DEVELOPMENT AND VALIDATION OF AN LC-MS/MS METHOD FOR NITROSAMINE IMPURITY DETECTION IN TAMSULOSIN HYDOCHLORIDE
DOI:
https://doi.org/10.22159/ijap.2025v17i2.52810Keywords:
Fragment ion, Tamsulosin, Nitrosamine impurities, APCI ( ve)Abstract
Objective: Regulatory oversight of pharmaceuticals containing nitrosamine contaminants has intensified in the past few years. Unites States Food & Drug Administration (USFDA),European Medicines Agency (EMA) and other regulatory agencies has been quite proactive in sending out warnings, instructions, and safety messages.This study presents a fast, accurate, and selective way to detect and quantify nitrosamine contaminants in Tamsulosin HCl.
Methods: The purification of Tamsulosin using Di Methyl Formamide (DMF) requires monitoring to avoid nitrosamine formation. A 150 × 4.6 mm Symmetry® C18 column (5 µm, 40 ± 1°C) was used with a mobile phase involving water (98%),acetonitrile (2%) with 0.1% formic acid, where flow velocity was 0.8 mL/min and 10 µL injection volume. After 1.20 minutes, the mobile phase composition gradually changed to 90% B (acetonitrile) and 10% A (water). Chromatographic separation took 10 minutes with a 5 ± 0.5°C auto-sampler temperature. Atmospheric Presurre Chemical Ionization (APCI) in positive ion mode, with clustering potentials of 36–50 V and collision energy of 9–30 eV, was used for quantification.
Results: Following International Conference Harmonization (ICHQ2R1), showed regression value more than 0.997 and a signal-to-noise ratio of 3.7-4.5 ppm.Approach achieved Limit Of Detection (LOD) values over 3.3-12.7 ppm and Limit Of Quantification (LOQ) values over 9.9-36.9 ppm, with signal-to-noise ratios greater than 3.7% and greater than 12.9.All of the method recoveries fell between 80% and 120%.
Conclusion: This Liquid Chromatography with Tandem Mass Spectroscopy (LC-MS/MS) technology detects and quantifies nitrosamine impurities in Tamsulosin quickly, sensitively and specifically, assuring regulatory compliance pursuant to USP General chapter <1469>.Impurities in Tamsulosin can be detected at a minimum level using the current technology, which allows for regular analysis.
Downloads
References
United States Pharmacopoeia. General Chapter, Nitrosamine Impurities. USP-NF. Rockville, MD: United States Pharmacopoeia. 2022. https://doi.org/10.31003/uspnf_m15715_02_01
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. https://www.federal register.gov/d/E8-29674
Ru Hwu Jih, Balaachary Magendran, Subhasish K. Chakraborty, Asish R. Das, Shwu Chen Tsay, Kuen Wang Sheu, Chun Mei Shu, Chin Kun Lu, Wei Min Chang. Process for preparation of Tamsulosin and its derivatives. European patent EP1734036A1. 2005.
Guideline, I. H. "Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk M7." International conference on harmonization of technical requirements for registration of pharmaceuticals for human use (ICH): Geneva. 2014.https://doi.org/10.1002/9781119551249.ch2
Mirvish SS. Formation of N-Nitroso compounds: chemistry, kinetics, and in vivo occurrence. Toxicol Appl Pharmacol. 1975;31(3):325-51.https://doi.org/10.1016/0041-008X(75)90255-0
Mitch WA, Sedlak DL. Formation of N-nitrosodimethylamine (NDMA) from dimethylamine during chlorination. Environ Sci Technol. 2002;36(4):588-95. doi: 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). Silver Spring (MD): U.S. Food and Drug Administration; 2019.https://doi.org/10.1002/9781119551249.ch2
European Medicines Agency. Update on Review of Valsartan Medicines Following Detection of Impurity in Active Substance, EMA/485921/2018. European Medicines Agency, London.2018, EMA 485921.
European Medicines Agency.EMA Review of Impurities in Sartan Medicines. EMA/643116/2018, European Medicines Agency, London.2018, EMA 643116.
U.S. Food and Drug Administration. Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry. Silver Spring (MD): U.S. Food and Drug Administration; 2021. https://www.fda.gov/media/141720/download
Narendra Reddy Nadendla, Mounika M, Ranjithadubba VS, Jahnavi M, Sowjanya S, Yakshitha Y, Suresh P V, Morla SP. Development and verification of UV spectrophotometric technique for determining N-acetylcysteine in tablet formulations. Int J Pharm Pharm Sci. 2024 Jun 11;16(10):30-35. doi: 10.22159/ijpps.2024v16i10.51004.
Bari SB, Bakshi AR, Jain PS, Surana SJ. Application of UV-spectroscopy and first order derivative method for determination of Tamsulosin hydrochloride in bulk and tablets. Pharm Anal Acta. 2011;2(2):1-2.doi: 10.4172/2153-2435.1000120
Gadhave NA, Ghante MR, Nikam AD, Sawant SD. Simultaneous estimation of Tamsulosin hydrochloride and finasteride in combined dosage form by UV spectroscopy method. J Pharm Res. 2011;4(8):2672-4.
Puranik M, Shambharkar S, Nimbalkar S, Mahapatra DK. Comparison of UV-spectrophotometric and RP-HPLC meth¬ods for estimation of deflazacort in solid dosage form. J Appl Pharm Sci, 2020 Jul 4; 10(07):082-088.https://dx.doi.org/10.7324/JAPS.2020.10711
El-Henawee MM, Abd El-Hay SS, Attala K, Eissa MS. Smart UV spectrophotometric methods based on simple mathematical filtration and classical methods for the simultaneous determination of Tamsulosin and Solifenacin: A comparative study of efficacy and spectral resolution. Spectrochim Acta Part A Mol Biomol Spectrosc. 2021 Feb 15;247:119151.doi: 10.1016/j.saa.2020.119151. Epub 2020 Nov 4. PMID: 33188970.
Mhaske PD, Bohari BA, Chaudhari SR, Jain PS, Shirkhedkar AA. Implementation UV-spectrophotometry approach for determination of Tamsulosin HCl in tablets using area under curve technique. Asian J Pharm Anal. 2020 May 7;10(2):86-90.http://dx.doi.org/10.5958/2231-5675.2020.00015.0
Amanlou M, Moghadam AG, Tehrani MB, Souri E. Validated Spectrophotometric method for determination of Tamsulosin in bulk and pharmaceutical dosage forms. Iran J Pharm Res. 2014;13(1):81-6. PMID: 24734058; PMCID: PMC3985241.
Rezk MR, Tantawy MA, Wadie M, Weshahy SA. Smart spectrophotometric assessment of Tamsulosin hydrochloride and tadalafil in their new pharmaceutical formulation for treatment of benign prostatic hyperplasia and erectile dysfunction. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2020 Feb 15;227:117547.doi: 10.1016/j.saa.2019.117547. Epub 2019 Oct 12. PMID: 31734571.
Thimmaraju MK, Rao V, Gurrala S, Reddy GJ. UV spectrophotometric method for simultaneous determination of finasteride and Tamsulosin in combined dosage form. Int J Pharm Biol Sci. 2011;1(3):303-10.
Rani GD, Rao CN, Rao CN, Venkateswarlu P.Development and Validation of Ultraviolet-Spectrophotometric Method for the Determination of Tamsulosin. Indian J Adv Chem Sci. 2015;3(4):323-7.
Chandorkar JG, Kotwal VB, Dhande NS, Gurav SG, Pande VV, Yadav PV. A sensitive HPLC method for simultaneous estimation of Tamsulosin hydrochloride and its impurity. Pak J Pharm Sci. 2008 Jul 1;21(3).
Anusha T, Prasanthi R, Tirunagari M, Buggana SJ, Mitta C, Remidicherla SS. QbD-Driven Approach to Cleaning Method Development and Validation for Darunavir Analysis in Oral Films. Int J Pharm Qual Assur. 2024 Aug 31;15(3):1575-1580. doi: 10.25258/ijpqa.15.3.72
Jothula H, Navuluri S, Mulakayala NR. Stability based HPLC method for cyclophosphamide related substances in finished drug products: development and validation. Int J Curr Pharm Res. 2024 May 1;16(3):42-51. doi: 10.22159/ijcpr.2024v16i3.4061.
Sawant, V., C. Mali, and vandana jain. “Development And Validation Of Novel RP-HPLC Method For The Simultaneous Estimation Of Salicylic Acid And Beclomethasone Dipropionate In A Topical Ointment Dosage Form”. Asian J Pharm Clin Res.2024; 17 (1); 125-8.doi:10.22159/ajpcr.2024.v17i1.48682
Sangshetti JN, Chivte DK, Imran M, Mahaparale P. Development of HPLC method for determination of Tamsulosin using quality by design (QbD) approach. Eur Chem Bull. 2019;8(12):409-15. http://dx.doi.org/10.17628/ecb.2019.8.409-415
Kumari R, Dash PP, Lal VK, Mishra A, Murthy PN. RP–HPLC method for the estimation of Tamsulosin Hydrochloride in Tablet Dosage Form. Indian J Pharm Sci. 2010 Nov;72(6):785-7.doi: 10.4103/0250-474X.84596. PMID: 21969754.PMCID: PMC3178983.
Ding L, Li L, Tao P, Yang J, Zhang Z. Quantitation of Tamsulosin in human plasma by liquid chromatography–electrospray ionization mass spectrometry. J Chromatogr B. 2002 Feb 5;767(1):75-81.doi: 10.1016/s0378-4347(01)00546-1. PMID: 11863298.
Upreti R, Homer NZ, Naredo G, Cobice DF, Hughes KA, Stewart LH, Walker BR, Andrew R. Measurement of Tamsulosin in human serum by liquid chromatography–tandem mass spectrometry.J Chromatogr B. 2013 Jul 1;930:121-8.https://doi.org/10.1016/j.jchromb.2013.04.020
Mahajan B, Miniyar PB. Identification, separation, and characterization of degradation products of Triamcinolone hexacetonide using LC and LC-MS/MS. Int J Appl Pharm. 2024 Mar 1;16(3):326-331.https://doi.org/10.22159/ijap.2024v16i3.50122
Mohamed D, Mowaka S, Mostafa A. Simultaneous quantitative analysis of Tamsulosin and Finasteride in pharmaceutical dosage form by U-HPLC tandem mass spectrometry. Eur J Chem. 2014;5(1):181-5.https://doi.org/10.5155/eurjchem.5.1.181-185.942
Rao RN, Talluri MK, Raju AN, Shinde DD, Ramanjaneyulu GS. Development of a validated RP-LC/ESI-MS–MS method for separation, identification and determination of related substances of Tamsulosin in bulk drugs and formulations. J Pharm Biomed Anal. 2008;46(1):94-103.https://doi.org/10.1016/j.jpba.2007.09.009
Matsushima H, Takanuki KI, Kamimura H, Watanabe T, Higuchi S. Highly sensitive method for the determination of Tamsulosin hydrochloride in human plasma dialysate, plasma and urine by high-performance liquid chromatography–electrospray tandem mass spectrometry. J Chromatogr B Biomed Sci Appl.1997 Aug 1;695(2):317-27.https://doi.org/10.1016/s0378-4347(97)00200-4 PMID:9300868.
Ramakrishna NV, Vishwottam KN, Manoj S, Koteshwara M, Wishu S, Varma DP. Rapid, simple and highly sensitive LC-ESI-MS/MS method for the quantification of Tamsulosin in human plasma. Biomed Chromatogr. 2005 Dec;19(10):709-19. doi: 10.1002/bmc.498. PMID: 15828055.
Patel DB, Patel NJ. Validated stability indicating HPTLC method for the determination of Tamsulosin hydrochloride in pharmaceutical dosage forms. Int J Chem Tech Res. 2010 Jan;2(1):646-52.
Choudhari VP, Nikalje AP. Stability-indicating HPTLC method for the determination of Tamsulosin in pharmaceutical dosage forms. Chromatographia. 2009 Jun;69:1463-7.https://doi.org/10.1365/s10337-009-1060-9
El-Kimary EI, Khamis EF, Belal SF, Abdel Moneim MM. Novel Validated HPTLC Method for the Analysis of Two Binary Mixtures Containing Tamsulosin Hydrochloride with Antimuscarinic Agents. J Chromatogr Sci. 2018 Jan 1;56(1):81-91. doi: 10.1093/chromsci/bmx081. PMID: 28977351.
Patel DB, Patel NJ. Validated reversed-phase high-performance liquid chromatographic and high-performance thin-layer chromatographic methods for simultaneous analysis of Tamsulosin hydrochloride and dutasteride in pharmaceutical dosage forms. Acta Chromatogr. 2010 Sep 1;22(3):419-31.https://doi.org/10.1556/ACHROM.22.2010.3.6
Abou El-Alamin MM, Toubar SS, Mohamed DA, Helmy MI. Development of Green HPTLC method for simultaneous determination of a promising combination Tamsulosin and Mirabegron: stability-indicating assay was examined. BMC Chem. 2023 Sep 30;17(1):130.https://doi.org/10.1186/s13065-023-01043-9
Tuesuwan B, Vongsutilers V. Current threat of nitrosamines in pharmaceuticals and scientific strategies for risk mitigation. J Pharm Sci.2023 May 1;112(5):1192-209.doi: 10.1016/j.xphs.2023.01.028. Epub 2023 Feb 4. PMID: 36739905.
Chidella KS, Dasari VB, Anireddy J. Ultra-sensitive LC-MS/MS method for the trace level quantification of six potential genotoxic nitrosamine impurities in telmisartan. Am J Anal Chem. 2021 Jun 10;12(6):227-40.http://dx.doi.org/10.4236/ajac.2021.126014
Remidicherla SS, Chakravarthi G, Reddy AR, Rao GS. Method Development and Validation for quantification of Imatinib mesylate spiked In Vitro saliva by LC-MS/MS. Indian Drugs. 2024 Apr;61(4):46-56. doi:https://doi.org/10.53879/id.61.04.13917
Khorolskiy M, Ramenskaya G, Vlasov A, Perederyaev O, Maslennikova N. Development and Validation of four Nitrosamine Impurities Determination Method in Medicines of Valsartan, Losartan, and Irbesartan with HPLC-MS/MS (APCI). Iran J Pharm Res. 2021 Summer;20(3):541-552. doi: 10.22037/ijpr.2021.115102.15195. PMID: 34904007; PMCID: PMC8653666.
Öncü Ü, Yüksel BY, Binay E, Şen N. LC-MS/MS investigation of nitrosamine impurities in certain Sartan group medicinal products available in Istanbul, Türkiye. Ann Pharm Fr. 2024;82(1):72-83. doi: 10.1016/j.pharma.2023.08.002.
Baksam V, Nimmakayala S, Devineni DR, Jain M, Kumar P, Shandilya S, Kumar P. A Critical N-Nitrosamine Impurity of Anticoagulant Drug, Rivaroxaban: Synthesis, Characterization, Development of LC–MS/MS Method for Nanogram Level Quantification. Chromatographia. 2022;85(1):1-10. doi: 10.1007/s10337-021-04115-x.
Gopireddy RR, Maruthapillai A, Mahapatra S. A Multi-Analyte LC-MS/MS Method for Determination and Quantification of Six Nitrosamine Impurities in Sartans like Azilsartan, Valsartan, Telmisartan, Olmesartan, Losartan and Irbesartan. J Chromatogr Sci. 2024;62(2):147-167. doi: 10.1093/chromsci/bmac059. PMID: 35830866.
Rao A, Kumar KP, Rao AN, Malothu N, Desu B, Bandaru NR. Rapid quantitative estimation of glipizide and sitagliptin in rat plasma by liquid chromatography and mass spectroscopy (LC-MS). Research Journal of Pharmacy and Technology. 2022;15(4):1675-9.doi:10.52711/0974-360X.2022.00280
Remidicherla SS, Chakravarthi G, Malothu N. A Validated LC-MS/MS Method for Determination at Trace Level of Nitrosamine Impurities in Doxofylline API. Indian Journal of Pharmaceutical Education and Research. 2024;58(4s):s1262-70. doi:10.5530/ijper.58.4s.121.
Published
How to Cite
Issue
Section
Copyright (c) 2024 SWETHA SRI REMIDICHERLA, GUNTUPALLI CHAKRAVARTHI, ARRAM MADHAVI, NARENDER MALOTHU
This work is licensed under a Creative Commons Attribution 4.0 International License.
