| Drug suspension has wide applications in both traditional and new drug delivery system.However,there are inherent deficiencies in traditional methods for preparing drug suspensions,for example,organic solvent residue in the liquid phase is difficult to remove thoroughly.SFEE is a green,cutting edge technology for super fine microspheres preparation,which combines both the SCF particle production technology and traditional emulsion-based particle production technology.In SFEE microspheres take form directly in aqueous system,featuring uniform particle size distribution,high sphericity and high dispersity among other advantages,which make SFEE especially suitable for the preparation of drug suspensions.However,SFEE is still a relatively new technology,and most related research is experiment-oriented with research interest quite limited.Study on the extraction process remains insufficient and there is still a significant lack of understanding regarding the mechanism of the SFEE process.In addition,most related studies choose O/W emulsion as microsphere template,and studies on using W1/O/W2 double emulsion as template still remain at a preliminary level.In this study,first special effort was made to delve into the mechanism of the two sub-processes which combined constitute the SFEE process,i.e.,the mixing of organic solvent and the removal or organic solvent from the solvent/scCO2 mixture.This was to provide the theoretical basis for optimal selection of operational parameters.Based on this,SFEE was employed to treat both O/W emulsion and W/O/W double emulsion as templates for the production of drug nanosuspension and drug/polymer compound microspheres suspending in aqueous system with different structures and functions.The main content and conclusions of this thesis is as follows:The high pressure vapor liquid equilibrium and mixture density of the solvent/CO2 binary system wereanalyzed to predict the mixing mechanism of solvent/scCO2 in the aqueous system as the emulsion is treated by SFEE.A view cell was used to allow a visualized study of the mixing process,which not only verified the prediction,but also could allow an examination of the influence of operational conditions in SFEE on the solvent removal efficiency.Mass transfer path of the solvent and CO2 during the mixing process was examined to deepen the understanding of mixing mass transfer in SFEE.Results showed that albeit above the mixture critical pressure,complete miscibility could only happen when there was a strong turbulence at the gas-liquid interface,otherwise the existence of interface could have a severely negative impact on the mixing efficiency.During the mixing process,the direct contact of solvent and CO2 in the aqueous phase and the convective diffusion that occurred at the gas-liquid interface constituted the main mass transfer path for the mixing of solvent and CO2.Meanwhile,molecular diffusion in the aqueous phase was often taken as the means for mass transfer in erstwhile studies.In addition,the mixture density of the solvent/C02 binary system could cause destabilization of the emulsion,which had a complicated impact on the mixing of solvent and CO2 in the aqueous phase.The flow field and concentration field of the solvent/scCO2 mixture in the extracting vessel were analyzed in this study.Under a high operating pressure,particle image velocimetry method was used to quantitatively visualize the flow field of the solvent/scCO2 mixing flow to capture the flow information on the supercritical fluid as well as to test the reliability of the model.PIV results showed that the solvent/scCO2 mixture took on a circular flow in the vessel and orientation of the circular flow was dependent on the temperature of scCO2 infusion.The change of solvent concentration distribution in the extracting vessel over time showed that the inefficiency for solvent extracted into the gas phase to be removed from the extracting vessel was a key limiting factor for SFEE in terms of solvent removal efficiency.By introducing multiple extraction steps and intense magnetic stirring to SFEE process,the solvent removal efficiency was remarkably enhanced and the solvent residue was greatly reduced,the latter of which was proved to be proportionate to the solubility of the solvent in water.Response surface analysis showed that among all extraction conditions in SFEE with multiple extraction steps,pressure of the first extraction step P1 had the most significant influence on solvent residue.This was because the efficiency of mixing and separation of solvent and scCO2 during the first extraction step was the determinative factor for solvent removal efficiency in a multi-extraction-step SFEE.SFEE method was employed to treat O/W emulsion as template for microspheres preparation,first quercetin nano-suspension was produced with Tween 80 as stabilizer.Furthermore,using polycaprolactone as polymer carrier,quercetin/polymer microcapsule suspension was also produced by SFEE method.The influence of operational parameters on the morphology and size of the nanoparticles/microcapsules in the suspension was examined.FT-IR and XRD were used to characterize the chemical structure and crystallization behavior of quercetin and the polymer carriers before and after SFEE processing.Also,both methods were used to verify that quercetin was indeed encapsulated in polymer and the effects of different operational parameters on drug loading efficiency were experimentally investigated.Results showed that adjustment of quercetin concentration cquer and PCL concentration CPCL were the most efficient way for changing the size of nanoparticles/microcapsules in quercetin and quercetin/PCL suspension.For the latter,the effect of surfactant concentration CTWeen on drug loading efficiency was the most significant.However,as emulsion stability was concerned,increasing PCL concentration CPCL was the practical method for enhancing drug loading effiency.Also,release characteristics of the compound microspheres were determined by fitting the release data in the simulated intestinal fluid using release kinetic equations.SFEE technology was incorporated with double emulsion technology to prepare porous microcapsules with closed pores,which could serve as drug carrier to load multiple drugs simultaneously.In the W1/O/W2 template double emulsion there was a chemical potential gap between different aqueous phases(W1,W2)which could cause water transport across the organic membrane(O).The water transmembrane diffusion model analysis showed that solubility C(?)and diffusivity D of water in the membrane phase were key factors for water permeability of the organic membrane.By adjusting double emulsion formula that could affect the membrane permeability such as solvent type,hydrophobic surfactant concertation cspan and polymer concentration CPCL,water transfer rate between W1 and W2 could be changed,whereby the internal structure of the porous microcapsules could be controlled.In addition,phase separation within the ternary system of PCL/solvent/CO2 under high pressure could induce the formation of polymer poor phase in the membrane phase,which could lead to the structural breakdown of the microcapsules.Therefore,the emulsion should be pre-solidified before being treated by SFEE.The influences of double emulsion formula and extraction parameters on the morphology and internal structure of the microcapsules were investigated experimentally.Also,loading efficiency as well as release characteristics of the hydrophobic and hydrophilic drugs in the microcapusles were experimentally examined.In conclusion,using the modified version of SFEE proposed in this paper,both O/W emulsion and W1/O/W2 double emulsion could be chosen as emulsion template,to produce drug nanosuspension,drug/polymer compound microspheres suspension and porous microcapsules with closed pores which can serve as carrier for multiple drugs.The modified SFEE has the advantages typical to traditional emulsion based methods for producing uniformly dispersed particles with controllable size and structure;also,it has the advantages typical to SCF related technologies such as super low organic solvent residue and its eco-friendliness.Therefore,SFEE is a promising technology to be applied in the field of designing and producing new drug delivery systems. |
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