Identification and validation of potential genotoxic impurities, 1,3-dichloro-2-propanol,and 2,3-dichloro-1-propanol,at subtle levels in a bile acid sequestrant,colesevelam hydrochloride,using hyphenated GC–MS technique |
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Authors: | S R Jythesh Kumar Junuthula Venkata Ramana Reddy Vandavasi Koteswara Rao |
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Institution: | 1. Department of Chemistry, GITAM School of Science, Hyderabad, Telangana, India
Department of Analytical Research, Aurobindo Pharma Limited Research Center-II, Indrakarn (V), Kandi (M), Sangareddy, Telangana, India;2. Department of Analytical Research, Aurobindo Pharma Limited Research Center-II, Indrakarn (V), Kandi (M), Sangareddy, Telangana, India;3. Department of Chemistry, GITAM School of Science, Hyderabad, Telangana, India |
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Abstract: | Potential genotoxic impurities (PGI) and N-nitrosamine impurities in active pharmaceutical ingredients (APIs) and their determination at low levels are substantial challenges for cholesterol-lowering agents in recent years. Herein we developed a robust, reliable, rapid, accurate and validated technique of gas chromatography equipped with a mass spectrometer (GC–MS) for quantifying subtle levels of 1,3-dichloro-2-propanol (PGI-I) and 2,3-dichloro-1-propanol (PGI-II) in colesevelam hydrochloride drug substance (bile acid sequestrant). The separation of colesevelam hydrochloride, PGI-I and PGI-II was executed with chromatographic technique using a capillary column, DB-624 measuring with 30 m × 0.32 mm × 1.8 μm specification of 6% cyanopropylphenyl-94% dimethylpolysiloxane copolymer and helium carrier gas. This developed technique gave a good intensity peak without any interference and extra masses at the retention times of 11.17 min for PGI-I and 11.59 min for PGI-II, which was adequate, with mass spectra (m/z) of 79 and 62, respectively. The method’s sensitivity and linearity are demonstrated by its detection and quantification limits at subtle levels with correlation coefficients of 0.9965 for PGI-I and 0.9910 for PGI-II. The determination is mainly focused on improving sensitivity with the limits of detection and quantitation far below the specifications, which can support tighter limits. This results in a cost-effective and easily adoptable methodology having precise and accurate results in colesevelam hydrochloride API at subtle levels. |
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Keywords: | analytical method development & method validation colesevelam hydrochloride GC–MS potential genotoxic impurities (PGI) selected ion monitoring |
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