Rapid method development for chiral separation in drug discovery using sample pooling and supercritical fluid chromatography-mass spectrometry |
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Authors: | Zhao Yining Woo Gregory Thomas Samuel Semin David Sandra Pat |
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Institution: | Discovery Analytical Science, Amgen Inc., One Amgen Center Drive, Mail Stop 29-M-B, Thousand Oaks, CA 91320, USA. yzhao@amgen.com |
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Abstract: | A novel strategy for rapid chiral method development has been implemented using sample pooling and supercritical fluid chromatography-mass spectrometry (SFC-MS) on four chiral stationary phases, namely Chiralpak AD and AS, and Chiralcel OJ and OD, and eight different modifier concentrations (5 to 40% methanol-0.2% isopropylamine). The screening is performed under an outlet pressure of 110 bar at 35 degrees C, and at a flow-rate of 2.5 ml/min for the initial 20 min and then ramped up to 4 ml/min and held for 4.5 min to elute all solutes from the column. The entire process is fully automated from injection to data processing, and operates unattended for 15 h overnight to obtain optimal chiral separation for multiple compounds. A unique feature of using SFC-MS to monitor chiral synthesis is the negligible interferences from achiral impurities. In addition, with SFC-MS, enantiomeric excess can be determined with much lower detection limits than UV and much shorter analysis times compared to normal-phase/reversed-phase liquid chromatography. |
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