Stable isotopic characterization of active pharmaceutical ingredients.

Stable isotopic characterization or "fingerprinting" of active pharmaceutical ingredients (APIs) is a highly-specific means of defining the provenance of these pharmaceutical materials. The isotopic analysts in this study were provided with 20 blind samples of four APIs (tropicamide, hydrocortisone, quinine HCL, and tryptophan) from one-to-five production batch(es) from one-to-five manufacturer(s). Only the chemical identity of the APIs was initially provided to the isotopic analysts. Depending on the API chemical composition, isotopic ratios of either three or four elements (13C/12C, 15N/14N, 18O/16O, and/or D/H) were measured by either elemental analyzer/isotope ratio mass spectrometry (EA/IRMS: carbon (delta13C) and nitrogen (delta15N)) or by thermal conversion-EA/IRMS (TCEA/IRMS; hydrogen (deltaD) and oxygen (delta15N)); in all cases, the isotopic results are reported in the standard delta-notation which represents part-per-thousand () variations from the isotopic ratios of international standards. The stable isotopic analyses of the four suites of APIs spanned broad ranges in absolute value (deltadelta) and in estimated specificity (a product of dynamic ranges (DR, unitless)--note that these are upper limits of specificity because some of these isotope values may be partially interdependent). The five samples of tropicamide from one production batch and one manufacturer demonstrated the narrowest ranges (deltadelta13C=0.13 ; deltadelta15N=0.52 ; deltadelta18O=0.24 ; deltadeltaD=2.8 ) and the smallest specificity of 1:30.9. By contrast, the five samples of tryptophan that came from five separate manufacturers had some of the widest isotopic ranges observed (deltadelta13C=21.32 ; deltadelta15N=5.26 ; deltadelta18O=22.07 ; deltadeltaD=55.3 ) and had the largest specificity of 1:19.6 x 10(6). The isotopic provenance of the four suites of APIs readily emerged from bivariate plots of selected isotope ratios, particularly deltaD versus delta18O.