## 2 Production of Nanoparticles by Using CO\({}_{2}\) as a Solvent
On the other hand, as the temperature increases, the solubility of solute/solutes in the supercritical mixture increases, leading to an increase in the supersaturation of the solution. It is possible to state that,  
Figure 3: A sketch of the rapid expansion of supercritical solution (RESS) process. as supersaturation increases, there is a reduction in the critical dimensions of the nuclei and, therefore, smaller particles precipitate; this is the prevailing phenomenon during the extraction step [51]. Mean particle size can also be reduced by increasing the extraction pressure [51]. Until now, several APIs have been processed by the RESS technique to produce nanoparticles/nanocrystals, mainly nonsteroidal anti-inflammatory drugs (NSAIDs) [38; 49; 50; 58]. In some cases, polymers/surfactants have also been used to prepare drug-loaded particles/crystals for different purposes, including the prevention of drug recrystallization or particle aggregation, as well as the control of drug dissolution [38; 41]. For example, [PERSON] et al. [41] avoided agglomeration of naproxen nanocrystals by using polylactic acid (PLA). [PERSON] et al. [38] attempted to produce ibuprofen nanoparticles using different surfactants. Sub-microparticles were obtained using polyethylene amine (PEI) with a molecular weight of 1300 Da and Tween-40, which led to the attainment of particles with the largest size. On the other hand, ibuprofen-loaded nanoparticles were produced using polyvinylpyrrolidone (PVP) and PEI with a molecular weight of 750,000 Da, which allowed reaching the smallest particle dimensions down to 7 nm. However, both PVP and 750,000 Da PEI assured drug particle sizes mostly below 100 nm. It was also shown that, in general, the particle size increased by increasing the surfactant concentration. The stability of the samples produced by RESS over time was also demonstrated. Although, in several cases, the RESS process was effective in obtaining nanoparticles/nanocrystals, this micromization/nanonization technique has some drawbacks, mainly the very low solubility of polar drugs in scCO\({}_{2}\) and the possible agglomeration of particles in the expansion zone [61]. The low solubility of polar active compounds in scCO\({}_{2}\) severely limits the practical applicability of RESS technology on an industrial scale. To overcome this limitation, but also to further reduce the particle growth and agglomeration, several modifications to the RESS technique have been proposed over the years, including RESS-SC, namely, the use of solid co-solvents. The solid co-solvent is dissolved together with the active compound by scCO\({}_{2}\) into the extractor, favoring the solubilization of the drug of interest. Through the subsequent rapid expansion, the solid co-solvent simultaneously precipitates around the drug molecules, thus avoiding the formation of surface-to-surface interactions between the drug particles, which generally cause their aggregations in the expansion chamber. Hence, the solid co-solvent can be removed from drug nanoparticles/nanocrystals by sublimation, generally performed by freeze-drying. Comparing the RESS and RESS-SC processes in obtaining phenytoin nanoparticles, [PERSON] et al. [61] proved that the use of menthol as a solid co-solvent not only increases the drug solubility in scCO\({}_{2}\) but also leads to the obtainment of particles characterized by a smaller mean size. Mendhol has been mainly selected to produce nanoparticles/nanocrystals [61; 62; 63; 64; 65] as it has the main properties required of a solid co-solvent for the RESS-SC process. Indeed, a good solid co-solvent has to be soluble in scCO\({}_{2}\) and must favor the solubility of the drug in the supercritical fluid; it has to be solid under the nozzle expansion conditions and characterized by a high vapor pressure to ensure easy sublimation, as well as being inert, nonflammable, nontoxic, and economical. However, [PERSON] et al. [65] proposed vanillin as an alternative solid co-solvent when aggregates are produced using menthol.