**1. Introduction**

168 Hydrodynamics – Advanced Topics

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Particle size and particle size distribution play an important role in many fields such cosmetic, food, textile, explosives, sensor, catalysis and pharmaceutics among others. Many properties of industrial powdered products can be adjusted by changing the particle size and particle size distribution of the powder. The conventional methods to produce microparticles have several drawbacks: wide size distribution, high thermal and mechanical stress, environmental pollution, large quantities of residual organic solvent and multistage processes are some of them.

The application of supercritical fluids (SCF) as an alternative to the conventional precipitation processes has been an active field of research and innovation during the past two decades (Jung & Perrut, 2001; Martín& Cocero, 2008; Shariati &Peters, 2003).Through its impact on health care and prevention of diseases, the design of pharmaceutical preparations in nanoparticulate form has emerged as a new strategy for drug delivery. In this way, the technology of supercritical fluids allows developing micronized drugs and polymer-drug composites for controlled release applications; this also meets the pharmaceutical requirements for the absence of residual solvent, correct technological and biopharmaceutical properties and high quality (Benedetti et al., 1997; Elvassore et al., 2001; Falk& Randolph, 1998; Moneghini et al., 2001; Reverchon& Della Porta, 1999; Reverchon, 2002; Subramaniam et al., 1997; Yeo et al., 1993; Winters et al.,1996), as well as giving enhanced therapeutic action compared with traditional formulations (Giunchedi et al., 1998; Okada& Toguchi, 1995).

The revised literature demonstrates that there are two principal ways of micronizing and encapsulating drugs with polymers: using supercritical fluid as solvent, the RESS technique (Rapid Expansion of Supercritical Solutions); or using it as antisolvent, the SAS technique (Supercritical AntiSolvent); the choice of one or other depends on the high or low solubility, respectively, of the polymer and drug in the supercritical fluid.

Although the experimental parameters influences on the powder characteristic as particle size and morphologies is now qualitatively well known, the prediction of the powder characteristics is not feasible yet. This fact it is due to different physical phenomena involved in the SAS process. In most cases, the knowledge of the fluid phase equilibrium is

Hydrodynamics Influence on Particles Formation Using SAS Process 171

these supercritical fluids have diffusivities that are two orders of magnitude larger than those of typical liquids, resulting in higher mass-transfer rates. Supercritical fluids show many exceptional characteristics, such as singularities in compressibility and viscosity, diminishing the differences between the vapor and liquid phases, and so on. Although a number of substances are useful as supercritical fluids, carbon dioxide has been the most widely used. Supercritical CO2 avoids water discharge; it is low in cost, non-toxic and nonflammable. It has low critical parameters (304 K, 73.8 bar) and the carbon dioxide can also be

The supercritical fluid technology has emerged as an important alternative to traditional processes of generation of micro and nanoparticles, offering opportunities and advantages such as higher product quality in terms of purity, more uniform dimensional characteristics, a variety of compounds to process and a substantial improvement on environmental

Previously, it was discussed that the different particle formation processes using SCF are classified depending on how the SCF behaves, i.e., the supercritical CO2 can play the role as

In the facilities of University of Cádiz, amoxicillin and ampicillin micronization have been carried out by SAS process (Montes et al., 2010, 2011a; Tenorio et al., 2007a, 2007b, 2008). Several experiments designs to evaluate the operating conditions influences on the particle size (PS) and particle size distribution (PSD) have been made. Pressures till 275 bar and temperatures till 338K have been used and antibiotic particle sizes have been reduced from

The concentration was the factor that had the greatest influence on the PS and PSD. An increase in the initial concentration of the solution led to larger particles sizes with a wider distribution. Moreover, ethyl cellulose and amoxicillin co-precipitation has been carried out by SAS process (Montes et al., 2011b). SEM images of these microparticles are shown in Figure 3. It was noted that increasing temperature particle sizes were increased. Anyway, SEM images are not accurate enough to observe the distribution of both compounds

antisolvent (AntiSolvent Supercritical process, SAS) or solvent (RESS process).

5-60 µm (raw material) to 200-500 nm (precipitated particles) (Figure 2).

Fig. 1. Pressure-temperature phase diagram

recycled (Özcan et al., 1998).

**3. Precipitation with SCF** 

considerations, among others.

necessary but not sufficient since for similar thermodynamic conditions, different hydrodynamics conditions can lead to different powder characteristics (Carretier et al., 2003).

So, the technical viability of the SAS process requires knowledge of the phase equilibrium existing into the system; the hydrodynamics: the disintegration regimes of the jet; the kinetics of the mass transfer between the dispersed and the continuous phase; and the mechanisms and kinetics of nucleation and crystal growth.

From the point of view of thermodynamics, the SAS process must satisfy the requirements outlined below. The solute must be soluble in an organic solvent but insoluble in the SCF. The solvent must also be completely miscible with the SCF, or two fluid phases would form and the solute would remain dissolved or partly dissolved in the liquid-rich phase. Thus, the SAS process exploits both the high power of supercritical fluids to dissolve organic solvents and the low solubility of pharmaceutical compounds in supercritical fluids to cause the precipitation of these materials once they are dissolved in an organic solvent, and thus spherical microparticles can be obtained.

On the other hand, characterization of hydrodynamics is relevant because of it is an important step for the success or the failure of the entire process, but with only some exception (Dukhin et al., 2005; Lora et al., 2000; Martín& Cocero, 2004), in the models developed for the SAS process, the hydrodynamics step received only limited consideration. For these reasons, the present review is focused on the investigation of the disintegration regime of the liquid jet into the supercritical (SC) CO2. There are many works where correlations between the morphologies of the particles obtained in the drug precipitation assays and the estimated regimes were established (Carretier et al., 2003; Reverchon et al., 2010; Reverchon& De Marco, 2011; Tenorio et al., 2009). It was demonstrated that there are limiting hydrodynamic conditions that must be overcome to achieve a dispersion of the liquid solution in the dense medium; this dispersion must be sufficiently fine and homogeneous to direct the process toward the formation of uniform spherical nanoparticles and to the achievement of higher yields (Tenorio et al., 2009).

In this way, Reverchon et al. (Reverchon et al., 2010, Reverchon& De Marco, 2011) tried to find a correlation between particle morphology and the observed jet, concluding that expanded microparticles were obtained working at subcritical conditions; whereas spherical microparticles were obtained operating at supercritical conditions up to the pressure where the transition between multi- and single-phase mixing was observed. Nanoparticles were obtained operating far above the mixture critical pressure. However, the observed particle morphologies have been explained considering the interplay among high-pressure phase equilibria, fluid dynamics and mass transfer during the precipitation process, because in some cases the hydrodynamics alone is not able to explain the obtained morphologies, demonstrating the complexity of SAS processes. Moreover, the kinetics of nucleation and growth must also be considered.
