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Characterization of Loratadine API and Simultaneous Quantification of Seven Potential Genotoxic Nitrosamine Impurities in Single Method by LC-MS/MS in Loratadine API and its Dosage Forms
Corresponding Author(s) : Gudibanda Chandrasekhar Reddy
Asian Journal of Chemistry,
Vol. 34 No. 6 (2022): Vol 34 Issue 6
Abstract
Active pharmaceutical ingredients (APIs) of loratadine were characterized using spectroscopic methods such as infrared spectroscopy, mass spectroscopy, differential scanning calorimetry (DSC), 1H NMR, 2D nuclear magnetic resonance (2D-NMR) and 13C NMR. Nitrosamine impurities, which are considered under concern cohort according to the S2 FDA and ICH M7 guidelines, are highly genotoxic and their trace-level quantity must be controlled in drugs for safe human consumption. In this study, an ultra-sensitive, rapid and simple LC-MS/MS technique is developed to detect seven nitrosamine impurities (N-nitroso dimethylamine (NDMA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso diethylamine (NDEA), N-nitroso ethyl isopropylamine (NEIPA), N-nitroso diisopropylamino (NDIPA), N-nitroso methyl phenylamine (NMPA) and N-nitroso dibutylamine (NDBA) in loratadine drug) with potential genotoxicity. Chromatographic separation was attained by employing the Zorbax SB C18 of 150 × 3 mm and a column of 3.5 µ with 0.1% formic acid in water and methanol as mobile phases A and B, respectively. At the total run time of 20 min, the flow rate was 0.3 mL/min in the gradient mode of elution. Through multiple reaction monitoring (MRM), all the seven nitrosamine impurities were successfully ionized and then quantified in the positive mode of atmospheric pressure chemical ionization (APCI). The method was validated according to the ICH guidelines by estimating quantification and detection limits. For all the seven nitrosamine impurities, the method provided excellent S/N ratios with a high linearity range of 0.8-5.30 ppm for loratadine sample concentrations with a regression coefficient of >0.99. The recovery for the method was established with a protocol of three-step sample preparation and was satisfactory within 15-115%. The proposed method can be employed for the routine detection of nitrosamines in loratadine APIs and its doses.
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- M.K. Church and D.S. Church, Indian J. Dermatol., 58, 219 (2013); https://doi.org/10.4103/0019-5154.110832
- United States Department of Health and Human Services, Food and Drug Administration, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches. United States Department of Health and Human Services, Food and Drug Administration, Silver Spring (2008).
- ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, European Medicines Agency, London (2017).
- S.S. Mirvish, Toxicol. Appl. Pharmacol., 31, 325 (1975); https://doi.org/10.1016/0041-008X(75)90255-0
- W.A. Mitch and D.L. Sedlak, Environ. Sci. Technol., 36, 588 (2002); https://doi.org/10.1021/es010684q
- U.S. Food and Drug Administration, FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan) (2019).
- European Medicines Agency, EMA 643116. EMA Review of Impurities in Sartan Medicines. EMA/643116/2018, European Medicines Agency, London (2018).
- U.S. Food and Drug Administration, Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry. U.S. Food and Drug Administration, Silver Spring (2021).
- U.S. Food and Drug Administration, Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of Six Nitrosamine Impurities in ARB Drugs. U.S. Food and Drug Administration, Silver Spring (2019).
- U.S. Food and Drug Administration, Liquid ChromatographyElectrospray Ionization-High Resolution Mass Spectrometry (LC-ESIHRMS) Method for the Determination of Nitrosamine Impurities in Metformin Drug Substance and Drug Product. U.S. Food and Drug Administration, Silver Spring (2020).
- Chemisches Und Veterinaruntersuchungsamt Karlsruhe, Test Method for the Determination of NDMA by LC/MS/MS in Valsartan Finished Products. Chemisches Und Veterinaruntersuchungsamt Karlsruhe, Karlsruhe (2018).
- C. Ripolles, E. Pitarch, J.V. Sancho, F.J. López and F. Hernández, Anal. Chim. Acta, 702, 62 (2011); https://doi.org/10.1016/j.aca.2011.06.024
- J.B. Cohen and J.D. Bachman, IARC Sci. Publ., 357 (1978).
- W. Wang, J. Hu, J. Yu and M. Yang, J. Environ. Sci., 22, 1508 (2010); https://doi.org/10.1016/S1001-0742(09)60281-3
- Validation of Analytical Procedures Methodology in Proceedings of International Conference on Harmonization, ICH Guidelines Q2B, . Rockville, USA, pp. 1-10 (1996).
References
M.K. Church and D.S. Church, Indian J. Dermatol., 58, 219 (2013); https://doi.org/10.4103/0019-5154.110832
United States Department of Health and Human Services, Food and Drug Administration, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches. United States Department of Health and Human Services, Food and Drug Administration, Silver Spring (2008).
ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, European Medicines Agency, London (2017).
S.S. Mirvish, Toxicol. Appl. Pharmacol., 31, 325 (1975); https://doi.org/10.1016/0041-008X(75)90255-0
W.A. Mitch and D.L. Sedlak, Environ. Sci. Technol., 36, 588 (2002); https://doi.org/10.1021/es010684q
U.S. Food and Drug Administration, FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan) (2019).
European Medicines Agency, EMA 643116. EMA Review of Impurities in Sartan Medicines. EMA/643116/2018, European Medicines Agency, London (2018).
U.S. Food and Drug Administration, Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry. U.S. Food and Drug Administration, Silver Spring (2021).
U.S. Food and Drug Administration, Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of Six Nitrosamine Impurities in ARB Drugs. U.S. Food and Drug Administration, Silver Spring (2019).
U.S. Food and Drug Administration, Liquid ChromatographyElectrospray Ionization-High Resolution Mass Spectrometry (LC-ESIHRMS) Method for the Determination of Nitrosamine Impurities in Metformin Drug Substance and Drug Product. U.S. Food and Drug Administration, Silver Spring (2020).
Chemisches Und Veterinaruntersuchungsamt Karlsruhe, Test Method for the Determination of NDMA by LC/MS/MS in Valsartan Finished Products. Chemisches Und Veterinaruntersuchungsamt Karlsruhe, Karlsruhe (2018).
C. Ripolles, E. Pitarch, J.V. Sancho, F.J. López and F. Hernández, Anal. Chim. Acta, 702, 62 (2011); https://doi.org/10.1016/j.aca.2011.06.024
J.B. Cohen and J.D. Bachman, IARC Sci. Publ., 357 (1978).
W. Wang, J. Hu, J. Yu and M. Yang, J. Environ. Sci., 22, 1508 (2010); https://doi.org/10.1016/S1001-0742(09)60281-3
Validation of Analytical Procedures Methodology in Proceedings of International Conference on Harmonization, ICH Guidelines Q2B, . Rockville, USA, pp. 1-10 (1996).