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Synthetic nicotine production at CNT. (Credit: CNT GmbH)
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The structures of S-nicotine and R-nicotine. The chiral carbon atom is highlighted by the red asterisk. In S-nicotine, the hydrogen on this carbon atom is pointing towards viewers, whereas in R-nicotine it is pointingaway from them. The two structures are non-superimposable mirror images and, thus, different from each other in a chiral environment. (Credit: https://chempics.wordpress.com)
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George Cassels-Smith, director of TTI, eLT, and Zanoprima. (Credit: Tobacco Technology, Inc.)
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Next Generation Labs’ c.e.o., Vincent Schuman. (Credit: New Generation Labs LLC)
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In CNT’s r&d lab. (Credit: CNT GmbH)
By Thomas Schmid
CNT: From Europe to the World
Operating out of the picturesque southern German town of Heilbronn, Contraf-Nicotex-Tobacco GmbH (CNT) has been the world’s leading manufacturer of tobacco-derived “natural“ nicotine for decades, supplying not only tobacco companies but the whole range of pharma companies as well. The company first took an interest in synthetic nicotine in 2015, commercial products becoming available in 2018.
“Long-term supply security for nicotine is our foremost focus, so adding synthetic S-nicotine to our portfolio was a logical step for CNT,“ managing director Torsten Siemann said.
The company’s synthetic nicotine exclusively contains S-nicotine isomer molecules because, according to CNT‘s r&d director, Dr. Thomas Ellerichmann, “only S-nicotine is meeting USP and EP standards.“ However, he added that “CNT currently uses R/S-nicotine as a production intermediate“ to derive the final product.“ The difference between an R- and S-nicotine isomers is in their respective molecule structure, of course (see graphic).
Synthetic nicotine, used in certain e-liquids, as well as smokeless products (mainly nicotine pouches), brings quite a few advantages to the table when compared to its “natural” counterpart. For instance, it can show an extremely even, neutral taste profile and does not contain any tobacco-derived impurities. Then, there is the practically unlimited production capacity. “Currently, CNT has a vast production capacity of over 500 metric tons of tobacco-derived nicotine per year, but since synthetic nicotine is made in an industrial setting using various chemical raw materials, there really is no cap as to how much we can potentially produce,“ said Torsten Siemann, managing director.
Existing regulations may look favorable to synthetic nicotine, at least for the time being. When used in a next-generation product (NGP), “natural“ nicotine is classified as a tobacco product in most countries, thus being subject to relevant legislations. On the other hand, regulators don’t seem quite sure yet how to handle synthetic nicotine. The situation is currently unclear. There is indeed the possibility that synthetic nicotine — deployed in NGPs — may eventually not be classified as a tobacco product in the US. “However, it may be classified as a pharmaceutical product [when used in NGPs],” explained Siemann. Whatever FDA eventually decides, other territories, including the EU, will likely follow suit (as has been the case on various occasions in the past).
Difficult to purify, thus costly
But, synthetic nicotine still is a rather new product that has to “prove itself“ first. CNT’s tobacco-derived nicotine, on the other hand, has a proven safety track record in the pharmaceutical arena that spans well over 30 years. “It does not contain any nitrosamines, pesticides, or tobacco-related impurities, for example myosmine or nornicotine, at detectable levels, and it is extensively tested for its properties,” Dr. Ellerichmann pointed out. Secondly, the cost factor of synthetic nicotine comes into play as well. Synthetic nicotine‘s elaborate production and purifying process currently makes it more expensive than its tobacco-extracted cousin – and that certainly is an important aspect for end-product manufacturers to consider.
And don’t count out the consumer, either. “Many e-liquid customers prefer tobacco-derived nicotine because [to them] ‘synthetic nicotine’ sounds chemical and artificial, and having a ‘drug character’,” said Siemann. “Most vapers are ex-smokers and don’t want to reference their habit with ‘drug use’.” As such, he said CNT was presently “only seeing a minor [vaping] market shift towards synthetic nicotine,” as overall “the market for synthetic nicotine is still not more than 1-2% of global demand.” But he nevertheless expected rising interest once the regulatory situation becomes settled as, “FDA regulations are going to be the main driver.”
But, Siemann nevertheless asserted that CNT saw “great future potential“ for synthetic nicotine. That was why the company poured “significant amounts into r&d and production resources into [this] product segment“ in the first place. Yet, he also warned that there currently was a certain hype enveloping the industry that might cause the false impression that synthetic nicotine was on the best way of replacing tobacco-derived nicotine altogether. “But CNT doesn’t see this happening at all and we‘d rather believe that there is a growing nicotine products market where synthetic is going to play an increasing role.“
That synthetic nicotine – at least at this point – still has a long way to go before catching up to its “natural“ counterpart is also illustrated by the fact that about 95% of all orders presently handled by CNT are coming in from the US. Another 5% trickle in from Asia, primarily South Korea, while so far there has been no demand (as in “zero“) from Europe. Yet, CNT’s S-nicotine products (see product table) are uncompromisingly manufactured under the company’s pharmaceutical-quality system (cGMP) and available as nicotine bitartrate dihydrate (a nicotine salt), nicotine solutions, nicotine polacrilex resin, and nicotine granulate. As the current US trend is rather sooner than later going to fan out more forcefully into other markets, CNT already finds itself in an excellent position to respond immediately.
TTI: An Old Friend With a Very New Product
Based in Eldersburg, Maryland, US, Tobacco Technology Inc. was founded in 1975 as a flavor supplier. In response to the rising vaping industry, the firm subsequently established sister company eLiquiTech Inc. (eLT) only a few years ago as an e-juice compounding facility. And then there is Zanoprima Lifesciences Limited, an intellectual property company located in the UK, and which holds the patent rights to SyNic®, a trademarked synthetic nicotine brand. Well-known industry figure George Cassels-Smith serves as director to all three outfits. It is, therefore, not surprising that eLT has been appointed the sole distributor of SyNic® to the global tobacco industry.
SyNic® is a USP/EP-grade S-nicotine, which eLT markets in three principal forms: 1) as a pure USP/EP-compliant liquid used in vaping products; 2) as SyNic® nicotine bitartrate “salt” it is primarily a compound in snus pouches, but of course also can be used for e-liquids; and 3) as polacrilex resin, which finds its way into nicotine gums and lozenges. “Generally speaking, SyNic® bitartrate is a white powdered salt that dissolves over time, releasing its nicotine until completely exhausted, while SyNic® polacrilex resin slowly releases its nicotine upon mastication; however, the resin never completely dissipates,” Cassels-Smith elaborated.
Avoid those nitrosamines!
One issue of “natural” (i.e. tobacco-derived) nicotine is, of course, that it often contains certain impurities when not properly processed. The problem is that these impurities – such as nitrosamines – are chemically very similar to the nicotine molecule. “That makes them very time-consuming and costly to remove,” Cassels-Smith said, adding that “nitrosamines are believed to potentially be converted to carcinogens in the [human] body.” That, he said, was a risk factor that could be completely avoided by utilizing synthetic nicotine.
However, as CNT already pointed out, not even synthetic nicotine is always completely devoid of all and any impurities. It still contains miniscule trace amounts of myosmine, a substance that is also present in tobacco-derived nicotine. But, Cassels-Smith assured that SyNic® was safe, as it is “manufactured under strict drug standards at an FDA-approved facility, resulting in a product whose pure nicotine content is greater than 99.95%, the remaining 0.05% being made up primarily of myosmine. Therefore, SyNic®’s impurity profile was “very small in comparison to naturally derived nicotine,” he asserted.
With the acceptance of SyNic® and other synthetic nicotine brands into the global tobacco industry, the standards for “natural” nicotine also would improve, Cassels-Smith predicted. “And this in turn will create a more lucrative market for farmers to sell their tobacco crop for natural pedigreed ESP/EP-grade nicotine.” However, he cautioned that “super cheap” USP nicotine that is not traceable or trackable will likely take the brunt of downsizing in this market. This in turn would benefit SyNic® and tobacco farmers who supply raw materials for pedigreed nicotine. “SyNic® will raise the bar of the natural nicotine industry by creating a market for pedigreed products that are fully trackable and traceable from the farm up, including seed, soil and residual pesticide testing.”
Pioneer of the First Hour: Next Generation Labs
San Diego-based Next Generation Labs LLC (NGL), is the market leader in the still relatively nascent synthetic nicotine arena. “We are often considered the poor cousin of other [synthetic nicotine] suppliers, when in fact we are the dominant and first player in the market,” insisted Ron Tully, one of the company’s co-founders. NGL supplies both the tobacco/vaping and pharmaceutical sectors with its TFN® and Pharmanic® branded synthetic nicotine products. However, the company’s customers are also using TFN® in a range of “smokeless” consumer products (see related story in this issue).
The gradual – if slow - shift from “natural” to synthetic nicotine that is currently happening particularly in the vaping sector has to be looked at from a risk reduction perspective. “[Vaping] Manufacturers are interested in eliminating tobacco residuals from nicotine, and consumers want as clean a nicotine as possible as they seek nicotine alternatives on their journey away from tobacco,” he explained.
“A chemically synthesized molecule is in many ways a more perfect version of its natural counterpart. Think synthetic diamonds versus natural diamonds,” Tully said. In the case of nicotine, the enantiomeric nature of the molecule allows the synthetic manufacturing process to isolate the specific characteristics of the S-, R/S-, and R-isomer mixtures. According to Tully, this potentially could open new avenues for supporting combinational reward pathway nicotine (R- and S-isomer adjusted ratios), rather than utilizing only tobacco-identical S-isomer nicotine in future consumer products. Next Generation Labs’ c.e.o., Vincent Schuman, added that the company “has taken the lead in developing this type of nicotine exploration, and will continue to do so going forward.”
Initially “starting with a very broad vision of redefining nicotine as a technology in multiple industry sectors,” the company’s two current synthetic nicotine brands were first launched in 2014, with TFN® now primarily targeting the vaping and “smokeless” industry (see product table). “We eventually homed in our focus on vape, tobacco, and pharmaceuticals, as these are the places where the company can have the greatest impact in finally giving manufacturers a non-tobacco choice about what to put in their products, while, at the same time, according adult consumers a choice about what nicotine is best for their individual lifestyles,” Tully elaborated.
An important pivot in interest
Meanwhile, Schuman recalled that “customer interest in synthetic nicotine initially focused on markets that seemingly presented regulatory opportunities for selling products containing synthetic nicotine, such as South Korea and the US.” But he added that manufacturers in the meantime have come to understand that increasing numbers of adult smokers are starting to look at ways to wean themselves of tobacco use, and synthetic nicotine could play an important role in achieving just that.
The interest in synthetic nicotine had now “pivoted to the technological application rather than simply exploring the ‘does the product solve a tax or regulatory problem in a market?’ question,” Schuman said. “Consequently, NGL has been seeing an upswing in business inquiries from all major tobacco and nicotine markets.” This “upswing” is evidenced by the almost phenomenal increases in NGL’s year-on-year volume turnovers of its synthetic nicotine products. In 2018, the company had clocked a 15% increase compared to the preceding year; in 2019 this had risen another 65% year-on-year; in 2020 (and Covid-19 notwithstanding) it settled in at 300%; and for 2021 Schuman projected a staggering 1,800%.
Yet despite the apparent success of synthetic nicotine, Schumann asserted that traditional combustible tobacco products and the use of tobacco-derived nicotine recon sheet will likely remain unaffected. “The real advances [of synthetic nicotine] will occur in vape, heat-not-burn, pouches, gums, transdermal patches, dry aerosols, and other novel nicotine delivery systems,” he said. The market for synthetic nicotine will grow through what Tully described as “a destabilizing period as companies joust for customers and opportunities.”
“The coming months are going to see the introduction of multiple so-called synthetic nicotine products that are specifically targeted at the US,” he said, adding that these products needed to be subjected to rigorous validation to ensure that they are not “fake” (as in: tobacco-derived nicotine falsely labeled and misleadingly marketed as “synthetic”).
“Synthetic nicotine was a zero market in 2014,” asserted Tully, with NGL having been “the leading pioneer and innovator globally since that time.” And while the California-based company believes that the future growth trajectory for synthetic nicotine is strong, Tully is realistic enough to expect that NGL will “be met with more aggressive competition from tobacco-extracted nicotine manufacturers as they innovate their processes and improve their product quality to an extent that they will likely always enjoy the bulk share of the market.” But only time will tell.