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Development and validation of UPLC‐MS/MS method for the determination of genotoxic impurities in Ceritinib active pharmaceutical ingredient

Potential genotoxic impurities (PGIs) are impurities that have a structural alert related to genotoxicity, whereas genotoxic impurities (GTIs) are PGIs that were proved to be genotoxic during toxicological assessment [1]. Both pharmaceutical industries and regulatory agencies have recognized the importance of GTIs in human health and regulatory issues related to the presence of GTIs in new drug formulations have been released in the last decade by the European Medicines Agency and U.S. Food and Drug Administration. Current regulatory issues are also included in the Pharmaceutical Research and Manufacturing Association. Threshold of Toxicological Concern was established and refers to a threshold exposure level of 1.5 μg/day, which is considered to be associated with an acceptable risk. Ceritinib (Figure 1) is a molecule that acts as an inhibitor of anaplastic lymphoma kinase (ALK) [2]. This pharmaceutical is therefore used to treat a specific type of lung cancer. Based on the maximum daily dosage of ceritinib (750 mg), the estimated permitted level of these impurities in ceritinib API is 2 ppm/day. In this work, an accurate, selective, precise and robust method was developed and validated for the quantitative determination of four genotoxic impurities in ceritinib by high performance liquid chromatography – tandem mass spectrometry (HPLC‐MS/MS). Method was linear for four analyzed impurities in the range from 0.5 ng mL–1 to100 ng mL–1, with detection and quantification limits of 0.5 ng mL–1 and 1 ng mL– 1, respectively.

Ceritinib, genotoxic impurities ; UPLC-MS/MS

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