Free-Base Nicotine Determination in Electronic Cigarette Liquids by (1)H NMR Spectroscopy

[Image: see text] E-liquids usually contain significant nicotine, which will exist primarily in two forms, monoprotonated and free-base, the proportions of which are alterable through the effective pH of the medium. The fraction of nicotine in the free-base form is α(fb), with 0 ≤ α(fb) ≤ 1. When dosed via aerosol, the two nicotine forms have different mechanisms and kinetics of delivery, as well as differing implications for harshness of the inhaled aerosol, so α(fb) is relevant regarding abuse liability. Previous attempts to determine α(fb) in electronic cigarette liquids and vapor have been flawed. We employed the exchange-averaged (1)H NMR chemical shifts of nicotine to determine α(fb) in samples of e-liquids. This method is rapid and direct and can also be used with collected aerosol material. The e-liquids tested were found to have 0.03 ≤ α(fb) ≤ 0.84. The α(fb) values in collected aerosol liquid samples were highly correlated with those for the parent e-liquids. E-liquids designed to combine high total nicotine level (addictive delivery) with low α(fb) (for ease of inhalation) are likely to be particularly problematic for public health.