Device Design And Process Research Of Membrane Emulsification To Prepare Narrow Size Distribution Microspheres

For long-term sustained or controlled injections,microspheres with large particle size can contribute to longer sustained release period and reduce burst release,thus,it's of great significance to research and develop Poly(lactic-co-glycolic acid)(PLGA)microspheres with particle size ranging from tens to hundreds of micrometers.At present,nano/micro-particle PLGA microspheres has been prepared with rapid membrane emulsification method,reaching a level of span(27)1.0.However,there are some technical problems in preparing large size PLGA microspheres.It is difficult to prepare particle to reach a level of span(27)1.0,ranging from tens to hundreds of micrometers.The purpose of this project is to prepare,with direct membrane emulsification method,narrow size distribution PLGA microspheres with median diameter of 60-200 ?m,to investigate effect of key process parameters on the particle size and to improve the size distribution of large particle size microspheres,providing data and ideas at earlier stage in realizing the continuous manufacturing of microsphere in actual production.The research content is divided into three parts.Firstly,the most commonly used SPG membrane was used to determine the experimental setup to ensure repeatability between batches.Effects of transmembrane pressure,average velocity of continuous phase in the membrane tube and dispersed phase concentration on the particle were investigated.By changing the flow direction of dispersed phase from external pressure to internal pressure,particle size uniformity of microspheres has been improved.Secondly,20 ?m round pores were manufactured with laser-drilling technology in stainless steel membrane,the embedded tube structure was added inside the membrane tube to improve the particle size distribution and batch-to-batch repeatability.The surface properties and pore parameters of the stainless membrane were studied to illustrate necessity of larger distance between laser drilled pores and the embedded tube structure.Effects of transmembrane pressure,average velocity of continuous phase in the membrane tube and dispersed phase concentration on the particle were investigated.Compared to SPG membrane emulsification microspheres,particle size of stainless membrane emulsification microspheres is more controllable and the span is reduced from 1.3 to 0.7.Finally,a post-processing device is designed and constructed,which was connected to the membrane emulsification tube to realize the integration of emulsification,collection,cleaning and solidification processes.The emulsification speed,product yield,and solvent residue of the membrane emulsified microspheres prepared by this apparatus were evaluated.And by changing the continuous phase cycle system to a non-circulating system,the emulsification rate and product yield of the device are increased.In summary,stainless membrane with the structure of the embedded tube can be used to stably prepare large diameter PLGA microspheres ranging from several tens to hundreds of micrometers.The use of the membrane tube connecting post-processing device has potential to achieve continuous manufacturing of microspheres,which is of great significance for membrane emulsification industrialization.