Preparing Budsonide Ultrafine Powder By Supercritical Anti-Solvent (SAS) Method

Micropaticles, especially the nanometer micropaticles, becomes a popular field in current high new technique, getting the extensive application in the realms, such as material, chemical engineering, light work, metallurgy, electronics and biomedical science, etc.Using the supercritical fluid( the SCF ) to get the ultrafine powder is a new technique by which wo could get ultrafine powder with small particle size (PS) and narrow particle size distribution (PSD). This work was to prepare the ultrafine powder of Budsonide (BUD). BUD, a potent anti-inflammatory corticosteroid is currently marketed as a dry powder inhaler and an aqueous nasal spray for the treatment of asthma. Dry powder inhaler and an aqueous nasal spray need small particle size, so it is need to micronize the BUD. The main purpose of this work was to prepare BUD powder 1-5μm PS and narrow PSD, in order to increase the absorptivity and curative effect of drug. This paper analysed the process of preparing of BUD, phase of production, morphorlogy and PS, influencing factor and mechanism of micronization.Because of the insoluble of BUD in supercritical CO₂ and low critical temperature (T_c=31.1℃), innocuity, apyrous and low price of CO₂, this work used CO₂ as supercritical fluid and Dichloromethane (DCM) as the solvent and the SAS method was used to prepare the BUD ultrafine powder. It contained as follows:Phase transformation was analyzed using XRD, and the result indicated that there was no phase transformation take place to BUD in the SAS experiment.The particle size (PS) and morphology was analyzed by SEM, and the results indicated that with the increase of the particle growth time, the particle size (PS) and morphology was controled by growth process instead of nucleation and the PS increased with the morphology change from sphere to polyhedral crystal and bulk.The distribution of the particle size was counted by microscope method which can also calculate the shap factor: circularity. It indicated that this work can prepared the prospective product.This paper also discussed the influence of exhaust position, collect position, size of the solution and CO₂ channels, the solution flow rate, solution concentration, temperature and pressure. The results indicated that: it was better to sit the exhaust position on the bottom of the precipitation column (PC); mass solution flow rate might induced classification precipitation; the particle size (PS) and particle size distribution (PSD) were smaller and narrower with the decrease of the solution channels; The powder will precipitate on the wall of the PC when the CO₂ channels is large, and the powder will be rushed to the bottom of the PC when decrease size of the CO₂ channels; The CO₂ channels also effected the final particle size and morphology, because the decreasing the size of CO₂ channels would make the CO₂ flow to spray which would force to disperse the solution, which would lead to gain smaller solution droplet and smaller particles, but the forced dispersal would lead to wider distribution of solution droplet which would lead to wider PSD; the effect of solution flow rate and concentration was more complex, it had two sides; one side, the PS increased with the increasing of the solution flow rate and solution concentration, on the other side, proper increasing the solution flow rate and solution concentration would gain smaller particles; when the temperature was low, the PS increased with increasing of the pressure, but when the temperature was high, the PS decreased with the increasing of the pressure; increasing the temperature would decrease the PS at high pressure but not at the low pressure.This paper also studied the mechanism of the preparation of micropaticles by SAS, and the study considered that the final particle size and morphology was determined by the critical nucleus size, paticle growth rate and the time of its growth.