We currently work on a drug and its 3 metabolites in plasma. The metabolites are much more polar than the drug. We have to use LC-MS API negative mode at pH higher that 9.0. The problem is that those analytes have very different RT on C18 columns so we have to use gradient. USually analytes of very different polarity show more similar RT on CN and C4 columns. Is there any CN, C4 or C5 columns that are stable at pH 9.0 or higher? What about perfluoronated phase like Fluorophase from Hypersil?

Thank you for sharing your experience.

Jimmy,
Have you tried column switching? For example, start the sample through a small precolumn, switch it to the end of the column after your poorly retained compounds have gotten onto the main column, and adjusting the chromatography so the peaks do not coelute?
Jim

Hi Jimmy,what is your sample concentration? Perhaps you should use a preconcentration SPE step before going on the analytical column. This you should do by column switching, as Jim mentioned. Regarding your metabolites I would try to run at pH 11! Problem will be column lifetime. In this case I would try a polymeric based RP column. But not a PSDVB based material (tailing and/or unresolved peaks), I would recommend a methacrylate-based resin. Runtime on such polymerbased resins is shorter, compared to silicabased RP-materials. It's just an idea, and these materials are only available with C18 groups. Please check out for a example the Tosoh Database www.Tosohbiosep.de! Hope this helps to solve your problem. Regards
Gerhard

I would compare the XTerra MS C8 column to an XTerra RP8 column. Both columns are stable at high pH values, pH 11 is quite OK. The difference in surface chemistry could give you the desired difference in retention character.