Study On The Impurities Analysis Methods Of Cefditoren Pivoxil

At present,cephalosporins occupies an important position in clinical anti-infective treatment.Cefditoren Pivoxil is a third-generation oral cephalosporin antibiotic.It has a broad-spectrum and high-efficiency antibacterial activity.It is stable to β-lactamase produced by various bacteria and is resistant to Staphylococcus,Streptococcus,Proteus,Escherichia coli etc,which shows strong antibacterial activity and outstanding performance in the treatment of upper respiratory tract infections,pneumonia,and urinary tract infections,especially for respiratory tract infections with strong bacterial resistance.At present,only the Korean Pharmacopoeia and the Japanese Pharmacopoeia reported this agent in the pharmacopoeias of various countries in the world,while there is no record in Chinese Pharmacopoeia,European Pharmacopoeia,and United States PharmacopoeiaAccording to the literature,quality of cefditoren pivoxil has not been further studied.Quality standards in the Japanese and Korean Pharmacopoeias only reported control methods to ensure the effectiveness of this product such as "identification,inspection,and content",and did not have the record of "impurity control" which did not meets the current requirements for medication safety.Up to date,few literature reports on impurity control research,and it is of great significance to establish a comprehensive,scientific,and easy-to-operate impurity control analysis method for Cefditoren Pivoxil.On the basis of this concept,combined with the production process and chemical structure,the potential impurities of cefditoren pivoxil were analyzed,and a relatively comprehensive impurity control method was studied according to the potential organic impurities and inorganic impurities and could provide basis for standard and quality control strategies.This thesis consists of following four parts.（1）Related substances The detection method of related substances of cefditoren pivoxil has been established,which can separate at least 18 potential impurities（including process impurities and degradation impurities）,and has carried out a comprehensive methodological verification.Combined with API chemical structure,synthetic process route and strong degradation test results,the source of impurities was analyzed.（2）Residual solvents Analysis of the solvents used in the synthesis process of cefditoren pivoxil found that the common solvents are methanol,ethanol,acetone,dichloromethane,ethyl acetate,n-hexane,isopropyl ether,N,N-Dimethylformamide.According to the study of solvent properties,the internal standard method of GC headspace injection and the external standard method of direct injection were established,which were used to detect low-boiling solvents and high-boiling solvents,and the methods were validated.（3）Elemental impurities According to the requirements of ICH Q3D,it is necessary to adopt more reliable methods to detect the residual amount of elemental impurities in medicines,especially those with higher toxicity,to ensure the safety of medicines.Due to the chromium catalyst was used in the synthesis process,it should be studied this elemental impurity with a limit of 8.3ppm.Using advanced inductively coupled plasma mass spectrometer,a high-sensitivity quantitative analysis method for element "chromium" was established and the method was verified,which solved the problem of poor specificity of conventional heavy metal inspection items and inaccurate quantification of dangerous heavy metals.（4）Genotoxic impurities According to the requirements of ICH M7,the structure of potential impurities was analyzed in combination with the process route.It was found that iodomethyl pivalate,methyl benzene sulfonate,and ethyl benzene sulfonate have genotoxic warning structures,which need to be followed by genes.Toxic impurities are controlled.The research established a high-sensitivity conventional gas-liquid chromatography method to detect genotoxic impurities,including gas chromatography,FID detector to detect iodomethyl pivalate and liquid chromatography,ultraviolet detector to detect methyl benzenesulfonate and benzene Ethyl benzenesulfonate,and method verification was carried out.