A preliminary multi-stable isotopic evaluation of three synthetic pathways of topiramate
The Network developingforensic applications of stable
Copy of research articlepublished in September issue
of the FIRMS Newsletter:(FIRMS Newsletter, 2004,
A Preliminary Multi-Stable Isotopic Evaluation of Three
2(2): 8 – 9)
Synthetic Pathways of Topiramate
J. P. Jasper1 , L. E. Weaner2, and B. J. Duffy2
Molecular Isotope Technologies LLC, 8 Old Oak Lane, Niantic,
Connecticut 06357-1815 USA; Johnson & Johnson Pharmaceutical
Research and Development, L.L.C., Welsh and McKean Roads, PO Box776, Spring House, Pennsylvania 19477-0776 USA.
Pharmaceutical products can be characterized or “fingerprinted” by measuring and comparingtheir highly-specific stable isotopic ratios via isotope-ratio mass spectrometric analysis (Jasper,2004; Jasper et al
., 2004, and refs. therein). The isotopic composition observed is dependent onboth the reactants used and the manufacturing process employed. A change in either of thesevariables produces a drug product having a different isotopic profile. Recent work has shown thatwhen both the source of the starting materials and the manufacturing process are presumably heldrelatively constant during manufacture of the bulk drug substance, similar product isotopic-ratiosare observed (Jasper et al
., 2004). By measuring the isotopic ratios for suspect samples in casessuch as drug counterfeiting and process patent infringement, it may be possible to obtain usefulinformation about the process and origin of raw materials used.
Fig.1. Structure of Topiramate (C12H21NO8S).
To test the utility of the natural stable-isotopic differentiation of batch samples produced bydifferent pathways, multi-stable isotopic analyses (d13C, d15N, d18O, and dD) of 53 Topiramate
samples produced by three different synthetic pathways (designated “A,” “B,” and “C”) wereperformed (Fig. 1). Examination of the data via the six possible bivariate isotope plots, revealsdistinct data clustering, though in some cases with some overlapping within standard errors. Ingeneral, the isotopic composition of Topiramate from the C pathway is distinct from those of theA and B pathways. The isotopic data from the A and B pathways typically abut each other,sometimes partially overlapping. The hydrogen/deuterium- (dD) and oxygen (d18O) isotopic
compositions of Topiramate are each significantly linearly correlated with the paired carbon(d13C) isotopic composition (Fig. 2). Given that H and O largely derive from meteoric water, the
linear correlations with d13C indicate that a mixture of carbon sources (viz
., perhaps terrestrial C3
photosynthetic organic carbon and marine C3 organic carbon) were used in the production of thebatches tested. If
the H and O analyzed derived from meteoric water, then an elementarycomparison of the span of the dD (DdD = 54.6 + 2.1‰) and d18O (Dd18O = 4.71 + 0.26‰) values
in the Topiramate samples to the global isotopic gradients indicates that the water retained in thesamples spanned from as much as 11o of latitude (or, ~760 statute miles north to south). Thepresent isotope results (d13C, d15N, d18O, and dD) form a database against which future samples
can be compared to infer specific synthetic pathways.
dD (‰ vs VPDB)
Fig. 2. A bivariate isotope plot (d13C vs. dD) of 53 Topiramate samples produced by three
Jasper, J. P. (2004) "Pharmaceutical Security: Using Stable Isotopes to Authenticate
. Tablets Capsules
Jasper, J. P., B. J. Westenberger, J. A. Spencer, L. F. Buhse, and M. Nasr (2004). Stable isotopic
characterization of active pharmaceutical ingredients. J. Pharm. Biomed. Anal.
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