Development of isotope dilution-liquid chromatography/mass spectrometry combined with standard addition techniques for the accurate determination of tocopherols in infant formula

•ID-LC/MS method showed biased results for tocopherols analysis in infant formula.•H/D exchange of deuterated tocopherols in sample preparation was the source of bias.•Standard addition (SA)-ID-LC/MS was developed as an alternative to ID-LC/MS.•Details of calculation and uncertainty evaluation of the SA-IDMS were described.•SA-ID-LC/MS showed a higher-order metrological quality as a reference method. During the development of isotope dilution-liquid chromatography/mass spectrometry (ID-LC/MS) for tocopherol analysis in infant formula, biased measurement results were observed when deuterium-labeled tocopherols were used as internal standards. It turned out that the biases came from intermolecular H/D exchange and intramolecular H/D scrambling of internal standards in sample preparation processes. Degrees of H/D exchange and scrambling showed considerable dependence on sample matrix. Standard addition-isotope dilution mass spectrometry (SA-IDMS) based on LC/MS was developed in this study to overcome the shortcomings of using deuterium-labeled internal standards while the inherent advantage of isotope dilution techniques is utilized for the accurate recovery correction in sample preparation processes. Details of experimental scheme, calculation equation, and uncertainty evaluation scheme are described in this article. The proposed SA-IDMS method was applied to several infant formula samples to test its validity. The method was proven to have a higher-order metrological quality with providing very accurate and precise measurement results.