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

Abstract

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 αfb, with 0 ≤ αfb ≤ 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 αfb is relevant regarding abuse liability. Previous attempts to determine αfb in electronic cigarette liquids and vapor have been flawed. We employed the exchange-averaged 1H NMR chemical shifts of nicotine to determine αfb 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 ≤ αfb ≤ 0.84. The αfb 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 αfb (for ease of inhalation) are likely to be particularly problematic for public health.

Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations

“…The high concentrations of nicotine in JUUL EC is coupled to a high concentration of benzoic acid, which protonates nicotine making it less harsh when inhaled by users. 14,15 The combination of the high nicotine concentration and its protonation by benzoic acid likely facilitates JUUL use and subsequent addiction, especially of adolescent or naïve consumers of JUUL products. The potential for addiction to JUUL products is compounded by the report that only 37% of the past 30-day consumers were aware that JUUL products always contain nicotine.…”

“…12 Unlike many other EC fluids, JUUL products contain high concentrations of nicotine and sufficient acid to protonate most of the nicotine; lower free-base nicotine levels have been associated with increased palatability on inhalation. [13][14][15] The JUUL utilizes pre-filled EC fluid "pods", originally sold exclusively by JUUL, but now offered by third parties. JUUL currently sells eight flavors of pods, which can be characterized as minty ("Cool Mint" and "Classic Menthol"), fruity ("Mango", "Fruit Medley" and "Cool Cucumber"), sweet ("Crème Brulee"), and tobacco ("Classic Tobacco" and "Virginia Tobacco").…”

An Analytical Perspective on Determination of Free Base Nicotine in E-Liquids

“…Duell et al [23], free base nicotine in e-liquids was determined by 1 H NMR spectroscopy. Briefly, e-liquids were prepared at concentration of 8 mg/mL using the same five different flavors (menthol, tobacco, fruit, sweet, and coffee).…”

“…NMR spectroscopy was carried out using precision coaxial NMR inserts with experimental parameters as described by Duell et al [23]. Free base nicotine was calculated using equations (5) and (6) [23] and (7), based on difference in chemical shifts between aromatic hydrogens and hydrogens of the methyl (-CH 3 ) group which connects to protonable nitrogen (N) atom of the pyrrolidine ring:…”

“…Water used for all preparations was HPLC grade purified water. Sample preparation for NMR analysis was carried out based on the method suggested by Duell et al [23].…”