title: Use and qualification of primary and secondary standards employed in quantitative ¹H NMR spectroscopy of pharmaceuticals.
abstract: Standards are required in quantitative NMR (qNMR) to obtain accurate and precise results. In this study acetanilide was established and used as a primary standard. Six other chemicals were selected as secondary standards: 3,4,5-trichloropyridine, dimethylterephthalate, maleic acid, 3-sulfolene, 1,4-bis(trimethylsilyl)benzene, and 1,3,5-trimethoxybenzene. The secondary standards were quantified using the primary standard acetanilide. A protocol for qualification and periodic checks of these secondary standards was developed, and used for evaluation of the stability of the compounds. Periodic monitoring of purity was performed for several years. The purity was higher than 99% for all secondary standards. All standards maintained the initial purity during the time period of monitoring, with very small variations in purity (0.3-0.4%). The selected secondary standards were shown to be suitable qNMR standards and that periodic requalification of the standards by qNMR ensures reliable analytical results. These standards have been used in our laboratory for compliance testing of pharmaceutical active substances and approved medicinal products as well as for analysis of suspected illegal medicines. In total more than 1000 samples have been tested using both internal and external standardization and examples are given.
authors.affiliation: Medical Products Agency, P.O. Box 26, SE-75103 Uppsala, Sweden. Electronic address: torgny.rundlof@mpa.se.
authors.forename: Torgny
authors.initials: T
authors.lastname: Rundlöf
authors.affiliation: Medical Products Agency, P.O. Box 26, SE-75103 Uppsala, Sweden.
authors.forename: Ian
authors.initials: I
authors.lastname: McEwen
authors.affiliation: Medical Products Agency, P.O. Box 26, SE-75103 Uppsala, Sweden; Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Medical Products Agency, P.O. Box 26, SE-75103 Uppsala, Sweden; Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Arvidsson
mesh_terms: D000083:Acetanilides / Q000737:chemistry; D004355:Drug Stability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000592:standards; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D012015:Reference Standards; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D000083:Acetanilides; D004364:Pharmaceutical Preparations; C508827:acetanilide
keywords: NMR; Qualification; Quantification; Reference substance; Standardization