BLANC - Blanc

Determination of the isotopic « finger-print » of the molecules: application to the detection of active principle counter-feiting. – IS-O-TOP

Submission summary

1- Scientific background and objectives The direct access to site-specific natural isotope fractionation provided by high resolution NMR (the SNIF-NMR method) is recognized, not only as a source of selective information in a context of basic research, but also as a powerful technique for controlling the origin of commercial products. However certain limitations have been highlighted: long measurement time; restricted number of accessible molecules because of limited availability, poor solubility or complexity of the NMR spectrum. For the method to be of real use in industrial application, it would be preferable to have shorter analytical times, to be able to test small sample sizes and to have access to a larger range of possibilities in terms of molecular complexity. The aim of this project is to propose a strategy of tracing of the origin of the molecules by generalizing the SNIF NMR approach to other nuclei (in particular carbon-13). The extension of the SNIF-NMR method to other nuclei than deuterium presents two major interests: (i) an increase in the parameters allowing the determination of the molecule finger-print; (ii) the possibility of analysing molecules for which 2H-NMR is particularly difficult or even impossible. 2- Description of project, methodology Two main difficulties are encountered in quantitative 13C-NMR for isotopic measurement purposes: (i) the Nuclear Overhauser Effect and the partial saturation should be eliminated leading to long experimental time and (ii) the variation of the 13C content is small in natural products (~ 5 %) compared to the scale of 2H deviation (~ 50 %). To appreciate such small variations in 13C/12C ratios, analytical methods must be very sensitive, accurate and precise (1 ‰). The global SNIF-NMR approach imposes therefore methodological developments in order to reduce the experimental time and to allow an analysis in a time compatible with an industrial application and without reduction of the accuracy and the precision. Methodological developments, and their validation, are thus essential. The scientific objectives of this project are thus: • Development of a fast protocol for an NMR measurement with very high precision and accuracy: coupling of sequences of magnetization transfer with the ERETIC method will allow a repetition time of the order of the proton T1. The time of acquisition of a quantitative 13C-NMR spectrum could therefore be brought back to approximately one minute without reduction of the accuracy or the precision. • Validation of the multi-nuclei SNIF-NMR approach on a target compound and comparison with the standard protocol (SNIF-NMR-2H and Isotopic Ratio Mass Spectroscopy (IRMS)). • Demonstration of these new and/or optimized tools to detect differences in the synthetic process of pharmaceuticals that could be linked to counterfeiting or patent infringement. 3- Expected results The innovative spin-offs which are expected in this proposal lie in the following scientific originalities: (i) use of lower amount of product, (ii) new contribution of the specific 13C/12C ratios over the global carbon 13 content available by IRMS and (iii) possibilities to establish correlations between the 2H content and 13C content of the same site within the molecule under investigation. Today, the cost of worldwide counterfeiting is evaluated at about 10% of gross domestic product. On this basis, the overall financial loss for France can be estimated at about 13.8 billion €. The development of new methods is a key point in the detection of counterfeiting, to reduce these losses and to protect jobs. Another key point is the respect of new cGMP European regulation that was introduced in October 2005. It is important for the safety of patients to be sure that there is no change in the process or in the suppliers of active pharmaceutical ingredients. This is especially important for generic compounds produced in foreign countries, particularly in Asia, where controls are not easy to organize.

Project coordination

Serge AKOKA (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Help of the ANR 235,000 euros
Beginning and duration of the scientific project: - 36 Months

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