## 4 Production of Nanoparticles by Using CO2 as a Co-Solute
Nevertheless, a longer time is required to solidify the droplets when higher temperatures are used, leading to the formation of larger particles. Consequently, [PERSON] et al. [131] noted only a slight increase in particle size with temperature. Conversely, in the study by [PERSON] et al. [37], a decrease in average particle size was noted as the mixing temperature was increased, as the viscosity of the mixture decreased more rapidly as the temperature increased. In particular, according to the results obtained by the authors, nanoparticles containing coenzyme Q\({}_{10}\) can be produced by operating at temperatures above 75 \({}^{\circ}\)C, which allowed them to reach an adequate viscosity for the formation of fine droplets by atomization. However, a further increase in temperature should be avoided due to the consequent difficult solidification of the atomized droplets. Basically, in all articles focusing on the production of nanoparticles by PGSS, bimodal [132] or even multimodal PSDs [37; 131] were mainly obtained under the tested process conditions. Although less pronounced, the other peaks in the reported PSDs also demonstrated the formation of sub-micrometric or even micrometric particles. This outcome can be considered a disadvantage in the preparation of particles via the PGSS technique. However, as stated by [PERSON] et al. [37], the preferential production of nanoparticles can be promoted by increasing the pressure employed in the mixer. An enhancement in drug dissolution rate in the case of PGSS nanoparticles compared to the unprocessed drug was demonstrated only in the work of [PERSON] et al. [131]. The main advantage of processing active compounds by PGSS is that no organic solvents are needed. On the other hand, the use of high temperatures to melt the solute is the main problem when thermosensitive materials such as pharmaceutical compounds are processed. Better control of particle morphology and PSD with high drug entrapment efficiencies appears to be assured by the SAA process, although, in this case, limited use of liquid solvents is necessary [36; 133]. Water, ethanol, methanol, and acetone are mainly employed, pure or mixed, to process active compounds using the SAA technique. However, until now, sub-micrometric particles have mostly been prepared by SAA [136; 137; 138; 139], while pharmaceutical nanoparticles have been produced in few papers [36; 133; 140]. Briefly, SAA is based on the solubilization of a controlled amount of scCO\({}_{2}\) in a liquid solution consisting of the solvents and solutes to be nanomized. Specifically, the scCO\({}_{2}\) and the liquid solution are mixed in a saturator (or mixer), which is a packed column. The presence of packings guarantees a proper residence time and a large contact surface between scCO\({}_{2}\) and the liquid solution, achieving complete mixing (i.e., saturation). Then, the expanded liquid obtained in the saturator is injected through a nozzle into a precipitation chamber, which is generally at pressures close to atmospheric or sometimes lower [36; 133; 141]. A gaseous thermal carrier, usually hot nitrogen, is fed to the precipitator during the injection of the liquid solution, for the complete evaporation of the solvents used. For this purpose, high temperatures (often between 80 and 90 \({}^{\circ}\)C) are also employed in the precipitator, depending on the selected solvents. Efficient atomization is assured by SAA (Figure 7) because the rapid expansion of scCO\({}_{2}\) from the primary droplets formed by the jet breakup at the exit of the injector causes secondary atomization into smaller droplets [141]. To avoid the coalescence of the particles, it is necessary to perform a rapid and total removal of liquid solvents. The mean size and PSDs of SAA-precipitated particles can be modulated by varying the operating conditions. One of the most important process parameters is the CO\({}_{2}\)/liquid solution mass feed ratio, also known as the \"gas-to-liquid ratio\" (GLR, \(w/w\)) [133; 139; 141].