Published in Analytical and Bioanalytical Chemistry (2013) 405:2879–2887 [DOI: 10.1007/s00216-013-6724-5] Received: 30 September 2012 / Revised: 12 December 2012 / Accepted: 11 January 2013 / Published online: 1 February 2013 © Her Majesty the Queen in Right of Canada 2013 REDUCTION OF MEASUREMENT UNCERTAINTY BY EXPERIMENTAL DESIGN IN HIGH- ORDER (DOUBLE, TRIPLE, AND QUADRUPLE) ISOTOPE DILUTION MASS SPECTROMETRY: APPLICATION TO GC-MS MEASUREMENT OF BROMIDE Enea Pagliano a,b , Zoltán Mester a and Juris Meija a, * (a) National Research Council Canada; Ottawa, Ontario K1A 0R6, Canada (b) Scuola Normale Superiore, Piazza dei Cavalieri 7, Pisa 56126, Italy * Corresponding author: juris.meija@nrc.ca ABSTRACT Since its introduction a century ago, isotope dilution analysis has played a central role in developments of analytical chemistry. This method has witnessed many elaborations and developments over the years. To date we have single, double and even triple isotope dilution methods. In this manuscript we summarize the conceptual aspects of isotope dilution methods and introduce the quadruple dilution, and the concept of exact-matching triple and quadruple dilutions. The comparison of isotope dilution methods is performed by determination of bromide ions in groundwater using novel ethyl-derivatization chemistry in conjunction with GC/MS. We show that the benefits of higher-order isotope dilution methods are countered with a greater need for careful experimental design of the isotopic blends. Just as for ID 2 MS, ID 3 MS and ID 4 MS perform best when isotope ratio of one sample/spike blend is matched with that of a standard/spike blend (exact-matching). r A r B r AB r A*B SAMPLE +SPIKE SAMPLE SPIKE ID 2 MS ID 3 MS ID 4 MS STANDARD +SPIKE KEYWORDS Isotope dilution analysis, Double dilution, Triple dilution, Quadruple dilution, Exact-matching, Bromide, Triethyloxonium tetrafluoroborate, GC/MS