Background/ObjectiveThe heating of the fluids used in electronic cigarettes (“e-cigarettes”) used to create “vaping” aerosols is capable of causing a wide range of degradation reaction products. We investigated formation of benzene (an important human carcinogen) from e-cigarette fluids containing propylene glycol (PG), glycerol (GL), benzoic acid, the flavor chemical benzaldehyde, and nicotine.Methods/Main resultsThree e-cigarette devices were used: the JUULTM “pod” system (provides no user accessible settings other than flavor cartridge choice), and two refill tank systems that allowed a range of user accessible power settings. Benzene in the e-cigarette aerosols was determined by gas chromatography/mass spectrometry. Benzene formation was ND (not detected) in the JUUL system. In the two tank systems benzene was found to form from propylene glycol (PG) and glycerol (GL), and from the additives benzoic acid and benzaldehyde, especially at high power settings. With 50:50 PG+GL, for tank device 1 at 6W and 13W, the formed benzene concentrations were 1.9 and 750 μg/m3. For tank device 2, at 6W and 25W, the formed concentrations were ND and 1.8 μg/m3. With benzoic acid and benzaldehyde at ~10 mg/mL, for tank device 1, values at 13W were as high as 5000 μg/m3. For tank device 2 at 25W, all values were ≤~100 μg/m3. These values may be compared with what can be expected in a conventional (tobacco) cigarette, namely 200,000 μg/m3. Thus, the risks from benzene will be lower from e-cigarettes than from conventional cigarettes. However, ambient benzene air concentrations in the U.S. have typically been 1 μg/m3, so that benzene has been named the largest single known cancer-risk air toxic in the U.S. For non-smokers, chronically repeated exposure to benzene from e-cigarettes at levels such as 100 or higher μg/m3 will not be of negligible risk.

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.

IntroductionThe distribution of nicotine among its free-base (fb) and protonated forms in aerosolised nicotine affects inhalability. It has been manipulated in tobacco smoke and now in electronic cigarettes by the use of acids to de-freebase nicotine and form ‘nicotine salts’.MethodsMeasurements on electronic cigarette fluids (e-liquids) were carried out to determine (1) the fraction of nicotine in the free-base form (αfb) and (2) the levels of organic acid(s) and nicotine. Samples included JUUL ‘pods’, ‘look-a-like/knock-off’ pods and some bottled ‘nicotine salt’ and ‘non-salt’ e-liquids.Resultsαfb= 0.12 ±0.01 at 40°C (≈ 37°C) for 10 JUUL products, which contain benzoic acid; nicotine protonation is extensive but incomplete.DiscussionFirst-generation e-liquids have αfb ≈ 1. At cigarette-like total nicotine concentration (Nictot) values of ~60 mg/mL, e-liquid aerosol droplets with αfb≈ 1 are harsh upon inhalation. The design evolution for e-liquids has paralleled that for smoked tobacco, giving a ‘déjà vu’ trajectory for αfb. For 17th-century ‘air-cured’ tobacco, αfb in the smoke particles was likely ≥ 0.5. The product αfbNictot in the smoke particles was high. ‘Flue-curing’ retains higher levels of leaf sugars, which are precursors for organic acids in tobacco smoke, resulting in αfb ≈ 0.02 and lowered harshness. Some tobacco cigarette formulations/designs have been adjusted to restore some nicotine sensory ‘kick/impact’ with αfb≈ 0.1, as for Marlboro. Overall, for tobacco smoke, the de-freebasing trajectory was αfb ≥ 0.5 → ~0 →~0.1, as compared with αfb= ~1 →~0.1 for e-cigarettes. For JUUL, the result has been, perhaps, an optimised, flavoured nicotine delivery system. The design evolution for e-cigarettes has made them more effective as substitutes to get smokers off combustibles. However, this evolution has likely made e-cigarette products vastly more addictive for never-smokers.

Electronic cigarette liquids (e-liquids) with sweetener additives such as sucralose, a synthetic chlorinated disaccharide, are popular among some e-cigarette consumers; sucralose can be added either by the manufacturer or by the consumer. The prevalence of sucralose in commercial e-liquids is not known, nor is the typical concentration of sucralose when present; labels are not required to disclose ingredient information. Here, we report the effects of sucralose on e-liquid degradation upon e-cigarette vaping as studied using 1H NMR spectroscopy, ion chromatography, and gas chromatography coupled with detection by mass spectrometry or flame ionization detector. Sucralose was found to be subject to degradation when included in propylene glycol + glycerol based e-liquids and vaped; the presence of sucralose in the e-liquids also resulted in altered and enhanced solvent degradation. In particular, production of aldehydes (carbonyls) and hemiacetals (which have implications for health) was enhanced, as demonstrated by 1H NMR. The presence of sucralose at 0.03 mol % (0.14 wt %) in an e-liquid also resulted in production of potentially harmful organochlorine compounds and catalyzed the cyclization of aldehydes with solvents to acetals upon vaping; the presence of chloride in e-liquid aerosols was confirmed by ion chromatography. Quantities of sucralose as low as 0.05 mol % (0.24 wt %) in e-liquids lead to significant production of solvent degradation products.

Tobacco products generally contain tobacco-derived nicotine (TDN; having ∼99+% (S)-(−)-nicotine). Recent United States regulation has led some producers to transition to synthetic (“tobacco-free”) nicotine. For example, Puff Bar is now marketed with tobacco-free nicotine (TFN; presumed to be racemic). To evaluate the claim that these new products contain TFN, we evaluated the presence of the two nicotine optical isomers by 1H NMR spectroscopy, polarimetry, and gas chromatography–mass spectrometry. Older Puff Bars were found to contain (S)-(−)-nicotine, and newer “TFN” Puff Bars were found to contain both (R)-(+) and (S)-(−) isomersindicating TFN, albeit with slightly more of the (S)-(−)-nicotine form.

In electronic cigarettes (“electronic nicotine delivery systems”, ENDS), mixtures of propylene glycol (PG) and/or glycerol (GL; aka “vegetable glycerin”, VG) with nicotine are vaporized to create a nicotine-containing aerosol. For a given composition, the temperature required to boil the liquid at 1 atmosphere must be at least somewhat greater than the boiling point (BP). The use of ENDS is increasing rapidly worldwide, yet the BP characteristics of the PG + GL system have been characterized as the mixtures; here we re-do this, but significantly, also study the effects of added water and nicotine. BP values at 1 atmosphere pressure were measured over the full binary composition range. Fits based on the Gibbs–Konovalov theorem provide BP as a function of composition (by mole-percent, by weight-percent, and by volume-percent). BPs of PG + GL mixtures were then tested in the presence of additives such as water (2.5 and 5 mol% added) and nicotine (3 mol%). Water was found to decrease the BP of PG + GL mixtures significantly at all compositions tested, and nicotine was found to decrease the BP of PG + GL mixtures containing ~75 GL: 25 PG (by moles) or more. The effect of added water (5, 10, and 15 mol% added) on electronic cigarette degradation production (some aldehydes and formaldehyde hemiacetals) was examined and found to have no significant impact on solvent (PG or GL) degradation for the particular device used.

An important design aspect of electronic cigarettes ("e-cigarettes") is the nature of the acid/base chemistry in the e-liquid phase. E-liquids having formulations similar to those of early products are mixes of propylene glycol/glycerol (PG/GL) plus free-base (fb) nicotine and (usually) flavor chemicals that are either rather weak or non-acid/base actors in PG/GL. The fraction of nicotine in the fb form is denoted (α fb ) e-liquid , with a possible range of 0 < (α fb ) e-liquid < 1. For e-liquids of an early design, (α fb ) e-liquid ≈ 1. Because e-cigarette aerosols high in fb nicotine are harsh upon inhalation, many commercial e-liquids now also contain variable levels of an acid additive (e.g., benzoic acid, levulinic acid, etc.) to protonate the nicotine and form dissolved "nicotine salts": (α fb ) e-liquid values significantly less than 1 are now common. A framework is developed for predicting α fb values in a given medium based on the following: (1) acid/nicotine ratios and (2) overall acid + nicotine protonation constant (K oa ) values. This framework is required for understanding (1) e-liquid design in regard to how acid additives affect (α fb ) e-liquid values, and (2) why (α fb ) e-liquid values cannot, in general, be measured by any method that involves significant dilution with water.

Heat-not-burn products, eg, I quit ordinary smoking (IQOS), are becoming popular alternative tobacco products. The nicotine aerosol protonation state has addiction implications due to differences in absorption kinetics and harshness. Nicotine free-base fraction (αfb) ranges from 0 to 1. Herein, we report αfb for IQOS aerosols by exchange-averaged 1H NMR chemical shifts of the nicotine methyl protons in bulk aerosol and verified by headspace-solid phase microextraction-gas chromatography-mass spectrometry. The αfb ≈ 0 for products tested; likely a result of proton transfer from acetic acid and/or other additives in the largely aqueous aerosol. Others reported higher αfb for these products, however, their methods were subject to error due to solvent perturbation.