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.
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 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;24:2566-8.
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.