Synthesis and Quantitation of Genotoxic impurity 5-cyano-2-((4-fluorophenyl) (hydroxy) benzyl 4-methyl benzene sulfonate in Escitalopram Oxalate by RP-UPLC
AbstractThe objective of the research work is to synthesize potential genotoxic impurity 5-cyano-2-((4-fluorophenyl) (hydroxyl) benzyl 4-methyl benzene sulfonate and to develop suitable UPLC method to quantify the above genotoxicimpurity in Escitalopram Oxalate at 15 ppm level. The above genotoxic impurity was synthesized by regio selective tosyaltionof Diol compound, under controlled temperature conditions at 0-5C with TsCl/pyridine/chloroform and characterized. A new UPLC method was developed by using UPLC BEH Shield RP18 100 x 2.1 mm, 1.7 column. The mobile phase used is the mixture of 0.05% ortho phosphoric acid and acetonitrile in the ratio of 8:2 (v/v) as solvent-A and 3:7 (v/v) as solvent-B at a flow rate of 0.4 mL/minute. Detector wavelength monitored at 228nm and column temperature was maintained at 27C. The UPLC method was validated as per International conference on harmonization guidelines. This method is proven as highly sensitive with a detection limit of 5ppm and quantification limit of 15 ppm. Regression analysis showed that the correlation coefficient value of 0.99999. The accuracy of the method was established based on the recovery obtained for 5-cyano-2-((4-fluorophenyl) (hydroxyl) benzyl 4-methyl benzene sulfonate. The present research work provided the route of synthesis as well as an advanced analytical methodology to quantify the above critical Genotoxic impurity known as 5-cyano-2-((4-fluorophenyl) (hydroxyl) benzyl 4-methyl benzene sulfonate in Escitalopram oxalate.
. Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended approaches (2008) US Department of Health and Human Services, Food and Drug administration, Centre for Drug Evaluation and Research CDER USA.
. Liu DQ, Sun M, Kord AS. Recent advances in trace analysis of pharmaceutical genotoxic impurities. J Pharm Biomed Anal 2010; 51: 999-1014.
. Yuabova, Holschlag ZY, Rodriguez DR, Qin SA, Papov C, et al. Genotoxic Impurities: A quantitative Approach. J Liq Chromatogr Relat Technol 2008; 31: 2318-2330.
. Guideline on Impurities in New Drug Substances, Q3A (R2), ICH.
. Muller L, Mauthe RJ, Riley CM, Andino MM, Antonis DD, et al. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul Toxicol Pharmacol 2006; 44: 198-211.
. IARC Monographs Program on the Evaluation of Carcinogenic Risks to Humans for ethyl methane-sulphonate 7 (1974) 245.
. Dobo KL, Greene N, Cyr MO, Caron S, Ku WW. The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. Regul Toxicol Pharmacol 2006; 44: 282-293.
. Kim C, Keum JE, Yu SH, Ko SY. Regioselective Mitsunobu-tosylation of 1, 2-diols. Bulletin of the Korean Chemical Society. 2009 Jul 20; 30(7):1671-4.
. Jouyban A, Parsa H. Genotoxic impurities in pharmaceuticals. InToxicity and Drug Testing 2012.
. ICH M7, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Current Step 4 version dated 23 June 2014.
. Edward JD. An impact analysis of the application of the threshold of toxicological concern concept to pharmaceuticals. J. Regul. Toxicol. Pharmacol, 2007; 49: 107-124.
. Kochi JK, Hammond GS. Benzyl tosylates. I. Preparation and properties. Journal of the American Chemical Society. 1953 Jul; 75(14):3443-4.
. Ding R, He Y, Wang X, Xu J, Chen Y, Feng M, Qi C. Treatment of alcohols with tosyl chloride does not always lead to the formation of tosylates. Molecules. 2011 Jul 1; 16(7):5665-73.
. Lohr LL, Jensen AJ, Sharp TR. NMR characterization of impurities. Separation Science and Technology. 2004 Dec 31; 5:301-39.
. Naga Malleswararao CS, Suryanaryana MV, Krishna K, Mukkanti K. Stability indicating uplc method for the rapid separation of related components of gemcitibine hydrochloride. Journal of Liquid Chromatography & Related Technologies. 2012 Jan 1; 35(18):2511-23.
. ICH, Q3A (R2) Guideline on Impurities in New Drug Substances, 2006. IFPMA, Geneva
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