title: NMR spectrometry isotopic fingerprinting: a tool for the manufacturer for tracking active pharmaceutical ingredients from starting materials to final medicines.
abstract: In the frame of increasingly stringent quality assessment required by the regulators, the pharmaceutical industry has to face increasingly sophisticated counterfeiting practices. Counterfeits based on deliberate copying of processes or on the infringement of current patents for generic medicines are not straightforward to detect, unless the molecular probe is the active molecule itself. In this context, impurity profiling is limited. A tool based on the determination of intramolecular isotopic profiles has been developed to provide manufacturers of APIs (Active Pharmaceutical Ingredients) with a new solution to meet this double requirement. Stable isotope analyses by NMR gives direct access to site-specific isotope content at natural abundance. In this report, it is shown how both ²H and ¹³C NMR spectrometry can provide complementary and valuable information that could be applied to link APIs to their manufacturing source. Isotopic ¹³C NMR offers additional benefits over ²H NMR in using robust adiabatic polarization transfer methods, leading to a tremendous reduction in experimental time. Two approaches are illustrated. Firstly, the use of ²H and single pulse ¹³C NMR spectra obtained on 20 commercial ibuprofen samples from different origins show that this combined strategy leads to (i) a unique intramolecular isotope identification and (ii) a preliminary classification of the samples according to the synthetic pathways of the main industrial processes. An approach employing polarization transfer methods applied to 11 commercial naproxen samples, for which ²H and single pulse ¹³C NMR spectra are not exploitable and/or are not accessible in reasonable time. The relative and partial intramolecular ¹³C distribution obtained on naproxen by applying this methodology is sufficiently informative to allow the same conclusions as for ibuprofen. The additional benefits that these approaches should bring to API manufacturers are discussed.
authors.affiliation: EBSI Team, University of Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR 6230, LUNAM University, 2 Rue de la Houssinière, BP 92208, F-44322 Nantes cedex 3, France. Electronic address: gerald.remaud@univ-nantes.fr.
authors.forename: Gérald S
authors.initials: GS
authors.lastname: Remaud
authors.affiliation: EBSI Team, University of Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR 6230, LUNAM University, 2 Rue de la Houssinière, BP 92208, F-44322 Nantes cedex 3, France.
authors.forename: Ugo
authors.initials: U
authors.lastname: Bussy
authors.affiliation: EUROFINS, Rue Pierre Adolphe Bobierre, BP 42301, F-44323 Nantes cedex 4, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Lees
authors.affiliation: EUROFINS, Rue Pierre Adolphe Bobierre, BP 42301, F-44323 Nantes cedex 4, France.
authors.forename: Freddy
authors.initials: F
authors.lastname: Thomas
authors.affiliation: CDP-Innovation SAS, Espace G2C, 63 Rue André Bollier, 69307 Lyon cedex 7, France.
authors.forename: Jean-Roger
authors.initials: JR
authors.lastname: Desmurs
authors.affiliation: EUROFINS, Rue Pierre Adolphe Bobierre, BP 42301, F-44323 Nantes cedex 4, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jamin
authors.affiliation: EBSI Team, University of Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR 6230, LUNAM University, 2 Rue de la Houssinière, BP 92208, F-44322 Nantes cedex 3, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Silvestre
authors.affiliation: EBSI Team, University of Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR 6230, LUNAM University, 2 Rue de la Houssinière, BP 92208, F-44322 Nantes cedex 3, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Akoka
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000191:economics; D002247:Carbon Isotopes; D002626:Chemistry, Pharmaceutical; D058110:Counterfeit Drugs / Q000737:chemistry*; D003903:Deuterium; D005607:Fraud / Q000517:prevention & control*; D007052:Ibuprofen / Q000737:chemistry* / Q000191:economics; D009682:Magnetic Resonance Spectroscopy; D009288:Naproxen / Q000737:chemistry* / Q000191:economics; D025341:Principal Component Analysis; D011786:Quality Control; D013678:Technology, Pharmaceutical
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002247:Carbon Isotopes; D058110:Counterfeit Drugs; D009288:Naproxen; D003903:Deuterium; D007052:Ibuprofen