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Day 2: TP25
Packed-column SFC Combined with LC-MS/MS for Metabolites and Impurities Elucidation in Drug Discovery

Yining Zhao, Jen Wilson, David Chow, David Semin and Ed Maliski
Small Molecule Analytical, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320

Structural elucidation of metabolites and impurities of lead compounds remains critical to study the drug metabolism and structure-activity relationship (SAR) for lead optimization in the drug discovery. This task requires high efficiency separations coupled to detections of high sensitivity and specificity. In the past decade, LC-MS/MS has been widely applied as the number one technique to this area. However, recently, packed-column SFC (pSFC) and its hyphenation techniques (e.g. pSFC-MS), which take advantage of higher separation efficiency over LC, are regaining its recognition. In this work, more than fifty structurally-diversified drug-like compounds have been analyzed by pSFC and LC side by side, three lead compounds' metabolic pathways have been determined by LC-MS/MS with the assistance of pSFC. This study has proven that pSFC is able to achieve better separation of the impurities and metabolites from the parent lead compounds. Moreover, pSFC demonstrates higher resolution and faster purification than conventional preparative scale LC, which becomes essential in fractionation of targeted metabolites or impurities that will ultimately be identified by NMR. Additionally, some issues regarding SFC column technology, mobile phase, instrument design and MS-hyphenation are addressed.

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