**2. Applications of scCO2 for preparation of polymeric nanoparticles as drug delivery systems**

### **2.1 Supercritical fluids and their properties**

SCFs can bring their contributions in different fields for certain applications as chromatography, fluid extractions, and micro- and nanoparticle formation. There are several compounds that can be used as supercritical fluids. Among them, hydrocarbons are toxic and inflammable, water has high critical parameters, but carbon dioxide has appropriate critical temperature and pressure, being suitable to be used as a green solvent.

### **2.2 Rapid expansion of supercritical solution**

Methods using supercritical fluids (SCFs) can produce particles with narrow size distribution. Because of their special properties, SCFs can be applied to micronization of several types of compounds: drugs, biopolymers, polymers, food, coloring maters, explosives, etc. Pharmaceutical micronizations using supercritical fluids have some advantages due to the absence of organic solvent, and the particle size distribution could be controlled by process parameters. During the micronizations by SCFs methods, the dissolution rate is increased. The use of scCO2 provides several advantages in comparison with the previous conventional techniques. The scCO2 can be used as a solvent, antisolvent, and extracting agent for the organic phase of oil-in-water emulsions or at particle formation from gas saturated solution and improve the spraying process in different techniques [13].

The RESS process is based on the saturation of the supercritical medium with a solute (polymer) followed by a rapidly depressurization of the solution through a heated nozzle at high speed. During the pressure drop, the system passes from supercritical to atmospheric conditions, the solvent power decreases, and a fast nucleation of the solute in the form of very small particles with uniform size takes place. The properties of the obtained particles are influenced by its solubility in scCO2; state parameters from precipitation vessel (temperature and pressure); size, length, and shape of the nozzle; distance of the jet stream; and impact angle onto the surface. A schematic representation of this process is presented in **Figure 1**.

The RESS technique has several advantages like the simple control of process parameters, the absence of organic solvents, and easy implementation on lab-scale when a single nozzle is used. RESS has also disadvantages as difficulty in scaling-up,

### **Figure 1.**

*Schematic representations of the RESS process.*

the possible particle aggregation and/or nozzle blockage, using an important amount of carbon dioxide, and low solubility of most pharmaceutical compounds in supercritical CO2. But, the scCO2 solvent power can be increased by using of a co-solvent.
