## 3 Production of Nanoparticles by Using CO2 as an Antisolvent
In other cases, although less frequently, the emulsion and the scCO\({}_{2}\) are also fed in co-current mode [25]. The use of a batch SFEE apparatus was also adopted in some papers [27, 111, 112]. In this case, the emulsion is previously placed inside the extractor; then, scCO\({}_{2}\) is fed to the extractor, at the desired temperature and pressure, until the selected operating time is reached. Finally, the vessel is depressurized and the suspension of nanoparticles in water is recovered. However, [PERSON] and [PERSON] [27] highlighted the possibility of reducing operation time and increasing production capacity by running a continuous mode in a packed column. Two different SFEE apparatuses are sketched in Figure 5(a,b), i.e., the continuous and countercurrent and the batch plant, respectively. Figure 6: A sketch of the Supercritical fluid extraction of emulsions (SFEE) technology: (**a**) continuous and countercurrent SFEE; (**b**) batch SFEE. The superiority of the SFEE process over conventional emulsion solvent evaporation or other traditional technologies has been highlighted in some papers [25; 26; 27]. In the study by [PERSON] et al. [25], medroxyprogesterone acetate, a poorly water-soluble hormone, WAS encapsulated into particles based on poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), using both SFEE and conventional emulsion solvent evaporation techniques. The effect of the PHBV molecular weight on the morphology and size of produced particles was studied in detail. Using both technologies, a shift from micrometric to nanometric particle dimensions was observed by decreasing the PHBV molecular weight from 210,379 Da to 14,080 Da. In all cases examined, through the SFEE technique, smaller particles and higher encapsulation efficiencies are obtained than those achieved with the conventional emulsion solvent evaporation technique. Furthermore, in the case of the traditional emulsion solvent evaporation, longer times are required for the elimination of the solvent from the final product than those required by the supercritical technique. Similarly, in the paper by [PERSON] and [PERSON] [27], lower encapsulation efficiencies were reached by loading vitamin E into polycaprolactone (PCL) nanoparticles by conventional emulsion solvent evaporation compared to the SFEE technique. Moreover, a higher residual concentration of acetone was observed in the nanoparticles prepared with the traditional technique. The scaleup of the processes based on the use of supercritical antisolvent may be easily achieved by increasing the batch volumes with respect to the bench scale while maintaining the antisolvent/solvent flow rates ratio and the pressure differentials unchanged [1; 113]. However, there are still some challenges related to the scaleup of these techniques, including the possible nozzle clogging and the need for large precipitation vessels resistant to high pressures that require high investments for industrial production [114]. Moreover, the primary difficulty is related to the recovery and handling of dried nanoparticles produced. For this purpose, filters are mainly used in the analyzed papers, since they are efficient for the collection of low quantities of small particles, i.e., at lab scale. However, filters are burdensome and not easily adaptable to the industrial scale. The use of processes that allow producing nanoparticles in suspensions (e.g., SFEE technology) could be a possible answer to this issue; however, additional filtration and purification steps are required to obtain dried nanoparticles, resulting in additional costs and process time. Nevertheless, several companies already employ pilot/industrial-scale plants involving the supercritical antisolvent, such as Thar (Pittsburgh, PA, USA), Phasex Corporation (North Andover, MA, USA), Crtitech (Lawrence, KS, USA), Aphios (Woburn, MA, USA), and Applied Separations (Allentown, PA, USA), CrystecPharma (Bradford, UK), Cerbios-Pharma (Lugano, Switzerland), and FeyeCon (Weesp, The Netherlands).