Analysis and differentiation of tobacco-derived and synthetic nicotine products: Addressing an urgent regulatory issue

Abstract

There is significant regulatory and economic need to distinguish analytically between tobacco-derived nicotine (TDN) and synthetic nicotine (SyN) in commercial products. Currently, commercial e-liquid and oral pouch products are available that contain tobacco-free nicotine, which could be either extracted from tobacco or synthesized. While tobacco products that contain TDN are regulated by FDA Center for Tobacco Products, those with SyN are currently not in the domain of any regulatory authority. This regulatory difference provides an economic incentive to use or claim the use of SyN to remain on the market without submitting a Premarket Tobacco Product Application. TDN is ~99.3% (S)-nicotine, whereas SyN can vary from racemic (50/50 (R)/(S)) to ≥ 99% (S)-nicotine, i.e., chemically identical to the tobacco-derived compound. Here we report efforts to distinguish between TDN and SyN in various samples by characterizing impurities, (R)/(S)-nicotine enantiomer ratio, (R)/(S)-nornicotine enantiomer ratio, and carbon-14 (14C) content. Only 14C analysis accurately and precisely differentiated TDN (100% 14C) from SyN (35–38% 14C) in all samples tested. 14C quantitation of nicotine samples by accelerator mass spectrometry is a reliable determinate of nicotine source and can be used to identify misbranded product labelled as containing SyN. This is the first report to distinguish natural, bio-based nicotine from synthetic, petroleum-based nicotine across a range of pure nicotine samples and commercial e-liquid products.

Adolescents, Young Adults, and Adults Continue to Use E-Cigarette Devices and Flavors Two Years after FDA Discretionary Enforcement

“…Conversely, a higher percentage of adult users reported using unflavored and tobacco-flavored e-cigarette devices relative to users in younger age categories. These data along with other recent studies [ 15 , 17 ] strongly indicate that selective policy action is unlikely to effectively address the problem of adolescent e-cigarette use, particularly as tobacco companies continue to develop new products and marketing tactics to maintain profits and circumvent regulations [ 38 , 39 ]. Given the limited effectiveness of e-cigarettes as adult smoking-cessation devices [ 40 , 41 ] and the role of flavors in promoting adolescent e-cigarette use [ 6 , 30 , 34 ], the FDA should adopt more comprehensive policies that prohibit all flavors, including menthol, in all types of e-cigarette devices to help achieve its stated goal of stopping the public health crisis of adolescent e-cigarette use [ 12 ].…”

A Systematic Review of Analytical Methods for the Separation of Nicotine Enantiomers and Evaluation of Nicotine Sources

“…A total of 362 records were removed at this stage and the full texts of the remaining 27 articles were scanned. Accordingly, a total of 23 articles were included in the review. ,− ,,− Figure shows the PRISMA diagram that summarizes the steps of the selection process.…”

“…However, if synthetic nicotine was purified to become 99% ( S )-nicotine, TFN becomes indistinguishable from TDN if the previously described analytical methods were used. Other analytical methods were found to be used for this purpose . In fact, it was suggested that TFN and TDN could be distinguished by detecting specific impurities like tobacco-specific nitrosamines, nicotine degradants, and metals in TDN samples from one hand and synthetic precursors and residual solvent impurities in TFN samples from the other .…”

“…Accelerator Mass Spectrometry . Cheetham and co-workers explored different techniques to distinguish between TDN and TFN including screening for impurities (nicotine degradants and metals), chiral separation of nicotine and nornicotine enantiomers, and radiocarbon analysis . However, only radiocarbon analysis of 14 C successfully differentiated TDN from TFN in all tested samples.…”

Qualitative and Quantitative Analysis of Nicotine, Nicotine Derivatives, and Nicotine-Related Alkaloid Optical Isomers: A Review

“…Today there exist a number of analytical challenges for the tobacco industry and nicotine testing communities (54)(55)(56)(57)(58).…”