**2. Supercritical CO2**

*Advanced Supercritical Fluids Technologies*

alginate, starch, or hyaluronic acid [9].

tive to prepare delay drug delivery systems.

processes, among others, could be occasioned [11–13].

crystallization and melting temperatures [14].

degrees of crystallinity itself [15].

characteristic.

producing the dissolution into the solvent and the consequent solvent expansion and precipitation of particles of polymer and active substance by antisolvent effect. The result could be a coprecipitation of both compounds separately, the inclusion of particles into a matrix of polymer called composites, or the production of microcapsules with polymer coating as the active substance. In general, to avoid the separated precipitation, the ratio of polymer/active substance should be high. Moreover, operating conditions as pressure, temperature, concentration, flow rate ratios, and nozzle device have a relative influence on the final product

However, some formulations require a long time drug delivery system as transdermal drug delivery where, for instance, hormone treatment could be carried out. Synthetic polymers, for example, polycaprolactone (PCL), polyvinyl alcohol (PVA), or polyvinylpyrrolidone (PVP), are good candidates to prepare for this kind of systems. An excellent alternative is the use of biopolymers, such as chitosan,

Extended or long delay drug delivery systems are not often achieved in supercritical microencapsulation. If the active substance was placed into the pores of a polymeric porous structure, the drug release would be delayed most of the time. Thus supercritical impregnation into the pores of a polymer is an excellent alterna-

In supercritical impregnation two processes could happen, the impregnation into the polymer pores and the foaming of polymer with the subsequent impregnated scaffold production. This fact will happen if the polymer structure is able to grow up in the depressurization step. For that many authors have carried out the foaming + impregnation one-step process and the other ones only the impregnation process. CO2 is widely used as blowing agent because it presents properties that are nontoxic, inexpensive, and reusable and have a high dissolution in polymers. When a polymer is put in contact with supercritical CO2, in a first step the polymer is saturated with the gas above supercritical conditions. In a second step, the system is driven to a supersaturated state, usually decreasing the pressure or increasing temperature. This causes nucleation and relative growth of the porous cells within the polymeric matrix [10]. The fact that the polymer is under supercritical conditions alter physical properties as melting point and heat, glass transition and crystallization temperatures, crystallization rate, and swelling or foaming

In general, as a solvent penetrated the polymer, it induced swelling and consequently facilitated the mobility of the chains, allowing reorientation of the chains to form the more thermodynamically favorable crystalline state and reducing the

Moreover, other authors conclude that crystallization rate of polymer-CO2 depends only on the local degree of swelling inside the amorphous regions and the

Campardelli et al. [9] investigated the pore formation of PCL under CO2 at 100– 200 MPa of pressure and 35–40°C of temperature; due to a higher temperature, the polymer was melted. Process time was varied between 4 and 8 h. They concluded that formation of pores and thus the foaming of the polymer were only favored at 8 h when 100 MPa was used, but at higher pressures the foaming is produced independent of processing time. As pressure increases a regular pore structure was obtained with lower average pore diameter. However, as the temperature increases, the polymer swells more, forming a single structure, sticking polymer granules. Thus polymer foaming could be achieved in some operating conditions producing scaffolds. The inclusion of active substance in these scaffolds is the focus of many new investigations. So when a polymer is going to be impregnated, it should

**196**

A supercritical fluid is a substance above its critical temperature and pressure. A typical pressure-temperature phase diagram is shown in **Figure 1**. At this condition the fluid has unique properties as diffusivities that are two orders of magnitude larger than those of typical liquids, resulting in higher mass transfer rates. Moreover this state presents many exceptional characteristics, such as singularities in compressibility and viscosity and diminishing difference in liquid and vapor phases, among others. It is a good candidate to do extraction or impregnation processes because density can be adjusted continuously by altering the experimental conditions of temperature and pressure so solvent power and selectivity can be tuned.

The requirement that should fulfill the supercritical fluid is on the one hand low danger and on the other hand the relative low cost. In this sense CO2 is GRAS solvent, noninflammable, nontoxic, and gaseous at room temperature which makes the separation process easy. Besides it does not present a high cost and presents relative mild conditions of its critical point (31.1°C and 71.8 bar), allowing the thermolabile solute processing.

**Figure 1.** *Pressure-temperature phase diagram.*
