Using flow technologies to direct the synthesis and assembly of materials in solution
© The Author(s) 2017
Received: 7 June 2016
Accepted: 2 December 2016
Published: 5 January 2017
The use of flow technologies for chemical applications has become a fast growing area with a wide range of reaction types identified as having benefited from flow processing . Flow environments are used to achieve conditions not accessible in batch such as: very fast or very slow mixing of reagents; ordering of reagents; physical confinement for control of geometry/habit; highly repeatable reaction/crystallisation conditions; isolation of reactants/products and use of very small volumes of reagents (pl–μl). These conditions are interlinked and are inherent to the nature of flow environments; for example, the ability to crystallise reproducibly material of a specific size or polymorph is reliant on the control of mixing conditions and temperature. The manner in which this can be achieved is dependent on the scale of the reactor; microreactors have excellent mixing properties usually induced by bends in the channels creating Dean vortices ensuring steady-state operation, mesoreactors require additional mixing elements such as segmentation for Taylor flow or static mixers e.g. Kenics type. As such the different scale of reactor is dictated by the application. Mesoreactors are more applicable for scale-up production of exquisite particles and crystallisation of particles incompatible with microreactors. Microreactors have the advantage of using very small volumes making them ideal for high-throughput applications for synthesis or assembly of expensive or precious materials at low volume. The control over fluid dynamics is outstanding in microreactors enabling the construction of very precisely controlled architectures such as spherical particles or foams. This review will highlight the different areas in which flow technologies have enabled the synthesis and directed-assembly of materials in both meso and microreactors.
Introduction to meso and microfluidic reactors
These variations in design are employed to ensure that all of the solution passing through the reactor experiences a homogeneous environment (mixing and temperature conditions) for any given point of the reactor. Evaluation on the efficacy of each reactor towards homogeneity can be performed by injecting tracer solutions  or by evaluating the homogeneity of the resultant product. In flow crystallisation experiments this is confirmed by the particle size distribution (PSD), the range of particles sizes obtained from each experimental run of the reactor. A narrow PSD implies a high level of homogeneity within the reactor and is typically the goal for flow crystallisation; this has the benefit that, if the size of product can be controlled, an experiment can potentially be designed to produce a targeted particle size.
Control of self-assembled shape
Production of functional substrates
The activity of surface active sensing techniques such as localised surface plasmon resonance (LSPR) and surface enhanced Raman spectroscopy (SERS) is highly dependent on the size and homogeneity of the nanoparticles which make up the substrate [29, 30]. The production of substrates with highly homogeneous nanoparticles of desirable particle size and shape is therefore of the utmost importance for progressing these techniques.
Directing solutions for printing and high-throughput applications
Alternative designs to the slip-chip allow automatic loading of precursors and enable either comparison of reagent ratios by combining differing well sizes  or investigation of crystallisation kinetics by incorporating channels of differing lengths between the two microwells of solution . A similar approach to the optimisation of crystallisation kinetics of proteins was devised by Quake et al., in which a splitter directs the flow of reagent into successive channels with differing lengths .
Timescales unattainable in batch conditions
At the opposite end of the scale, microfluidics has been widely used to achieve very fast reaction kinetics. This is most evident in flow chemistry applications in which the fast mixing of microfluidics has been used to intensify reaction processes and regulate temperature, allowing reactions to be performed in a fraction of the time  and at much higher temperatures  than is possible in traditional batch reactions. In flow crystallisation processes, fast mixing has been used largely to achieve homogeneous materials especially for anti-solvent/drowning out crystallisation conditions [1, 5, 6, 47–50]. For example the precipitation reaction of CaCO3 from CaCl2 and Na2CO3 can have three different polymorphic products which are largely dependent on initial mixing of the reagents . By tuning the initial mixing conditions de Mello and co-workers were able to access selectively either the calcite or vaterite forms of CaCO3 using a liquid segmented microfluidic chip .
Growth and nucleation studies
Because the mixing conditions can be tuned in flow crystallisation it is therefore a useful technique for evaluating growth conditions of analytes. Using a Couette-Taylor (CT) mesoreactor, Kim et al. investigated the CaCO3 crystal habit resulting from varying reagent ratios [53, 54]. By combining a solution of Ca(OH)2 with CO2 gas in the vortex type mixing environment of the CT reactor with varying gas: liquid ratios the habit of CaCO3 could be tuned. It was postulated that excess species would block the faces of growing crystals and so either spheres or cubes could be obtained by optimising the mixing conditions.
Control of PSD and scale-up—continuous crystallisation
Whilst previous examples in this review have shown that microfluidics can deliver a narrow PSD with relative ease, this section will focus on the application of self-assembly control in reactors/crystallisers designed for scale-up applications. In order to accommodate the large-scale production of particles that are often greater than 100 μm in dimension, the design of these crystallisers have increased internal dimensions (mm–cm) with respect to those employed in microfluidics. This increase in channel size results in a corresponding decrease in mixing intensity and so alternative apparatus designs and nucleation control techniques are required to recover control of assembly conditions.
The induction of primary nucleation is driven in one of two ways: homogeneous nucleation—where solute species come together in solution to form a nucleus; or heterogeneous nucleation—where solute species adsorb onto (often microscopic) solid surfaces . The former is typically concentration and mass transport driven; increasing the likelihood of collisions (through increasing density and/or velocity of solute species) increases the likelihood of sufficient species coming together to surmount the energy barrier to form a nucleus. The latter can occur due to suspended solids, e.g. impurities or already present crystals (seeds), or interaction of the solute with the crystalliser/reactor walls. The interaction with, and growth upon, crystalliser walls is termed fouling and is a significant challenge for continuous crystallisation as it threatens the homogeneity of product [57, 58]. Discussion of fouling is outside the focus of this review but it highlights the need for continuous crystallisation platforms to control the nucleation conditions in order to minimise this risk.
Control of nucleation is most easily achieved by ensuring its induction at a desired point. Nucleation induction by anti-solvent addition has been introduced in previous examples in this review, either in the form of a pure solvent in which the crystallising species is not soluble [14, 50] or using solvents in which the starting materials are soluble but reaction product is not; precipitation reactions [15, 19]. Myerson and co-workers followed the anti-solvent crystallisation of ketoconazole in a mesoreactor (3.2 mm ID) with static mixing elements . By changing the flow rate the effect of mixing intensity on the nucleation and growth of ketoconazole was investigated, showing that at low flow rates (and therefore low mixing intensity) the resultant crystal size (analysed by on-line focussed beam reflection measurement—FBRM) and yield was smaller than for higher flow rates. This is contrary to expectations for standard crystallisation experiments, in which faster mixing is expected to lead to a higher number of nuclei and thus smaller crystals; in this example once nuclei are formed the crystallisation process becomes growth driven and so is dependent on mass transfer for increased crystal growth. Critically for the success of this process, the mass transfer in flow environments is more effective than in batch, thus favouring this outcome. These findings were confirmed by off-line concentration analysis.
Nucleation can be induced through acoustic cavitation using an ultrasonic device , in which localised regions of low pressure and high concentration result in the formation of nuclei. Using a mesoreactor with a sonic probe and subsequent air-segmentation, Myerson et al. obtained a high yield of l-aspargine monohydrate (LAM) with a narrow PSD . The nucleation of LAM was controlled by the power amplitude of the sonic probe and crystal growth thereafter was controlled by cooling, smaller and more homogeneous crystals were obtained at higher power amplitudes as expected. Khinast and co-workers previously used a similar set-up but with a sonic bath rather than a sonic probe, which led to more inhomogeneity due to the increased residence time of the solution in the nucleation-inducing sonic portion of the reactor .
Mixing of solution feeds which are saturated at different temperatures can induce nucleation in a similar way to anti-solvent addition. The sudden drop in temperature for the hot solution results in precipitation whilst the remaining solute provides a plentiful supply of growth solution for cooling crystallisation. By combining streams of aqueous LAM solution saturated at 65 and 22 °C, Braatz and co-workers produced crystals with a narrow PSD . The achievement of narrow PSD was aided by a fines dissolution mechanism of hot/cold cycling along the reactor length; the heated sections are sufficiently long to re-dissolve small crystals but not the larger ones [63, 64].
Flow technologies have enabled control over self-assembled systems to be achieved in a way that is unobtainable under batch conditions. By employing very small amounts of material and/or excellent mixing conditions the concentration/ratio of reagents can be precisely controlled without concern over micromixed regions. This can be used to generate reproducible, homogeneous product or to investigate a wide range of synthesis or assembly parameters. The ordering of reagents in a flow assembly set-up is such that multi-step assembly is facile and does not require the long equilibration time required in batch. In particular, flow processing of nanoparticles is becoming very common as particle size homogeneity is of the utmost importance for these functional materials.
With the rapid development of flow technologies and their increasingly accessible cost, the use of these platforms is expanding over a wide range of chemistries and crystallisations. As more and more research groups are investigating flow methods, the pool of expertise and variety of applications available is broadening, enabling a new generation of innovative chemistry to be developed and applied.
The authors declare that they have no competing interests.
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