Study On The Preparation Of Drug Microparticles By The Supercritical Fluid Expansion Depressization Process

In recent years,the supercritical fluid techniques for preparing drug microparticles have attracted great attention.They have many advantages such as mild operation conditions, adjustable parameters and controllable particle diameters.Among these techniques,the supercritical fluid expansion depressurization(SFED) process has shown greater application potential in preparing micro- and nano-particles with controlled size.It can overcome the distadvantages of the conventional techniques such as large particle diameters and wide diameter distribution,make up for the deficiency of RESS and SAS processes and its derivative techniques in the yield of the final product and the micronization of the water-soluble drug,and takeover the advantages of the CAN-BD and SAA processes.Both lipid-soluble and water-soluble drug microparticles can be prepared by this new technique. However,at present little research work on this process has been done.The previous work focused only on the experimental research for some special cases.A systemically theoretical and experimental research has not been reported.This dissertation is aimed to study the technological foundation and operation characteristics of SFED process.By the study on the liquid volume expansion of organic solvent/CO₂ systems,the method to determine feasible range of SFED process is given.By the study on the ternary phase behavior of SFED process, the realationship between the content of each component and the operation pressure is determined.By the study on the atomization process through the nozzle,the realationship between the droplet diameters and the operation parameters is presented.By the study on the preparation process of lipid-soluble drug microparticles,water-soluble drug microparticles and drug carrier microparticles,the optimal operation conditions are given.The main research work and achievements are as following.(1) The liquid volume expansion ratios of the organic solvent/CO₂ system are calculated and the relationship of the liquid volume expansion ratio and the CO₂ solubility in liquid phase is investiaged.The results show that the liquid volume expansion ratios have little defference as long as the content of CO₂ in the liquid phase is same whether the temperature, pressure and organic solvent itself of the organic solvent/CO₂ system are same or not.When the liquid volume expansion ratio is below 500%,the change tendency of liquid volume expansion ratio is mild;when it is above 500%,the liquid volume expansion ratio increases sharply with the increase of the CO₂ content.The CO₂ content of 0.9,corresponding to liquid volume expansion ratio of 500%,can be defined as transition point of organic solvent/CO₂ system from SFED to SAS process.This definition is verified by experiments and it is in good agreement with the experimental results.(2) The ternary gas-liquid-solid phase equilibrium is calculated by PR state equation with vdW-1 mixing rule and the relationship between the content of each component and the operation pressure is investiaged.The results show that,with the increase of pressure,CO₂ content increases while the contents of solid and organic solvent decrease;at the same pressure,a higher temperature is more favorable for SFED process;for the same original organic solvent,with same temperature and pressure,a higher solid content in liquid phase is more favorable for SFED process.(3) For the flow of pure CO₂ through the nozzle,a simulating model of supercritical fluid rapid expansion through the nozzle is established.The rapid expansion process is simulated using the fluid calculation software of FLUENT and the evolution of pressure,temperature, density and flow rate along the nozzle axis are obtained.The results show that,the temperature and pressure of CO₂ decreases in the nozzle,while the flow rate increases rapidly.(4) With ethanol as model material,the liquid film atomization process through the nozzle is simulated and calculated by the air-assisted atomization model in the fluid calculation software of FLUENT and the relationship between the droplet diameter and the operation pressure,temperature and the solution flow rate is investiaged.Compared with the relationship between the microparticles prepared by SFED process and the operation paremeters,the calculation results are in good agreement with the experiment ones after the normalization of the droplet diameters and particle diameters.(5) The experiment apparatus and the related experiment technique of SFED process are established.The microparticles of different materials,namely water-soluble drug(cefadroxil, tetracycline),lipid-soluble drug(erythromycin,griseofulvin) and drug carrier(Poly-methyl methacrylate),are successfully prepared by SFED process.The influences of the operation parameters,including mixing vessel pressure,mixing vessel temperature,solution feed rate, solution concentration and precipitator temperature,on the particle morphology,size and size distribution are investigated.The optimal process conditions for these materials are obtained.