Revealing the Stable δ(2)H, δ(13)C, and δ(18)O Isotopic Patterns of Ibuprofen Drug Products and Commonly Used Pharmaceutical Excipients.

This study explored the use of stable light δ(2)H, δ(13)C, and δ(18)O isotope ratio mass spectrometry (IRMS) to identify unique isotopic signatures in 27 ibuprofen drug products and pharmaceutical 27 commonly used excipients. The 27 ibuprofen drug products were collected from six different countries containing active pharmaceutical ingredient varying from 20% to 82% of the total tablet mass and 6-18 excipients. The drug products were homogenized by ball milling, but no other sample preparation was required prior to analysis. Approximately 150 μg of sample material was encapsulated (n = 3) and analyzed through TC/EA IRMS calibrated against certified reference materials. The isotopic analyses were conducted over consecutive weeks with high data reproducibility, and the ibuprofen drug products and excipients presented the lowest isotopic variation by mass for the δ(13)C signal, followed by δ(2)H and δ(18)O. The isotopic standard deviations for the drug products (δ(2)H ≤ 5.29%, δ(13)C ≤ 0.37%, and δ(18)O ≤ 1.75%) were expectedly higher compared to monoingredient excipients but generally considered low. Unique isotopic signatures were determined for the drug products and excipients, and through the isotopic separation, it was possible to differentiate across pharmaceutical manufacturers and between drug products produced by the same manufacturer. The isotopic signal stability across pharmaceutical batches was determined through analysis (n = 3) of 9 drug products obtained from the same manufacturer having different batch numbers, expiration dates, and packaging material. The isotopic variation (δ(2)H = -44.78 ± 3.51‰, δ(13)C = -22.11 ± 0.46‰, and δ(18)O = 34.18 ± 1.73‰) within batches from a pharmaceutical manufacturer was lower than the isotopic variation across the different drug products making stable light isotopic analysis a powerful tool for unique identification and for health authorities and pharmaceutical manufacturers to detect falsified and substandard drug products, protect against patent infringement, and ensure high-quality drug products.