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Flow chemistry is a fast-advancing field involving the continuous combining of reactants which are fed into a reaction chamber, followed by the continuous output of product. When compared to batch methods, flow chemistry boasts better mixing, more efficient heat transfer and the ability to undergo self-optimisation.¹ Typically synthesised in batch, nanoparticles which display superior properties (e.g. chemical, thermal, optical) to their molecular counterparts are becoming increasingly in demand, however their large-scale synthesis, necessary for industry, is currently limited. One significant benefit to flow is the ease of scale-up whilst still retaining the desired particle properties. A range of nanoparticles from metal oxides to polymers have been produced via flow techniques, for example microfluidics.² Moreover, in flow the user has much greater control over the experimental parameters, i.e. reaction time can be fine-tuned much more easily than in batch which is useful for reactions which occur in a matter of seconds.

Continuous stirred tank reactors (CSTR) are commonplace in many large process reactions such as pharmaceutical manufacturing where they are predominantly used to synthesise organic compounds on the molecular level. Whilst CSTRs are generally involved in batch reactions they can be utilised in continuous flow processes too. The fReactor™ represents a versatile piece of flow equipment consisting of five connected CSTR modules, each of which form a discrete reaction zone. Each module has multiple ports making telescoping of reactions possible. Offering alternative routes of synthesis, this equipment can be used to conduct both single and multiphasic reactions. Additionally, the fReactor allows for the exploitation of traditional chemical and physical principles but provides that critical level of control not seen in batch, owing to its small size and modular design. Thus, bridging the gap between batch and classical flow/microfluidics.

Using the fReactor, this work describes the optimisation of poly(lactic-co-glycolic) acid (PLGA) nanoparticle synthesis by nanoprecipitation. This polymer presents itself as an ideal candidate for encapsulating active pharmaceutical ingredients owing to its biocompatible and biodegradable nature, coupled with its FDA approval for use in vivo.³ Initial optimisation experiments allowed the formation of spherical nanoparticles ~200 nm with polydispersity indices of 0.05, a significant improvement over the polydispersity observed when prepared using traditional bath methods. Furthermore, we describe a methodological design which was carried out as a systematic study to assess several parameters including type of PLGA, solvent, flow rate, residence time, agitation speed, use of surfactants, and encapsulation ability. Notably we found that as agitation speed within the fReactor was decreased in regular intervals from 1500 to 500 rpm during the synthesis, nanoparticles size increased linearly (R² = 0.98). However, for speeds lower than 500 rpm this control was lost and an increase in particle polydispersity was observed. A full comparison against PLGA prepared through batch nanoprecipitation demonstrated that this flow technique has the ability to tune particle properties readily, through greater control over process parameters and produced nanoparticles with a smaller size distribution.

We have further demonstrated the broad utility of this cascade of small volume CSTRs by optimising the synthesise of superparamagnetic iron oxide nanoparticles (8 nm diameter) and mesoporous silica nanoparticles with tuneable pore diameters, which can be used as medical imaging agents and drug delivery carriers, respectively. All particles made in the fReactor were comparable to the equivalent batch materials.

References
1 Chem. Rev., 2017, 117, 11796.
2 React. Chem. Eng., 2020, 5, 1619.
3 J. Mater. Chem. B, 2018, 6, 2065.

Co-Author(s): Leslie Hughes (AstraZeneca), Duncan Browne (University College London), Gemma-Louise Davies (University College London)

Sam Ackerley

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