## 1 Introduction  
In the medical and pharmaceutical fields, improving the therapies currently used for the treatment of various diseases is an ongoing challenge. An active pharmaceutical ingredient (API) can be administered via injection, orally, topically, or via other routes. The limited therapeutic efficacy of many pharmaceutical forms is often related to an inadequate drug release rate for a specific pathology, as well as to drug particle size not suitable for reaching a certain site of action [1, 2]. For example, the drug particles have to be small enough (<200 nm) for subcutaneous, intramuscular, or intravenous injections [3]. Similarly, in the case of APIs contained in aerosolizable drugs, mean particle dimensions below 1 um and controlled particle size distributions (PSDs) are desirable. It is also important to underline that many frequently prescribed drugs are characterized by low bioavailability, mainly caused by low solubility and poor dissolution rate in an aqueous environment [4, 5, 6, 7, 8, 9]. Furthermore, the first-pass metabolism also affects the drug efficacy when it is orally administered [10, 11]. Due to these disadvantages characteristics, it is necessary to administer high and/or repeated dosages of drugs to achieve the desired therapeutic effect, which leads to several side effects on the patient's health. Over the years, various methods have been proposed to enhance the therapeutic efficacy of the APIs, such as the micromization of polymer/drug systems [12, 13] or the application of nanoparticles or nanocrystals with controlled and/or targeted release [2, 14, 15]. In the latter case, the nanosized drug can effectively reach a specific site of action in the human body, as well as inducing an improvement in terms of dissolution rate and, consequently, bioavailability [16]. Indeed, the particle size reduction generally generates an increase in the specific surface of the API, leading to better contact with the water molecules surrounding the nanoparticles/nanocrystals of the drug. Since nanomaterials are similar in scale to biological molecules, they can be exploited for the prevention and treatment of various diseases [17]. Indeed, nanomaterials allow for the transport of diagnostic or therapeutic agents across biological barriers. Currently, more than 50 nanoparticle-based formulations have been approved for clinical use and marketed for the treatment of cancer, rare genetic diseases, and fungi, such as anesthetics and others [15; 18; 19; 20]. Nanoparticles and nanocrystals containing APIs can be obtained with different techniques, such as spray-drying, freeze-drying, coacervation, jet-milling, and solvent evaporation [21; 22; 23; 24; 25; 26; 27]. However, toxic organic solvents are widely used in these traditional processes; high temperatures and long postprocess treatments are also employed to remove liquid solvents from the particles/crystals produced. High process temperatures can cause possible degradation of the active compound, in addition to the fact that the removal of the solvent from the final product is often not complete. Moreover, traditional micronization/nanonization techniques usually lead to the achievement of products characterized by irregular morphology and broad PSDs [21; 22; 23; 24]. Many literature studies have demonstrated the possibility of overcoming all these drawbacks by using supercritical carbon dioxide (scCO\({}_{2}\)) for the drug micromization/nanonization [21; 22; 23; 24; 28; 29; 30]. A pure substance is in the supercritical fluid state if its temperature and pressure conditions are above the critical point value (Figure 1). In comparison to other supercritical fluids, scCO\({}_{2}\) has mild critical temperature (\(T_{c}\)) and pressure (\(P_{c}\)), i.e., 31.1 \({}^{\circ}\)C and 7.3 MPa, respectively. The versatility of scCO\({}_{2}\) has made it possible to propose and develop different micromization/nanonization technologies over the years, exploiting the supercritical fluid as a solvent, antisolvent, co-solute, or co-solvent [31; 32].