For a 6-point 0.05–10 ppb calibration on an Orbitrap, 1/x weighting trims low-end residuals but I still see about 12% positive bias at 0.05 ppb using an isotopically labeled IS, and the slope drifts 6–8% after about 100 injections despite daily mass calibration. Are you sticking with 1/x^2 or segmenting the range, and do you run mid-sequence bracketed standards (e.g., 0.2 ppb every 20 samples) to correct the curve or just flag and re-calibrate?
I segment ‘0.05–0.5 ppb’ with 1/x^2; bracket 0.2 every 30 injections; drift drops about 5%.
I only got rid of that “12% at 0.05 ppb” by subtracting a reagent blank from all cal/unknowns and not forcing through zero; with that, 1/x over 0.05–10 ppb behaved fine on the Orbitrap. For the 6–8% slope creep after about 100 injections, I drop a 0.2 ppb every about 25 samples and apply a single-point response-factor update rather than re-fit — small caveat: it can mask source fouling, so I still divert to waste for the first 0.3 min. @OP does blank-subtracting fit your workflow?
I cut the drift and that 0.05 ppb bias by adding a 2–3 min ESI source rinse (50:50 IPA/water + 0.1% NH4OH) every about 40 injections and using matrix‑matched calibrators; bracketing 0.2 ppb like @elara_chem49 helps, but the rinse moved the needle. I keep 1/x with an intercept and insert a post‑high 0.0 ppb blank to flag carryover — think of it as a coffee break for the source; have you tried diverting the first minute to waste?