Delineation of prototypical degradation mechanism, characterization of unknown degradation impurities by liquid chromatography-quadrupole-time-of-flight-tandem mass spectrometry and stability-indicating analytical method of selumetinib.

Selumetinib (SELU) was recently approved by the US Food and Drug Administration (US FDA) in 2020. However, the degradation impurities of SELU have not been characterized or identified to date. The mechanism for impurity formation and the degradation behavior have not been previously studied. This study aims to elucidate the prototypical degradation mechanism of SELU. Furthermore, the degradation impurities have been identified using LC-quadrupole-time-of-flight tandem mass spectrometry and are reported in this article for the first time. In addition, a stability-indicating analytical method (SIAM) has been developed for this drug. Forced degradation studies revealed the degradation of SELU under various stress conditions, including hydrolytic stress (acid and base), oxidative stress, and photolytic stress (ultraviolet and visible). Three degradation impurities were identified. This article presents the first validated SIAM, capable of accurately quantifying SELU in the presence of its degradation impurities. Furthermore, we have proposed the degradation pathway for SELU and its degradation impurities, a first in the field. The developed SIAM can find applications in process development and quality assurance of SELU in both research laboratories and pharmaceutical industries. Moreover, the identified degradation impurities may serve as impurity standards for quality control testing in pharmaceutical industries.

Metabolite profiling of IMID-2, a novel anticancer molecule of piperazine derivative: In silico prediction, in vitro and in vivo metabolite characterization using UPLC-QTOF-MS/MS.

IMID-2, a newly identified piperazine-based anticancer molecule, has been shown to be cytotoxic against various cancer cell lines. The primary aim of this research was to identify and characterize possible metabolites of the molecule formed during biotransformation. A metabolite identification study was first executed using an in silico tool to predict the possible metabolism sites of IMID-2. Thereafter, metabolites generated in vitro (rat liver microsomes, rat S9 fractions and human liver microsomes) and in vivo (rat plasma, urine and feces) were identified and characterized employing UPLC-QTOF-MS/MS. A total of eight metabolites, among which were six in phase I and two in phase II reactions, were recognized. The plausible structure of the metabolites and probable metabolic pathway have been established based on the mass fragmentation pattern, mass ppm error, ring double bond calculation and nitrogen rule. The majority of phase I metabolites were generated by N-oxidation, hydroxylation, oxidative deamination followed by reduction, oxidative dechlorination, N-dearylation, and N-dealkylation. Glucuronidation played a significant role in the formation of phase II metabolites of the molecule.