CITAC Best Paper Award 2013

Transcription

1 CITAC Best Paper Award 2013 Michael Weber Director, R&D and Marketing Analytical Standards and Reagents

2 qnmr Performance - From Past to Present Jancke et al described qnmr as a potential primary ratio method They reported uncertainties in the range od 1-2 % relative [1,2] Ihara and Saito et al described qnmr experiments leading to uncertainties of down to 0.3% relative [3,4] In this publication it was demonstrated for the first time that qnmr can be optimized to measurement uncertainty (U) levels of below 0.1% relative [1] Jancke H (1998), CCQM/98 98:1-12 [2] Malz F, Jancke H (2005) J. Pharm. Biomed. Anal 38: [3] Ihara T, Saito T, Sugimoto N (2009), Synthesiology English Edition 2:12-22 [4] Saito T, Ihara T, Koike M, Kinugasa S, Fujimine Y, Nose K, Hirai T (2009) Accred Qual Assur 14:

3 Features of Quantitative NMR (qnmr) Primary ratio method peak areas are proportional to number of corresponding nuclei signal intensity is indepentend of chemical nature no need for chemically identical reference material Direct traceability to the reference direct measurement of analyte/ sample signal no indirect = way around approaches (i.e. mass balance) Impurities do not affect the result* only one sample signal must be pure (minimum requirement) even true for undetectable impurities (salts, solvents, water) * as long as no interaction of impurity with sample occurs 3

4 Metrological Traceability Scheme acc. to [5] SI NMI CRM producer U w,khp = U w, = U w,caffeine = 0.2 mass fraction of total acid exp as KHP in primary calibrator w PHP = mass fraction of in calibrator w = mass fraction of Caffeine in sample w Caffeine = primary calibrator KHP calibrator sample of Caffeine primary meas. system coulom. titrator balance NMR instr. balance NMR instr. Primary measurement procedure coulometry HP-qNMR procedure HP-qNMR procedure UNCERTAINTY (U, relative [%]) QUANTITY CALIBRATOR or SAMPLE ACTION MEASURING SYSTEM MEASURING PROCEDURE [5] De Bièvre P, Dybkaer R, Fajgelj A, Hibbert B, (2011) Pure Appl. Chem.Vol 83 (10):

5 Validation Scheme / Consistency (1H-qNMR) SI NIST SRM 350b NIST SRM 39j KHP DNB DMS Benzoic acid Potassium hydrogen phthalate Maleic acid Dinitro benzoic acid Dimethyl sulfone KHP NIST SRM 84l DNB Weighing [6] Mettler-Toledo UMT-5 Air buoyancy corrected values 10 individual samples NMR Bruker Avance-III 600 MHz mg sample weight scans / sample 90 degree single pulse with D1 of 60 sec manual shape and baseline correction DMS [6] Reichmuth A, Wunderli S, Weber M, Meier VR (2004), Microchim. Achta 148:

6 [% mass fraction] Purity of Maleic Acid () Validation Scheme / Consistency (1H-qNMR) NIST- 350b NIST- 39j NIST-KHP NIST-PPM 84l Exp. A Exp. B Exp. C DNB DMS Exp. D Exp. E All six results are consistent (ANOVA) DNB DNB DMS Exp. F 6

7 From SI to Certified Reference Materials Pesticies Org. pollutants (PHA, PCBs) SI Primary calibrators (2-3) Calibrators for qnmr (10-20) FA / FAMEs Amino acids Drugs / APIs Impurities Phytochemicals Metabolites ppm... Not avalable today cooperation with NIST new primary reference(s) for qnmr Today >200 new CRM based on qnmr certification are ready

8 Limitations of qnmr Lowest uncertainties are only achieved with pure samples - Complex mixtures lead to high uncertainties - Matrix samples can not be measured at all Volatile/ hygroscopic samples lead to higher uncertainties - Special handling techniques are required Limited NMR sensitivity requires a minimum sample amount - With less than 1-10 mg of sample only few replicates are possible - Weighing uncertainty becomes significant Good understanding of metrological weighing is a must Upfront investment for the instrument 8

9 Our Latest Publications about qnmr Applications 9

10 10