Degradation kinetic study ascertains the shelf life of drugs under different environmental conditions. It can facilitate the prediction of specific critical factors that can affect the quality of pharmaceuticals during storage. To date, general systematic strategies for performing degradation kinetics of drugs have not been discussed in any literature. Moreover, no regulatory guideline is available on the degradation kinetic study of pharmaceuticals. Owing to this, the kinetic behavior of drugs is not being analyzed uniformly. This article provides a detailed insight into degradation kinetic approaches including criticality in selecting different variables for the study. Factors that can affect the quality of degradation kinetic study data have been critically discussed. In addition, a systematic strategy to perform degradation kinetic study with advanced degradation models has been discussed. This article will be helpful for the researcher working in the field of stability analysis and guide to select a logical path for determining the kinetic behavior of drugs. High-quality degradation kinetic data through the properly designed study will help to establish accurate storage conditions of pharmaceuticals. This article is unique and novel of its kind and would have a significant contribution to the field of stability analysis.
Rationale
Capmatinib (CMT) has been recently approved for the treatment of non‐small cell lung cancer by the United States Food and Drug Administration (USFDA). Till date, the degradation mechanism of CMT in different stress conditions is not known. Moreover, degradation products (DPs) of the drug are yet to be identified. Characterization study on degradation products of CMT has not been reported before. Furthermore, no previously reported literature is available on the stability‐indicating method of CMT.
Methods
Owing to the lack of such scientific reports, we developed a sensitive, stability‐indicating method for CMT which can resolve it from all its degradation products. The method was validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH Q2 [R1]) guideline. We studied and established the degradation mechanism of CMT in different stress conditions. One degradation product (DP2) was isolated and characterized using 1H NMR.
Results
The degradation products (DP1, DP2 and DP3) of the drug have been identified and characterized for the first time by using high‐resolution mass spectrometry and 1H NMR spectroscopy. CMT was found to become degraded under acidic, basic and photolytic stress conditions in the solution phase to yield three major DPs. The drug was found to be stable in neutral hydrolysis, oxidation and thermal stress conditions.
Conclusions
DP1 was formed under acidic and basic hydrolytic conditions, whereas DP2 and DP3 were formed under photolytic conditions. Characterization of all the DPs has been carried out to establish their structures and understand the molecular mechanism behind the degradation of the drug. Few studies reported quantitative analysis of CMT and its metabolites in biological fluids. However, this is the first study to identify the unknown DPs of CMT and the mechanism of its degradation. Moreover, this article reports a stability‐indicating analytical method for CMT which has not yet been reported in any literature.
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