Studies On Analytical Methods And Sensitization Of Ceftriaxone Sodium Impurities

Ceftriaxone sodium belongs to β-lactam antibiotics.Ceftriaxone sodium has the characteristics of strong antibacterial effect,wide antibacterial spectrum,long half-life period and remarkable curative effect.It is one of the most widely used antibiotics in clinical practice.According to the adverse reaction monitoring report,the number of serious adverse reactions reported by ceftriaxone sodium ranks first among cephalosporins,especially the allergic reactions.It is clinically reflected that the quality of domestic products of this variety is lower than that of imported products.Therefore,it is important to study the quality of ceftriaxone sodium,especially impurities and sensitization.On the basis of establishing a more exc lus ive method and in vitro allergic reaction models,the purpose of the research is to find the correlation between the material basis and the biological response and to compare the quality differences of different enterprise products.At present,the pharmacopoeia of each country fails to accurately and effectively control all known impurities and high molecular polymer impurities.The sensitization of impurities and the relationship between allergic reaction and impurities are not known.There are few studies on the difference in sensitization between domestic generic drugs and original drugs.Therefore,based on the previous study of impurity spectra,this experiment used a variety of analytical methods and more advanced sensitization prediction methods to study the analys is methods and sensitization of impurities,and to study the difference in sensitization between domestic and foreign products.This experiment provides theoretical basis and reference for the quality control,allergic reaction and quality evaluation of ceftriaxone sodium.It provides ideas for the study of polymer impurities of cephalosporin antibiotics.The main contents are as follows:1.Study on analytical method of small molecular impurities of ceftriaxone sodiumThe analytical method of small molecular impurities of ceftriaxone sodium was studied and established.By selecting appropriate ion pair reagents and establishing a gradient elution procedure,effective control of known impurities of ceftriaxone sodium was achieved.The experimental results show that ceftriaxone and 7 known impurities could be detected under the gradient conditions of this experiment.The separation between ceftriaxone and each known impurity could reach 1.5,and the detection limit was 0.0088 ng.Impurities under various failure conditions didn’t affect the detection of main peaks and known impurities.The number of detected impurities is more than that of the pharmacopoeia.The analytical method established in this experiment improves the defic ienc ies of the pharmacopoeial method in terms of resolution and impurity control,and has the advantages of good separation,high sensitivity,strong specificity,good durability,and high impurity detection.It is more suitable for the control of small molecular impurities of ceftriaxone sodium.2.Study on the analysis method of ceftriaxone sodium polymer impurityBy establishing the gel chromatography,mass spectrometry and a2D-LC-MS spectrometry system,the "polymer impurity peaks" before the main peak of the gel chromatography system were analyzed one by one by column switching,the "polymer impurity peaks" were found to be a mixture,and the pointer impurity related to the polymer impurity quality have been found.The experiment also established a more universal polymer impurity reversed-phase high performance liquid chromatography method.This experiment established a polymer impurity analys is method,which has high specific ity,strong specificity,good resolution and high separation efficiency.It can accurately and effectively control ceftriaxone compared with the Chinese Pharmacopoeia 2015 method.3.Study on the allergenicity of ceftriaxone sodium impuritiesDPRA(direct peptide chain reaction)test was used to predict the sensitization of known impurities of ceftriaxone sodium,and its known impurity AE-active ester,2-mercaptoben zothiazole(s ingle M),7-amino cephalosporin(7-ACT),7-aminocephalos poranic acid(7-ACA)and trans-cefradone have strong sensitization,and the sensitization of impurities is significantly higher than the drug itself,indicating that the cause of allergic reactions to ceftriaxone sodium may be related to these allergenic impurities.These impurities should be strictly controlled to the reasonable limits.Through DPRA and PLNA,it is preliminarily believed that there is no significant difference in sensitization between domestic and foreign manufacturers.