Kinetics of Aldehyde Flavorant-Acetal Formation in E-Liquids with Different E-Cigarette Solvents and Common Additives Studied by ¹H NMR Spectroscopy

Abstract

Flavorants, nicotine, and organic acids are common additives found in the e-liquid carrier solvent, propylene glycol (PG) and/or glycerol (GL), at various concentrations. Some of the most concentrated and prevalent flavorants in e-liquids include trans-cinnamaldehyde, vanillin, and benzaldehyde. Aldehyde flavorants have been shown to react with PG and GL to form flavorant-PG and -GL acetals that have unique toxicity properties in e-liquids before aerosolization. However, there is still much that remains unknown about the effects of different e-cigarette solvents, water, nicotine, and organic acids on the rate of acetalization in e-liquids. We used 1H NMR spectroscopy to determine the first-order initial rate constant, half-life, and % acetal formed at equilibrium for flavorant-acetal formation in simulated e-liquids. Herein, we report that acetalization generally occurs at a faster rate and produces greater yields in e-liquids with higher ratios of GL (relative to PG). trans-Cinnamaldehyde acetals formed the fastest in 100% PG-simulated e-liquids, followed by benzaldehyde and vanillin based on their half-lives and rate constants. The acetal yield was greatest for benzaldehyde in PG e-liquids, followed by trans-cinnamaldehyde and vanillin. Acetalization in PG e-liquids containing aldehyde flavorants was inhibited by water and nicotine but catalyzed by benzoic acid. Flavorant-PG acetal formation was generally delayed in the presence of nicotine, even if benzoic acid was present at 2-, 4-, or 10-fold the nicotine concentration, as compared to the PG e-liquids with 2.5 mg/mL flavorant. Thus, commercial e-liquids with aldehyde flavorants containing a higher GL ratio (relative to PG), little water, no nicotine, nicotine with excess organic acids, or organic acids without nicotine would undergo acetalization the fastest and with the highest yield. Many commercial e-liquids must therefore contain significant amounts of flavorant acetals.

E-cigarette Flavors, Sensory Perception, and Evoked Responses

“…157 Interestingly, acetalization has been reported to occur at a faster rate and to produce higher yields when vapers utilize e-liquids with higher ratios of VG relative to PG. 158 These data reinforce the issue that reaction products formed between flavor aldehydes and excipient chemicals likely have differential toxicological properties as compared to their parent compounds and may thus contribute to the health effects of vaped aerosols within the lungs of e-cigarette users. 113,157,159,160 A study by Tierney and colleagues that identified and quantified the flavoring constituents in 30 popular e-cigarette products reported menthol concentrations ranging from 5.7 to 21.6 mg/mL (0.57 to 2.16% w/v), which are comparable to concentrations reported for the menthol content of traditional menthol cigarettes, that is, 3 to 20 mg per cigarette.…”

“…Indeed, menthol’s effectiveness in reducing both the perceived airway irritation and overall harshness that is typically produced during the inhalation of e-liquids containing high nicotine concentrations is thought to contribute to the sensory impact of the e-liquid when vaped and may increase nicotine intake. , The chemical itself is known to evoke oxidative and inflammatory responses and may lead to issues with the maintenance of epithelial barrier function within the lung. , Common e-cigarette flavorants such as menthol and various aldehydes (e.g., vanillin) are also known to react with alcohols (such as PG and VG) to form acetals . Interestingly, acetalization has been reported to occur at a faster rate and to produce higher yields when vapers utilize e-liquids with higher ratios of VG relative to PG . These data reinforce the issue that reaction products formed between flavor aldehydes and excipient chemicals likely have differential toxicological properties as compared to their parent compounds and may thus contribute to the health effects of vaped aerosols within the lungs of e-cigarette users. ,,, …”

A Wide Range of Flavoring–Carrier Fluid Adducts Form in E-Cigarette Liquids

“…Furfural PG and VG acetals, valeraldehyde PG and VG acetals, veretraldehyde PG and VG acetals, p-anisaldehyde PG and VG acetals, and piperonal VG acetal were confirmed for the first time, expanding on the acetals identified in previous studies. 7,8,16,17,25 Adducts were shown to form under general eliquid storage conditions (room temperature, partial light) when aldehydes were exposed to PG and VG. No flavoring molecules other than aldehydes and ketones within this project were identified to react with PG or VG.…”

“…Recently, a paper published by Kerber and Peyton examined the PG acetal formation rates and yields in the presence of water, nicotine, benzoic acid, and vegetable glycerine using 1 H NMR spectroscopy. 25 It was found that acetals form more rapidly and at higher yields when aldehydes are in the presence of higher VG ratios (relative to PG), little water, no nicotine, nicotine with excess organic acids, or organic acids without nicotine. This kinetics study strengthens the results presented here, as it confirms that the rates of reaction for aldehyde acetal formation is varied and dependent on the parent flavor molecule.…”

Effects of E-Cigarette Flavor Enhancing Capsules on Inhalable Aerosols

“…We have established a variety of methods for determining the flavorant and toxicological profiles of e-liquids before and after aerosolization using GC–MS and NMR spectroscopy. − GC–MS has higher sensitivity in analyzing volatile compounds compared to NMR and is typically used to determine the flavorant profile. However, NMR can identify and quantify some species not detectable by GC–MS.…”