A preliminary multi-stable-isotopic evaluation of three synthetic pathways of Topiramate.

As a preliminary study of the utility of the natural stable-isotopic differentiation of batch samples produced by different synthetic pathways, multi-stable-isotopic analyses (delta(13)C, delta(15)N, delta(18)O, deltaD) of 53 samples of the antiepileptic drug, Topiramate, produced by three different synthetic pathways (designated "A," "B," "C") were performed. From the outset, we note that there are two fundamental variables that determine the stable-isotopic composition of materials-the stable-isotopic composition of the reagents and starting intermediates, and the isotope fractionation that occurs during manufacture of the product. In this study, the stable-isotopic composition of the raw materials was not controlled and we report here data obtained for a suite of samples that was produced by three synthetic pathways. Graphical examination of these data reveals marked data clustering by synthetic pathway, though in some cases with some overlapping values within standard errors. In general, the isotopic composition of Topiramate from the A and B pathways is distinct from the C pathway. The isotopic data from the A and B pathways typically abut each other, sometimes partially overlapping. The deuterium/hydrogen- (deltaD) and oxygen (delta(18)O) isotopic compositions are each significantly linearly related with the paired carbon (delta(13)C) isotopic composition indicating possible isotopic end-members for the raw materials of the present sample suite. Given that H and O typically derive from meteoric water, the linear correlations with delta(13)C 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 the batches tested. If the H and O analyzed were derived from meteoric water, then an elementary comparison of the span of the deltaD (DeltadeltaD = 54.6 +/- 2.1 per thousand) and of the delta(18)O (Deltadelta(18)O = 4.71 +/- 0.26 per thousand) values in the Topiramate samples to that of the global isotopic gradients indicates that the water retained in the samples spanned from as much as 11 degrees of latitude (or, approximately 760 statute miles North-to-South). The present isotope results (delta(13)C, delta(15)N, delta(18)O, deltaD) form an initial database against which future samples can be compared to infer specific synthetic pathways. It is clear that to perform a rigorous test of the variables controlling the stable-isotopic composition of pharmaceutical materials that both the stable-isotopic composition of the starting materials and synthetic isotope fractionation must be controlled in future studies.