**1. Introduction**

460 Mass Transfer - Advanced Aspects

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Nanoplates by UV Irradiation: Tailored Optical Property and Enhanced Stability.

The particle precipitation into micro and nanoparticles has been an active research field for decades (Chattopadhyay & Gupta, 2001; Kalogiannis et al., 2005; Rehman et al., 2001; Reverchon, 1999; Velaga et al., 2002; Yeo&Lee, 2004). The greatest requirement in the application of nanomaterials is its size and morphology control which determine the potential application of the nanoparticles, as their properties vary significantly with size. Micro and nanoparticles can be obtained by different techniques. Conventional techniques (spray drying, solute recrystallization, coacervation, freeze-drying, interfacial polymerization) present drawbacks such as excessive use of solvent, thermal and chemical solute degradation, structural changes, high residual solvent concentration, and mainly, difficulty of controlling the particle size (PS) and particle size distribution (PSD) during processing (He et al., 2004), so these techniques for particle formation may not be advisable.

However, the application of supercritical fluids (SCFs) is an attractive alternative for this particle formation because remove these drawbacks. These supercritical fluids have larger diffusivities than those of typical liquids, resulting in higher mass-transfer rates. Moreover its solvent power and selectivity can be tuned altering the experimental conditions.

There are two main ways of precipitating micro and nanoparticles 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 between one or another depends on the active substance high or low solubility in the supercritical fluid.

The RESS process consists of solubilising the active ingredient of interest in the supercritical fluid and then rapidly depressurising this solution through a nozzle, thus causing the precipitation, extremely fast, of this compound. In other words, the process is based on the transition of active compound from soluble to insoluble state when the carbon dioxide passes from the supercritical to the gaseous phase. This technique has been applied on the particle precipitation and co-precipitation of many active ingredients/polymers (Kongsombut et al., 2009; Sane & Limtrakul, 2009; Turk et al., 2006; Vemavarapu et al., 2009; Wen et al., 2010).

The SAS technique, in all its variants, generally consists of spraying a solution of the solute to be precipitated into the supercritical fluid. The mass transfer behavior of the droplets is thought to be a key factor affecting particle morphology (Werling & Debenedetti, 1999). The volumetric expansion of the solvent reduces the solvation capacity of the solvent, causing the supersaturation of the liquid phase and the consequent generation of the particles. The SAS process has been carried out for many particles precipitation and polymeric encapsulation of particles of active ingredients (Ai-Zheng et al., 2009; Chong et al., 2009a;

Particles Formation Using Supercritical Fluids 463

In order to design a supercritical precipitation process several aspects must be taken into account. First, the solubility of the solute to micronize in supercritical fluids must be known in order to choose RESS or SAS process. Then, a solvent able to turn the solute soluble must be chosen, and elucidate the ternary phase equilibrium diagram solvent-solute-CO2 or the binary phase equilibrium solvent-CO2 when the solubility of the solute into CO2 is neglected. Volumetric expansion curves and volumetric equilibrium data are required. Not only the thermodynamic data but also the hydrodynamic of the process should be

Over the last few decades, the solubilities of solids and liquids in supercritical fluids (SCF) have been measured extensively. For instance, in the facilities of University of Cádiz, the solubility of solid dyes like 1,4-dimethylaminoanthraquinone (Disperse Blue 14) in supercritical carbon dioxide has been determined in the pressure range of 100-350 bar and in the temperature range of 313-353 K and correlated with empirical and semi empirical equations based model and models based on thermodynamic aspects and the use of equations of state (Gordillo et al., 2003). The solubility of palmitic acid in supercritical carbon dioxide was determined experimentally in the pressure range, 100 to 350 bar, and the temperature range, 308 to 323 K. A cubic equation of state and an empirical equation were used to correlate the solubility of this fatty acid in supercritical carbon dioxide (Gordillo et al., 2004). Such information takes an important part of establishing the technical and economic feasibility of any supercritical fluid process. Most of the investigations on solubility have been concerned about binary systems consisting of a single solute in contact with a single SCF. The solubility of solutes in supercritical fluids is related to its physical and chemical properties such as polarity, molecular structure, and nature of the material particles, and it is also related to the operating conditions such as temperature, pressure, density of solvent and co-solvents, and solvent flow rate in the supercritical region. From the 90s to now, many

Fig. 1. Pressure-temperature phase diagram

investigated.

**3.1 Solubility** 

**3. Precipitation using supercritical fluids** 

Franceschi et al., 2008; Heyang et al., 2009; Kalogiannis et al., 2006; Kang et al., 2008; Thote & Gupta, 2005; Reverchon et al., 2008a; Ron et al., 2010; Tozuka et al., 2010).

The application of SAS processing has until now been explored in a wide range of fields including: explosives (Teipel et al., 2001), polymers (Garay et al., 2010), pharmaceutical compounds (Chen et al., 2010; Park et al., 2010), colouring matter (Reverchon et al., 2005), superconductors (Reverchon et al., 2002), catalysts and inorganic compounds (Lam et al., 2008). SAS exhibits the capacity of producing free-flowing particles in a single step at moderate pressure and temperature. In the pharmaceutical field, products with a high level of purity, suitable dimensional characteristics such as PS in the micrometer and submicrometer ranges, narrow PSD and spherical morphologies, have been obtained for use in developing delivery systems for drug targeting and controlled release.

In the facilities of University of Cádiz, amoxicillin (AMC) and ampicillin (AMP) micronization and polymer-drug co-precipitation have been carried out by SAS process. Several designs of experiments to evaluate the operating conditions influences on the PS and PSD have been made. In SAS, supercritical CO2, is used as an antisolvent. The solution, containing solute, is shape as tiny droplets, produced by a nozzle through which the solution is sprayed into a high pressure vessel. When the droplets contact the supercritical CO2 a very rapid diffusion takes place, including phase separation and precipitation of the solute (Chong et al., 2009b).

In the particle precipitation, mass transfer occurs between a droplet of organic solvent and a compressed antisolvent. In miscible conditions, above mixture critical point, there is no obvious way to define the interface between the two fluids. Dukhin et al. has evidenced the transient existence of droplets at conditions slightly above the mixture critical point, due to the existence of a dynamic interfacial tension, so a description of mass transfer from a droplet even in miscible conditions seems reasonable (Dukhin et al., 2003).

Two ways diffusion process, between a solvent droplet and its antisolvent environment at supercritical conditions, take place. There are evidences that antisolvent–solvent mass transfer is more important than jet break-up and droplet formation in determining particle size and morphology (Heater & Tomasko, 1998; Randolph et al., 1993).

However, the complexity of SAS process, which involves the interaction of thermodynamics, mass transfer, jet hydrodynamics and nucleation kinetics, makes it difficult to isolate one phenomenon as being responsible for a given trend in particle characteristics (Werling & Debenedetti, 2000).

### **2. Supercritical fluids**

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. These supercritical fluids have diffusivities that are two orders of magnitude larger than those of typical liquids, resulting in higher mass-transfer rates. Properties of SCFs (solvent power and selectivity) can also be adjusted continuously by altering the experimental conditions (temperature and pressure). Supercritical fluids show many exceptional characteristics, such as singularities in compressibility and viscosity, diminishing difference in vapor and liquid phases and so on. Although a number of substances are useful as supercritical fluids, like water, carbon dioxide has been the most widely used. Supercritical CO2 avoids water discharge; it is low in cost, non-toxic and non-flammable. It has low critical parameters (304 K, 73.8 bar) and the carbon dioxide can also be recycled (Özcan et al., 1998).

Franceschi et al., 2008; Heyang et al., 2009; Kalogiannis et al., 2006; Kang et al., 2008; Thote &

The application of SAS processing has until now been explored in a wide range of fields including: explosives (Teipel et al., 2001), polymers (Garay et al., 2010), pharmaceutical compounds (Chen et al., 2010; Park et al., 2010), colouring matter (Reverchon et al., 2005), superconductors (Reverchon et al., 2002), catalysts and inorganic compounds (Lam et al., 2008). SAS exhibits the capacity of producing free-flowing particles in a single step at moderate pressure and temperature. In the pharmaceutical field, products with a high level of purity, suitable dimensional characteristics such as PS in the micrometer and submicrometer ranges, narrow PSD and spherical morphologies, have been obtained for use in

In the facilities of University of Cádiz, amoxicillin (AMC) and ampicillin (AMP) micronization and polymer-drug co-precipitation have been carried out by SAS process. Several designs of experiments to evaluate the operating conditions influences on the PS and PSD have been made. In SAS, supercritical CO2, is used as an antisolvent. The solution, containing solute, is shape as tiny droplets, produced by a nozzle through which the solution is sprayed into a high pressure vessel. When the droplets contact the supercritical CO2 a very rapid diffusion takes place, including phase separation and precipitation of the solute (Chong et al., 2009b). In the particle precipitation, mass transfer occurs between a droplet of organic solvent and a compressed antisolvent. In miscible conditions, above mixture critical point, there is no obvious way to define the interface between the two fluids. Dukhin et al. has evidenced the transient existence of droplets at conditions slightly above the mixture critical point, due to the existence of a dynamic interfacial tension, so a description of mass transfer from a

Two ways diffusion process, between a solvent droplet and its antisolvent environment at supercritical conditions, take place. There are evidences that antisolvent–solvent mass transfer is more important than jet break-up and droplet formation in determining particle

However, the complexity of SAS process, which involves the interaction of thermodynamics, mass transfer, jet hydrodynamics and nucleation kinetics, makes it difficult to isolate one phenomenon as being responsible for a given trend in particle characteristics (Werling &

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. These supercritical fluids have diffusivities that are two orders of magnitude larger than those of typical liquids, resulting in higher mass-transfer rates. Properties of SCFs (solvent power and selectivity) can also be adjusted continuously by altering the experimental conditions (temperature and pressure). Supercritical fluids show many exceptional characteristics, such as singularities in compressibility and viscosity, diminishing difference in vapor and liquid phases and so on. Although a number of substances are useful as supercritical fluids, like water, carbon dioxide has been the most widely used. Supercritical CO2 avoids water discharge; it is low in cost, non-toxic and non-flammable. It has low critical parameters (304 K, 73.8 bar) and the carbon dioxide can also be recycled (Özcan et al., 1998).

Gupta, 2005; Reverchon et al., 2008a; Ron et al., 2010; Tozuka et al., 2010).

developing delivery systems for drug targeting and controlled release.

droplet even in miscible conditions seems reasonable (Dukhin et al., 2003).

size and morphology (Heater & Tomasko, 1998; Randolph et al., 1993).

Debenedetti, 2000).

**2. Supercritical fluids** 

Fig. 1. Pressure-temperature phase diagram
