I am trying to develop a QC main peak assay for an oligonucleotide on a G6135B but I've noticed that there is a steady downward drift of response during my sequences. The signal decrease is quite significant for the first few injections, and does slow down somewhat, but it's quite significant and is up to 15% relative to the first standard injection, which is far more than I can accept for the specification criteria. I'd hoped that this might be an issue that would be resolved by some "conditioning" blank or standard injections at the start of the sequence, but even after 15 standard injections I still see drift.
I'm working in negative ion ESI, in SIM mode at around m/z 1800. Eluents include water. methanol, 200mM HFIP and 2mM of a tertiary amine.
I am going to look at adding an internal standard to try to address this, but a suitable compound will be difficult and expensive to source, so if anyone had any ideas about what might be happening here or how I can address/minimise this I'd be really grateful!!
Let me know if there's any additional information that would be helpful.