Nicola Tirelli is a professor and senior researcher at the Laboratory of Polymers and Biomaterials, Italian Institute of Technology

Nicola Tirelli

	Targeted nanoparticle-based drug delivery has been a subject of interest for more than 20 years, and it offers a number of benefits over conventional treatment options. Encapsulation of an API in a carrier particle can protect it from degradation and allow its dispersion into an aqueous environment-the body-where typical APIs are poorly soluble. Furthermore, targeting groups can be used to address specific biological settings, maximizing the efficacy of the API while reducing the dose and, as a result, the potential for side effects.

	Important goals in nanoparticle production are ensuring homogeneous particle composition, minimizing particle size distribution, and maximizing API loading. Of these, particle size distribution has arguably the most significant implications for drug delivery, because nanoparticle size determines the rate of diffusion through a tissue, and different sized particles will be taken up by cells using different mechanisms. Release of the API-either by simple diffusion or nanoparticle degradation-will also be strongly influenced by size. Smaller nanoparticles will have a greater surface area-to-volume ratio and are therefore likely to release the drug much more rapidly. This rapid release may result in high API concentrations that could potentially lead to harmful side effects. Consequently, a broad size distribution means poor control over how the API is released, making it harder to determine whether or not the patient is receiving the required therapeutic dose. This lack of control is driving the demand for production methods that reduce polydispersity.

	Nanoprecipitation is the most common method for obtaining particles less than a micron in diameter. Industrially feasible production techniques have traditionally relied on a three-stage process: dissolution of a hydrophobic polymer in a waterâmiscible solvent, mixing of this organic phase with an aqueous solution, and precipitation of the polymer. Conducting the precipitation in the presence of surfactants-or using polymers that in themselves are surfactants-preventing polymer aggregation, and co-dissolving the API in the organic phase in the first instance leads to its encapsulation within the nanoparticles.

	Batch processes have typically offered the benefit of producing a large volume of material in a short period of time, as well as being conceptually easy to assemble. One-pot pouring or dropwise addition of the organic phase to the aqueous solution is the standard technique for nanoprecipitation, yet this simplicity is offset by a key disadvantage; it is difficult to set up or scale up a batch process with perfectly reproducible mixing. Even a trivial parameter, such as the distance between the magnetic stirrer and the point of injection of the organic phase, can have a profound effect on both the size dispersity and the average particle size.

In contrast to batch processes, microfluidics-based devices (see

), offer a higher level of control, because the mixing of liquids takes place in channels of controlled size and geometry, and almost invariably under laminar flow. In a cross-shaped microfluidic chip (Asia system, Syrris), for example, the organic phase passes through a central channel and concentrates in the middle region when water is added laterally 

 the two remaining perpendicular and counter-flowing channels. The mixing is relatively slow, laminar, and consistent, and this reproducibility makes the nanoprecipitation process easy to replicate. Furthermore, the size of the particles precipitated can strongly depend on the aqueous-to-organic ratio, which can be controlled in a microfluidic process. Finally, the production can be scaled up by running several microfluidic chips in parallel.

	The end result of this increased control is the reproducible production of homogeneous particles with a considerably narrower size distribution than most equivalent batch processes.  Homogeneity not only offers clear benefits for drug delivery, it also delivers significant upstream advantages. During research and development, it is easier to rationalize biological results when one is confident of consistent particle size, 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 the product.

	The future of nanoprecipitation for drug delivery is likely to lie with flow techniques, but it is important not to downplay the role of batch processes, which are still key. The simplicity of batch techniques makes them ideal for exploring new materials or experimental conditions, and performing initial screenings without running the risk of, for example, obstructing the microfluidic channels. Once nanoprecipitation has been confirmed and refined under batch conditions, it can be transferred to a flow scheme for better reproducibility and control of the average nanoparticle diameter and size distribution.

	The continued development of the ability to finely tune nanoparticles for drug delivery will remain a key objective in this growing area of research. The microfluidics-based flow technologies now available to academia and industry offer an alternative to batch processes for reproducible generation of homogenous nanoparticles and will continue to be catalysts for innovation and experimentation in the future. 

olid Dosage Drug Development and Manufacturing

	When referring to this article, please cite it as N. Tirelli, "Improving Nanoprecipitation Control," 

	Nicola Tirelli is a professor and senior researcher at the Laboratory of Polymers and Biomaterials, Italian Institute of Technology.

Articles

The performance of nanoparticles used as carriers in drug delivery is intimately linked to their physical properties. Nanoprecipitation is a common method for the preparation of drug-loaded polymer nanoparticles, but until recently, the reproducibility of the two primary dimensional descriptors-the average particle size and the breadth of the size distribution-has been a challenge due to the intrinsic variability of batch processes. Microfluidics-based flow techniques, however, reduce variation in drug-loaded polymer nanoparticle synthesis. 