## 3 Production of Nanoparticles by Using CO2 as an Antisolvent
The SAS technique has been widely proposed both to process single active compounds and to coprecipitate drugs with polymeric carriers with different aims. The production of polymer-based nanoparticles allows to stabilize the active principle by reducing its recrystallization, to preserve it from oxidation and deactivation, or to influence the dissolution of the drug in aqueous media. Polymers are sometimes used to improve the SAS processability of active compounds in terms of morphology and/or powder recovery when they have been extracted by the solvent/antisolvent binary mixture [22; 44; 83]. To date, PVP is the most widely used carrier to produce pharmaceutical nanoparticles by the SAS process [44; 83; 93; 94; 95; 96; 97; 98], followed by HPMC [29; 88; 89; 99] and, to a lesser extent, Eudragit L100 [42] and ethyl cellulose [81; 100]. The results of the dissolutions studies have  
Figure 5: SEM images of (**a**) unprocessed diclofenac sodium and (**b**) nanoparticles of diclofenac sodium produced by the SAS process. shown that the dissolution rate of the active compound generally increases when it is released from PVP-based and HPMC-based nanoparticles; instead, Eudragit L100 delayed the drug release. [PERSON] et al. [58] compared RESS and SAS technologies in the preparation of naproxen particles. Coalescing and irregular nanoparticles of smaller size (60-220 nm) were mainly produced by RESS, sometimes even with the presence of large crystals; otherwise, the particles precipitated by SAS tend to be larger (in the range 80-1300 nm) but more homogeneous. From the XRD analyses, a lower degree of crystallinity was observed in the case of SAS powders. In recent years, modified versions of the conventional SAS process have been proposed, aiming, in particular, to produce smaller nanoparticles with narrower PSDs. In this context, [PERSON] and [PERSON] [101; 102] employed supercritical antisolvent precipitation with enhanced mass transfer (SAS-EM) to process an antifungal compound (griseofulvin) and an antibiotic (tetracycline), obtaining nanosized products. The main difference between the two SAS versions is that, in the case of the SAS-EM technique, the jet of the solution is deflected by a vibrating ultrasonic surface, and then it is atomized into smaller droplets than those obtained by conventional SAS. Furthermore, the ultrasound field generated by the vibrating surface increases the turbulence and the mixing of the solution and the supercritical antisolvent, resulting in a high mass transfer. Droplet agglomeration is also avoided with the improved and faster mixing promoted in SAS-EM, leading to the formation of droplets and, consequently, smaller particles than those produced by the conventional SAS process. [PERSON] et al. [103] used the supercritical CO\({}_{2}\) antisolvent-assisted nano spray-drying (SASD) process to control the polymorphism of carbamazepine nanoparticles; in the SASD process, CO\({}_{2}\) mixes with the solution containing the active principle in a small-volume high-pressure coaxial nozzle, in which supersaturation occurs. In this process, the atomization is involved in the method itself, resulting in the generation of a spray of ultrafine droplets in which the solvent is removed by thermal means. ASES, GAS, and SEDS techniques are considered previous modifications of the SAS process. The AES technique involves spraying the solution and scCO\({}_{2}\) through an atomization nozzle into the precipitator filled with scCO\({}_{2}\) at the desired pressure and temperature [39]. In the GAS process, the scCO\({}_{2}\) is introduced into the precipitation vessel containing the liquid solution, i.e., the solute/solutes to be precipitated dissolve in the liquid solvent [84; 85; 86]. In the SEDS process [43; 104; 105], the scCO\({}_{2}\) and the liquid solution are both injected through a coaxial nozzle, which causes a tangential impact between the two phases of the fluid, in a pre-mixing chamber.