(602e) Modeling of Particle Size Distribution in Supercritical Antisolvent Recrystallization Process

ABSTRACT

In the pharmaceutical industry, there are conventional techniques such as milling, spray drying, liquid antisolvent process to micronize the drug particles in order to increase the bioavailability by increasing the surface area. But the particles produced from these techniques have certain disadvantages such as a broad particle size distribution, thermal degradation, presence of toxic solvent on drugs etc. Therefore, there is a need to develop effective particles technologies which could overcome the disadvantages of traditional micronization techniques. Supercritical fluid-based micronization techniques are an attractive alternative to the traditional micronization techniques capable of producing pharmaceutical compounds with a narrow particle size distribution and without any thermal and chemical degradation as well as no residual solvent content.

A fluid is described as a supercritical fluid when its temperature and pressure is above its critical temperature and pressure. Carbon dioxide (CO₂) is the most widely used fluid in supercritical fluid-based micronization techniques as its critical temperature and pressure are mild. In this work, a supercritical antisolvent process in which carbon dioxide is acting as an antisolvent has been modeled. The drug molecule considered in this work is rifampicin. This drug is first dissolved in dimethyl sulfoxide and this solution is then atomized into droplets through a nozzle into a vessel which is filled with supercritical CO₂. These droplets, which are a binary mixture of drug molecules and solvent, become a ternary mixture in the vessel as supercritical CO₂ diffuses into the droplet. Rifampicin is insoluble in supercritical CO₂ and there is a high miscibility between supercritical CO₂ and the solvent which leads to a high and fast diffusion of supercritical CO₂ into the droplet. Due to this antisolvent effect of supercritical CO₂, the solubility of rifampicin in the ternary mixture decreases sharply leading to the start of nucleation and growth. In the mathematical model presented in this work, the ternary system of rifampicin-dimethyl sulfoxide- carbon dioxide has been considered. Supersaturation is calculated as the ratio of actual mole fraction of rifampicin to the equilibrium mole fraction of rifampicin at any time interval. When the supersaturation becomes greater than one, the ternary mixture becomes unstable and the amount of rifampicin excess to equilibrium solubility starts depleting by nucleation and growth. Supersaturation is a driving force for nucleation and growth. The supersaturation profile has been predicted in the model. The model equations have been solved by MATLAB 7.1. These equations have been solved for a very small time interval (10^-3s). In this model, the average particle size and particle size distribution has been predicted. The effects of process parameters such as flow rate, nozzle diameter and solution concentration has been studied on the average particle size and particle size distribution. From the results obtained from our simulation, it is found that the results show the same effects of process parameters on the particle size and particle size distribution as observed by many researchers experimentally.