The International Forum on Process Analytical Chemistry (IFPAC-07) (Baltimore, MD, USA; January 28-31, 2007)

Ambient Stable-Isotopic Records of Pharmaceutical Compounds:
Implications for Process Patent Protection and Process Analytical Chemistry (PAC)

John P. Jasper1, Larry E. Weaner2, Robbe C. Lyon3, and John M. Hayes4

1Molecular Isotope Technologies, LLC, 8 Old Oak Lane, Niantic, CT 06357-1815, USA;
2Johnson & Johnson Pharmaceutical Research and Development, L.L.C., PO Box 776,
Welsh and McKean Roads, Spring House, PA 19477-0776, USA;
3Division of Product Quality Research, CDER, FDA, Silver Spring, MD 20993-0002 USA;
4Woods Hole Oceanographic Institution, Woods Hole, MA 02543 USA

At the last two IFPAC meetings, we showed the utility of ambient stable isotopes for identifying pharmaceutical materials (product authentication) and elucidating the synthetic-isotopic process that was used to manufacture them (process authentication). Since then, we have developed a complete mathematical description of the isotopic compositions of all precursors and products in a synthetic pathway from the raw starting materials through intermediates to products. Product authentication, or “isotopic fingerprinting,” uses precise measurements of ratios of 13C to 12C, 15N to 14N, etc. to uniquely characterize authentic products, thus enhancing authenticity. Process analysis examines the mechanisms responsible for isotopic differences between reaction intermediates and products during synthesis. It thus provides information about reaction pathways and about the efficiency with which reactant are converted to products and is an active forensic tool for process patent protection.

The four factors that control the isotopic compositions of synthetic products are the stoichiometries of the reactants, the isotopic compositions of the starting materials and precursors, the isotope effects associated with the synthetic reactions, and the extent to which precursors are transformed to yield products. To discuss these factors systematically, we explore mass balances, isotope effects and the resulting isotopic fractionations and isotopic budgets within a complete synthetic pathway. For illustration, a numerical example is presented of the isotopic record of a reaction sequence with four synthetic steps that generates large isotopic fractionations (> 2‰) and easily measurable values. Collectively these factors can be utilized as a tool for PAC and to investigate and mitigate cases of process patent infringement