Foaming + Impregnation One-Step Process Using Supercritical CO2

*Antonio Montes, Clara Pereyra and Enrique Martínez de la Ossa*

### **Abstract**

Polymers are widely used in everyday life due to their properties as toughness, viscoelasticity, and the possibility to form glasses and semicrystalline structures. For that reason, it is used in mostly drug delivery systems and tissue engineering and in pharmaceutical and biomedical investigations. Foaming process allows creating porous structure into the polymer leading to scaffolds. Scaffolds are the focus of many investigations as prolonged drug delivery systems and implants or injections which are used to deliver cells, drugs, and genes into the body. Particulate leaching, freeze-drying, thermally induced phase separation, rapid prototyping, powder compaction, sol–gel, and melt molding are the main techniques in front of supercritical fluid technology to prepare scaffolds. Supercritical foaming process using CO2 presents advantages as a high dissolution in polymers and a green process because CO2 is nontoxic, inexpensive, and reusable. Moreover, supercritical technology allows to do an impregnation with an active substance together with the foaming at the same time. Thus active substances entrapped into scaffolds could be fabricated in a one-step green process.

**Keywords:** supercritical, foaming, scaffold, polymer, impregnation

### **1. Introduction**

For decades, drug delivery systems are the focus of many investigations [1–4] because it increases the effectiveness of formulations, avoiding the first-pass effect, and reduces the drug dosage of patients, producing delayed drug delivery to increase the patient comfort. Polymers are the coating agent frequently used in pharmaceutical technology due to their properties as toughness, viscoelasticity, and the possibility to form glasses and semicrystalline and porous structures.

Microencapsulation of active substance with polymers allows to produce drug delivery systems where the release phenomena is controlled by the diffusion of the active substance through the polymer and/or the erosion and degradation of the polymer at acid or basic media. Many authors have carried out investigations to prepare controlled drug delivery systems using supercritical technology [5–8]. In most of the cases, supercritical antisolvent process (SAS) has been the chosen technology because most of the active substances are insoluble in supercritical fluids. In this process an organic solution that contains the polymer and active substance is sprayed into a chamber filled with bulk supercritical fluid. The generated microdroplets improve the mass transfer between the supercritical fluid and the solution

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 characteristic.

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, alginate, starch, or hyaluronic acid [9].

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 alternative to prepare delay drug delivery systems.

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

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 crystallization and melting temperatures [14].

Moreover, other authors conclude that crystallization rate of polymer-CO2 depends only on the local degree of swelling inside the amorphous regions and the degrees of crystallinity itself [15].

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

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*Foaming + Impregnation One-Step Process Using Supercritical CO2*

be taken into account if the foaming process will carry out to produce scaffolds or the impregnation of the active substance happens mostly on the polymer surface.

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

During the past two decades, biomedical research has advanced extensively to develop potentially applicable scaffolds. Several methods are used decades ago to

The solvent-casting particulate leaching (SCPL) technique is a standard method to produce polymer-based scaffolds. A polymer is dissolved in an organic solvent that contains mainly salts, with specific dimensions. Then, the mixture is shaped into a three-dimensional mold to produce a scaffold. Thus, when the solvent is removed by simple evaporation, it creates a structure of composite material consisting of the particles together with the polymer. At the end, particles are dissolved in a bath leaving behind a porous structure. In this way, Sola et al. fabricated

*DOI: http://dx.doi.org/10.5772/intechopen.91304*

**2. Supercritical CO2**

thermolabile solute processing.

**3. Scaffold fabrication**

*Pressure-temperature phase diagram.*

**Figure 1.**

manufacture these porous structures.

*Foaming + Impregnation One-Step Process Using Supercritical CO2 DOI: http://dx.doi.org/10.5772/intechopen.91304*

be taken into account if the foaming process will carry out to produce scaffolds or the impregnation of the active substance happens mostly on the polymer surface.
