## 2 Production of Nanoparticles by Using CO\({}_{2}\) as a Solvent
The authors successfully prepared theophylline nanocrystals by processing them with vanillin. In nearly all studies focused on RESS and RESS-SC techniques [38; 41; 48; 50; 57; 58; 61; 62; 63; 64; 65], the ultimate goal of drug size reduction at the nanoscale is to increase bioavailability and dissolution of the active compound of interest; however, dissolution tests are not performed to compare the dissolution kinetics of the drug in pure or processed form using scCO\({}_{2}\) as a solvent. Only in the paper written by [PERSON] et al. [51] was it shown that nanoparticles of raoxifene, an anticancer drug, prepared by RESS accelerated the drug dissolution rate about sevenfold compared to untreated raoxifene. Lastly, solid co-solvents are unable to redissolve the processed drug, which is possible when liquid co-solvents are used. However, the need for an additional postprocess for the final removal of the solid co-solvent has to be considered from an economic point of view. The RESS technique was also compared with the RESOLV/RESSAS process for the attainment of nanosized pharmaceutical systems [52]. Unlike the RESS process, in the case of the RESOLV technology, the expansion of the supercritical mixture containing the solute/solutes to be nanomized takes place in a liquid solvent placed in the precipitation unit. Sometimes, organic solvents such as methanol (possibly containing stabilizers) are used [59; 60]. However, the precipitation vessel is filled most frequently by water, which is often used as a receiving solvent since most of the treated active compounds are poorly soluble in water. In the latter case, the acronym RESOLV is replaced by RESSAS. The main purpose of using solvents in the precipitator, as well as polymers/stabilizers, is to inhibit the agglomeration of the nanoparticles/nanocrystals produced during/after expansion. In the paper of [PERSON] et al. [52], nanoparticles of olanzapine, which is a drug prescribed for the treatment of diseases such as schizophrenia or bipolar disorder, were prepared by both RESS and RESSAS processes. The particles produced by the two techniques showed similar dimensions. The dissolution rate of olanzapine was improved in the case of both nanoparticles obtained by RESS and those prepared by RESOLV. The influence of different polymers used as stabilizers, namely, hydroxypropylmethylcellulose (HPMC), poly(ethylene glycol) (PEG), and polysorbate, was also investigated. In particular, dissolution was improved with all three carriers selected; HPMC-based particles exhibited slower kinetics, despite the use of PEG- and polysorbate-caused particle growth. Despite the advantages of using the RESOLV process to nanonize APIs, the nanoparticles/nanocrystals produced are often susceptible to aggregation in the receiving solvents/solutions [47; 53]. To overcome this main drawback, ultrasonication has recently been coupled with RESOLV to improve drug nanomization [46; 47]. Ultrasound generates pressure fluctuations in the liquid medium, leading to the formation of gas pockets that act as nuclei; as a result, the formed microbubbles grow and collapse rapidly, causing micro-implosions that provide high temperature and pressure [66; 67]. [PERSON] et al. used the US-RESOLV technique to process an antihistamine drug and an antiarrhythmic drug,loratadine [46] and amiodarone hydrochloride [47], respectively. In the case of loratadine [46], employing RESSAS mean particle sizes smaller than those obtained by US-RESSAS were achieved under all process conditions investigated, in the ranges 124-680 nm and 26-271 nm, respectively. Indeed, the ultrasonic waves allowed preventing the agglomeration of the drug particles. As a result,loratadine nanoparticles obtained by US-RESSAS showed faster dissolution than the particles produced by RESSAS. Specifically, after 30 min of ultraviolet (UV)-visible light (vis) analysis, about 30% of the unprocessed drug dissolved in the aqueous medium, while approximately 70% and 80% of loratadine was released from RESSAS and US-RESSAS powders, respectively.