Fraction of free-base nicotine in fresh smoke particulate matter from the Eclipse "cigarette" by 1H NMR spectroscopy.
Pankow James F,Barsanti Kelley C,Peyton David H
Chemical research in toxicology
Solution 1H NMR (proton-NMR) spectroscopy was used to measure the distribution of nicotine between its free-base and protonated forms at 20 degrees C in (a) water; (b) glycerin/water mixtures; and (c) puff-averaged "smoke" particulate matter (PM) produced by the Eclipse cigarette, a so-called "harm reduction" cigarette manufactured by R. J. Reynolds (RJR) Tobacco Co. Smoke PM from the Eclipse contains glycerin, water, nicotine, and numerous other components. Smoke PM from the Eclipse yielded a signal for the three N-methyl protons on nicotine at a chemical shift of delta (ppm) = 2.79 relative to a trimethylsilane standard. With alpha fb = fraction of the total liquid nicotine in free-base form, and alpha a = fraction in the acidic, monoprotonated NicH+ form, then alpha a + alpha fb approximately 1. (The diprotonated form of nicotine was assumed negligible.) When the three types of solutions were adjusted so that alpha a approximately 1, the N-methyl protons yielded delta a = 2.82 (Eclipse smoke PM); 2.79 (35% water/65% glycerin); and 2.74 (water). When the solutions were adjusted so that alpha fb approximately 1, the N-methyl protons yielded delta fb = 2.16 (Eclipse smoke PM); 2.13 (35% water/65% glycerin); and 2.10 (water). In all of the solutions, the rate of proton exchange between NicH+ and Nic was fast relative to the 1H-NMR chemical shift difference in hertz. Each solution containing both NicH+ and Nic thus yielded a single N-methyl peak at a delta given by delta = alpha a delta a + alpha fb delta fb so that delta varied linearly between delta a and delta fb. Since alpha fb = (delta a-delta)/(delta a-delta fb), then delta = 2.79 for the unadjusted Eclipse smoke PM indicates alpha fb approximately 0.04. The effective pH of the Eclipse smoke PM at 20 degrees C may then be calculated as pHeff = 8.06 + log[alpha fb/(1-alpha fb)] = 6.69, where 8.06 is the pKa of NicH+ in water at 20 degrees C. The measurements obtained for the puff-averaged Eclipse smoke PM pertain to the chemistry of the smoke PM as it might be initially inhaled at 20 degrees C. Upon inhalation, the volatilization of nicotine and other acid/base active compounds (as well as a warming toward a body temperature of 37 degrees C) will alter the pHeff value of the smoke PM during the time that it resides and ages in the respiratory tract.
Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents.
Ferris Wayne G,Connolly G N,Henningfield J E
The recent availability of internal tobacco industry documents provides significant insight into industry knowledge and manipulation of tobacco smoke delivery. One critical area of research is the role of smoke chemistry in determining the absorption and effects of smoke constituents, especially harm producing or pharmacologically active compounds. Independent scientific research has suggested that the nicotine dosing characteristics, hence the addiction potential of cigarettes, may be determined in part by the amount of free-base nicotine in cigarette smoke and its effects on the location, route, and speed of absorption in the body and on the sensory perception effects of the inhaled smoke. Tobacco industry documents describe the use of a number of methods internally for measuring free-base nicotine delivery. These include the common use of cigarette "smoke pH" as a means to estimate the fraction of free-base nicotine in the particulate matter (PM) in cigarette smoke, as well as efforts to measure free-base nicotine directly. Although these methods do not provide accurate absolute measures of free-base nicotine in smoke, consistencies observed in the findings across the various manufacturers indicate: (1) real relative differences in the acid/base chemistry of the smoke from different brands of cigarettes; (2) a connection between differences in free-base levels and brand-dependent differences in sensory perception and smoke "impact"; and (3) levels of free-base nicotine that are greater than have typically been publicly discussed by the industry. Furthermore, the results of these methods are generally consistent with those of a recent study from the Centers for Disease Control and Prevention which directly measured the free-base fraction of nicotine across a range of cigarette types. Consideration of the likely fundamental importance of free-base nicotine levels in cigarette smoke, together with the efforts discussed in the tobacco industry documents to measure such levels, indicates that the public health community would benefit from additional research to assess directly the delivery of free-base nicotine in cigarette smoke across brands. This may be especially useful for those products ("light", "ultralight", "reduced carcinogen", etc) that have been promoted, either explicitly or implicitly, as "harm reducing".
Tobacco smoke particulate matter chemistry by NMR.
Barsanti Kelley C,Luo Wentai,Isabelle Lorne M,Pankow James F,Peyton David H
Magnetic resonance in chemistry : MRC
The submicron liquid droplets constituting the particulate matter of mainstream tobacco smoke (PMMTS) are viscous and of a composition that is complex and poorly understood. PMMTS is often approximately 80% w/w 'tar' where 'tar'=total PMMTS- (nicotine+water). Many of the chemical agents in MTS responsible for smoking-related cancers are found at least partially in the PMMTS portion of MTS. The properties of PMMTS vary with brand and with puffing patterns. The chemical forms and total levels of nicotine, the identities/levels of other compositionally dominant compounds, and the identities/levels of carcinogens are of interest. Most studies of the composition of PMMTS have involved extraction then chromatography. Such methods allow the determination of low-level constituents, but alter the samples such that direct information regarding chemical conditions within the PMMTS cannot be obtained. Here, we utilize nuclear magnetic resonance spectroscopy (NMR) to examine native PMMTS in conventional cigarettes, including measurements of the brand-dependent fraction of PMMTS nicotine that is in the free-base form (increasing this fraction in inhaled tobacco smoke affects the rates of the processes governing nicotine deposition in the respiratory tract, and so has implications for smoking behavior and addiction). We also demonstrate the use of NMR for characterizing the composition of PMMTS (including the levels of selected cigarette additives) when the cosolvent DMSO-d6 is added to improve spectral resolution. The native and solvent-assisted results open the door to a range of future studies.
Analysis of refill liquids for electronic cigarettes.
Etter Jean-François,Zäther Eva,Svensson Sofie
Addiction (Abingdon, England)
AIMS:To assess levels of nicotine, nicotine degradation products and some specific impurities in commercial refill liquids for electronic cigarettes. DESIGN AND SETTING:We analyzed 20 models of 10 of the most popular brands of refill liquids, using gas and liquid chromatography. MEASUREMENTS:We assessed nicotine content, content of the known nicotine degradation products and impurities, and presence of ethylene glycol and diethylene glycol. FINDINGS:The nicotine content in the bottles corresponded closely to the labels on the bottles. The levels of nicotine degradation products represented 0-4.4% of those for nicotine, but for most samples the level was 1-2%. Cis-N-oxide, trans-N-oxide, myosmine, anatabine and anabasine were the most common additional compounds found. Neither ethylene glycol nor diethylene glycol were detected. CONCLUSION:The nicotine content of electronic cigarette refill bottles is close to what is stated on the label. Impurities are detectable in several brands above the level set for nicotine products in the European Pharmacopoeia, but below the level where they would be likely to cause harm.
Chemical hazards present in liquids and vapors of electronic cigarettes.
Hutzler Christoph,Paschke Meike,Kruschinski Svetlana,Henkler Frank,Hahn Jürgen,Luch Andreas
Archives of toxicology
Electronic (e-)cigarettes have emerged in recent years as putative alternative to conventional tobacco cigarettes. These products do not contain typical carcinogens that are present in tobacco smoke, due to the lack of combustion. However, besides nicotine, hazards can also arise from other constituents of liquids, such as solvents, flavors, additives and contaminants. In this study, we have analyzed 28 liquids of seven manufacturers purchased in Germany. We confirm the presence of a wide range of flavors to enhance palatability. Although glycerol and propylene glycol were detected in all samples, these solvents had been replaced by ethylene glycol as dominant compound in five products. Ethylene glycol is associated with markedly enhanced toxicological hazards when compared to conventionally used glycerol and propylene glycol. Additional additives, such as coumarin and acetamide, that raise concerns for human health were detected in certain samples. Ten out of 28 products had been declared "free-of-nicotine" by the manufacturer. Among these ten, seven liquids were identified containing nicotine in the range of 0.1-15 µg/ml. This suggests that "carry over" of ingredients may occur during the production of cartridges. We have further analyzed the formation of carbonylic compounds in one widely distributed nicotine-free brand. Significant amounts of formaldehyde, acetaldehyde and propionaldehyde were only found at 150 °C by headspace GC-MS analysis. In addition, an enhanced formation of aldehydes was found in defined puff fractions, using an adopted machine smoking protocol. However, this effect was delayed and only observed during the last third of the smoking procedure. In the emissions of these fractions, which represent up to 40 % of total vapor volume, similar levels of formaldehyde were detected when compared to conventional tobacco cigarettes. By contrast, carbonylic compounds were hardly detectable in earlier collected fractions. Our data demonstrate the necessity of standardized machine smoking protocols to reliably address putative risks of e-cigarettes for consumers.
Free-Base and Protonated Nicotine in Electronic Cigarette Liquids and Aerosols.
El-Hellani Ahmad,El-Hage Rachel,Baalbaki Rima,Salman Rola,Talih Soha,Shihadeh Alan,Saliba Najat A
Chemical research in toxicology
As with other tobacco aerosols, nicotine delivery from e-cigarettes (ECIG) depends on the total nicotine and its partitioning between free-base (Nic) and protonated (NicH(+)) forms. Previous studies of ECIG nicotine emissions have generally reported "nicotine yield" without attention to whether the methods employed resulted in quantification of the total nicotine or only one of its forms, making reported results difficult to compare across studies or to evaluate against reported blood exposure. This study reports a convenient solvent extraction method for determining total nicotine and its partitioning in ECIG liquids and aerosols by gas chromatography. Commercial ECIG liquids and aerosols were analyzed, and it was found that most of the nicotine was in the Nic form, with aerosols exhibiting higher Nic fraction than the parent liquids. Apparent pH was found to correlate with nicotine partitioning and can provide a useful indirect measure when chromatography is unavailable. Finally, labeled ECIG liquid nicotine concentration in commercial products was often inconsistent with measured nicotine.
Free-Base Nicotine Is Nearly Absent in Aerosol from IQOS Heat-Not-Burn Devices, As Determined by H NMR Spectroscopy.
Meehan-Atrash Jiries,Duell Anna K,McWhirter Kevin J,Luo Wentai,Peyton David H,Strongin Robert M
Chemical research in toxicology
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 (α) ranges from 0 to 1. Herein, we report α for IQOS aerosols by exchange-averaged H NMR chemical shifts of the nicotine methyl protons in bulk aerosol and verified by headspace-solid phase microextraction-gas chromatography-mass spectrometry. The α ≈ 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 α for these products, however, their methods were subject to error due to solvent perturbation.
Characterization of Nicotine Salts in 23 Electronic Cigarette Refill Liquids.
Harvanko Arit M,Havel Christopher M,Jacob Peyton,Benowitz Neal L
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco
INTRODUCTION:Many electronic cigarette manufacturers have begun offering liquids containing "nicotine salts," which are formed when an acid is mixed in a solution with free-base nicotine. Type of salt could play a significant role in the abuse liability of electronic cigarette liquids. As a first step to understanding nicotine salts, this study sought to identify the types of acids present in 23 commercially available electronic cigarette liquids. AIMS AND METHODS:Twenty-three electronic cigarette liquids advertised as containing nicotine salts were purchased for analysis. These liquids were tested for the presence of 11 different organic acids that were deemed likely to be used in a nicotine salt formulation. Liquids were analyzed using a combination of liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry methods, then compared to authentic acid standards for identification. RESULTS:Six of the 11 possible acids were identified in the liquids, from most to least common: lactic, benzoic, levulinic, salicyclic, malic, and tartaric acid. Acid(s) could not be identified in one of the liquids. Though most liquids contained only one type, three of the liquids contained multiple acids. CONCLUSIONS:These data demonstrate that several types of salts/acids are currently being used in electronic cigarette liquids. The type and concentration of salt(s) used in these liquids may differentially alter sensations in the throat and upper airway, and overall pharmacology of the aerosols by altering liquid pH and from flavor and sensory characteristics of the acids themselves. IMPLICATIONS:This study demonstrates that at least six different types of acids are being used to create the nicotine salts in electronic cigarette liquids, with the acids lactic, benzoic, and levulinic being the most frequently identified. Identification of these acids can serve as the foundation for future research to determine if type of nicotine salt alters pharmacological and toxicological effects of electronic cigarettes.
Free-Base Nicotine Fraction α in Non-Aqueous versus Aqueous Solutions: Electronic Cigarette Fluids Without versus With Dilution with Water.
Pankow James F,Duell Anna K,Peyton David H
Chemical research in toxicology
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), with a possible range of 0 < (α) < 1. For e-liquids of an early design, (α) ≈ 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) values significantly less than 1 are now common. A framework is developed for predicting α values in a given medium based on the following: (1) acid/nicotine ratios and (2) overall acid + nicotine protonation constant () values. This framework is required for understanding (1) e-liquid design in regard to how acid additives affect (α) values, and (2) why (α) values cannot, in general, be measured by any method that involves significant dilution with water.
E-Cigarette Quality Control: Impurity and Nicotine Level Analysis in Electronic Cigarette Refill Liquids.
Bennani Ismail,Alami Chentoufi Madiha,El Karbane Miloud,Cheikh Amine,Bouatia Mustapha
This work targets mainly the quality control of electronic cigarette liquids. It relies on an analytical control of a "32-product" sample made of several types of e-cigarette liquids taken from various supermarkets and tobacconist's offices in Morocco. All along this study, we made sure to check both the conformity of the nicotine level indicated in the packaging of each product and the existence of any other components inside the product, especially toxic or unknown impurities. The method used for this study is known under the name of high-performance liquid chromatography. For statistical analysis, we used Student's -test for a single sample in order to analyze the relative differences between nicotine quantity reported in the product and the one measured during our experiment. Finally, we used linear regression test to determine the relationship between the nicotine level accuracy on the packaging and the level of toxic impurities in the products. The differences between the nicotine concentrations reported in the packages and the measured ones varied from -100% to +3.3%. The study showed that 31% of analyzed products have an accurate indication of the level of nicotine on the packaging. However, 47% of the studied products showed more than 20% difference between measure and packaging indication. In all analyzed samples, the level of impurities altered from 0 to 32.6%. Furthermore, the level of the nicotine breakdown products did not exceed 2% of the nicotine content in pretty much all of the samples. The actual nicotine content of electronic cigarette refill liquids is not always as precise as what is stated on the packaging; in addition to the level of impurities detected in several brands and that exceeds the European Pharmacopoeia standards, some may even present a risk of causing toxicological damage.