Molecular Isotopic Engineering (MIE): Industrial Manufacture of Naproxen of Predetermined Stable Carbon-Isotopic Compositions for Authenticity and Security Protection and Intellectual Property Considerations

摘要

Molecular Isotopic Engineering (MIE) is the directed stable-isotopic synthesis of chemical products for reasons of product identification and of product security, and also for intellectual property considerations. We report here a generally excellent correspondence between the observed and predicted stable carbon-isotopic (δ~(13)C) results for a successful directed synthesis of racemic mixture from its immediate precursors. The observed results are readily explained by the laws of mass balance and isotope mass balance. Oxygen-and hydrogen isotopic results which require an additional assessment of the effects of O and H exchange, presumably due to interaction with water in the reaction solution, are addressed elsewhere. A previous, cooperative study with the US FDA-DPA showed that individual manufacturers of naproxen could readily be differentiated by their stable-isotopic provenance (δ~(13)C, δ~(18)O, and δD; ref. 1). We suggest that MIE can be readily employed in the bio/pharmaceutical industry without alteration of present manufacturing processes other than isotopically selecting and/or monitoring reactants and products.