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Factors Affecting Supercritical Anti-Solvent (SAS) Process

Particle formation and aggregation mechanism

Due to the different shapes of the observed particles and the variety of experimental devices, it is very difficult to describe the observed phenomena systematically.

But for the continuous operation mode, some scholars have proposed a strict relationship between the volume expansion of the liquid and the shape of some particles.

If the volume expansion rate of the solution is small, the supercritical fluid cannot completely remove the solvent from the precipitation chamber, and there will be solvent at the bottom of the precipitation chamber.

Since the particles precipitate in it, the particles prepared at this time are aggregated particles. In a medium liquid expansion rate, expanded liquid droplets can be formed, which form hollow spherical solute aggregates after drying.

When the volume expansion rate is very large, the expanded liquid droplets break up to form ultrafine particles. These particles are usually It is the target of the micronization process, the particles are very small (100~200m), and the particle size distribution is very uniform.

Particles usually aggregate in two ways

In addition, there are some formation mechanisms related to particle aggregation: particles usually aggregate in two ways.

Physical aggregates

Species can be physical aggregates, which are characterized by weaker interactions between particles, such as impact during deposition.
The particles aggregated in this way can be separated by ultrasonic waves;

Chemical aggregation

The second type of aggregation is chemical aggregation.

In this case, the particles fuse together with the solvent molecules to form a mass, and the individual particles no longer have the original unique properties. This aggregation occurs through the interaction between the solvent and solute dissolved in the supercritical antisolvent

After crystal nucleation, solid particles will grow further in the solution in the precipitation chamber.This process strongly affects the morphology of the particles and is an important stage for the formation of complex morphology.

Influence of pressure and temperature

Changes in supercritical fluid pressure will cause changes in the degree of solution expansion during the SAS process. The greater the degree of solution expansion, the smaller the precipitated particles.

Pressure increase rate

In the SAS process, the pressure increase rate is the most important parameter to control the particle size and morphology.

The pressure increase speed is fast, it is easy to form a large supersaturation, the generated particles will be relatively small, and the particle size distribution is relatively uniform.

In the gas-phase batch and continuous modes, there are many different conclusions about the influence of temperature and operating pressure on the particle size of deposited particles:

  • Randolph et al found that when polylactic acid particles were prepared by the GAS method, as the temperature and pressure decreased, the particles the diameter decreases accordingly;
  • Yeo et al used the SAS process to prepare bioactive protein particles with a particle size of less than 5m, they found that temperature and pressure had no effect on the particle size;
  • Some researchers found that the particle size of the product with temperature and pressure decrease and increase.

Effect of concentration

Different researchers have reached different conclusions about the effect of concentration when conducting research.

  • Chon and other studies have shown that during the SAs of samarium, yttrium, and neodymium acetate, the particle size and its distribution increase with the increase of solute concentration.
  • However, there are also reports in the literature that the solute concentration is from 1% to 3%, and the particle size of polystyrene and polylactic acid particles are reduced.It is believed that the solute concentration increases and the mass transfer path is closer to the critical point.
    Therefore, in the metastable polymer phase the growth time becomes shorter and the particle size of the resulting particles becomes smaller.
  • Betemo et al used the GAS method to prepare hydroquinone ultrafine particles and found that the particle size of the resulting particles increased with increasing solution concentration, but the particle morphology remained almost unchanged.
  • Tak et al used SAS to treat poly-L-lactic acid, they found that a higher polymer concentration resulted in a higher viscosity, which reduced the atomization effect, so that it was not enough to break the solute into droplets. Under this condition, the precipitation ratio Drop formation proceeds faster, eventually forming fibers or films instead of particles.

Influence of liquid solvent chemical composition

Changing the liquid solvent can observe completely different behavior.

For example, when SAS was used to precipitate amoxicillin and tetracycline from dimethyl sulfoxide and nitromethylpyrrolidone solutions, dimethyl sulfoxide could not be prepared, but nitromethylpyrrolidone was successfully used to prepare these antibiotics particle.

Therefore, in order to successfully achieve micronization, the possible interaction between liquid solvents, supercritical antisolvents and solutes must be considered.

Influence of nozzle structure

The use of the nozzle device can strongly affect the precipitation process, and the size of the droplets, the condensation of the droplets, and the mixing of different fluids must be considered.

Generally speaking, the larger the aspect ratio of the nozzle, the finer the precipitated particles;

when the aspect ratio decreases, the aspect ratio of the precipitated product increases to form a filament; the nozzle aperture increases, and the diameter of the formed filament also increases.

The nozzle structure directly affects the droplet size formed by atomization and the mixing between fluids.

Solution expansion and SCF mixing occur in the downstream area of ​​the nozzle. The optimal value of the nozzle length-to-diameter ratio is 5~10.

The advantage of this choice is that the pressure energy loss when the solution passes through the capillary is minimal, and it can effectively convert potential energy into kinetic energy.

When the nozzle aperture is 20~100m and the length is 0.1~0.2m, the fluid can obtain a higher flow rate at the nozzle outlet.

Influence of the ratio of anti-solvent and solution addition rate

For the continuous operation process, the flow rate of the anti-solvent and solution has a greater influence on the precipitation process.

The higher the flow rate of the anti-solvent, the higher the mass transfer rate between the droplets, which tends to form a larger supersaturation and then generate smaller particles.

Randolph and other studies have found that when the solution rate is high, the particle size of the generated particles is relatively large. The reason for this phenomenon may be that the rate of solution passing through the anti-solvent is relatively fast, which reduces the mass transfer quality between the anti-solvent and the droplets, forming a low degree of supersaturation, resulting in fewer crystal nuclei, resulting in more Big particles.

However, some scholars have found that the initially formed droplets have no effect on the final particle size.

The higher the ratio of the addition rate of antisolvent and solution, the smaller the particle size of the resulting product, but if this ratio is too large, the particle size distribution shows a double peak, so there is a ratio between the addition rate of antisolvent and solution Critical value.

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