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Supercritical Fluid Anti-Solvent (SAS) Technology

Definition of SAS

Supercritical Anti-Solvent technology (SAS) is a method for preparing microparticles using the antisolvent effect of supercritical fluids.

Research on supercritical antisolvent technology has become a hot spot in supercritical micronization technology.


In the process of supercritical antisolvent method, the solute is first dissolved in a suitable solvent to form a solution of a certain concentration. Supercritical CO2 is usually used as an antisolvent. This antisolvent does not dissolve solid solutes, but it is miscible with the solvent.

Therefore, when supercritical carbon dioxide is introduced into a solution in which non-volatile solids are dissolved, rapid interdiffusion occurs between them, the volume of the solvent expands, the density decreases, and the solution’s ability to dissolve the solute decreases, resulting in a high degree of excess in a short time Saturation, precipitation of ultra-fine particles with high purity and uniform particle size distribution.

Advantages of Supercritical CO2 Anti-Solvent (SAS) SAS

Compared with the traditional liquid anti-solvent process, SAS has the following advantages:

  • The separation of liquid solvent and SC-CO2 is achieved by reducing the pressure, which simplifies the purification process of the solvent;
  • It is carried out at room temperature, which is conducive to the treatment of heat-sensitive substances;
  • The extraction of solvent by SCCO2 reduces the residue of organic solvent on the precipitated particles;
  • Adjust the pressure or temperature of the system to change the phase transition kinetics, thereby controlling the particle size distribution and morphology of the particles

Operation method of supercritical anti-solvent technology

Supercritical anti-solvent technology has two operation methods: batch and continuous.

Batch operation

The batch operation mode is divided into liquid phase batch operation and gas phase batch operation.

Liquid phase intermittent operation

First add a quantitative liquid solution to the precipitation kettle, and then pass CO2 until the set pressure is reached, the solid particles precipitate out in the liquid phase, the rate of CO2 addition is the main factor controlling its morphology and size, this method is called liquid phase intermittent operation.

Gas phase intermittent operation

It is also possible to pass CO2 into the precipitation tank first, and then spray the solution into the space of the kettle through a nozzle, and the solid particles are precipitated out in the supercritical phase.

This method is called gas phase intermittent operation, and the key parameters that affect the process are Pressure, temperature, initial concentration of solution, and nozzle aperture.


After the precipitation process, continue to pass supercritical fluid for cleaning, and take away residual solvent. These two methods are carried out in an unsteady state, so it is difficult to investigate the influence of process parameters on the final particle morphology. In many cases, intermittent operation is not suitable for industrial production.

Continuous operation

In continuous operation, first pass CO2 into the precipitation tank to reach the set temperature and pressure, and then dissolveliquid and CO2 enter the precipitation chamber continuously in a co-current or counter-current manner according to a certain flow ratio. The solution is crushed into small droplets by the spray device, and mass transfer occurs with SCCO2, and fine particles are precipitated. After the precipitation process, it needs to be cleaned with pure SCCO2

Development of supercritical antisolvent technology

Among the various supercritical fluid micronization technologies, the research on the preparation of microparticles by supercritical antisolvent technology is relatively in-depth and has broad application prospects.

At present, there are many different processes and devices. The process can be subdivided into the following four methods according to the control conditions: gas antisolvent method, supercritical antisolvent method (or compression antisolvent precipitation method), supercritical fluid enhanced solution dispersion method and enhanced mass transfer supercritical antisolvent method , As described below.

Gas anti-solvent method (GAS)


Used a batch operation method to mix high-density compressed gas with a solution. After the solvent swelled, the dissolution capacity dropped sharply, and solute was precipitated after reaching supersaturation.

This process is called the gas anti-solvent method.

Process of gas anti-solvent method

In this method, a certain amount of solution is first added to the precipitation chamber, and then supercritical anti-solvent CO2 is added to pressurize to a predetermined pressure.

In the precipitation chamber, the anti-solvent dissolves the organic solvent, and the dissolving power of the organic solvent is reduced, resulting in supersaturation of the solution, and the solute is crystallized out of the solution.

In the final stage of the precipitation operation, the pure anti-solvent CO2 is passed into the precipitation chamber to clean.

Supercritical anti-solvent method (SAS)


Aero-sol Aolvent Extraction System

Shim et al. improved the SAS process and proposed the ASES (aero-sol solvent extraction system) precipitation technology to enhance the contact mixing of SC and solution.

The ASES process is also known as the PCA process (precipitation with a compressed fluid anti-solvent), also known as the SAS process.

Operation process

This operation process is different from the GAS method.

First, the supercritical anti-solvent CO2 continuously enters the precipitation chamber from the top or side wall at a certain flow rate through a high-pressure pump.

When the system reaches the set temperature and pressure, the solution is atomized into droplets through the nozzle jet and enters the precipitation chamber. In the precipitation chamber, the anti-solvent and atomized droplets diffuse to each other, so that the solubility of the solvent in the droplets quickly decreases, resulting in a large degree of supersaturation, so that the solute is quickly and uniformly precipitated.

Supercritical fluid enhanced solution dispersion (SEDS)

In order to further strengthen the mass transfer process between the solution and the supercritical fluid and prepare smaller particles, Hanna proposed the supercritical fluid enhanced solution dispersion method.

The supercritical fluid CO2 and the solution enter the precipitation chamber through the two channels of the coaxial dual-channel nozzle, and the high-speed SCCO2 crushes the solution flow into small droplets at the nozzle end of the nozzle, while contacting and dispersing the solution The solvent in the solution is extracted, and ultrafine particles are precipitated.

Compared with SAS

Compared with the traditional SAS method, the SEDS method uses a coaxial dual-channel nozzle structure to achieve a high supersaturation of the solute, thereby achieving rapid nucleation and being able to control the growth rate of the crystal.

Supercritical anti-solvent-enhanced mass-transfer (SAS-EM)

SAS-EM is the latest development of supercritical antisolvent micronization technology.

Chattopadhyay etc in the conventional ASES operation equipment, an oscillator vibrating at ultrasonic frequency is introduced, and the SASEM technology is proposed to improve the atomization effect of the solution and enhance the mixed mass transfer of the liquid and SCF.

The addition of an ultrasonic oscillator at the outlet of the solution can promote the breakage and atomization of the jet into smaller droplets and enhance the turbulence of the system, thus enhancing the mass transfer process between the solution and the anti-solvent.
The reduction of droplets and the enhancement of mass transfer make the particle size of this method to be 1/10 of the traditional SAS method

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