2.2.4. Supercritical Fluid Method

The supercritical fluid (SCF) method means drugs dissolve in a supercritical fluid (e.g., CO2) and precipitate nanocrystals with the rapid vaporization of the supercritical fluid as the fluid is atomized under reduced pressure through a nozzle with a tiny aperture [11]. According to the function of supercritical fluid in the crystallization process, supercritical fluid methods include rapid expansion of supercritical solution (RESS) and supercritical antisolvent (SAS). According to the different nozzle positions, the rapid expansion of a supercritical fluid method was improved to yield the rapid expansion of a supercritical solution into a liquid solvent (RESOLV) method, in which the former places the nozzle in the air while the latter places the nozzle in aqueous solution. The state parameters of the supercritical fluid in the process, the morphology of the nozzle, and the concentration of the drug will influence the particle size of the nanocrystals [7]. This process does not require organic solvent to produce high purity products. However, the consumption of supercritical fluids is large and it is only suitable for drugs dissolved in supercritical fluids [16]. Zhang et al. [49] prepared apigenin (AP) nanocrystals using the SAS method. No substantial changes in the crystal structure were observed in the nanocrystals, but decreased particle size and smooth spherical surface were noticed. The AP nanocrystals exhibited faster dissolution profiles than the original AP in dissolution media.

#### 2.2.5. Emulsion Polymerization Method

API is dissolved in volatile organic solvents or solvents partially mixed with aqueous as the dispersed phase, then the organic solvent is emulsified dropwise into the aqueous phase (usually including stabilizers) to form an O/W emulsion [11]. The emulsion droplet size is easy to control. After that, the emulsions are evaporated, stirred, and extracted to obtain drug nanocrystals. Factors such as emulsifier, stirring speed, evaporation rate, temperature gradient, and pH value have significant effects on product quality. Because this emulsion polymerization method requires the assistance of homogenization or ultrasound, it is suitable for laboratory operations but not for large-scale pilot production [11]. Chen [50] obtained florfenicol nanocrystals with a mean particle size of 226.1 ± 11.3 nm using the emulsification solvent volatilization method. Compared with the original powder, the solubility and dissolution of florfenicol nanocrystals were remarkably improved.

#### *2.3. Combinative Technology*

There are always many limitations to obtain the desired nanocrystals using a single preparation technology due to the properties of various drugs and characteristics of the instruments. When top-down technology is selectively united with bottom-up technology, forming combinative technology, the disadvantages of a single preparation technique can be overcome and the efficiency of particle size reduction can be improved. Combinative

technology is divided into the Nanoedge® technology developed by Baxter [51] and the SmartCrystal® technology (Abbott/Soliqs, Ludwigshafen/Germany). Combinative technology (Figure 2) combines pre-treatment and a particle size reduction step. It can eliminate the drawbacks of instrument clogging [52] and improve the stability of nanocrystals. Combinative technology can take full advantage of various technologies and are also suitable for a wide range of insoluble drugs. However, there are limitations in terms of economics and process complexity.

**Figure 2.** The correlation of different preparation technology.

#### 2.3.1. Nanoedge Technology

Nanoedge technology was the first combined method for particle size reduction developed for nanodrug production. It utilizes the HPH method assisted by the precipitation method. Initial crystal particles are obtained by precipitation, reducing the high pressure homogenizer slit blockage and improving the efficiency of reducing particle size during the homogenization process [53]. Subsequently, the homogenization process from the HPH method is used to further crush the particles, preventing secondary growth and overcoming the problem of uneven particle size distribution and Oswald ripening in the precipitation method, which increases the physical stability of the nanocrystal particles. Furthermore, other alternative techniques such as ultrasound or microfluidization can be used for the high-energy process [33].

#### 2.3.2. SmartCrystal Technology

SmartCrystal® technology mainly combines a pre-treatment step followed by a high pressure homogenization step. The pre-treatment step can be, for example, wet bead milling, spray drying, freeze drying, or precipitation, followed by HPH [54]. SmartCrystal technology is recognized as a second-generation nanocrystal preparation method. Specifically, the joint method in this technology takes the form of collection, which is a toolbox of technology optimization for the preparation of drug nanocrystals [55]. It includes H69, H42, H96, and combination technology (CT) techniques.

#### 1. H69

H69 is similar to NanoEdge technology, combining nanoprecipitation and HPH methods. The formation of nanocrystals occurs in the high pressure homogeneous cavitation region, which contributes to ultra-small and homogeneous particle size. Li et al. [56] tried to prepare ursodeoxycholic acid nanosuspension by homogenization technology and high pressure precipitation tandem homogenization technology. The dissolution rate of ursodeoxycholic acid nanocrystalline powder was quicker than that of the raw and physical mixture powder.
