Development And Application Of Supercritical Fluid Pharmaceutical Fine Particle Preparation Device

A large number of studies have shown that supercritical fluid technology is an effective technology for preparing fine drug particles.However,due to the limitation of existing equipment,especially nozzles,which cannot meet mass production,the technology is still in the laboratory research stage and cannot realize industrialization.It is of great engineering significance to develop nozzles and supercritical fluid devices that can meet the needs of mass production in industrialization.On the basis of summarizing and analyzing the characteristics and research status of supercritical fluid technology and equipment for preparing drug fine particles,this paper has independently designed an impinging stream annular gap adjustable nozzle with adjustable inlet diameter that can meet the requirements of large-scale preparation of drug particles,and has developed a set of supercritical fluid drug fine particle preparation device with the nozzle as the core component.The experimental research on the preparation of ezetimibe and aspirin fine particles by the device was further carried out.Firstly,an experimental study on the preparation of ezetimibe ultrafine particles by supercritical CO2 antisolvent method based on Box-Behnken design(BBD)and Surface Response Method(RSM)was carried out.The ezetimibe ultrafine particles were prepared at different ezetimibe concentrations(40,60,80 g/L),reaction temperatures(50,60,70 ?)and reaction pressures(8,11,14 MPa).Secondly,the size of the prepared ezetimibe ultrafine particles was characterized by particle size analyzer.Finally,RSM model was used to analyze the significance,regularity and optimal preparation conditions of the parameters on the prepared ezetimibe ultrafine particles.The results showed that ezetimibe concentration had the most significant effect,followed by reaction temperature and finally reaction pressure.The particle size of ezetimibe increases with the increase of reaction concentration,decreases first and then increases with the increase of reaction temperature,and decreases with the increase of reaction pressure.The optimal preparation conditions after optimization of the model are as follows: reactant concentration 40 g/L,reaction temperature 60.4 ?,reaction pressure 13.8 MPa.The accuracy of the predicted value is verified by experiments.The actual particle size is 10.1 ?m,and the experimental error is within 100 nm.This shows that the experimental model is indeed authentic and can play a guiding role in experimental research.At the same time,an experimental study on preparation of aspirin ultrafine particles by supercritical CO2 rapid expansion method based on single factor method was carried out.Firstly,the preparation experiments of aspirin ultrafine particles under different reaction temperatures and pressures were carried out.Secondly,the size of aspirin ultrafine particles was characterized by malvin laser particle size analyzer,and the crystal form was characterized by X-ray diffraction analysis.The results show that with the increase of reaction temperature,the particle size firstly decreases and then increases,while with the increase of reaction pressure,the particle size decreases,the crystal form of the particle does not change,but the crystallinity decreases.The above results indicate the feasibility of impinged flow annulus nozzles for the preparation of insoluble drug ultrafine particles,which provides a theoretical basis for the further improvement of the nozzle structure of supercritical fluid technology for the preparation of drug ultrafine particles,and further promotes the industrial production of supercritical fluid technology for the preparation of drug ultrafine particles.The above results prove the feasibility of using the impinging stream annular gap adjustable nozzle for mass preparation of drug fine particles,and provide an equipment foundation for realizing industrialization of supercritical fluid drug fine particle preparation technology.