Establishment Of Allergic Polymerized Impurities Analysis System For Cephalosporins Based On MALDI-TOF MS/MS Technology Platform And Study On Impurity Profile Of Cefetamet Pivoxil

Cephalosporins are widely used in human therapy because of their high activity against micro-organisms.Cephalosporin may cause immediate hypersensitivity,allergic reaction,and death in severe cases.A large number of studies and clinical trials have comfirmed the allergen were polymerized impurities in cephalosporin.This paper identified structures of polymerized impurities and degradation impurities in cephalosporins with modern analytical technique and guaranteed the safety and efficiency of clinical medication.1、Establishment of allergic polymerizd impurity analysis system for cephalosporins based on MALDI-TOF MS/MS technology platform.MALDI-TOF MS/MS technique was used for the first time to identify the structures of polymeried impurities in cefetamet pivoxil hydrochloride and cefuroxime axetil in this paper.Fragmentation pattern of impurities in cephalosporins was revealed.Compared with ESI,the MALDI-TOF MS/MS technology had the following advantages:The ion source was milder and had no internal polymerization;The impurities were detected without chromatographic separation and the structures were quickly identified and no missing.On the basis of structural identification,the source of polymeried impurities was studied in this paper,thus the enterprises can improve production technology to reduce the content of impurities,thus improve the safety of the drugs and reduce the allergic reaction of patients.2、Study on the impurity profile of cefetamet pivoxil hydrochlorideThe structures of impurities in cefetamet pivoxil hydrochloride were separated and identified by LC-Q TOF MS technology.The fragmentation pattern of ESI mass spectrometry of cefetamet pivoxil hydrochloride was revealed.Three impurities cefetamet pivoxil hydrochloride were prepared by preparative high performance liquid chromatography and identified by modern spectroscopy(UV,IR,¹H NMR,¹³C NMR,DEPT,HMQC,HMBC,MS).The ADMET predictor prediction software was used to evaluate the toxicity of impurities in cefetamet pivoxil hydrochloride,providing a scientific basis for the rational formulation of impurities limits in cefetamet pivoxil hydrochloride quality standard.Besides,we established a control method for impurities in cefetamet pivoxil by HPLC gradient elution to replace the isometric method,and we detected more impurities in cefetamet pivoxil which provided a scientific basis for the revision of the quality standard of cefetamet pivoxil hydrochloride in Chinese Pharmacopoeia.Based on the identification structures of impurity,we finded out the cause of impurities,guided enterprises to improve technology,reduced impurity content,improved drug quality and international competitiveness.