## 2 Production of Nanoparticles by Using CO\({}_{2}\) as a Solvent
In the other paper by [PERSON] et al. [47], the ultrasound-assisted RESOLV technique was compared with both conventional RESOLV and RESS to nanonize amidarone hydrochloride. Two different hydrophilic polymers, namely, PVP and HPMC, were employed to stabilize the drug particles. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses demonstrated a lower degree of crystallinity when amiodarone was nanomized by US-RESOLV compared to unprocessed and processed powders, especially to unprocessed and RESS-processed drug. All samples obtained using scCO\({}_{2}\) as a solvent showed smaller particles and a faster dissolution rate than the pure antiarrhythmic drug. However, RESS-prepared particles had a mean size in the range 101-393 nm, while similar particle dimensions were obtained by US-RESOLV (in the range 48-255 nm) and RESOLV (in the range 51-265 nm) with a slightly faster dissolution in the case of the ultrasound-assisted process. In summary, with the exception of the RESOLV/RESSAS technique which allows producing nanoparticles, the formation of agglomerates or particles/crystals with larger size and wider PSDs is observed by RESS-derived processes compared to other supercritical nanonization techniques. The main limiting factor in RESS-based processing is the low solubility of most active compounds in scCO\({}_{2}\). The drug solubility can be increased by increasing the pressure, which leads to an increase in the scCO\({}_{2}\) density and solvent power, but technological limitations have to be considered. In addition, although high tempera tures in RESS technologies may promote drug solubility in scCO\({}_{2}\), possible degradation of the active compound may occur. Pharmaceutical nanoparticles and nanocrystals prepared using scCO\({}_{2}\) as a solvent have been proposed for several applications, including oral [41; 46; 51; 54; 56], topical [56], intravenous injection, or infusion routes [55; 59; 61]. From an industrial point of view, there has not been a wide implementation of RESS-based technologies on a commercial scale (and, basically, of all supercritical micromization processes) as high productivity would entail high investment costs in equipment of adequate size for commercial production. The high costs due to energy consumption per unit of the product due to the high pressures involved in all supercritical methodologies have to be also considered [68]. However, the RESS technique can potentially be adapted to existing conventional spray-dryers in the pharmaceutical industry, reducing the investment costs and allowing operation on an industrial scale. Currently, RESS-based methodologies on a pilot/industrial scale are successfully applied by some companies, such as Thar, Phasex, and Applied Separations (United States of America, USA), Pierre Fabre and Hitex (France), and Feyecon (the Netherlands). In Table 1, a summary of the active compounds processed to obtain nanoparticles/nanocrystals by techniques based on the use of scCO\({}_{2}\) as a solvent is reported. The operating conditions that mainly affect the size of the drug particles/crystals produced are indicated, such as the pressure and temperature of the extraction, as well as pre-expansion or expansion steps. The morphology and size of the pharmaceutical product are also specified, as well as the use of a possible co-solvent.