Toward Better Characterization of a Free-Base Nicotine Fraction in e-Liquids and Aerosols

Abstract

Given that nicotine salts are a growing market, methods are needed to characterize nicotine forms in e-cigarette vaping products. By lowering the free-base nicotine fraction (α fb ) in favor of protonated forms, the addition of organic acids to the eliquid mix greatly modulates nicotine pharmacokinetics and improves vapers' craving. This research investigated (1) the performance of pH measurement, liquid−liquid extraction (LLE), and acid/nicotine molar ratio calculation methods for α fb estimation in 6 nicotine benzoate and nicotine salicylate e-liquids and (2) nicotine protonation in the aerosol post vaporization. Aerosols were generated with a JUUL device and another mod-pod on a vaping machine to assess device effects. E-liquid and aerosol samples were then analyzed after further analytical optimization of previous methods and careful consideration of biases. Globally, performances were comparable between methods. α fb accounted for less than 5% of nicotine content regardless of experimental conditions. α fb were consistent between e-liquids and aerosols irrespective of e-cigarette devices. Hence, e-liquids are adequate surrogates for aerosols, facilitating the establishment of regulations. pH measurement is one of the most used methods and enables the establishment of relative scales for e-liquid classification but lacks automation possibility. Until now, the extent of sample dilution remained arbitrary. The dilution factor was fixed at 10, as usually achieved, since no effect of dilution was noted. pH values ranged from 5.3 to 6.3 in accordance with the literature. By contrast, LLE relies on the specificity of organic solvent for free-base nicotine extraction, causing discrepancies in previous studies. Here, the results were similar to α fb values from pH determination. Yet, LLE presented the highest variability and was the most time-consuming protocol. Finally, α fb calculation from molar ratio was the most robust and versatile method. Estimations can be made in silico from reported composition data and/or after liquid chromatography routine analysis.

Quantification of Free Radicals from Vaping Electronic Cigarettes Containing Nicotine Salt Solutions with Different Organic Acid Types and Concentrations

“…All pH measurements were measured in triplicate. Bourgart et al found that a dilution factor from 2 to 200 yielded similar pH measurements . Note that the pH measurement by Harvanko et al of commercial nicotine salts matched the pH measurements in all the formulated nicotine salts in this study, except for LA.…”

“…Note that the term “pH” in this work and others should be used for relative comparisons between e-liquids only. Although pH measurements of PG/VG-based e-liquids with a potentiometric probe are stable upon addition of water and provide a good approximation of the acid content in solution, the values obtained may not be an accurate quantification of hydronium ion activity due to the lower water environment in e-liquids, even upon dilution. , Freebase nicotine e-liquids are generally available at a 3–20 mg/mL nicotine concentration. The freebase nicotine e-liquids have a measured pH of generally 9–10 in commercial formulations, but such alkaline nicotine formulations can cause a bitter and harsh sensation in the throat when inhaling the aerosol, which have been reported as unappealing to users. − The role of the organic acid is to allow users to vape at higher concentrations of nicotine without compromising taste as well as increasing nicotine delivery deeper into the lungs, resulting in higher overall user satisfaction .…”

In vitro toxicological evaluation of aerosols generated by a 4th generation vaping device using nicotine salts in an air-liquid interface system

“…The nicotine concentration in European e-liquids can range from 0 to a maximum of 20 mg/mL as required by the European Tobacco Products Directive [ 8 ]. Finally, nicotine can also exist in a variety of forms depending on its protonation state driven by pH of the solvent and nicotine pKa [ 42 ] and protonated nicotine salts can be generated with a variety of weak organic acids, including benzoic acid, salicylic acid, or lactic acid, among at least six others [ 43 ]. We have previously discussed the consequences of the heterogeneity of devices and e-liquids, which leads to a large number of in vitro studies with different experimental designs and aims, ultimately making consistent comparisons and robust conclusions on the toxicity of e-cigarette aerosols difficult [ 44 ].…”

A Quick Method for the Determination of the Fraction of Freebase Nicotine in Electronic Cigarettes

“…Previous studies have indicated that toluene has a tendency to extract acids, particularly benzoic acid, which was identified in the extracted samples. 48 Additionally, toluene has been found to extract flavors and nicotine. 46 , 48 Consequently, this extraction process can lead to a shift in the fb fraction values, thereby elucidating the larger discrepancies observed between the two methods.…”