Abstract
A rapid and sensitive LC-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative analysis of four potential genotoxic impurities Imp-A (2-chloro-5-nitroaniline), Imp-B (1-chloro-2-iodo-4-nitrobenzene), Imp-C (1-(2-chloro-5-nitrophenyl)ethan-1-one) and Imp-D (2-chloro-5-nitrobenzoic acid) in Vismodegib API drug sample. This trace analysis was achieved on CSH C18, 15.0 cm x 3.0 mm, 1.7 micron column maintained at 45°C. Optimal mobile phase consisted of 0.05% formic acid in water was used as mobile phase A and acetonitrile used as mobile phase B in gradient mode with the flow rate of 0.5 mL/min. The developed method had the short run time of 12 minutes. Quantification of four potential genotoxic impurities were carried out using mass detection with electrospray ionization in multiple reaction monitoring mode. The method was linear in the range of 0.03 ppm to 1.50 ppm for four potential genotoxic impurities with a correlation coefficient not less than 0.999. The recoveries were found satisfactory over the range between 96.67 and 106.90% for all selected impurities. The developed method was able to quantitate all four PGIs at a concentration level of 0.03 ppm (0.03 ppm with respect to 20 mg /mL Vismodegib).
Highlights
The Vismodegib is sulphar containing small molecule inhibitor of the Hedgehog signaling pathway
Vismodegib (Fig. 1), the active pharmaceutical ingredient in Erivedge [2] is the first inhibitor of the Hedgehog pathway to be approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) [3] and represents an important treatment option for patients where surgery is not recommended
Vismodegib drug substance and IMP-B was purchased from Chemieliva pharmaceutical and Sigma Aldrich, India respectively
Summary
The Vismodegib is sulphar containing small molecule inhibitor of the Hedgehog signaling pathway. This signalling regulates embryonic development, ensuring that tissues reach their correct size and location, maintain tissue polarity and cellular content [1]. The Hedgehog pathway is critical for regulating sebaceous gland and hair follicle development. Hedgehog signalling normally remains inactive in most adult tissues. Inappropriate reactivation of the Hedgehog pathway has been linked to several human cancers, most often caused by exposure to UV radiation. In basal cell carcinoma (BCC), abnormal Hedgehog pathway signalling is the key molecular driver of the disease and more than 90% of BCCs have abnormal activation of Hedgehog pathway signalling
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