to become experts in microfluidics or engineering. Continuous flow is, no doubt, set to become increasingly common across both research and development and manufacturing, as chemists discover the incredible possibilities afforded by this transformative technology.
1.  Baxendale I et al. Chem Commun 2006:2566-258.
2. Sutili F et al. J Mol Catal B-Enzym 2013;85-86:37-42.
3. Ivaldo J et al. J Mol Catal B-Enzym 2012;77:53-8.
4. Sutili F et al. RSC Adv 2015;5:37287-91.
5. Fullin L et al. Chem Eng Process 2015;98:1-12.
6. Fontoura J et al. J Appl Polym Sci 2003;90:1273–89.
7. Donno R et al. Int J Pharm 2017;534:97-107.