In the name of GodApplication of supercritical

antisolvent method in drug encapsulation

Maryam kazemi Ph.D student of pharmaceutics

Shiraz university of medical sciences

The ideal drug delivery method:

Safe InertComfortable for patient Biocompatible Easily administered or removable High drug loading Using biodegradable polymers for drug en-capsulation is one of the best ways to achieved this ideal method .

Supercritical fluid properties:

• SCF is a solvent

• Tempreture & pressure are greater than its critical T , P.

• It remains as a single phase

The best SCF is CO2:• Non toxic

• Inert

• Low critical T=304 k & low critical P =7.38 MPa.

• Poor solubility for many polymers & drugs /rapid mixing with the solvent.

• Low viscosity like a gas , Its density similar to the liquid

• Its ability to provide a non degrading and nonoxidizing environment for sensitive compounds.

Limitation of SCF:

Non biocompatibility or toxicity of the polymers.

Unwanted by product of degradation .

Higher cost

The anti solvent application

Bleich and coworkers firstly discovered .

CO2= anti solvent percipitation of the solute from an organic solvent.

The base of this technique is:

• Dissolving a large volume of a SCF by an organic solvent .

• Reciprocal miscibility of the SCF CO2 & an organic solvent

• The low afinity of SCF for solute.

Mechanism of SAS• SC Co2 is pumped in to the high pressure vessel to a

specific pressure .

• Solution (drug+biodegredable polymer+organic solvent ) is sprayed in the reactor via a suitable nozzle.

• CO2 diffused in the solvent evaporated in the gas phase & the solvent diffuses rapidly from the solution droplet in to the bulk SCF percipitation the solute.

• Formed particles are collected on a filter

Washed with SCF to remove the resitual solvent

SCF dissolving into the liquid droplet

Evaporation of the organic solvent in the SCF phase

Later percipitate

Disadvantages of this method

• Long washing period aggregation particlesTo minimize :intensivly mixing SAS & solution Method : Using Ultra sonic nozzles 10-100 kHZIncrease mass transfer between SCF & solution

Smaller droplet

Effects of the process parameters on the particle size in the supercritical antisolvent (SAS) process

Effects of pressure:

At higher pressure, obtained smaller particle size. At higher pressure, the deforming pressure forces must be increased to break the droplets into smaller particles. Moreover, particle nucleation and its growth are other important factors affecting particle size. Rapid mass transfer of antisol-vent and solvent causes high supersaturations for the solute. High su-persaturation results in rapid nucleation and growth of more than one particle per primary droplet.

At lower pressure, obtained smaller particle size. In a situation above the critical condition, reduction in pressure is observed to decrease the solu-bility which then results in higher maximum supersaturation in the reac-tor; therefore, smaller particles are produced.

Pressure variations have no significant effect on particle size because the free intermolecular volume of the polymer will be occupied at the saturation pressure.

Effects of temperature

At higher temperature smaller size and more spherical particles obtained. But the temperature must be lower than the Tg of the polymer.

At lower temperaturesmaller particle size,obtained due to higher volatility.

Effects of chemical composition of the organic solvent Particle size decreases with increase in volatility of the solvent. Particle size decreased by using a stronger solvent. Solubility of the biodegradable polymer in the or-

ganic solvent must be higher than the solubility of its drug Contents.

Effects of chemical composition of the drug

Lower solubility of the drug in a supercritical fluid enhances rapid precipitation.

Enhancement of drug lipophilicity reduces the loading drug efficiency in the SAS process

Effects of chemical composition of the biodegradable polymer

The crystalline polymer forms smaller particle size with narrower particle size distribution.

Drug stability in amorphous polymers is higher than in crystalline polymers

Effects of the nozzle geometry

A smaller nozzle diameter reduces the particle size and produces more spherical-shaped particles.

The effect of the nozzle diameter is not highly significant.

Co-axial nozzle, is especially designed for improvement of the morphology.

Effects of flow rates of CO2 and liquid phase

Increasing the ratio of CO2 flow rate over the organic solution flow rate reduces particle size.

• References:

• M. Kalani, R. Yunus, Application of supercritical antisolvent method in drug encapsulation: a review, International Jour-nal of nanomedicine 6 (2011) 1429‐1442.