Preparation Of Cefquinome Sulfate Superfine Particles By Seds Process

Cefquinome sulfate is the fourth generation animal cephalosporins antibiotics,with broad antibacterial spectrum,high antibacterial activity,and suitable for parenteral administration.It mainly used for dairy cow mastitis,pig respiratory system infection and sow without milk syndrome caused by sensitive bacteria.However,because the Cefquinome sulfate is a fat-soluble compounds,its suspension,with low bioavailability,play efficacy slowly.In the study of percutaneous administration,because of its larger particle size,transdermal rate of Cefquinome sulfate is very low and the effect is poor.Because Cefquinome sulfate is a new type of animal cephalosporin antibiotics,research about its superfine particles preparation technology,mainly focus on traditional preparation method,is not a lot.Although these traditional methods can prepare Cefquinome sulfate superfine particles,some problems still exist such as much organic solvent leading to environment pollution and high operating temperature affecting drug effect.In Solution Enhanced Dispersion by Supercritical Fluids(SEDS)process,supercritical carbon dioxide(SC-CO2)was used as antisolvent.SEDS process can control particle size and distribution easily with merit of environment friendly and easy to operate.This technology is used widely in drug particles preparation,whereas no reports about application of SEDS in Cefquinome sulfate was found in literatures.This study focused on process,nozzle and mechanism of preparing Cefquinome sulfate superfine particles in SEDS process.The main research contents and results were showed as follows:1.The basic principles of solvent selection of SEDS process for preparation of Cefquinome sulfate superfine particles were determined.DMSO was selected as solvent used in the process according to the principles and by study.Phase behavior,liquid volume expansion rate(LVER)and liquid molar volume expansion rate(LMVER)of CO2-DMSO binary system in SEDS process were analyzed and calculated by equation of state method.Soave-Ridlich-Kwang(SRK)equation and Peng-Robinson(PR)equation were used to associate experimental results of CO2-DMSO binary system in literatures.Average absolute relative deviation(AARD)of CO2 mole fraction between calculated values and experimental values was selected as objective function.It was found that the AARDs of SRK equation were all higher than that of PR equation by comparing to five groups of results in literatures.The AARD of PR equation is between 6.33%and 9.65%,which can meet the basic requirements of the practice.Therefore,PR equation was used to calculate the phase equilibrium data for subsequent experiments.Phase balance diagram,LVER curves and LMVER curves of CO2-DMSO binary system in different temperatures were obtained by PR equation calculation.The best gas-liquid mass flow ratio was determined by phase balance diagram and LMVER curves.At the same time,experiments of preparing Cefquinome superfine particles by SEDS process were conducted.It was found by experiments that,LVER and LMVER can be used to predict the shape of Cefquinome prepared and select suitable operating parameter range.The experimental results obtained by changing the pressure,gas-liquid mass flow ratio and temperature were correlated with the equilibrium phase diagram and the LMVER.It indicated that smaller particle average size can be obtained as pressure at 13MPa;The optimal value of gas-liquid mass flow rate R is 5;the temperature should be above the critical temperature of CO2,but not too high.Otherwise it will raise the critical pressure and increase equipment requirements and costs.The phase equilibrium mechanism analysis established the theoretical basis for the follow-up experiments.2.The process of preparing Cefquinome sulfate superfine particles by SEDS process with traditional pinhole nozzle was optimized by orthogonal experiments.And the influence mechanism of process parameters on the particle size and particle size distribution was analyzed according to the crystallization kinetic model and the atomization quality prediction model.It indicated in orthogonal experiment that in SEDS process of preparing Cefquinome sulfate superfine particles using five-hole nozzle,the concentration of Cefquinome sulfate/DMSO solution has the greatest effect on average particle size,followed by solution flow rate,pressure and temperature.The optimum conditions for this process are that solution concentration is 100g·L-1,solution flow rate is 1.5mL·min-1,operating pressure is 13MPa,operating temperature is 306K.In the optimum conditions,confirmatory experiment was conducted and the average particle size is 0.71?m.It was found by analyzing particle size distribution(PSD)and particle specific surface area(SSA)that the process can control particle size and a narrower PSD is obtained.By analyzing the effect of single factor on the average particle size,PSD and SSA,it were found that with the increase of solution concentration,particle size increased.With the increase of solution flow rate,particle size decreased and the PSD range is narrowed.The effect of pressure and temperature on particle size and PSD,being influenced by multiple mechanisms,is more complex.With the increase of pressure,particle size decreased at first and then increase,whereas D97,reflecting the characteristics of rough end,increased.With the increase of temperature,particle size increased at first and then decrease.The changing trend of PSD was the same.The magnitude of the change is small.The results of SEM,XRD and FTIR of Cefquinome sulfate showed that processed Cefquinome sulfate particles were changed from blocks before processing to sheet,but with agglomeration.The crystallinity degree of processed Cefquinome sulfate was slightly lower than raw material,which was beneficial to improve its dissolution rate and bioavailability.There was no change in the chemical structure before and after treatment,and the process was able to maintain the structural stability of the drug.3.The annular-gap nozzle is suitable for enlarge study of preparing Cefquinome superfine particles by SEDS process.Flow characteristics of pure CO2 spray process and SEDS process in annular-gap nozzle was analyzed and researched by Computational Fluid Dynamics(CFD)method.By comparing the velocity distribution and the turbulence intensity distribution in the pure CO2 process and in SEDS process,it was found that the trend of the parameter distribution of the two processes was almost the same in the nozzle and precipitation tank.However,the velocity and turbulence intensity in pure CO2 process were higher than that in the SEDS process at the same location,which indicated that although the proportion of DMSO was lower,the effect of DMSO on the flow field parameters can not be ignored.By the contour of turbulence intensity in pure CO2 process and in SEDS process it was found that a high turbulence intensity triangle region formed beneath the annular-gap nozzle.According to literatures,it was confirmed that the region is a nuclei forming zone,defined as high-turbulence intensity nuclei forming zone.This zone has a major impact on primary and secondary nuclei forming.The turbulence intensity in the other region of the precipitation tank was relatively small,which is called the low turbulence intensity nuclei growth region.The d ivision of the two regions can be used to investigate the effect mechanism of flow field inside the precipitation tank on the particle morphology.The value of the incident angle a,the two inlet spacings L1 and the DMSO inlet dimension L2 were selected as variables.DMSO volume fraction distribution curve at nozzle outlet,DMSO volume fraction distribution curve and turbulent intensity distribution curve at 3mm and 30 mm down of nozzle outlet were selected as comparison object.It was found by comparison that all of these annular-gap nozzles can meet the requirements of SEDS process theoretically,but with difference.Turbulent intensity and DMSO volume fraction distribution,which have an important influence on solution dispersion in SEDS process,were taken as judgment indicators and the optimal nozzle structure parameters were determined,that is,the incident angle a was 30°,the two inlet spacings L1 was3mm and the DMSO inlet dimension L2 was 3mm.4.According to CFD simulation optimization results,a new annular-gap nozzle for SEDS process was made and the experimental equipment was improved so that a new equipment based on annular-gap nozzle formed.It showed in orthogonal experiment that in SEDS process of preparing Cefquinome sulfate superfine particles using annular-gap nozzle,the concentration of Cefquinome sulfate/DMSO solution has the greatest effect on average particle size,followed by solution flow rate,pressure and temperature.The optimum conditions for this process are that solution concentration is 100g·L-1,solution flow rate is 9mL·min-1,operating pressure is lOMPa,operating temperature is 316K.In the optimum conditions,confirmatory experiment was conducted and the average particle size is 0.73p.m.Comparing with the five-hole nozzle,it was found that under the optimal operating conditions,the average particle diameter of Cefquinome prepared by annular-gap nozzle was only 2.8%larger than that by five-hole nozzle(0.71?m).D97 of Cefquinome sulfate prepared by annular-gap nozzle was 2.12?m,which was 22.34%smaller than that by five-hole nozzle(2.73?m).Therefore the particle size distribution of Cefquinome sulfate prepared by annular-gap nozzle was narrower.Specific surface area of Cefquinome sulfate prepared by annular-gap nozzle was 4255.68m2/kg,which was 7.89%lower than that by five-hole nozzle(4620.38 m2/kg).These comparisons showed that the annular-gap nozzle achieved a particle mass closer to five-hole nozzle on the basis of a sixfold increase in feed rate.Moreover,the particle size distribution of the prepared particles is more uniform.It was found by analyzing PSD and SSA that the process can control particle size and a narrower PSD is obtained.By analyzing the effect of single factor on the average particle size,PSD and SSA,it were found that with the increase of solution concentration,particle size and PSD increased.With the increase of solution flow rate,particle size decreased and the PSD range is narrowed.These trends were same with that of five-hole nozzle.The change trend of pressure showed different characteristics as the five-hole nozzle.As the pressure increases,the average particle size and particle size distribution become larger.With the increase of temperature,particle size increased at first and then decrease and the change magnitude is small.The results of SEM,XRD,FTIR,TGA and DTA of Cefquinome sulfate showed that the processed Cefquinome sulfate particles were changed from blocks before processing to sheet,but with agglomeration.The crystallinity degree of processed Cefquinome sulfate was slightly lower than raw material.There was no change in the chemical structure and thermal stability before and after being processed.In summary,by the analysis and interpretation of the phase behavior in SEDS process,this study reveals the correlation between process phase behavior and particle morphology,which can be used to guide the experimental research.Orthogonal experiments were carried out to optimize the SEDS process of preparing Cefquinome sulfate particles based on the traditional pinhole nozzle experimental equipment,which provided the basic data and theoretical reference for laboratory research and pilot scale amplification of the process.The flow field distribution in the new annular-gap nozzle was analyzed by CFD,the hydrodynamic mechanism of SEDS process was revealed,and the structural of annular-gap nozzle was optimized.By the large flow experiments based on annular-gap nozzle device,the process of preparing Cefquinome sulfate ultrafine particles by SEDS method were magnified,which provided optimized nozzle structure and basic theoretical guidance for industrial application and promotion of the process.