Preparation Of Microparticles Using Supercritical Fluid Assisted Atomization With An Enhanced Mixer

Design and application of microparticles in pharmaceutical formulation is very popular and difficult for the pharmaceutics. The microparticles of drugs and medical polymers with controlled morphology and size distribution can impressively improve the performance of traditional form, controlled release form and targeted drug. Supercritical fluid assisted atomization (SAA) is a very promising and green technique for micronization by utilizing the interactions between supercritical fluid and liquid solution. This technique can successively produce the microparticles of organic-soluble, water-soluble and thermal sensitive materials without any organic solvent residues. It can also provide mild process conditions and a good control ability of particle size distribution. However, this technology is still developing with few investigations on process mechanisms.In this work, we made a thorough summary of supercritical antisolvent technique (SAS) and grasp its consistent thread. Comparing SAS and SAA, the purpose of this work would focus on the technical improvement, process investigations and the study of mechanisms with the experimental methods of SAS. It provided insight into the mechanisms that govern morphology in microparticles processed using SAA. Several key problems, such as engineering stability, the optimal design in organic solution and the application of this technique into more water-soluble materials, had been perfectly solved. Meanwhile, two possible mechanisms could be separately involved in crystal formation and protein particles formation. These investigations on the SAA mechanism may provide good technical guidance on the micronization of insoluble drugs and pharmaceutical proteins.An estimation method based on the Peng-Robinson equation of state (PR-EOS) with two different mixing rules (vdW-1and vdW-2) was presented here with which to calculate vapor-liquid phase equilibrium of CO2-acetone, CO2-ethanol, CO2-methanol and CO2-dichloromethane. The most appropriate binary interaction parameters at a given temperature had been obtained by regressing the model against experimental data. The liquid volume expansion data had been predicted by the vapor-liquid phase equilibrium calculation of four binary systems using Peng-Robinson equation of state. Supercritical fluid assisted atomization with a hydrodynamic cavitation mixer (SAA-HCM), which was invented by our group, had been successfully improved. Using cholesterol as a model drug, the relation between microparticles morphology and liquid volume expansion had been established. Hence, the data of the liquid volume expansion could normally be used as a practical and accessible thermodynamic criterion to successfully implement the SAA-HCM process avoiding undesirable precipitation in the mixer. According to the thermodynamic criterion, well-defined spherical cholesterol microparticles could be prepared successfully by SAA-HCM process where acetone, ethanol or methanol was used as a solvent. This practical criterion could be very helpful when micronizing traditional Chinese medicines with limited information.Supercritical fluid assisted atomization with an enhanced mixer was used to produce the chitosan and sodium cellulose sulfate (NaCS) microparticles with water as a solvent. The process parameters such as mixer temperature and pressure, the mass flow ratio, precipitator temperature, solute concentration and the molecular weight of polymer were investigated in detail to evaluate their influences on the morphologies and size distributions of precipitates. Well-defined spherical polymer microparticles with controlled particle size distribution between1.0μm and5.0μm could be prepared at optimum operating conditions. Compared with the unprocessed polymer, there was no significant change on the primary structure and stability of the microparticles treated by SAA-HCM. A slight change in crystalline state with lower thermal stability was observed after SAA-HCM processing.SAA-HCM had been used to prepare bovine serum albumin (BSA) microparticles with water as the sole solvent. Well-defined spherical protein microparticles with controlled particle size distribution between1.0μm and5.0μm could be prepared at optimum operating conditions. Significantly, under different conditions, the prepared BSA microparticles had various morphologies, such as corrugated particles, smooth hollow spherical particles and cup particles. The microparticle formation mechanism was developed with the shell formation and central bubble mechanism. Compared with native BSA, BSA microparticles didn’t show significant change in primary structure, according to SDS-PAGE. No new peaks were observed after SAA-HCM processing with the help of FT-IR. In addition, the crystalline structure of the BSA microparticles was demonstrated to be amorphous because of the sudden supersaturation in the precipitation process. The SAA-HCM process is expected to be a promising technique for producing microparticles suitable for pulmonary delivery of therapeutic macromolecules.In a word, when operating at the optimum conditions, SAA-HCM could be used to produce microparticles of drugs, polymers and proteins successfully with organic solvent or water as a solvent. The microparticles presented well-defined spherical morphology with controlled particle size distributions. The SAA-HCM process is expected to be a promising technique for drug delivery system.