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. 2022 Apr 14;17(4):e0267049.
doi: 10.1371/journal.pone.0267049. eCollection 2022.

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

Andrew G Cheetham  1 , Susan Plunkett  1   2 , Preston Campbell  2 , Jacob Hilldrup  1 , Bonnie G Coffa  1 , Stan Gilliland 3rd  2 , Steve Eckard  1
Affiliations

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

Andrew G Cheetham et al. PLoS One. .

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.

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Conflict of interest statement

The authors are paid employees of their respective companies. Enthalpy Analytical, LLC, a wholly owned subsidiary of Montrose Environmental Group, Inc., is an independent contract research laboratory with a focus on nicotine-containing products that provides analytical testing services for a wide range of clients, including tobacco manufacturers and government regulatory authorities. Consilium Sciences provides consulting services, offering scientific and regulatory solutions for materials science, nicotine, and cannabis organizations with a focus on potentially harm-reduced products.

Figures

Fig 1
Fig 1. Nicotine enantiomers and their pharmacological properties.
Fig 2
Fig 2. Nicotine production pathways.
Fig 3
Fig 3. Analysis of select nicotine degradants in tobacco-derived and synthetic nicotine samples.
Fig 4
Fig 4. Chiral analysis of the (S)- and (R)-nicotine enantiomers.
(a) Example chromatograms for an (S)-nicotine (left) and racemic (R)/(S)-nicotine (right) standards, and (b) relative amounts of (S)- and (R)-nicotine (as percentages) in various tobacco-derived and synthetic nicotine samples and formulations.
Fig 5
Fig 5. Chiral analysis of the (R)- and (S)-nornicotine analysis in tobacco-derived and synthetic nicotine samples.
(a) Example chromatography in a racemic nornicotine standard, TDN-1, and SyN-2 (left-to-right), and (b) comparison of the (R)/(S)-nornicotine ratio to the corresponding (R)/(S)-nicotine ratio.
Fig 6
Fig 6. Radiocarbon analysis of neat tobacco-derived and synthetic nicotine samples.
Fig 7
Fig 7. Radiocarbon analysis of blended nicotine mixtures, comparing the observed pMC result to the theoretical value.
See this image and copyright information in PMC

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