Micronization Of PEG And BSA Using Supercritical Antisolvent-Atomization (SAS-A)

Microparticles with narrow particle size distributions are widely used in many fields, such as biochemistry, materials, pharmaceuticals, cosmetics, etc., due to their excellent chemical properties and physical effects. As a result, the generation of microparticles has been the focus of numerous research projects in the past decade. Supercritical fluid assisted technologies allow the generation of particles that are difficult or even impossible to be achieved by classical methods such as milling, crystallization, spray drying or chemical reaction, particularly for substances with thermal sensitivity, structure instability or bioactivity. In this thesis, a supercritical antisolvent-atomization (SAS-A) apparatus was established for micronization of polymer, protein, and their microcomposites from organic or aqueous solutions. The SAS-A process combined the advantages of PGSSTM and the SEDSTM process, could vary two operating pressures to control particle size and morphology.Prior to the micronization of the studied systems, the vapor-liquid equilibrium (VLE) of the binary CO2/acetone, CO2/ethanol, CO2/water, and water/ethanol systems, and the ternary CO2/ethanol/water system were investigated by the Peng-Robinson equations of state (PR-EoS) under various temperature and pressure in order to provide theoretical points for directing the micronzation process. The studies showed that the PR-EoS was suitable for describing the VLE of the mentioned systems, and therefore will be used for discussing the states of the processing fluids in the SAS-A process.The SAS-A process was applied to the generation of polyethylene glycol 6000 (PEG) microparticles by using high pressure CO2 or N2 from PEG/acetone solutions under the downstream pressure of 0.1MPa and other operating conditions. The effects of the nozzle size, pre-expansion pressure, PEG/acetone solution flow rate and PEG concentration in acetone on the particle morphology and particle size were investigated at 50°C. Results showed that the N2-assisted process could produce spherical particles with mean sizes of 1-5μm, while the CO2-assisted process produced spherical, irregular, or agglomerated particles. No obvious difference could be found in acetone residue, crystallinity and melting point of the PEG particles obtained from the two processes. What more, using the same apparatus, PEG microparticles were successfully generated by using ethanol/water instead of acetone. Through changing the operating pressure, the process was possible to switch between atomization or anti-solvent precipitation, and spheres, crystals or both were obtained. A low value of the pressure before the nozzle (such as of 8 MPa that is close to the critical pressure of the binary ethanol/CO2 mixture), and a low value of the pressure after the nozzle (such as atmospheric pressure) were suggested to obtain desired particles.The SAS-A process was employed to produce bovine serum albumin (BSA) protein particles from ethanol/water solutions at 50°C. The effect of the operating pressure, the flow-rate of the protein/ethanol/water feed, the protein concentration, and the ethanol content in the ethanol/water, on the morphology, size and bioactivity of the produced BSA particles was evaluated. The formed primary particles were spherical and discrete with sizes of 0.1-3μm; the statistical number- average particle size was 0.4-1.1μm. The loss of the activity of the BSA powders varied between 0 to 25% of the original BSA materials depending on the processing conditions, in particular, on the flow-rate of the protein/ethanol/water solution and the ethanol content in the solution. At mild operating pressure of 8MPa, relatively low temperature of 50°C, relatively high solution flow rate about 3-5mL/min, protein concentration about 20-30mg/mL, and the ethanol fraction less than 25% in mass, it was possible to produce BSA microparticles with almost no loss of its bioactivity by the SAS-A process.As a continuation, BSA/PEG composite microparticles were investigated by using the SAS-A process. The effects of the BSA to PEG mass ratio on the particle morphology and the release profiles of BSA of the produced composites were examined. Results showed that BSA was encapsulated by PEG successfully, but the encapsulation efficiency should be improved further.