ICH guidelines require that impurities of the active pharmaceutical ingredients (API) or key intermediates be identified and/or qualified once they exceed certain levels. The identification of these impurities/degradants can be quite challenging. In this presentation, the use of LC-MSn technique in conjunction with mechanism-based stress study is shown to be a very effective way in the elucidation of unknown drug degradation products and degradation pathways. Typically, samples are first analyzed using LC-MSn through which molecular ions, major fragments, and their structural relationship can be established. Based on these LC-MSn results, possible degradation mechanism may be inferred; a particular type of stress study (forced degradation) of the API is then designed and carried out accordingly. The formation of the degradant in the stress study is confirmed by LC-MSn through matching of retention times, UV spectra, and more importantly MS/MS fragmentation patterns between the stress-generated degradant and the one observed in the original sample. MS/MS fragmentation patterns generated with suitable collision energy not only provide a unique molecular fingerprinting in tracking and ensuring the targeted degradant be made in an adequate amount in the stress study but also reveal structural information critical to the elucidation of the degradant structure. With the elucidated structures of the degradant and its intermediates, degradation pathways can be proposed, which is essential for adequate formulation and packaging design to ensure suitable drug stability. This overall approach will be demonstrated through several case studies involving corticosteroid APIs.

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