## 4 Production of Nanoparticles by Using CO2 as a Co-Solute  
To date, several active compounds have also been processed using scCO2 as a co-solute through the following technologies:  
* Particles from gas-saturated solutions (PGSS);
* Supercritical-assisted atomization (SAA);
* Supercritical-assisted injection in a liquid antisolvent (SAILA). However, drug nanoparticles have been produced using CO2 as a co-solute in a reduced number of papers [36; 37; 131; 132; 133]. Some amount of scCO2 is soluble in some substances such as polymers, lipids, or high-molecular-weight drugs, particularly molten materials when considering the PGSS process (Figure 4). Briefly, the PGSS technique consists of mixing of scCO2 and molten substances (e.g., drug and polymer), usually into a static mixer. This mixture is rapidly expanded through a nozzle into a precipitation chamber generally at pressures close to atmospheric. The rapid expansion of the solution containing scCO2 causes a cooling effect on the small droplets formed, which are quickly blocked. Furthermore, the scCO2 solubilized in the molten substance acts as a plasticizing agent by depressing the melting and glass transition temperatures of the solute [134; 135], thus promoting the breakup into small droplets during the depressurization. The produced particles are usually separated from the CO2 employing a filter or a cyclone. Composite nanoparticles containing drugs have been mainly produced by the PGSS technique [37; 131; 132]. To this end, until now, PEG seems to be the most effective polymeric carrier for the PGSS process. [PERSON] et al. [132] studied in detail the effect of PEG molecular weight (varied from 2000 to 35,000 Da) to prevent the aggregation of riboflavin-loaded particles when suspended in water. Using a PEG molecular weight equal to 2000 Da, the smallest nanoparticles (83 \(\pm\) 0.36 nm) were produced, followed by PEG 35,000 Da (104 \(\pm\) 5.7 nm) and PEG 10,000 Da (131 \(\pm\) 40.2 nm). On the other hand, the encapsulation efficiency increased by increasing the PEG molecular weight from 10,000 Da to 20,000 Da, followed by a decrease at 35,000 Da. The morphology and size of the PGSS product are influenced by different process parameters, including the scCO2 concentration in the molten substances, the precipitation temperature and pressure, and the nozzle geometry. However, the effect of the temperature and pressure conditions used to mix scCO2 and compounds to be nanomized is among the most studied [37; 131; 132]. The mixing pressure is often between 10 and 25 MPa to assure dissolution of scCO2 in the molten compounds. In general, particle size decreases with increasing mixing pressure, as better atomization is promoted, as well as a decrease in the melting temperature of compounds [37; 131; 132]. Moreover, from SEM analyses, [PERSON] et al. [131] noted that irregular ibuprofen/PEG particles were obtained at the lower pressures investigated (in the range 10-15 MPa) compared to the smaller, spherical, and more dispersed nanoparticles produced at high pressures (up to 25 MPa). On the other hand, [PERSON] et al. [132] observed that the highest encapsulation efficiency was reached at the lowest pressure studied (i.e., 10 MPa); hence, the latter can be considered the best, although the particle size is enlarged. As for the operating temperature [37; 131], its increase reduces the viscosity of the melting mixture, which plays a key role in the formation of small \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Technique** & **Active** & **Polymer** & **Solvent** & **Operating** & **Morphology** & **Reference** \\ \hline SFEE & Indomethacin, & Tripalmitin, & & & & \\  & ketoprotein & Tristearin, & CHF, H2O & \(P\) = 8 MPa; & NP & [40] \\  & Medroxyprogesterone & PHW & & & & \\  & acetate & PVA & DCM, H2O & \(P\) = 10 MPa; & NP & [25] \\  & Omega-3 & PCL & AC & \(P\) = 40 °C & (188) nm & [11] \\  & & & & & & \\  & & & & & & \\  & & & & & & \\  & & & & & & \\  & & & & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Cont. droplets via PGSS.