Study On Genotoxic Impurities In Api Bosutinib

Genotoxic impurities are DNA-reactive substances that can cause DNA damage,mutation and cancer at low concentrations.Recently,the research on genotoxic impurities in new drugs has attracted extensive attention from pharmaceutical enterprises and governments from around the world,because of its great potential danger to human body.Therefore,in this paper,we selected Bosutinib,which is a new drug of choice for the treatment of chronic myelocytic leukemia(CML),as the research object to study its genotoxic impurities based on the regulations and guidelines of the European Medicines Agency(EMA)and the Food and Drug Administration(FDA).The possible genotoxic impurities was being analyzed,synthesized and characterized.Firstly,based on the current industrial synthetic routes,the probable genotoxic impurities in the starting materials and in each reaction steps are analyzed and studied,according to the ICH M7 evaluation and control of DNA reactivity(mutagenicity)impurities in drugs to limit the warning structural fragments or groups listed in the potential cancer risk.The results showed that halogenated alkanes,aniline and nitrobenzene groups as warning structures were usually used as raw materials for the production process of Bosutinib.So the related by-products,the related intermediates and the residues in the starting materials and all synthesis route were regarded as genotoxic impurities.Studies of the transfer,transformation and removal of these impurities should be carried out in the subsequent processes if these impurities were detected.Then,the genotoxic impurities in the seven chemical reaction steps of Bosutinib were synthesized and characterized.We successfully synthesized 5 warning structural impurities in intermediate-1,3 warning structural impurities in intermediate-2,3 warning structural impurities in intermediate-3,4 warning structural impurities in intermediate-1,8 warning structural impurities in intermediate-5 and 2 warning structural impurities in API.They were well characterized by NMR and MS.In summary,the warning structural impurities involved in each steps of Bosutinib were systematically studied.All impurities were synthesized and characterized,which structures were identified.These studies provide theoretical and technical support for further study of the quality standard and potential risk of Bosutinib.