What Is the Nicotine in E-Liquid Made From: Natural, Tobacco-Free, or Synthetic?

As some companies begin to sell e-liquids made from what they call tobacco-free and synthetic nicotine, the debate over nicotine is intensifying. The source of nicotine provides manufacturers with sales arguments and some seemingly plausible legal denials, as most regulations link nicotine to tobacco. Is reverting to synthetic production a solution?
 
In this market, various brands from the food industry to cosmetics have launched organic, natural, and non-GMO labeled e-liquids. Is returning to synthetic or lab-made substances a step forward?

Tobacco Nicotine

Nicotine is a molecule, an alkaloid, naturally produced by some Solanaceae plants, commonly referred to as nicotine. Solanaceae plants include not only tobacco but also peppers, tomatoes, potatoes, eggplants, and petunias. Among these plants, tobacco (Nicotiana tabacum) is one of the richest in nicotine content, ranging from 8% to 14%, which is why it is used in cigarettes, dried, and burned.

Nicotine and tobacco have been linked for over a century. Nicotine provides psychological stimulation to smokers and can lead to addiction. In burning cigarettes, the tobacco leaves undergo minimal processing aside from drying. Bright green tobacco leaves are ready for harvest when they turn yellow-green, reaching their maximum nicotine content, and they are cured to a deep golden color with a mild flavor. Tobacco companies use additives to enhance this flavor, which is controversial as these additives are considered enhancers of cigarette addiction.

After World War II, nicotine was also used as a pesticide, but its use has diminished since the chemical industry has provided other cheaper molecules.

Liquid Nicotine Extracted from Plants

In e-liquids for electronic cigarettes, tobacco leaves are no longer used; instead, liquid nicotine solution, typically derived from tobacco leaves, is utilized.

Nicotine, 3 - [1-methylpyrrolidin-2-yl]pyridine, contains what chemists refer to as chiral carbon. This molecule typically has two non-superimposable structures known as enantiomers. They have the same chemical formula, but their atomic arrangements may differ, making the two molecules non-superimposable, like left and right hands; they are mirror images or enantiomers of each other. In chemistry, these two enantiomers are S- and R-nicotine.

Since S-nicotine rotates plane-polarized light to the left (levorotatory) and R-nicotine rotates it to the right (dextrorotatory), S-nicotine and R-nicotine can be optically distinguished. A recent fundamental concept in stereochemistry is that a mixture of two enantiomers in a 1:1 ratio is called a racemic mixture (the deviation of plane-polarized light is zero). In the case of nicotine, the racemic mixture is referred to as RS-nicotine.

In fresh tobacco, the alkaloid composition typically consists of 93% S-nicotine, 1.3% S-anabasine, 2.4% S-nornicotine, and 0.5% S-anatabine.

The extraction of alkaloids is achieved through organic solvents and distillation of crushed crops. Nicotine and alkaloids are soluble in solvents such as alcohol, chloroform, ether, petroleum ether, kerosene, and water. Using microwave heating and solvent mixing can improve the extraction rate of nicotine, shorten extraction time, and ensure product purity reaches 99.9% pharmaceutical grade.

Another method involves treating with salts and converting the liquid into sulfates. This method requires bleaching agents to remove impurities. Then, reagents are used to reduce the sulfates to usable forms. Bleach appears clearer, mistakenly thought to be of higher purity.

What is Tobacco-Free Nicotine?

Tobacco leaves, rather than eggplants or potatoes, are used to obtain nicotine because they have a high nicotine content, specifically in the active enantiomer S-nicotine.

Tobacco-free nicotine can be defined as nicotine extracted from other species. The yield and extraction time of nicotine extracts depend on the chosen plant.

Chemical Synthesis of Nicotine

Nicotine presents a comprehensive challenge for chemists. Until recently, the downside of synthetic nicotine was cost; the most economical way to obtain the required enantiomer was through the separation of racemic mixtures (RS-nicotine). Another step, recrystallization, would allow for the selection of the desired enantiomer (e.g., S-) and produce S-nicotine.

The main issue with racemic mixtures is that, compared to natural tobacco extracts, the presence of 50% non-psychoactive R-nicotine and 50% psychoactive S-nicotine divides the potential activity of the e-liquid into two parts. #p#分页标题#e#

Since labels only show nicotine content, the strength of synthetic nicotine racemic mixtures at 10mg/ml is effectively equivalent to 5mg/ml in e-liquids.

After purification, fresh synthetic liquid is colorless, just like nicotine extracted from tobacco leaves. The brown color of liquid nicotine is a natural process resulting from exposure to light, heat, and oxygen, sometimes occurring in the dark, even in sealed bottles. The discoloration of nicotine is purely "cosmetic"; clearer liquids do not imply greater purity or higher quality.

Who is Synthesizing Nicotine?

Next Generation Labs LLC (San Diego, California) is one of the few companies producing tobacco-free nicotine (TFN). Under the leadership of Ron Tully, the company is now focused on synthesizing nicotine "for large-scale production of pure (R, S)-nicotine, as well as its use in tobacco cessation and/or recreational vaping applications."

Next Generation Labs has also trademarked its synthetic nicotine, as pharmaceutical companies are interested in the primary product nicotine but also in its analogs (for treating brain diseases such as Parkinson's, Alzheimer's, ADHD, or epilepsy).

In an interview with Vape Radio, Ron Tully explained what TFN (synthetic derived nicotine) is and how it is viewed as a great alternative to traditional nicotine products. Its price has been discounted, initially at $125,000 per liter, but now net down to $5,000 per liter, competing with natural S-nicotine (around $4,000 per liter, Sigma-Aldrich). According to tobacco industry veterans, it has advantages over natural extracts, such as being odorless, tasteless, and having high purity.

Purity as a New Selling Point

Only a few vaping e-liquid brands, such as Coastline, CRFT Labs, and KVASS (a total of 14), use tobacco-free nicotine, while most of the market uses tobacco-derived nicotine. According to the founder, tobacco extracts still carry the plant's odor, which forces e-liquid manufacturers to use sweeteners and aggressive flavors to mask the off-flavors.

According to Next Generation Labs, the three main selling points of TFN nicotine are:

1. The absence of many impurities found in tobacco-derived nicotine,

2. Almost colorless and tasteless,

3. Significantly improves e-liquid flavor while providing the same biological effects as tobacco-derived nicotine.

The latest technology for synthetic nicotine claims that kerosene is often used as a solvent for extracting nicotine from tobacco, but purification cannot achieve complete cleanliness of the extract. It states, "Many of these contaminants are harmful to human systems, and many have been shown to be carcinogenic, enhancing the addictive nature of 'nicotine.'" The synthetic manufacturing scheme involves a multi-step synthesis method with ethyl nicotinate as the main chain, adding various atoms through specific reactions with low-toxicity or toxic compounds.

It remains unclear whether the FDA has jurisdiction over tobacco-free or synthetic nicotine products. The FDA has stated that it will review these products on a case-by-case basis.