Determination Of Trace Level Of Geno Toxic Impurities In Two Drugs By LC-MS/MS And GC-MS

Genotoxic impurity is a kind of impurity that needs the most stringent control,which would cause directly or indirectly damage to DNA.The detection and control of trace genotoxic impurity in drugs are a hot topic recently in drug analysis.In this thesis,the modern analytical techniques LC-MS/MS and GC-MS are used to study and establish the detection methods of trace genotoxic impurities in two drugs for ensuring the safety and reliability of the medicine.The first part of the thesis develops a new HPLC-MS/MS method for the determination of trace genotoxic impurity N,N-dimethylaniline in flucytosine.Based on the analysis method of flucytosine in Chinese Pharmacopoeia,the mobile phase is adjustd to suit the liquid chromatography-mass spectrometry.Meanwhile,the study investigated and selected the mass spectrometry parameters such as ion detection and collision energy with electrospray ionization source(ESI),positive ion acquisition mode,MRM multi-reaction monitoring mode and established the methodology validation.The method is specific and sensitive.The second part destablishes a HPLC-MS/MS method for determination of trace genotoxic impurity methyl p-toluenesulfonate in two kinds of crystal forms of clopidogrel hydrogen sulfate.The experimental conditions,such as the mobile phase,ion source parameters and the collision energy,were studied and optimized.Then the methodology validation was established.The method is proved to be sensitive,accurate and reliable.The third part researches the GC-MS method determination of trace genotoxic impurity dimethyl sulfate in two kinds of crystal forms of clopidogrel hydrogen sulfate.According to the properties of dimethyl sulfate,the gas chromatography-mass spectrometry was selected with electron impact ion source and SIM acquisition mode.The diluent injection temperature were studied and selected so that dimethyl sulfate would not decompose during the experiment.Last the methodology validation was established providing technical support for the detection of dimethyl sulfate in clopidogrel hydrogen sulfate.