Multiplicative effects model with internal standard in mobile phase for quantitative liquid chromatography–mass spectrometry

Liquid chromatography–mass spectrometry assays suffer from signal instability caused by the gradual fouling of the ion source, vacuum instability, aging of the ion multiplier, etc. To address this issue, in this contribution, an internal standard was added into the mobile phase. The internal standard was therefore ionized and detected together with the analytes of interest by the mass spectrometer to ensure that variations in measurement conditions and/or instrument have similar effects on the signal contributions of both the analytes of interest and the internal standard. Subsequently, based on the unique strategy of adding internal standard in mobile phase, a multiplicative effects model was developed for quantitative LC–MS assays and tested on a proof of concept model system: the determination of amino acids in water by LC–MS. The experimental results demonstrated that the proposed method could efficiently mitigate the detrimental effects of continuous signal variation, and achieved quantitative results with average relative predictive error values in the range of 8.0–15.0%, which were much more accurate than the corresponding results of conventional internal standard method based on the peak height ratio and partial least squares method (their average relative predictive error values were as high as 66.3% and 64.8%, respectively). Therefore, it is expected that the proposed method can be developed and extended in quantitative LC–MS analysis of more complex systems.