Stability-indicative, validated, fast HPLC method for quantification of two genotoxic impurities in imatinib mesylate

The objective of the current study is to develop a validated, specific and stability-indicating reverse phase liquid chromatographic method for the quantitative determination of genotoxic impurities in the drug substance imatinib mesylate. This report includes a brief review of the toxicology of impurities in imatinib mesylate and the strategies used to set acceptance criteria for genotoxic impurities in imatinib mesylate. A preliminary examination of different approaches to determine genotoxic impurities in the drug substance imatinib mesylate susceptible to its presence either as residue from the synthesis or from degradation are described based on the toxicology studies. Controlling the impurities during drug development enhances product quality and minimizes risk with respect to safety to the patient. Recent regulatory guidance on genotoxic impurities require lower reporting, identification, and qualification limits but the overall impurity control strategy is also driven by appropriate “as low as reasonably practicable” (ALARP) procedures that include assessment of process capability and associated analytical development techniques. The bulk drug imatinib mesylate containing the two genotoxic impurities impurity-1 and impurity-2 are subjected to stress conditions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH)-prescribed stress conditions to show the stability-indicating power of the method. These two genotoxic impurities are also observed as degradation impurities during acid and base hydrolysis. The chromatographic conditions are optimized using an impurity-spiked solution and the generated samples are used for forced degradation studies. In the developed HPLC method, the resolution between impurity-1, impurity-2 of imatinib mesylate is found to be greater than 2. The chromatographic separation is achieved on a Develosil C8 UG-5 150 mm x 4.6 mm, 5-μm column. The HPLC method employed a linear gradient elution, and the detection wavelength is set at 240 nm. The developed HPLC method is validated with respect to linearity, accuracy, precision and robustness.