**3. Precipitation with SCF**

170 Hydrodynamics – Advanced Topics

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

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

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

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

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

A supercritical fluid can be defined as a substance above its critical temperature and pressure. At this condition the fluid has unique properties, where it does not condense or evaporate to form a liquid or gas. A typical pressure-temperature phase diagram is shown in Figure 1. Properties of SCFs (solvent power and selectivity) can also be adjusted continuously by altering the experimental conditions (temperature and pressure). Moreover,

mechanisms and kinetics of nucleation and crystal growth.

and to the achievement of higher yields (Tenorio et al., 2009).

spherical microparticles can be obtained.

growth must also be considered.

**2. Supercritical fluids** 

2003).

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 considerations, among others.

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

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

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

Hydrodynamics Influence on Particles Formation Using SAS Process 173

present on the surface is faster than in cases these elements were not. Anyway, all the co-

On the other hand, in the RESS method, the sudden expansion of supercritical solution (solute dissolved in supercritical carbon dioxide) via nozzle and the rapid phase change at the exit of the nozzle cause a high super-saturation, thus causing very rapid nucleation of the substrate in the form of very small particles that are collected from the gas stream. Hence, the conditions inside the expansion chamber are a key factor to control particle size and the particles grow inside the expansion chamber to their final size. This result clarifies the influence of two important process parameters on particle size. Both, a shorter residence time and, hence, less time available for particle growth as well as a higher dilution of the

Mass transfer is one of the key factors that control the particle size in the SAS process. This is influenced by both the spray hydrodynamics of the organic solution and the

In the last years, the hydrodynamic of the SAS process has been the subject of several papers. Most authors face up to this problem considering that the jet of organic solvent behaves like a liquid jet injected into a gas, allowing to apply the classic theory of jet breakup. This theory could be applied successfully at subcritical conditions, below the mixture critical point solvent-CO2, where there is surface tension. The mixture critical point denotes the limit of the two-phase region of the phase diagram. In other words, this is the point at which an infinitesimal change in some thermodynamic variable such as temperature or

However, in supercritical conditions, above the critical point of the mixture organic solvent and CO2, it is not possible to distinguish droplets nor interfaces between the liquid solution and the phase of dense CO2 gas. Surface tension decreases to zero in a shorter distance than characteristic break-up lengths. Thus, the jet spreads forming a gaseous plume and will be characterized by the degree of turbulence associated with the vortices produced in the SC CO2 (Chehroudi et al., 2002; Kerst et al., 2000; Reverchon et al., 2010). Lengsfeld et al. were the first group that investigated fluid dynamics of the SAS process, studying the evolution and disappearance of the liquid surface tension of fluids injected in supercritical carbon dioxide. They concluded that a gas-like jet is formed after the jet break-up (Lengsfeld et al., 2000). In this way, Kerst et al. determined the boundaries between the different modes and they noted a strong interdependence between mass transfer and fluid dynamics (Kerst et al.,

In the SAS related literature there is a general agreement about the flow regimes observable when a liquid is injected in a vessel. The way in which the liquid solution is dispersed in the CO2 when the operating conditions are below the mixture critical point (MCP), which is strongly influenced by the operating pressure and the flow rate of liquid solution at fixed temperature, can be described according to one of the following four regimes: 1) the dripping mode, which requires lower flow speed so that drops can detach themselves from the orifice, 2) the Rayleigh break up regime, which is characterized by a rupture of the jet in the form of monodisperse droplets, 3) the sine wave break up regime, in which a helicoidal oscillation of the jet occurs, leading to its rupture into droplets with a polydisperse distribution, and 4) atomization, in which the jet is smooth when it leaves the orifice, until it reaches the zone of highly chaotic rupture where a cone of atomized liquid is formed.

precipitated materials allowed a slower drug release rate than pure drug.

particles in the expansion chamber result in smaller particles.

thermodynamic properties of the supercritical fluid phase.

pressure will lead to separation of the mixture into two distinct phases.

**3.1 Parameters influence on hydrodynamic** 

2000).

Fig. 2. SEM images of commercial a) amoxicillin and b) ampicillin, c) precipitated amoxicillin (Montes et al., 2010) and d) precipitated ampicillin (Montes et al., 2011a)

Fig. 3. SEM images of amoxicillin ethyl cellulose co-precipitated (Montes et al., 2011b).

because all the active substance could be situated on the surface of these microspheres and/or into the core. So, X-ray photoelectron spectroscopy (XPS) was used to determine the success of the encapsulation process by the chemical analysis of the particles on the precipitated surface (Morales et al., 2007). In this case, the elements that differentiate amoxicillin from ethyl cellulose are sulphur (S) and nitrogen (N) atoms. Therefore, these elements could indicate the location of the drug in the precipitated powders. On the other hand, amoxicillin delivery studies in simulated fluids from the co-precipitated obtained were carried out .The XPS spectra results were related to these drug delivery experiments and it was probed that the release of amoxicillin from precipitates in which N and S were

**b) d)**

**a) c)**

 Fig. 2. SEM images of commercial a) amoxicillin and b) ampicillin, c) precipitated amoxicillin (Montes et al., 2010) and d) precipitated ampicillin (Montes et al., 2011a)

**308K 323K 338K** 

Fig. 3. SEM images of amoxicillin ethyl cellulose co-precipitated (Montes et al., 2011b).

because all the active substance could be situated on the surface of these microspheres and/or into the core. So, X-ray photoelectron spectroscopy (XPS) was used to determine the success of the encapsulation process by the chemical analysis of the particles on the precipitated surface (Morales et al., 2007). In this case, the elements that differentiate amoxicillin from ethyl cellulose are sulphur (S) and nitrogen (N) atoms. Therefore, these elements could indicate the location of the drug in the precipitated powders. On the other hand, amoxicillin delivery studies in simulated fluids from the co-precipitated obtained were carried out .The XPS spectra results were related to these drug delivery experiments and it was probed that the release of amoxicillin from precipitates in which N and S were present on the surface is faster than in cases these elements were not. Anyway, all the coprecipitated materials allowed a slower drug release rate than pure drug.

On the other hand, in the RESS method, the sudden expansion of supercritical solution (solute dissolved in supercritical carbon dioxide) via nozzle and the rapid phase change at the exit of the nozzle cause a high super-saturation, thus causing very rapid nucleation of the substrate in the form of very small particles that are collected from the gas stream. Hence, the conditions inside the expansion chamber are a key factor to control particle size and the particles grow inside the expansion chamber to their final size. This result clarifies the influence of two important process parameters on particle size. Both, a shorter residence time and, hence, less time available for particle growth as well as a higher dilution of the particles in the expansion chamber result in smaller particles.
