In this approach, the sample is spiked with a species (internal standard) which is used to normalise the response of analyte, compensating for variables at any stage of the sample preparation and analysis, including ion suppression.
It is important that the internal standard displays very similar (ideally identical) properties, with respect to detector response (i.e. ionisation), as the analyte of interest. To simplify the selection of internal standard, most laboratories use an analogous stable isotope in an isotope dilution type analysis. The stable isotope is almost guaranteed to be chemically and physically as close as possible to the analyte of interest, hence producing an almost identical detector response in addition to behaving identically during sample preparation and chromatographic resolution. To this end, the ion suppression experienced by both the analyte and the internal standard should be identical. It is important to note that an excessively high concentration of stable isotope internal standard may cause ion suppression itself, since it will co-elute with the analyte of interest. Hence, the internal standard should be added at an appropriate concentration.