Study on (Q)SAR Evaluation and Ames Test of Mutagenicity of Impurities in Ceritinib

OBJECTIVE To evaluate the genotoxicity(mutagenicity) of potential process impurities with warning structure in the synthetic process of ceritinib, so as to provide guidance and basis for the classification and control of related substances of ceritinib. METHODS Two complementary(quantitative) structure-activity relationships(Q)SAR evaluation systems(Derek and Sarah) based on expert knowledge rules and statistics were used to predict and classify the impurities in ceritinib. Ames test was then used to further verify the (Q)SAR positive impurities. RESULTS Derek prediction results for impurity 6(CAS:1032903-50-6), impurity 7(CAS:1032903-62-0) and impurity 13(CAS:1032903-63-1) were all positive, and were classified into Class 3 according to the ICH M7 guidelines. In Ames test, the number of revertant colonies of three impurity in the presence or absence of metabolic activation system S9 in the range of 22-1 800 μg per plate of test substance was less than 2 times of that in the solvent control group, and the test result was negative. CONCLUSION The bacterial mutation test results of impurity 6, impurity 7 and impurity 13 are all negative, which can overturn the doubts based on the structure, and these impurities can be controlled as Class 5 in ICH M7, which namely non mutagenic impurity.