Optimization of LC-MS/MS Analytical Method for Trace Level Quantification of Potential Genotoxic Impurities in Siponimod Pure Drug and Formulations
Potential Genotoxic Impurities in Siponimod Pure Drug and Formulations
Abstract
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.
Keywords:
Alcohol impurity, Aldehyde impurity, Genotoxic impurities, LC-MS analysis, Pharmaceutical formulation
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References
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Reddy, C. S., Babu, C. N., Tatavarti, B. K., Vijaya, N., & Anna, V. R. (2023). Development of a stability-indicating HPLC method for Lasmiditan and its process related impurities with characterization of degradation products by LC-MS/MS. Journal of Chemical Metrology, 17(1), 52. http://doi.org/10.25135/jcm.89.2304.2767
Shaikh, F., Khan, S., Shaikh, A., Shivsharan, S., Lal, M., Sheikh, I. A., & Baig, M. S. (2024). Formulation and Evaluation of Ocusert Embeded with Ciprofloxacin Loaded Nanoparticles. International Journal of Advancement in Life Sciences Research, 7(1), 130-138. https://doi.org/10.31632/ijalsr.2024.v07i01.014
Shakeri-Nejad, K., Aslanis, V., Veldandi, U., Gardin, A., Zaehringer, A., Dodman, A., &Legangneux, E. (2017). Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. International Journal of Clinical Pharmacology and Therapeutics, 55(1), 41.https://doi.org/10.5414/CP202588
Varma, B. H. R., &Rao, B. S. (2023). Gas chromatography-head space-mass spectrometry sensor based quality control of dobutamine hydrochloride bulk material for a mutagenic impurity, 2-bromopropane. Res J Chem Environ, 27, 54-61. http://dx.doi.org/10.25303/2702rjce054061
Varma, R. B., &Rao, B. S. (2022). Gas Chromatography-Head Space-Flame Ionization Sensor based assessment of four residuary solvents in rivaroxaban bulk medication. Research Journal of Pharmacy and Technology, 15(11), 5158-5163. https://doi.org/10.52711/0974-360X.2022.00868
Wang, T., Yang, H., Yang, J., Guo, N., Wu, G., Xu, X., &An, M. (2022). Quantitative determination of four potential genotoxic impurities in the active pharmaceutical ingredients in TSD-1 using UPLC-MS/MS. Molecules, 27(13), 4129. https://doi.org/10.3390/molecules27134129
Bhupatiraju, R. V., Rao, B. S., Rao K. M. Venkata Narayana, & Reddy, M. V. (2022). A Novel Rivaroxaban Degradation Impurity Detection by Rp-HPLC, Extraction by Preparatory Chromatography, and Characterization By LCMS, NMR, and FT-IR: Analysis of Novel Impurity In Batch Samples and Tablets of Rivaroxaban. Rasayan Journal of Chemistry, 15(4). 2373-2381. https://doi.org/10.31788/RJC.2022.1547008
Dong W., Luo L., Peng Y. et al. (2022) Detection of Two Genotoxic Impurities in Drug Substance and Preparation of Imatinib Mesylate by LC–MS/MS, Chromatographia, 83, 821–828 https://doi.org/10.1007/s10337-020-03903-1
Ghasemi, N., Razavi, S., &Nikzad, E. (2017). Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. Cell Journal (Yakhteh), 19(1), 1.https://doi.org/10.22074/cellj.2016.4867
International council for harmonisation of technical requirements for pharmaceuticals for human use, ICH harmonised guideline, analytical procedure development, Q14, 2022
Kappos, L., Bar-Or, A., Cree, B., Fox, R., Giovannoni, G., Gold, R., ...& Wallström, E. (2014). Siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis: Design of the phase 3 EXPAND trial. Multiple Sclerosis and Related Disorders, 3(6), 752.https://doi.org/10.1016/j.msard.2014.09.185
Kethipalli A, Ramachandran, D (2022). New method for the simultaneous estimation of siponimod and ponesimod by using ultra performance liquid chromatographic system in active pharmaceutical ingredient form, YEMR, 21(2), 571-584.https://doi.org/10.37896/YMER21.02/56
Khalil, H. A., Hassanein, N. A., & El-Yazbi, A. F. (2023). Recent analytical methodologies for the determination of anti-COVID-19 drug therapies in various matrices: A critical review. RSC Advances, 13(19), 13224-13239. https://doi.org/10.1039/D3RA00654A
Kundu, D., & Halder, K. (2024). Signaling Pathway Governed by Lipid Derived Molecules as Secondary Messenger. International Journal of Advancement in Life Sciences Research, 7(1), 1-14. https://doi.org/10.31632/ijalsr.2024.v07i01.001
Li, W., Luo, S., Smith, H. T., & Francis, L. S. (2010). Quantitative determination of BAF312, a S1P-R modulator, in human urine by LC–MS/MS: prevention and recovery of lost analyte due to container surface adsorption. Journal of Chromatography B, 878(5-6), 583-589. https://doi.org/10.1016/j.jchromb.2009.12.031
Menz, J., Götz, M. E., Gündel, U., Gürtler, R., Herrmann, K., Hessel-Pras, S., Kneuer, C., Kolrep, F., Nitzsche, D., Pabel, U., Sachse, B., Schmeisser, S., Schumacher, D. M., Schwerdtle, T., Tralau, T., Zellmer, S., &Schäfer, B. (2023). Genotoxicity assessment: Opportunities, challenges and perspectives for quantitative evaluations of dose-response data. Archives of Toxicology, 97(9), 2303–2328.https://doi.org/10.1007/s00204-023-03553-w
Pan, S., Gray, N. S., Gao, W., Mi, Y., Fan, Y., Wang, X., & Nuesslein-Hildesheim, B. (2013). Discovery of BAF312 (Siponimod), a potent and selective S1P receptor modulator. ACS medicinal chemistry letters, 4(3), 333-337. https://doi.org/10.1021/ml300396r
Patel, A. B., Asnani, A. H., Vyas, A. J., Patel, N. K., Patel, A. I., & Lumbhani, D. A. N. (2021). A brief review on genotoxic impurities in pharmaceuticals. Asian Journal of Pharmaceutical Research, 11(3), 187-193. https://doi.org/10.52711/2231-5691.2021.00034
Piponski, M., Stoimenova, T. B., Melnyk, T., Kovalenko, S., Todevska, E. L., Velkovski, M., Deeb, S. E., Mysula, Y., & Logoyda, L. (2022). Concepts for new rapid simple HPLC method for quantification of fosfomycintrometamol in pharmaceutical dosage forms with direct UV detection. Scientia Pharmaceutica, 90(2), 35. https://doi.org/10.3390/scipharm90020035
Raman, N. V. V. S. S., Prasad, A. V. S. S., & Reddy, K. R. (2011). Strategies for the identification, control and determination of genotoxic impurities in drug substances: A pharmaceutical industry perspective. Journal of pharmaceutical and biomedical analysis, 55(4), 662-667.https://doi.org/10.1016/j.jpba.2010.11.039
Reddy, A. V. B., Jaafar, J., Umar, K., Majid, Z. A., Aris, A. B., Talib, J., &Madhavi, G. (2015). Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review. Journal of Separation Science, 38(5), 764-779. https://doi.org/10.1002/jssc.201401143
Reddy, C. S., Babu, C. N., Tatavarti, B. K., Vijaya, N., & Anna, V. R. (2023). Development of a stability-indicating HPLC method for Lasmiditan and its process related impurities with characterization of degradation products by LC-MS/MS. Journal of Chemical Metrology, 17(1), 52. http://doi.org/10.25135/jcm.89.2304.2767
Shaikh, F., Khan, S., Shaikh, A., Shivsharan, S., Lal, M., Sheikh, I. A., & Baig, M. S. (2024). Formulation and Evaluation of Ocusert Embeded with Ciprofloxacin Loaded Nanoparticles. International Journal of Advancement in Life Sciences Research, 7(1), 130-138. https://doi.org/10.31632/ijalsr.2024.v07i01.014
Shakeri-Nejad, K., Aslanis, V., Veldandi, U., Gardin, A., Zaehringer, A., Dodman, A., &Legangneux, E. (2017). Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. International Journal of Clinical Pharmacology and Therapeutics, 55(1), 41.https://doi.org/10.5414/CP202588
Varma, B. H. R., &Rao, B. S. (2023). Gas chromatography-head space-mass spectrometry sensor based quality control of dobutamine hydrochloride bulk material for a mutagenic impurity, 2-bromopropane. Res J Chem Environ, 27, 54-61. http://dx.doi.org/10.25303/2702rjce054061
Varma, R. B., &Rao, B. S. (2022). Gas Chromatography-Head Space-Flame Ionization Sensor based assessment of four residuary solvents in rivaroxaban bulk medication. Research Journal of Pharmacy and Technology, 15(11), 5158-5163. https://doi.org/10.52711/0974-360X.2022.00868
Wang, T., Yang, H., Yang, J., Guo, N., Wu, G., Xu, X., &An, M. (2022). Quantitative determination of four potential genotoxic impurities in the active pharmaceutical ingredients in TSD-1 using UPLC-MS/MS. Molecules, 27(13), 4129. https://doi.org/10.3390/molecules27134129
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Vaka, P., Rao, B., Bharathi, N., & Rekha, K. (2024). Optimization of LC-MS/MS Analytical Method for Trace Level Quantification of Potential Genotoxic Impurities in Siponimod Pure Drug and Formulations. International Journal of Advancement in Life Sciences Research, 7(2), 81-91. https://doi.org/https://doi.org/10.31632/ijalsr.2024.v07i02.006
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