Supercritical Anti-Solvent Micronization

As mentioned previously, the low solubility of a part of pharmaceutical products of interest limits the use of SC-CO2 as a solvent in the micro or nano production of particles.

To solve this problem it was decided to use the SC-CO2 as an anti-solvent and not as a solvent. In this case, the solute is insoluble in the anti-solvent, while the anti-solvent must be miscible with the liquid solvent.

The process is based on a quite simple concept: when a liquid solution is sufficiently expanded by a gas, the liquid phase is no longer a good solvent for the solute causing the precipitation with the formation of particles.

SAS diagram

Supercritical Anti-Solvent (SAS), according to its name, applies the supercritical fluid as an anti-solvent. Hence the solute to be micronized has to be quasi non-soluble in the supercritical fluid.

This process is structured in a different way than previous RESS and PGSS. The SCF is first pumped to the top of the high-pressure vessel until the system reaches a constant temperature and pressure. Subsequently, active substance solution is sprayed as fine droplets into above SCF bulk phase through an atomization nozzle.

The large volume expansion of drug solution in the vessel results in the dissolution of SCF into liquid droplets and, subsequently, in supersaturation — due to the reduction in solvent power leading to nucleation and formation of small and monodisperse particles.

Particles are collected on a filter at the bottom of the vessel. The SCF and organic solvent mixture flow down to a depressurized tank where suitable temperature and pressure condition allow gas-liquid separation. After the collection of a sufficient quantity of particles, the spraying of the liquid solution has to be stopped. Furthermore, to remove residual solvent, pure SCF continues to flow through the vessel.

Variations of the SAS process include;

  • ASAIS (Atomization of Supercritical Anti-Solvent Induces Suspension). In ASAIS process, anti-solvent induced precipitation occurs in a small tube, where anti-solvent mixed with the solution to generate a suspension. This suspension of particles is then sprayed into a precipitator at the atmospheric condition for solvent separation, which eliminates the high volume and high-pressure precipitator. In addition, very small to moderate anti-solvent concentration is required. Contrary to the SAS process, the particles recovery is performed by cyclone separator rather than using a filter.
  • SEDS (Solution Enhanced Dispersion by Supercritical fluids). This is a modification of the SAS process in which the SCF and drug solution are introduced simultaneously into the precipitation vessel at a particular temperature and pressure through the coaxial nozzle. The design of the co-axial nozzle is such that to facilitate the dispersion of drug solution by SCF, thereby enhancing mass transfer and formation of fine particles. In addition, the high velocity of SCF allows intense mixing with the drug solution. Here, the SCF serves both as an anti-solvent and as a dispersion medium.