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As a potential DNA damaging substance, genotoxic impurities have been concerned by regulatory authorities in various countries. Two genotoxic impurities were found in imatinib mesylate which was a classical small molecule inhibitor of tyrosine kinase, and the analysis method has never been reported. A LC–MS/MS method was developed for the analysis...
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... Application of the method to formulations successfully identified and quantified genotoxic impurities, showcasing its suitability for quality control purposes. Overall, the developed method offers a reliable and sensitive approach for the analysis of alcohol and aldehyde impurities alongside siponimod, ensuring product safety and quality in pharmaceutical formulations (Dong et al. 2022). ...
The generation of single or multiple genotoxic impurities during synthesis of siponimod should be avoided for production of safe formulation. Technically, complete elimination of genotoxic impurities was not possible and hence there is a need to propose an accurate method for trace level detection of genotoxic impurities.Method optimization studies were conducted by analysis standard solution in various method parameters. The results noticed in every varied method condition were tabulated for finalizing the appropriate conditions for analyzing siponimod. The optimized method consists of waters C18 (150 × 4.6 mm; 5 μm) column, ammonium acetate (0.02M) at pH 4.2 (fixed with 1 % formic acid) and methanol in 45:55 (v/v) at 0.5 mL/min flow rate. The mass analyser was operated in multiple reaction positive ion mode with characteristic mass transition at m/z of 517 (parent ion)and 213 (product ion) for siponimod, 434(parent ion) and 173 (product ion)for alcohol and 432(parent ion) and172 (product ion)for aldehyde impurity. No impurity or unwanted compounds detected in both LC chromatograms and mass spectra, confirming the method specificity.Validation of method for parameters including linearity, precision, recovery, ruggedness, and robustness yielded acceptable results. The method is suitable for assessing potential genotoxic impurities during the synthesis of siponimod and the manufacturing of pharmaceutical products.
... GTIs are usually compounds that can directly or indirectly damage cell DNA, produce gene mutations or in vivo mutagenesis, and have the possibility or tendency to cause cancer [4]. GTIs mainly come from starting materials, intermediates, reagents, and reaction byproducts in the process of APIs synthesis [5,6]. In addition, drugs may degrade to produce such impurities during synthesis, storage, or preparation [7,8]. ...
To promote the quality control of midazolam and ensure the life safety of patients, a sensitive and simple ultra-high performance liquid chromatography–mass spectrometry (UPLC–MS/MS) method was developed for the trace determination of two potential genotoxic impurities (PGIs) in midazolam raw materials under the positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM). The two PGIs were well separated in a gradient elution mode at a 0.4 mL/min flow rate on an ACQUITY UPLC BEH C18 column (2.1 mm × 100 mm, 1.7 µm) that was maintained at 40 °C. 0.01 mol/L ammonium formate aqueous solution (0.1% formic acid) and acetonitrile (0.1% formic acid) were mobile phase A and mobile phase B, respectively. The m/z of 343.00/123.00 for PGI-1and m/z of 331.20/301.20 for PGI-2 were detected in a triple quadrupole mass detector. The calibration curves showed that the two PGIs have good linearity between the concentration range of 0.004 and 0.8 ppm. The correlation coefficients of PGI-1 and PGI-2 were 0.9996 and 0.9998, respectively. The recoveries of the two PGIs at three concentration levels were in the range of 81–103%. The limits of quantification (LOQ) for PGI-1 and PGI-2 were 0.0545 and 0.0111 ng/mL respectively. The precision relative standard deviation (RSD) of each impurity was observed less than 3.0%. Method validation results indicated that the linearity, accuracy, precision, and sensitivity of the developed UPLC–MS/MS method are satisfactory. Thus, the method can quantitatively detect the two trace PGIs in midazolam. This study can provide a reference for manufacturers and relevant researchers of midazolam, reduce the quality risk of midazolam drugs and ensure the safety of patients.
Erdafitinib is a potent and selective tyrosine kinase receptor inhibitor used to treat advanced or metastatic urothelial carcinoma. The purpose of this study is to explore the degradation behavior of erdafitinib when exposed to various stress conditions as per ICH, along with its compatibility with various excipients under accelerated stability conditions. The degradation and interaction products formed under various conditions were separated using phenomenix Gemini C18 column (250 × 4.6 mm; 5 μm) with 10 mM ammonium acetate (pH 4.50) buffer and methanol as mobile phase in gradient elution mode at a flow rate of 1 mL/min. Erdafitinib was found to be labile in hydrolytic, photolytic and oxidative stress conditions. It was also found to be incompatible with polyethylene glycol-4000, polyvinyl pyrrolidone-K30, crospovidone and carboxymethylcellulose when exposed to accelerated stability conditions. A total of eight novel degradation products and one interaction product were generated. LC-Q TOF-MS/MS studies were conducted to propose the structures of degradation and interaction products formed by comparing with the fragmentation pattern of the drug. NMR study was also conducted to confirm the chemical structures of two degradation products (DP7 and DP8). Subsequently, the degradation pathway of erdafitinib was also laid down. Further, in silico toxicity and mutagenicity data was generated using DEREK and Sarah software. DP1, DP4, DP5, DP6, DP7 and DP9 show mutagenicity as endpoint.
A systematic literature survey published in several journals of pharmaceutical chemistry and of chromatography used to analyze impurities for most of the drugs that have been reviewed. This article covers the period from 2016 to 2020, in which almost of chromatographic techniques have been used for drug impurity analysis. These chromatography techniques are important in the analysis and description of drug impurities. Moreover, some recent developments in forced impurity profiling have been discussed, such as buffer solutions, mobile phase, columns, elution modes, and detectors are highlighted in drugs used for the study. This primarily focuses on thorough updating of different analytical methods which include hyphenated techniques for detecting and quantifying impurity and degradation levels in various pharmaceutical matrices.
In the past few decades impurity profiling has continuously gained the attention of regulatory bodies due to the rise in the number of drugs frequently entering the market. International regulatory agencies like ICH, FDA, Canadian Drug and Health Agency emphasize carrying out impurity profiling of drugs in strict compliance with the regulatory guidelines that have been laid down intending to ensure production of high quality and safe pharmaceutical drugs to serve mankind. Simple impurities can be easily evaluated by conventionally available methods whereas impurities present within complex matrix structure pose significant challenges to the analyst and require a more sophisticated approach. The work has been carried out with great efforts to make the study possible distinctively and comprehensively.
