Isolation, Characterization, and Structural Assessment of Novel Isomeric Dimer Impurities Discovered During the Manufacture of Lapatinib Ditosylate Using Preparative HPLC, HRMS, and NMR Techniques

ABSTRACT Lapatinib is a tyrosine kinase inhibitor primarily employed in the treatment of breast cancer; the compound is typically available as a ditosylate salt to enhance its solubility and stability. It is specifically designed to target the epidermal growth factor receptor and the human epidermal growth factor receptor 2. The synthesis of lapatinib ditosylate has multiple stages, commencing with the generation of intermediate molecules that are progressively assembled to provide the final product. Essential phases involve the incorporation of fluorine and chlorine atoms, which are vital for the drug's binding affinity and specificity. During the manufacture of the drug substance, two significant unknown impurities have been detected, beyond the control limits established by regulatory guidelines. Due to the harmful nature of impurities, regulatory agencies are rigorous and prompt in assessing the characteristics and chemical interactions of any unidentified impurity found during manufacturing, forced degradation, or shelf‐life stability studies. The present study concentrates on employing LCMS for identification and flash chromatography and preparative HPLC for isolation; the structures of the impurities were conclusively assessed using HRMS and NMR. The distinctive unknown impurities were identified as novel impurities of the drug substance, conclusively established as dimers of Lapatinib base, possessing the identical molecular formula C 58 H 50 Cl 2 F 2 N 8 O 8 S 2 , a molecular weight of 1160.10 g per mole, differing solely in their chiral centers, thus classified as isomers of one another.