## 3 Production of Nanoparticles by Using CO2 as an Antisolvent
This impingement promotes better mixing between the solution and the antisolvent that can lead to the production of finer powders than those obtained by the conventional SAS process. However, for the production of lysozyme nanoparticles, [PERSON] et al. [85] compared GAS technology with PCA, which is practically based on the same principles as the SAS process. The nanoparticles obtained by PCA, having dimensions in the range 18-197 nm, were smaller than those produced by GAS (particle size in the range 233-300 nm). In summary, the morphology and the size of powders precipitated by SAS-derived technologies generally depend on the binary system high-pressure VLEs (Figure 2). Specifically, the position of the operating point with respect to the mixture critical point (MCP) of the binary mixture formed by the solvent and the antisolvent plays a key role [106]. Briefly, when the operating point pressure is lower than the MCP pressure, the operating point falls in the biphasic region, and crystals are generally observed. Operating above the MCP and at scCO\({}_{2}\), high molar fractions of (preferentially greater than or equal to 0.95) spherical (and generally amorphous) particles are produced. The dimension of the precipitated particles is influenced by the distance between the operating point pressure and the MCP of the solvent/antisolvent binary system. By increasing the operating pressure, particle size generally decreases, switching from the formation of microparticles at pressures slightly above MCP pressure to the formation of nanoparticles a pressure far above the MCP. This outcome has been interpreted in terms of competition of two characteristic times: the jet breakup time and the surface tension vanishing time [107, 108]. In SAS-based techniques, it has been observed that the jet breakup is the controlling mechanism at pressures close to the MCP of the solvent/scCO\({}_{2}\) binary system; thus, micro-droplets are formed that are the native structure of the microparticles formed as a result of the scCO\({}_{2}\) drying. On the other hand, at pressures far above the MCP, the surface tension vanishing occurs fast, prevailing on the jet breakup and leading to the precipitation of nanoparticles from a gaseous phase. Additionally, the switch from microparticles to nanoparticles strongly depends on the type of solvent. Some solvents, such as ethanol or dimethylsulfoxide (DMSO), present a broad transition zone from the two-phase to the single-phase mixing; microparticles can be produced using these solvents. On the other hand, solvents such as acetone have a narrow pressure range to switch from two-phase to single-phase mixing; in this case, nanoparticles generally precipitate [109, 110]. The SFEE technique, which combines the advantages of traditional emulsion-based technologies (e.g., surface properties) with the advantages of scCO\({}_{2}\)-assisted processes (e.g., shorter processing time and final product high purity) allows easily obtaining nanoparticles [25, 26, 27, 40, 111, 112]. The SFEE technology also allows processing of substances in continuous mode. In short, in SFEE technology, scCO\({}_{2}\) acts as an antisolvent to extract an organic solvent from the droplets of previously prepared oil-in-water (O/W) or water-in-oil (W/O) emulsions. O/W emulsions are more often used; in this case, the hydrophobic active compounds to be maximized are dissolved in the oily phase, which typically consists of organic liquid solvents. The emulsion is generally fed from the top to an extraction column containing packing elements, while the scCO\({}_{2}\) is delivered in countercurrent from the bottom of the tower [26, 40]. The countercurrent flow between the emulsion and the supercritical fluid favors the extraction of the organic solvent from the emulsion droplets. Consequently, the compounds of interest precipitate in the form of nanosuspensions in water collected at the bottom of the column, while the solvent is recovered in a separator at the top.