Development and Comparison of Orthogonal Chromatographic Techniques for the Analysis of Potential Mutagenic Impurities

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Jennifer Simeone, Paula Hong
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There are many steps during the manufacturing process of an active pharmaceutical ingredient (API) where impurities can be introduced, whether as reagents, byproducts, intermediates, etc.  Some of these impurities may be mutagenic, or those that have the potential to interact with DNA and ultimately cause carcinogenicity.  Methodologies associated with monitoring API purity levels are often HPLC-UV based, which frequently do not provide the sensitivity levels needed to detect potential mutagenic impurities at the levels required by regulatory agencies.  However, the use of tandem quadrupole mass spectrometry can provide both high sensitivity and specificity for analytical methods.  Additionally, mass spectrometry is known to be suitable for use with both RPLC and SFC methodologies.

Ondansetron is a pharmaceutical used in the prevention of nausea and vomiting, and contains two process impurities that are potentially mutagenic, imidazole and 2-methyl imidazole.  Quantitative methods for the analysis of ondansetron and five process impurities, including the two potential mutagenic impurities, imidazole and 2-methyl imidazole, were developed using two orthogonal chromatographic methods- reversed phase liquid chromatography and supercritical fluid chromatography, yet both methods employed tandem quadrupole mass detection.  Method parameters, such as limit of quantitation, linearity, and run time will be compared between the two orthogonal chromatographic methods to determine the benefits of each technique in the analysis of ondansetron and its potentially mutagenic impurities.

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