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Research paper : Expansion of organic reference materials for the analysis of hazardous substances in food and the environment (T. Ihara et al.)−18−Synthesiology - English edition Vol.2 No.1 (2009) approach with priority on measurement accuracy[5].In addition to the two elemental technologies described above, the Authors found that to improve the reproducibility of measurement results, phase correction, baseline correction, and peak area integration setting (range) were more important compared to other minor factors.5.2 Use of transfer materialsAlthough quantitative NMR requires 1H as the PS, the analyte does not have to be the same substance. The PS (limited to pure substances in this discussion) must satisfy the following conditions:1) It must have as little impurities as possible, to keep the uncertainty for its purity value small.2) It must dissolve easily in wide range of solvents, and must be stable in solution.3) It must have low volatility (sublimability) and absorbency, so its mass (weight) can be measured easily.4) Its chemical shift must not overlap with that of the target substance.Although some national RMs satisfy these conditions for PS, many national RMs do not satisfy requirement 2), because a suitable solvent for dissolving both the PS and the analyte has not been found. Also, some national RMs do not satisfy 4), as the PS used depends on the analyte, and different PSs must be used with certain analytes.The number of national RMs cannot be reduced if different PSs must be prepared according to various analytes. The Authors solved this problem using the calibration methods illustrated in Fig. 7, marshaling the advantages of quantitative NMR. We achieved this by selecting the transfer materials or chemical compounds whose chemical shifts do not overlap with either the PSs or the analytes. In Step 1, the PS (national RM) is used to calibrate the characteristic peak of the transfer material using quantitative NMR. In Step 2, the characteristic peak of the calibrated transfer material is adopted as the standard for calibration of the analyte. By adopting this two-step calibration method, the number of national RMs, which anchor the traceability system, can be minimized. Moreover, the transfer material does not need to be homogeneous or long-term stable like the RMs, so a wide range of materials is available for selection according to their match with a given analyte. The introduction of transfer materials to quantitative NMR was an important technological development in the process of synthesizing the elemental technologies.5.3 Evaluating the integrated technologiesIn sections 5.1 and 5.2, we described how several elemental technologies were integrated to construct a calibration technology using quantitative NMR. Next, we demonstrated the reliability of the technologies by comparing them with long-established techniques. To do this, we first selected several target substances from commercially available, high-purity compounds. Their purity values were determined using the freezing point depression method, a well-established primary direct method that AIST has been using for the valuation of national RMs (see Table 1). Then we measured the same samples with the newly developed quantitative NMR to find the purity value, and checked whether the two values matched in the range of their respective uncertainties. As the PS for measurements using quantitative NMR, we used benzoic acid (NIST SRM 350a, 99.9958 % ± 0.0027 %), a national RM distributed by the National Institute of Standards and Technology (NIST) of the United States. We performed the two-step calibration process described above using dimethyl sulfone or 1,4-bis-trimethylsilylbenzene-d4 (1,4-BTMSB-d4) as the transfer material, as the peak of the chemical shift for several substances overlaps the peak for benzoic acid. To dissolve the PS and the analyte, solvents were selected from a number of deuterated solvents, to minimize skewing of results from the protons of any impurities in the solvent. The solubility and other characteristics of the PS and analyte were also taken into consideration, and a solution with a concentration of about 1000 mg/L was prepared.The analytical results are summarized in Table 2. Although in many cases the uncertainty was larger for the purity values by quantitative NMR compared to freezing point depression method, the values for the two methods matched within the uncertainty ranges, demonstrating that our calibration technology using quantitative NMR was sufficiently reliable[6]. The uncertainty for quantitative NMR was between 0.3 % and 1.2 % (k=2, 95 % confidence interval). Although this accuracy as a purity measurement technology is somewhat inferior to the freezing point depression method, quantitative NMR can be used to calibrate substances to which the freezing point depression method cannot be applied, including a wide range of organic compounds, and OOOClClClClClClOOOClClClClClClOOHClClClClCalibrationAnalyteTransfer materialPrimary standardStep 2: Calibration of analyte using transfer materialStep 1: Calibration of transfer material using primary standard (National RM)Transfer materialCalibrationCalibrationChemical Shift (ppm)Chemical Shift (ppm)Fig. 7 Use of transfer material in quantitative NMR.

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