Study On Quality Standard Of Imatinib Mesylate API

Chronic myeloid leukemia(CML)is a common chronic leukemia.Environmental pollution is becoming more and more serious,the number of patients in China is growing rapidly.Imatinib mesylate(IM)is a tyrosine kinase inhibitor with antitumor activity,and it is produced by the combination of imatinib and mesylate.The trade name is Gleevec.CML is closely related to tyrosine kinase(TK),imatinib can specifically bind to the active site of BCR-ABL1 tyrosine kinase,inhibit the activation of multiple signal transduction pathways,prevent cancer cells growth and promote their Apoptosis.Because of low clinical toxicity and significant curative effect,IM is recognized as the first choice drug in the treatment of CML.At present,the United States has already put forward the draft related to the quality standards of imatinib mesylate APIs and tablets.The European Pharmacopoeia has included the imatinib mesylate APIs.In recent years,the market sales of imatinib mesylate in China has been increasing,however,the quality standard of imatinib mesylate has not been officially included in the Chinese Pharmacopoeia,and only enterprise standards and import standard are available.In this case,it is necessary to establish a unified quality standard for imatinib mesylate,and further perfect the 2020 edition of Chinese Pharmacopoeia to ensure drug safety.The main research contents and conclusions are as follows:(1)The physicochemical properties and structures of imatinib mesylate produced by two major domestic enterprises,CSPC and Haosen pharmaceutical,are studied.The main contents include appearance,solubility,melting point,acidity,UV absorption,X-ray diffraction and infrared spectrum.The results of X-ray diffraction and infrared spectrum show that imatinib mesylate produced by CSPC is β crystal type,and imatinib mesylate produced by Haosen Pharmaceutical is α crystal type.On the basis of these,the identification items of imatinib mesylate are established.(2)The impurities of imatinib mesylate produced by domestic enterprises are comprehensively analyzed and phase quality standards are established respectively.The main impurities include pyrimidine and nitropyrimidine,methyl methanesulfonate,ethyl methanesulfonate,isopropyl methanesulfonate,related substances,residual solvents,3-acetylpyridine and dimethylaminopyridone,N-methylpiperazine,mesylate,dimethylamine and palladium.The main contents are as follows: pyrimidine and nitropyrimidine are determined by LC-MS/MS,and nitropyrimidine is listed as potential genotoxic impurity for the first time;the method of headspace sampling and GC-MS are used to determine methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate;eight related substances in imatinib mesylate are determined by HPLC,and five new impurities are not reported in foreign pharmacopoeia;seven residual solvents,including methanol,ethanol,acetone,isopropanol,ethyl acetate,tetrahydrofuran and DMF,are determined by GC;HPLC method is used to determine3-acetylpyridine and dimethylaminopyridone;N-methylpiperazine is determined by GC with direct injection,avoiding the complicated operation of traditional derivation method;the contents of dimethylamine and methanesulfonic acid are determined by ion chromatography;the content of palladium is determined by atomic absorption spectrophotometry.The above impurities are verified by complete methodology.(3)In order to provide a basis for the future establishment of quality standards for similar drugs,the fragmentation mechanism of imatinib,dasatinib and nilotinib is studied.Methanol is used as a solvent,and a high-resolution linear ion trap equipped with an ESI source is used as a detector to obtain first-order and multi-stage mass spectrometry.The possible cracking process is analyzed.The potential impurities produced by the degradation of these three drugs are analyzed in combination with their respective synthetic processes.