## 2 Production of Nanoparticles by Using CO\({}_{2}\) as a Solvent  
Over the years, several processes based on the use of scCO\({}_{2}\) as a solvent have been developed to produce drug nanoparticles/nanocrystals. The following techniques belong to this category:  
- Rapid expansion of supercritical solution (RESS);  
- Rapid expansion of supercritical solutions with solid co-solvent (RESS-SC);  
- Rapid expansion of a supercritical solution into a liquid solvent (RESOLV), which, if the water is used as the receiving solvent, is called rapid expansion of supercritical solution into aqueous solutions (RESSAS). Figure 2: Sketch of vapor–liquid phase equilibria (VLEs) of a type I binary system. Recently, some modified versions of the aforementioned technologies have been proposed, such as the ultrasonic-assisted RESOLV (US-RESOLV or US-RESSAS) [46; 47]. These processes share the dissolution of the active compound in scCO\({}_{2}\) alone [38; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56] or mixed with liquid co-solvents, such as methanol and ethanol [57; 58; 59; 60]. When an active compound is processed with the RESS-SC technique, solid co-solvents, generally menthol, have sometimes been used [61; 62; 63; 64; 65]. Co-solvents, surfactants, stabilizers, or even ultrasound are used to improve the dissolution/extraction of solutes. The solvent power of scCO\({}_{2}\) and, consequently, the solubility of solute/solutes in the scCO\({}_{2}\) itself are modulated by varying the operating temperature and pressure. The RESS process (sketched in Figure 3) was the first proposed technique that uses scCO\({}_{2}\) as a solvent. Briefly, it is based on the ability of the supercritical fluid to dissolve a certain amount of solute/solutes to be micronized, generally in saturation or near-saturation conditions. The scCO\({}_{2}\) is fed to a saturation vessel/extractor containing the solutes to be dissolved and, therefore, micronized. Specific pressure and temperature conditions are employed in the extractor to dissolve a certain amount of solute/solutes. Then, the supercritical solution is delivered into a pre-expansion zone, which is usually at a higher temperature than that reached in the extractor. After the solutes have been solubilized in scCO\({}_{2}\), a fast expansion of the mixture (solutes+ scCO\({}_{2}\)) occurs through a nozzle in a precipitation/collection chamber. Depressurization down to a lower pressure, generally atmospheric pressure, leads to supersaturation and, consequently, to the precipitation of solutes, while CO\({}_{2}\) is vented out. The size of the drug particles produced by the RESS process is affected by the extraction, pre-expansion, and expansion conditions, as well as the spray distance and the nozzle geometry. In general, the mean particle size is reduced by increasing the spray distance, which is often varied in the range of 5-10 cm [57; 51]. Indeed, the residence time of the particles in the expansion vessel decreases the shorter the spray distance. Furthermore, by reducing the spray distance, the possibility of particle agglomeration due to a decrease in the angles between the particles increases. Pre-expansion and extraction temperatures and pressures are also among the most investigated parameters [57; 51]. In particular, an increase in particle size is observed by increasing the pre-expansion temperature [57]. Close to the critical pressure, a moderate increase in temperature causes a large decrease in CO\({}_{2}\) density; this leads to a reduction in the solubility of the solute/solutes in the supercritical fluid. This influence plays a key role in the supersaturation of the solution along the expansion path, causing early precipitation of the solute/solutes and the formation of larger particles when higher pre-expansion temperatures are employed. Conversely, a decrease in the mean particle size is often noted by increasing the extraction temperature, because the density and the solvent power of CO\({}_{2}\) decrease [51].