Nanoprecipitation: turning to microfluidics for improved control

By Richard Gray, Director at Blacktrace Group - 05/09/2018

Richard Gray, Director at Blacktrace Group, explains how microfluidics offers a new approach to nanoprecipitation, with better control over particle size, for the encapsulation of compounds in nanoparticles and liposomes.
Nanoprecipitation was first reported in 1989,1 and has applications in drug delivery, cosmetics and agriculture, where nanoparticles are used to introduce antibiotics and vitamins into animal feedstocks. Encapsulation of an active pharmaceutical ingredient (API) in a nanoparticle improves solubility and bioavailability, and protects the API from degradation. The nanoparticles themselves can also be adapted with functional groups to target specific biological settings, maximizing the efficacy of the API, reducing the overall loading dose and minimizing side effects. In addition, the external polymer layer helps to overcome some of the problems associated with taste and odour when drugs are delivered orally.
The importance of size and dispersity
Homogeneous particle composition, a narrow particle size distribution and maximum API loading are critical goals in drug nanoparticle production. Of these, particle size distribution is arguably the most important, as a number of variables – diffusion through the target tissue, the mechanism of cellular uptake and subsequent API release – depend on nanoparticle diameter. Smaller particles have a greater surface area-to-volume ratio, and are likely to release the drug faster. If the API is released too quickly, this can result in a spike in concentration and potentially harmful side effects. In contrast, if the API is released too slowly, the patient may not receive a therapeutic dose. A broad size distribution leads to poor control over how the API is delivered.
The benefits of microfluidics
Traditionally, nanoprecipitation has relied on a three-stage batch process, enabling production of large volumes of nanoparticles in a short space of time. However, these benefits are undermined by a number of significant drawbacks, including poor control over average particle size, broad polydispersity, inefficient API encapsulation and a lack of reproducibility.
Conducting nanoprecipitation in a microfluidic set-up has come to the fore, thanks to the availability of benchtop, all-in-one systems. In microfluidics, mixing takes place – almost invariably under laminar flow – in channels with defined diameters and geometries, offering superior control over the nanoprecipitation environment. The benefits of this control are hard to overstate; uniform, almost 100%, encapsulation of the API can be reproducibly achieved in monodisperse nanoparticles with a CV of less than 5%. In addition, the average particle diameter can be fine-tuned by altering the flow rate ratio.
The evolution of microfluidics
New chip designs and methods such as microfluidic hydrodynamic focusing (MHF)2 continue to refine the technique for nanoprecipitation. MHF relies on chips with a cross-flow geometry; typically, the organic phase flows through the central channel of a chip and is intersected and sheathed by two co-axial streams of the aqueous phase. This focuses the organic phase into a narrow sheet with a rectangular cross-section, leading to nanoprecipitation at the interface. Adapting the technique to new chip designs – such as the five-input chip from Dolomite Microfluidics – has further enhanced throughput and monodispersity. In this instance, incorporating two additional lateral channels creates a second organic-aqueous interface, increasing productivity, as well as preventing nanoprecipitation on the channel walls, which can lead to blocking.  
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The obstacle of throughput
Throughput remains the greatest challenge for microfluidics. Drug production typically requires kilograms of nanoparticles per day, but there is a growing demand for larger volumes, particularly from animal feed suppliers aiming for hundreds of kilograms per hour. An obvious solution is to scale up production with multiple chips in parallel. For example, the Telos high-throughput microfluidic platform from Dolomite Microfluidics (pictured) can be scaled to 70 channels with a throughput of 109 to 1012 particles per second. However, the long-term solution may lie in a combination of engineering and chemistry. Rather than simply increasing the number of channels, equipment manufacturers are looking to maximize the throughput of each individual chip, experimenting with surfactants or even the composition of the organic and aqueous phases.
Here to stay
Microfluidic approaches to nanoparticle production offer control that is unfeasible in a batch process, and the continued development of the ability to fine tune nanoparticles for drug delivery will remain a key objective. While increasing throughput is a challenge facing both batch and microfluidic processes, the ease of production scale-up and ongoing investment in reagents and chip design suggest that microfluidics will lead the way in tackling this obstacle. Whatever the future holds, microfluidics is here to stay, having established itself as a desirable alternative to batch processes for the reproducible generation of homogeneous nanoparticles.
  1. Fessi H et al. Int J Pharm, 1989;55:R1-4.
  2. Jahn, A et al. J Am Chem Soc, 2004;126:2674-5.
Richard Gray, Director at Blacktrace Group, Anglian Business Park, Orchard Road, Royston, Hertfordshire, SG8 5TW, UK
T: +44 (0) 1763 252 149