Control Of Residual Impurity In Large Volume Injection Products Package

Large volume injection is a basic and important therapeutic product in clinic.It plays an irreplaceable role in the rescue of critically ill patients by infusion of drugs,supplementation of nutrition,maintenance of body water,electrolyte and acid-base balance.At present,non-PVC soft bags are the preferred packaging materials for large volume injection products.A small amount of isopropylbenzene is introduced into the non-PVC soft bag forming process as the binder between the port tube and the delivery tube and the injection tube,but the residual isopropylbenzene can not be completely removed in the subsequent process.When the filling is completed,isopropylbenzene is degraded to isopropylbenzene hydrogen peroxide,acetophenone and 2-phenyl-2-propanol after the process of wet-hot steam sterilization.These three substances remain in large volume injection products.In this work,starting from the control of isopropylbenzene raw materials,the detection and control system of residual solvents in large volume injections was established.This paper consists of five parts.The first chapter introduces the development of large volume injection and packaging materials;the properties and hazards of isopropylbenzene and its degradation products;the regulations and requirements for residual solvents and the purpose and significance of this study.The second chapter establishes test method to analysis the purity of high-purity isopropylbenzene raw materials and the determination of benzene,which can guarantee the quality control of isopropylbenzene raw material when recevied.Method:The purity of isopropylbenzene and its benzene content were determined by gas chromatography with HP-1,50 m×0.32 mm×0.52?m.The temperature of the sample inlet was 275?,the volume of the sample is 1?L,the detector is FID,the temperature of the detector was 300?,the injection mode was shunt with ratio of100:1,and the column temperature was programmed to rise.Temperature mode(starting temperature 35?,holding for 10 min,then rising to 275?at a rate of 5?/min).The results show that the method is specific and has no interference peak at the retention time of n-butylbenzene(n-BB),which is the internal standard material for isopropylbenzene,the precision is good and the purity test%RSD=0.0019%(n=9),accuracy is good,when impurity level is 0.5%,0.7%,1.0%and 1.2%,recovery test results are 100.038%,100.029%,100.032%and 100.033%,the linear relationship of benzene content in the range of 0~150 ppm was good,Y=0.001x+0.0006,r~2=0.9999;the accuracy of benzene content in the range of 0~150 ppm was good,the recovery rate was 98.3%~101.6%,the results of intermediate precision test are good,%RSD=0.0095%(n=6).The method used in this thesis is efficient,fast and accurate,and can be used for quality control in actual production.In the third chapter,the effects of air,vibration,sampling and initial cumene hydrogen peroxide content on the degradation of cumene were analyzed by using Minitab software,and the optimal storage conditions and duration were set as follows.The raw material of isopropylbenzene can be stored for three months in full bottle,at25?and without shaking,during which the content of isopropylbenzene hydrogen peroxide remains below 0.18%;the raw material of isopropylbenzene hydrogen peroxide with initial content of 0.10%should not be stored for more than 20 days under full bottle,35?and without shaking conditions,It provides guidance for the actual acceptance of qualified isopropylbenzene storage.In the fourth chapter,a method for the determination of trace hydrogen peroxide isopropyl,acetophenone and 2-phenyl-2-propanol in large volume injection products by high performance liquid chromatography was established.Method:The chromatographic column is Agilent,Zorbax SB-C18,4.6 mm×150 mm,3.5?m,flow rate is 1.2 mL/min,column temperature is 25?±2?,automatic injector disc temperature is 5?,injection volume is 100?L,detection wavelength is 210 nm.The method is simple and novel.With the help of relative response factor,the content of three impurities can be calculated simultaneously by using one standard,which is more efficient and convenient.The fifth part summarizes the entire content of this investigation,illustrating the significance of this study and the prospect of new technology and new materials.