**1. Introduction**

 Nowadays, particle formation technology is continuously finding out how to solve the problems that conventional crystallization finds as residues of organic solvent in final product, thermal and chemical solute degradation, heterogeneous batches, and difficult to control the particle size distribution [1]. These problems are essential and must be overcome in pharmaceutical, cosmetic, and food industries. Controlling thermodynamic and kinetic factors together with mass and heat transfer and nucleation and growth of crystal is the key to carry out successfully the crystallization phenomena. Moreover, these forces interplay between them making it difficult to establish trends about it. Anyway, supercritical fluid technology tends to reduce or remove most of the drawbacks previously cited, so active substance with controlled particle size distribution in the micro- and nanometer range and quite stable is achieved. Solvent power and selectivity of supercritical fluids can be

tuned altering the experimental conditions. Moreover, their large diffusivities result in higher mass transfer rates.

 There are two main particle formation processes using supercritical fluids: rapid expansion of supercritical solution (RESS) and supercritical antisolvent (SAS) processes. The high or low solubility of the active substance in the supercritical fluid will determinate the choice between one and another process.

Numerous investigations in particle formation with supercritical fluids have been carried out to shed light the parameter to govern the crystallization mechanism using CO2 as antisolvent (SAS) [2–15] or as solvent (RESS) [16–28].

The SAS process consists of spraying a solution of the solute to be precipitated into the vessel that contains the bulk supercritical fluid. Then, there is a rapid solubilization of supercritical fluid into the solvent causing its volumetric expansion and thus reducing the solvation capacity of the solvent. This fact causes the supersaturation of the liquid phase and the consequent generation of the particles. Thus, mass transfer of the process seems to be a key factor affecting particle morphology [29].

SAS technique has been investigated using solutes in a wide range of industrial fields with applications as polymers [30, 31], explosives [32], pharmaceutical compounds [2, 3], superconductors [33], catalysts [34], coloring matter [35], and functional food [6, 7], among others. On the other hand, the application of RESS technique has been enclosed to pharmaceutical field [19–27].

Once SAS process involves the interaction of several phenomena as thermodynamics, mass transfer, jet hydrodynamics, and nucleation kinetics, it is difficult to isolate one of them as responsible for a particle feature trend [36]. Anyway, the mass transfer which occurs between a droplet of organic solvent and a compressed antisolvent is a crucial step of the process especially below mixture critical point in partially miscible conditions. It is well known that in miscible conditions, above mixture critical point, there is no obvious way to define the interface between the two fluids. However, Dukhin et al. have evidenced the existence of a dynamic interfacial tension to the transient existence of droplets at conditions slightly above the mixture critical point (MCP) [37].

Particle size and morphology are influenced by the antisolvent-solvent mass transfer ruled by diffusion process and by the jet breakup, although it seems that the first phenomenon has often more importance [38, 39] in isothermal mixing.

Heat transfer should also be taken into account in this kind of process due to the temperature can be an effective parameter to modulate the lifetimes of the droplets [40]. Thus, there is another way to change the mixing time without pressure and temperature modifications, if the process occurs in non-isothermal conditions. The mixing time will increase if a colder solution is immersed into a warmer CO2 and will decrease if a warmer solution is immersed in colder CO2 [40]. Thus, size of microparticles could be tuned.

On the other hand, RESS process takes advantage of the solubility of the solute to be precipitated into supercritical fluids. In this case the supercritical solution, CO2 plus solute, is rapidly depressurized to atmospheric pressure through a nozzle, thus causing the precipitation, extremely fast, of the solute.

With regard to RESS process, nucleation, condensation, and coagulation models for crystallization of solute have been explored [41–44]. In order to evaluate these models, it is crucial to predict the thermophysical properties and flow characteristics in the nozzle, where supercritical solution comes from the nozzle inlet to the outlet of the expansion chamber [45].

In the work SAS and RESS processes are described making incidence on the main aspects which should be controlled to get a successful precipitation of fine particles.
