## 4 Production of Nanoparticles by Using CO2 as a Co-Solute
The mass flow rates of the liquid solution and the CO\({}_{2}\) have to guarantee an adequate residence time of the mixture in the saturator. When too high CO\({}_{2}\) flow rates are used, the liquid could be solubilized in the scCO\({}_{2}\), causing the so-called \"antisolvent effect\" and the consequent precipitation of the solute/solutes in the saturator. Typically, the particle size decreases and the PSD shrinks as the GLR increases, as more CO\({}_{2}\) is solubilized in the liquid solution and, thus, the viscosity and surface tension of the mixture decrease. When operating at low GLR values, as well as at low temperatures in the precipitator, the time required for the complete evaporation of the liquid solvents increases; thus, the precipitation of the solute/solutes occurs slowly. A GLR value of 1.8 has often been found to be the most effective for the attainment of spherical particles by SAA [133; 136; 137; 139; 141]. The concentration of the solute/solutes in the liquid solution can also strongly influence the particle size [133; 138; 142]. For example, in the study by [PERSON] and [PERSON] [133], erythromycincin nanoparticles were produced only by working with drug concentrations in the solution below 40 mg/mL. Therefore, as a rule, it is advisable to inject solutions at low concentrations to produce nanometric particles by SAA. Indeed, the size of the precipitated particles generally increases as the overall concentration of the liquid solution rises, due to an increase in the viscosity and surface tension of the solution [133; 138; 142]. When composite particles are prepared, the polymer/drug ratio in the solution can also influence the morphology and PSDs of SAA powders [36; 137]. [PERSON] et al. [36] selected poly(D,L-lactide) (PDLLA) as the carrier to prepare rifampicin-loaded nanoparticles for a sustained release of the antibiotic. The effect of the PDLLA/rifampicin \(w/w\) ratio on the particle size and drug dissolution was investigated. In particular, as often observed, the dimensions of the nanoparticles decrease as the polymer/drug ratio decreases, while the antibiotic release is more prolonged the greater the quantity of polymeric carrier in the composite particles. A limitation of the SAA process is certainly that it is difficult to process thermoplastic materials due to the high process temperatures employed. For this reason, the use of lower than atmospheric operating pressures has been suggested for thermosensitive compounds [141]. Figure 7: A sketch of supercritical assisted atomization (SAA). Recently, a modified version of SAA with an enhanced mixer has been proposed, namely, supercritical assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) [140; 143; 144; 145]. A hydrodynamic cavitation mixer was introduced in the SAA process to intensify the mass transfer between the solvent and the scCO\({}_{2}\) in the packed saturator. Mixing efficiency plays a key role in SAA particle production, as it affects secondary atomization due to the rapid expansion of scCO\({}_{2}\) dissolved in the droplets. A homogeneous mixing allows obtaining, as desired, particles with narrow PSD. The cavitation is a rapid expansion that involves the collapse of bubbles or voids within a liquid medium [143]. The collision of liquid elements creates micro-jets, leading to an improvement of the mixing. The hydrodynamic cavitation mixer generates the collapse of bubbles and cavities through a localized pressure drop in a liquid stream. [PERSON] et al. [140] managed to produce nanoparticles of a chemotherapy drug, namely, doxorubicin hydrochloride, using the SAA-HCM technique. The effect of the molecular weight of chitosan, selected as the polymeric carrier, on the morphology and particle size was investigated. However, this parameter did not have a significant influence, as the PSDs only shrank slightly by decreasing the molecular weight of chitosan.