Counterfeit and substandard medicines remain an ongoing threat, which is why the development of precision tools that can ensure drug authenticity and manufacturing integrity remain crucial. A study by researchers at Stanford University and the University of Copenhagen introduces a method using stable isotope ratio mass spectrometry to profile the isotopic signatures of pharmaceutical products.
Focusing on ibuprofen drug products and commonly used excipients, the study highlights how stable isotope ratios can serve as forensic markers to detect counterfeits and assess manufacturing consistency.
Stable isotope ratio mass spectrometry (IRMS) is a mainstay in geochemistry and food traceability, but is considerably less well known in the pharmaceutical world. The researchers analyzed 27 ibuprofen drug products sourced from six countries, alongside 27 widely used excipients, and found that each drug product exhibited a unique multi-isotope fingerprint, shaped by its formulation, manufacturing conditions, and raw material origins.
Through thermal combustion elemental analysis (TC/EA-IRMS), the team measured isotope ratios with high reproducibility using only ~150 μg of sample material – an amount small enough to leave the tablet essentially intact.
Insights into consistency
Among the key findings was insight into isotopic consistency across multiple batches of the same branded product. For example, nine different batches of GSK’s Advil purchased in California, and varying in expiration dates, bulk sizes, and packaging, showed minimal isotopic variability, suggesting a high level of production control and supply chain integrity.
Drug products produced by the same manufacturer but with different dosages (e.g., 200 mg versus 400 mg ibuprofen) displayed distinguishable isotopic profiles. These differences are likely due to variation in excipient composition and processing, further emphasizing the sensitivity of isotope ratios to formulation changes.
Using 3D isotopic plots, the research visually separated ibuprofen products by brand and by country of origin. While overlapping excipient types were common among products from Europe, the isotopic profiles remained distinct, reflecting subtle but traceable formulation or raw material sourcing differences.
Of note, products from Japan and South Korea exhibited the most negative δ²H values, meaning that the hydrogen within is less heavy than the standard and likely indicative of regional manufacturing practices or ingredient origins. For example, these tablets included caffeine or anhydrous calcium phosphate, which may have influenced their isotope profiles.
While the United States Pharmacopeia currently references isotopic characterization as a potential application of mass spectrometry, it has not yet formalized IRMS for drug authentication. However, the “United States Pharmacopeia describes the potential application of stable light isotopes under section ⟨1736⟩ Applications of Mass Spectrometry, 7.1.3. Isotopic Characterization, where authentication and identification of contaminants in drug products and raw ingredients are highlighted as some of the strengths of IRMS analysis, but no monographs utilize the isotopic methodology,” the authors state.
By identifying both inter- and intra-manufacturer variations with a high degree of specificity, stable isotope profiling offers an added layer of traceability that could complement existing chemical and physical QC methods, particularly in global supply chains where counterfeiting is rife and raw material provenance is obscured.
The study concludes: “stable light isotopic analysis, thus, is a powerful tool for health authorities and pharmaceutical manufacturers to detect falsified and substandard drug products, protect against patent infringement, and evaluate raw material supply lines to ensure high-quality products.”
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