Colloidal particulate systems have attracted the growing interest of the scientific community in the last decades due to their interesting properties as drug carriers for therapeutic applications. Drugs could be entrapped in polymeric matrices resulting in increased therapeutic benefits and minimized side effects. The particulate carrier must have a controlled Particles Size Distribution (PSD), in fact, in order to avoid negative interactions with the Reticulo-Endothelial System (RES) particle size must be smaller than 250 nm, guaranteeing an adequate circulation half-life, and a continuous and controlled drug release.

In polymeric nanoparticles the drug can be dissolved, entrapped, encapsulated or attached to the polymeric matrix, depending on the method of preparation, namely: emulsification-evaporation, salting-out, emulsification-diffusion and solvent displacement [1, 2]. Rapid solvent displacement precipitation can be also used to assemble therapeutic biomacromolecules such as proteins and nucleic acids onto the surface of suitable excipient particles [3, 4], such as sugars or amino acids, while preserving structural integrity and biological activity of biotherapeutics.

In this work we investigated formation of two classes of nanoparticles for drug delivery applications through solvent displacement (anti-solvent precipitation). Poly-ε-Capro-Lactone (PCL) nanoparticles for controlled drug release applications were prepared by using acetone and/water as solvent and anti-solvent, respectively. Nanoparticles of DL-valine, an amino acid, were prepared by using water and isopropanol as solvent and anti-solvent respectively.

This methodology for obtaining nanoparticles involves two main steps: dissolution of the carrier (polymer or excipient) and the drug into a solvent and rapid mixing of the obtained solution with the anti-solvent leading to spontaneous particle formation. The solvent displacement method offers several important advantages, such as reproducible carrier sizes in the nanometer range and the use of ingredients with low toxic potential. However, since particle formation is extremely rapid, mixing must be very fast, and therefore special continuous mixers must be used and in this work Confined Impinging Jets Reactors (CIJR) are employed [5, 6]. In CIJR the two solutions of solvent and anti-solvent mix in a very small volume in the centre of a cylindrical chamber, where due to collision and impingement of the two jets, turbulent kinetic energy is generated and then quickly dissipated, inducing very rapid mixing. In turns rapid mixing involves very high nucleation rates and therefore results in the production of very small particles.

The effect of the most important operating parameters such as initial solute concentration, mixing rate and solvent-to-antisolvent ratio on the final PSD was investigated, analyzed and rationalized. The mixing rate in CIJR is quantified by the flow rate with which the two solutions are fed into the mixer, and it is often expressed in terms of the Reynolds number in the feeding pipe. The flow rate in our experiments was varied between 3 and 120 ml/min resulting in Reynolds numbers ranging from 500 to 3000. Eventually the solvent/anti-solvent ratio was kept between 1 and 4.

Experimental results show that the effect of mixing on the PSD is crucial. We found that increasing the feeding rate of the solution of solvent and anti-solvent in the CIJR, and therefore improving mixing, nucleation of smaller particles is favored and the mean size is remarkably reduced. We also found that at constant Reynolds numbers a significant reduction of the mean particle size is detected increasing the anti-solvent to solvent ratio. This is probably caused by the fact that the carrier solubility is lower at higher anti-solvent concentrations, resulting in increased super-saturation levels and higher nucleation rates. Moreover there is also a dilution effect with increasing anti-solvent to solvent ratio, which can further stabilize the nanoparticle suspension, suppressing agglomeration and therefore reducing the final mean particle size.

Our experimental data clearly show that the controlling parameter for nanoparticle precipitation is solute supersaturation. This quantity is defined as the ratio between the actual carrier concentration in the solvent/anti-solvent mixture and the carrier solubility in the mixture (the equilibrium concentration experimentally determined in this work). Another very important parameter is the interfacial tension between the solid particles and the mixture, that changes dramatically with the mixture composition, and therefore changes with the anti-solvent to solvent ratio.

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[3] Kreiner, M.; Moore, B.D.; Parker, M.C. Chem. Comm., (2001), 1096-1097.

[4] Kreiner, M.; Fuglevand, G.; Moore, B.D.; Parker, M.C. Chem. Comm., (2005), 2675-2676.

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[6] Johnson, B.K. ; Prud'Homme, R.K., AIChE J., 49, (2003), 2264-2282.