PURIFICATION OF NICOTINE

Abstract

The disclosure describes methods for providing nicotine isolates, including: receiving a solution containing nicotine derived from green tobacco biomass of a plant of the Nicotiana species; converting the nicotine to nicotine sulfate; concentrating the resulting nicotine sulfate-containing solution; adjusting the pH of the resulting nicotine sulfate concentrate to a pH of about 9.5 or greater to convert the nicotine sulfate to nicotine in free base form; extracting the resulting basic concentrate with an organic solvent to partition the nicotine into the organic solvent; and distilling the nicotine-containing organic solution to afford a nicotine isolate comprising about 90% or more nicotine by weight.

Claims

1. A method for providing a nicotine isolate, comprising: a) receiving a solution comprising nicotine derived from green tobacco biomass of a plant of the Nicotiana species; b) converting the nicotine to nicotine sulfate, giving a nicotine sulfate-containing solution; c) concentrating the nicotine sulfate-containing solution to give a nicotine sulfate concentrate; d) adjusting the pH of the nicotine sulfate concentrate to a pH of about 9.5 or greater to convert the nicotine sulfate to nicotine in free base form, providing a basic concentrate; e) extracting the basic concentrate with an organic solvent to partition the nicotine in free base form into the organic solvent, providing a nicotine-containing organic solution; and f) distilling the nicotine-containing organic solution to afford a nicotine isolate, wherein the nicotine isolate comprises about 90% or more nicotine by weight.

2. The method of claim 1, wherein the solution in step a) is a byproduct of a method to provide one or more of protein, sugar, salt, organic acids.

3. The method of claim 1, wherein the converting in step b) comprises treating the solution comprising nicotine with sulfuric acid.

4. The method of claim 1, wherein the nicotine sulfate-containing solution has a pH of about 2 to about 6.

5. The method of claim 1, wherein the nicotine sulfate-containing solution comprises about 90% or more nicotine sulfate by dry weight.

6. The method of claim 1, wherein the nicotine sulfate-containing solution comprises about 3% or less myosmine by dry weight, and about 2% or less nicotine N-oxide by dry weight

7. The method of claim 1, wherein the concentrating in step c) comprises subjecting the nicotine sulfate-containing solution to vacuum evaporation or distillation.

8. The method of claim 7, wherein the concentrating in step c) comprises vacuum evaporation at a temperature of about 40 C. to about 50 C. and at a pressure of about 25 in Hg to 27 in Hg.

9. The method of claim 1, wherein the concentrating in step c) comprises subjecting the nicotine sulfate-containing solution to counter-current extraction.

10. The method of claim 1, wherein the adjusting in step d) comprises adding a sodium hydroxide solution to the nicotine sulfate concentrate.

11. The method of claim 1, wherein the adjusting in step d) comprises adjusting to a pH of about 12 or greater.

12. The method of claim 1, wherein the adjusting in step d) comprises adjusting to a pH of about 13.

13. The method of claim 1, further comprising removing solids from the basic concentrate prior to step e).

14. The method of claim 13, wherein the removing solids comprises filtering the solids from the basic concentrate.

15. The method of claim 1, wherein there is no intervening processing step between step d) and e).

16. The method of claim 1, wherein the organic solvent in step e) comprises cyclohexane.

17. The method of claim 1, wherein the nicotine-containing organic solution in step e) comprises at least about 40% nicotine by weight.

18. The method of claim 1, wherein the distilling of step f) comprises a first stage to remove organic solvent and a second stage to distill and collect the nicotine isolate.

19. The method of claim 18, wherein the first stage is conducted at elevated temperature and atmospheric pressure and wherein the second stage is conducted under vacuum.

20. The method of claim 1, wherein the nicotine isolate comprises about 98% or more nicotine by weight

21. The method of claim 1, wherein the nicotine isolate comprises about 99% or more nicotine by weight.

22. A nicotine isolate provided according to the method of claim 1.

23. A pharmaceutical product comprising the nicotine isolate of claim 22.

24. An electronic cigarette comprising the nicotine isolate of claim 22.

25. A cartridge for an electronic cigarette comprising the nicotine isolate of claim 22.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to provide an understanding of embodiments of the disclosure, reference is made to the appended drawings, which are not necessarily drawn to scale, and in which reference numerals refer to components of exemplary embodiments. The drawings are exemplary only, and should not be construed as limiting the scope of the disclosure.

[0027] FIG. 1 is a flowchart of method steps associated with one embodiment of the present disclosure;

[0028] FIG. 2 is a flowchart of method steps associated with another embodiment of the present disclosure; and

[0029] FIG. 3 is a sectional view through a control body of an electronic smoking article according to one embodiment disclosed herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The present invention now will be described more fully hereinafter. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. As used in this specification and the claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. Reference to dry weight percent or dry weight basis refers to weight on the basis of dry ingredients (i.e., all ingredients except water).

[0031] The present disclosure provides methods for obtaining and/or purifying nicotine-containing materials derived from plant biomass. Nicotine (3-(1-methylpyrrolidin-2-yl)pyridine) is a compound produced by certain plants, e.g., plants of the Nicotiana species. Nicotine can have the enantiomeric form S()-nicotine, R(+)-nicotine, or a mixture of S()-nicotine and R(+)-nicotine. Most preferably, nicotine provided and/or purified according to the disclosed methods is in the form of S()-nicotine (e.g., in a form that is virtually all S()-nicotine) or a racemic mixture composed primarily or predominantly of S()-nicotine (e.g., a mixture composed of about 95 weight parts S()-nicotine and about 5 weight parts R(+)-nicotine). It is noted that tobacco-derived nicotine is typically about 99.3% S enantiomer with 0.7% R enantiomer; while the nicotine provided according to the present disclosure may be consistent with (or close to) this ratio, it is not limited thereto.

[0032] The term biomass and related terms such as biomatter and plant source are understood to refer to any portion of a harvested plant that may be processed to extract, separate, or isolate components of interest therefrom. The processing may be carried out in relation to various plants or portions thereof, such as seeds, flowers, stalks, stems, roots, tubers, leaves, or any further portions of the plant.

[0033] The present disclosure more specifically provides methods for obtaining and/or purifying nicotine from plant biomass-derived, nicotine-containing materials from a plant of the Nicotiana species. Certain such methods, described herein, provide nicotine in a purified form, e.g., suitable for use in aerosol delivery devices and pharmaceutical products. Advantageously, according to the disclosed methods, nicotine is obtained and purified from fresh plant biomass. By fresh plant biomass is meant biomass that has not been cured (e.g., via traditional tobacco curing processes). Such fresh plant biomass can also be referred to as green biomass.

[0034] Traditional processes for the extraction and purification of nicotine involve deriving the nicotine from cured tobacco material. According to the present disclosure, in some embodiments, the processing of fresh/green tobacco material (rather than cured tobacco material) to obtain nicotine simplifies the process of providing nicotine of the desired purity. Typically, fresh tobacco material comprises less impurities such as nitrosamines, than corresponding cured material. As such, by providing a method by which nicotine can be derived from fresh/green tobacco, different and fewer processing steps can be required. For example, the process can involve fewer steps and/or can replace certain reagents/processes traditionally required with milder reagents/simpler processes. In some embodiments, chromatography is not required (although the disclosed methods are not to be read to necessarily exclude chromatographic steps). In some embodiments, the process can result in the generation of less hazardous waste (requiring disposal or storage) than typical nicotine extraction/purification processes and, in some embodiments, the process can result in minimized overall cost associated with obtaining nicotine of the desired purity as compared with typical nicotine extraction/purification processes.

[0035] The process of the present disclosure generally can be outlined as depicted in FIG. 1. In FIG. 1, process 100 for the isolation and purification of nicotine begins with obtaining a nicotine-containing material 14. Nicotine-containing material 14, as referenced above, is advantageously a material derived from a plant of the Nicotiana species, and has not been subjected to curing conditions (i.e., material 14 is in fresh or green form). In some embodiments, material 14 is a byproduct of a tobacco treatment process. In some embodiments, material 14 is a nicotine-containing aqueous solution derived from fresh tobacco biomass. For example, material 14 can be a nicotine-containing solution (e.g., aqueous solution) that results (as a byproduct) from a process to obtain other components from green tobacco, including, but not limited to, tobacco-derived protein (provided, e.g., as disclosed in U.S. Pat. No. 9,301,544 to Mua et al., which is incorporated herein by reference).

[0036] In one particular embodiment, material 14 is obtained from the process 200 shown in FIG. 2, comprising the steps of: extracting green tobacco biomass 2 with an aqueous buffer and separating the liquid component therefrom; subjecting the liquid component 4 to clarification (e.g., via decanter, disc stack, and/or filter press) to remove, e.g., starch, cells, and chlorophyll, giving clarified solution 6; fractionating and concentrating the clarified solution to provide a protein-enriched material 8 and byproduct 10. The byproduct of this process generally comprises small molecules that can be further processed, e.g., via evaporation to separate out a mixture of sugar, salt, and organic acids 12, which can be further individually isolated. The byproduct of the evaporation is a distillate 14, containing nicotine, which, as referenced above, may in some embodiments serve as the source of nicotine in the process of FIG. 1.

[0037] Advantageously, in some embodiments, to promote stability and/or for processing purposes, the nicotine in nicotine-containing material 14 is optionally processed, e.g., by filtering, evaporating, and/or condensing and is then treated (via step A) to convert the nicotine contained therein to the form of nicotine sulfate. Step A can be done, e.g., immediately following production of material 14 and/or can be conducted at a later time, e.g., after material 14 has been subjected to storage for some period of time.

[0038] Advantageously, this step A is conducted shortly after the production of material 14, e.g., within a short time period after distillate 14 is collected (e.g., within a few days, or within 24 hours).

[0039] Step A is generally conducted by the addition of sulfuric acid to material 14 to give nicotine sulfate-containing solution 16. The amount of sulfuric acid added to material 14 necessarily varies, e.g., based on the amount of material 14 and the amount of nicotine contained therein. Typically, however, the amount of sulfuric acid added in step A is at least that amount sufficient to convert substantially all (or all) of the nicotine within material 14 to nicotine sulfate. The amount of nicotine sulfate present in the solution can vary, e.g., as a result of the concentration of nicotine present in material 14. The addition of sulfuric acid generally modifies the pH of the solution as well. In some embodiments, nicotine sulfate-containing solution 16 has a pH of about 1 to about 6 or about 2 to about 6, e.g., in certain embodiments, about 2. Typically, where equipment employed for subsequent steps of the process comprise stainless steel, it may be advantageous to ensure that solution 16 has a pH at the higher end of this range (e.g., about 4 to about 6).

[0040] Advantageously, nicotine sulfate-containing solution 16 can contain fewer/different impurities than nicotine sulfate-containing solutions obtained via cured tobacco materials. For example, in some embodiments, nicotine sulfate-containing solution 16 includes fewer (including little to no) nicotine degradation products, such as nicotine oxide or myosmine.

[0041] For example, in some embodiments, nicotine sulfate-containing solution 16 contains greater than 90% nicotine sulfate by dry weight, greater than 92% nicotine sulfate by dry weight, about 95% or greater nicotine sulfate by dry weight, about 96% or greater nicotine sulfate by dry weight, or about 97% or greater nicotine sulfate by dry weight. Typically, the solution 16 contains about 92% to about 98% nicotine sulfate by dry weight or about 95% to about 98% nicotine sulfate by dry weight. In some embodiments, nicotine sulfate-containing solution 16 contains about 3% or less myosmine (3-(4,5-dihydro-3H-pyrrol-2-yl)pyridine) by dry weight, and about 2% by weight or less nicotine N-oxide (1-methyl-2-(pyridine-3-yl)pyrrolidine-1-oxide). In some embodiments, nicotine sulfate-containing solution 16 contains less than 3% myosmine by dry weight or less than 2% myosmine (such as about 0.5 to about 3% or 0.5 to about 2% myosmine by dry weight, including about 1% or about 2% by dry weight). In some embodiments, nicotine sulfate-containing solution 16 contains less than 2% nicotine oxide by dry weight or less than about 1% nicotine oxide by dry weight (such as about 0.1 to about 2% nicotine oxide, about 0.5 to about 2% nicotine oxide, about 0.1 to about 1% nicotine oxide, or about 0.5 to about 1% nicotine oxide). In particular embodiments, nicotine sulfate-containing solution 16 contains less than 3% by weight myosmine and less than 2% by weight nicotine oxide, based on dry weight of the solution. In some embodiments, nicotine sulfate-containing solution 16 contains less than 2% by weight myosmine and less than 1% by weight nicotine oxide, based on dry weight. These referenced values are based on total alkaloids, and in some embodiments, water and some residual sulfuric acid may be present in nicotine sulfate-containing solution 16.

[0042] Nicotine sulfate-containing solution 16 is further processed via concentrating step B to give a nicotine sulfate-containing concentrate 18. Step B can be conducted by any methodology known in the art for concentrating a solution/removing liquid from a solution. Such methodologies can be conducted at various temperatures (e.g., room temperature or elevated temperature) and at various pressures (e.g., atmospheric pressure or vacuum). For example, in some embodiments, step B comprises vacuum evaporation.

[0043] In some embodiments, step B comprises distillation. In some embodiments, step B comprises counter-current extraction.

[0044] In one particular embodiment, step B comprises vacuum evaporation at a slightly elevated temperature (e.g., about 40-50 C.) at about 25 to about 27 in Hg to provide concentrate 18. Concentrate 18 generally contains a high concentration of nicotine sulfate, e.g., at least about 20% nicotine sulfate by weight, at least about 25% nicotine sulfate by weight, at least about 30% nicotine sulfate by weight, at least about 35% nicotine sulfate by weight, or at least about 40% nicotine sulfate by weight, based on the entire weight of the concentrate, e.g., about 20% to about 45%, about 25% to about 45%, about 30% to about 45%, about 35% to about 45%, about 38% to about 42%, about 20% to about 40%, about 25% to about 40%, or about 30% to about 40% nicotine sulfate by weight, based on the entire weight of the concentrate. In one particular embodiment, concentrate 18 contains about 40% nicotine sulfate by weight, based on the entire weight of the concentrate.

[0045] Nicotine sulfate-containing concentrate 18 is then pH adjusted to a basic pH (step C) to provide basic concentrate 20, wherein the nicotine is in free-base form (and the sulfate is, correspondingly, in the form of a sulfate salt, e.g., sodium sulfate based on the specific reagent used for pH adjustment). The reagent(s) used in step C to provide basic concentrate 20 can vary and a range of bases are known for pH adjustment. In certain embodiments, a sodium hydroxide solution is used to adjust pH. The pH of basic concentrate 20 is generally equal to or greater than that pH required for nicotine to be present as a free base (e.g., a pH of at least about 9.5). In some embodiments, step C comprises adjusting the pH of the concentrate to a pH of about 9.5 or greater, about 10 or greater, about 11 or greater, about 12 or greater, or about 13 or greater. In certain embodiments, the pH range is about 12 to about 14, e.g., about 130.1. Where step C results in the formation of solids, basic concentrate 20 can be filtered (e.g., by simple/crude filtration) to remove such solids before further treatment. For example, the pH adjustment may result in the formation of sodium sulfate, which can be removed from basic concentrate 20 via crude filtration. Further, where step C generates heat, basic concentrate 20 can, in some embodiments, be cooled before further treatment.

[0046] It is noted that, in preferred embodiments, there is no intervening processing step between step B and step C. Various conventional methods for processing nicotine-containing solutions to purify nicotine therefrom include an organic extraction step between concentration and pH adjustment. Typically, this step is conducted to remove non-nicotine organic impurities (including, e.g., other alkaloids). However, due to the composition of the starting material 14, and, correspondingly, the composition of intermediate 16 in the disclosed process (which comprises little to no non-nicotine organic impurities, as detailed herein), no such organic extraction is necessary to ultimately provide nicotine at the desired level of purity (employing the subsequent steps, as described herein below).

[0047] The pH adjusted material is subsequently subjected to liquid/liquid extraction/partitioning step D to give organic nicotine-containing solution 22. In step D, the basic concentrate 20 is extracted with an organic solvent, which can vary. In some embodiments, the organic solvent comprises cyclohexane, but the solvent employed for extraction is understood to be not limited thereto. Various hydrocarbon solvents are effective for this stage. Advantageously, the organic solvent employed in step D is a solvent suitable for the extraction of nicotine therein, which is not substantially miscible with water, and which does not to any significant extent form an emulsion that is unsuitable for separation of aqueous and organic phases. In some embodiments, the organic solvent has a low boiling point so as to accommodate easy removal at a later stage of the process. Organic solvents other than cyclohexane, such as methyl tert-butyl ether (MTBE), kerosene, n-heptane, and/or n-hexane may, in some embodiments be used in step D. The ratio of organic solvent to basic concentrate 20 can vary; in preferred embodiments, the volume of organic solvent is less than the volume of basic concentrate 20, but the method step is not limited thereto. In one embodiment, a roughly 1:2 v/v ratio of cyclohexane to water is used.

[0048] The specific method of extraction can vary. In some embodiments, simple liquid/liquid extraction is used. In some embodiments, an industrial process such as countercurrent extraction, mixer-settler-based processes, and/or centrifugal extraction is used. Extraction is advantageously conducted at room temperature; however, in some embodiments, heat may be employed so as to conduct the extraction at an elevated temperature. The extraction can be conducted one time or multiple times to obtain the desired partitioning between aqueous and organic phases. In one embodiment, the basic concentrate 20 is mixed with organic solvent for 1 hour and phase separated to partition the nicotine into the organic phase, providing the organic nicotine-containing solution 22 (one extraction).

[0049] The result of step D is an organic phase containing a majority of the nicotine originally present in the basic concentrate 20. This organic nicotine-containing solution 22 advantageously contains at least about 85% of the nicotine or at least about 90% of the nicotine originally present in the basic concentrate 20, wherein even higher amounts are more desirable to increase overall nicotine yield. The concentration of nicotine in the organic nicotine-containing solution 22 can vary, e.g., as a result of the amount of organic solvent employed in step D. In some embodiments, organic nicotine-containing solution 22 comprises about 40% to about 80% nicotine or more in cyclohexane, based on the entirety of the solution. Dry weight of nicotine in this solution (based on removal of cyclohexane) is generally about 95% or greater.

[0050] The organic nicotine-containing solution 22 is then treated via fractional distillation E, providing purified nicotine isolate 24. Methods for fractional distillation are generally known to one of skill in the art, and a typical process involves heating a solution (here, organic nicotine-containing solution 22) to a temperature at which one or more components of the solution vaporizes, and the vaporized component(s) are isolated from the solution, condensed, and collected (giving a fraction). Various fractions are collected as the temperature of the solution is increased and, depending on the vaporization properties of the desired product (and the anticipated impurities in the solution), certain fractions will be discarded, and certain fractions will be collected and combined to give a purified solution of the desired product.

[0051] In certain embodiments, step E involves a 2-stage distillation. First, the organic solvent (e.g., cyclohexane) is typically removed from solution 22. The boiling point of cyclohexane is around 80 C. and, in some embodiments, this first stage is conducted over a temperature range of about 60 C. to about 100 C., at atmospheric pressure. Given the composition of solution 22, careful control over collection of the cyclohexane is not typically required, as the solution generally does not contain a high concentration of compounds that will volatilize within this range. In some embodiments, the distillate thus collected contains principally cyclohexane, although in some embodiments, it may contain trace amounts of other components (e.g., trace amounts of certain organic compounds/impurities and/or small amounts of nicotine). In some embodiments, the cyclohexane distillate can be recycled following distillation for use in additional processes 100 as the organic solvent in step D.

[0052] The second stage of 2-stage distillation step E generally involves modifying the pressure of distillation to produce a vacuum (e.g., 3 Torr, e.g., 30.1 Torr absolute). At this pressure, the boiling point of nicotine is roughly 85 C.; accordingly, the temperature of the solution at this stage is raised to about 80-90 C. at the noted pressure. After collection of a small amount of forerun, the nicotine is distilled from the solution, condensed, and collected until only a small portion of the original solution remains (e.g., about 5% by volume). Although not intending to be limited by theory, it is believed that this second stage of distillation removes trace amounts of various other compounds present in the organic nicotine-containing solution (e.g., other alkaloids).

[0053] The enhanced purity of the nicotine isolate 24 provided according to the disclosed process can vary. The purified nicotine isolate 24 provided according to the processes herein can be, in various embodiments, at least 99.0% nicotine, at least 99.1% nicotine, at least 99.2% nicotine, at least 99.3% nicotine, at least 99.4% nicotine, at least 99.5% nicotine, at least 99.6% nicotine, at least 99.7% nicotine, at least 99.8% nicotine, or at least 99.9% nicotine. For example, in certain embodiments, the disclosed process provides a purified nicotine isolate meeting the purity standards outlined in the USP guidelines. The USP guidelines require, e.g., that a nicotine extract contain not less than 99.0 percent and not more than 101.0 percent C.sub.10H.sub.14N.sub.2, calculated on an anhydrous basis. In some embodiments, the disclosed process provides a purified nicotine isolate meeting EP standards. The EP standards require, e.g., that a nicotine extract contain less than 0.8% impurities in total, with no single impurity being present in an amount of greater than 0.4%. In some embodiments, the nicotine isolate 24 meets such criteria based on analysis by nicotine-specific high performance liquid chromatography, targeting typical impurities such as myosmine, nornicotine, nicotine oxide, cotinine, nicotyrine, anatabine, and anabasine.

[0054] In some embodiments, the purified nicotine isolate exhibits little to no color by visual inspection upon production and is substantially clear (e.g., including clear). It is noted, however, that the isolate may exhibit some yellow color over time. In some embodiments, the specific rotation as measured by a polarimeter is within the range of 130 to 152, such as 130 to 143 or 140 to 152. In some embodiments, the water content in the purified nicotine isolate is less than 0.5% water, as measured by Karl Fischer/toluene distillation. In some embodiments, the purified nicotine isolate comprises less than 500 ppm residual solvent as measured by headspace gas chromatography/flame ionization detection. In some embodiments, the heavy metal content of the purified nicotine isolate is less than 20 ppm (e.g., less than 20 ppm lead), as measured by a muffle furnace.

[0055] Of course, it is to be understood that various additional processes can be used within the disclosed method or in addition to the disclosed method. For example, typical separation processes can include one or more process steps such as solvent extraction (e.g., using polar solvents, organic solvents, or supercritical fluids), chromatography (e.g., preparative liquid chromatography), clarification, distillation, filtration (e.g., ultrafiltration), recrystallization, and/or solvent-solvent partitioning. Also, the parameters of various method steps can be varied. In some embodiments, it may be advantageous to conduct solvent extraction using a cold extracting liquid (e.g., water), particularly prior to a subsequent filtration step. Extractions may be conducted at elevated temperature; however, subjecting extracts resulting from such extractions directly to filtration may damage the filters, due to the heat associated with the extracts and, as such, hot/warm extracts are typically cooled prior to subsequent filtration steps. This cooling step can be avoided in some embodiments by conducting extractions at room temperature, in which case the resulting extracts can be advantageously directly treated by filtration.

[0056] As such, in some embodiments, further processing steps are incorporated within process 100 (e.g., additional heating steps, filtering steps, extraction steps, and the like). In other embodiments, process 100 consists essentially only of the steps disclosed herein (steps A-E), i.e., no significant additional processing steps (e.g., additional extractions, distillations, or the like) are conducted within process 100. The present disclosure is applicable, in some embodiments, for (in addition to laboratory, or small scale production), large/industrial scale production, where the term large scale production refers to processing large quantities of a biomass or a biomass byproduct (e.g., material 14 of the process of FIG. 2) on a mass production level.

[0057] It is noted that, in some embodiments, pharmaceutical-grade nicotine is provided by employing pharmaceutical quality systems and practices in manufacturing and handling the starting materials, intermediates, and products of each step of process 100.

[0058] The process disclosed herein can employ starting material 14 derived from various forms of a plant of the Nicotiana species, as described for example, in U.S. Pat. No. 9,254,001 to Byrd et al., which is incorporated by reference herein. Exemplary tobacco types from which material 14 can be obtained include, but are not limited to, Virginia (e.g., K326), burley, Indian, Kurnool, and Oriental tobaccos (including Katerini, Prelip, Komotini, Xanthi and Yambol tobaccos), Maryland, Passanda, Cubano, Jatin and Bezuki tobaccos, North Wisconsin and Galpao tobaccos, Red Russian and Rustica tobaccos, as well as various other rare or specialty tobaccos and various blends of any of the foregoing tobaccos. Descriptions of various types of tobaccos, growing practices and harvesting practices are set forth in Tobacco Production, Chemistry and Technology, Davis et al. (Eds.) (1999), which is incorporated herein by reference. Various representative other types of plants from the Nicotiana species are set forth in Goodspeed, The Genus Nicotiana, (Chonica Botanica) (1954); U.S. Pat. No. 4,660,577 to Sensabaugh, Jr. et al.; 5,387,416 to White et al., U.S. Pat. No. 7,025,066 to Lawson et al.; U.S. Pat. No. 7,798,153 to Lawrence, Jr. and 8,186,360 to Marshall et al.; each of which is incorporated herein by reference. Exemplary Nicotiana species include N. tabacum, N. rustica, N. alata, N. arentsii, N. excelsior, N. forgetiana, N. glauca, N. glutinosa, N. gossei, N. kawakamii, N. knightiana, N. langsdorffi, N. otophora, N. setchelli, N. sylvestris, N. tomentosa, N. tomentosiformis, N. undulata, N. x sanderae, N. africana, N. amplexicaulis, N. benavidesii, N. bonariensis, N. debneyi, N. longiflora, N. maritina, N. megalosiphon, N. occidentalis, N. paniculata, N. plumbaginifolia, N. raimondii, N. rosulata, N. simulans, N. stocktonii, N. suaveolens, N. umbratica, N. velutina, N. wigandioides, N. acaulis, N. acuminata, N. attenuata, N. benthamiana, N. cavicola, N. clevelandii, N. cordifolia, N. corymbosa, N. fragrans, N. goodspeedii, N. linearis, N. miersii, N. nudicaulis, N. obtusifolia, N. occidentalis subsp. Hersperis, N. pauciflora, N. petunioides, N. quadrivalvis, N. repanda, N. rotundifolia, N. solanifolia, and N. spegazzinii. In some embodiments, material 14 is obtained by processing white burley tobacco, e.g., KY14 (KY14L8) tobacco.

[0059] Descriptions of various types of tobaccos, growing practices and harvesting practices are set forth in Tobacco Production, Chemistry and Technology, Davis et al. (Eds.) (1999), which is incorporated herein by reference. Additional information on types of Nicotiana species suitable for use in the present invention can be found in U.S. Pat. No. 9,107,453 to Dube et al., which is incorporated by reference herein. In some embodiments, harvested tobacco can be sprayed with a buffer or antioxidant (e.g., a sodium metabisulfite buffer) to prevent the green plants from browning prior to further treatment, to provide material 14. Other exemplary processing techniques are described, for example, in U.S. Pat. No. 7,946,295 to Brinkley et al. and 8,955,523 to Coleman, III et al., which are incorporated by reference herein. At least a portion of the plant of the Nicotiana species can be treated with enzymes and/or probiotics before or after harvest, as discussed in US Pat. Appl. Pub. No. 2013/0269719 to Marshall et al. and U.S. Pat. No. 9,485,953 to Moldoveanu, which are incorporated herein by reference. Nicotiana species from which tobacco can be obtained for treatment as disclosed herein can be derived using genetic-modification or crossbreeding techniques (e.g., tobacco plants can be genetically engineered or crossbred to increase or decrease production of components, characteristics or attributes). See, for example, the types of genetic modifications of plants set forth in U.S. Pat. No. 5,539,093 to Fitzmaurice et al.; U.S. Pat. No. 5,668,295 to Wahab et al.; U.S. Pat. No. 5,705,624 to Fitzmaurice et al.; U.S. Pat. No. 5,844,119 to Weigl; U.S. Pat. No. 6,730,832 to Dominguez et al.; U.S. Pat. No. 7,173,170 to Liu et al.; U.S. Pat. No. 7,208,659 to Colliver et al. and 7,230,160 to Benning et al.; US Patent Appl. Pub. No. 2006/0236434 to Conkling et al.; and PCT WO2008/103935 to Nielsen et al. See, also, the types of tobaccos that are set forth in U.S. Pat. No. 4,660,577 to Sensabaugh, Jr. et al.; 5,387,416 to White et al.; and 6,730,832 to Dominguez et al., each of which is incorporated herein by reference.

[0060] The purified nicotine isolate 24 provided following the process described herein can advantageously be used in various applications. As such, the disclosure encompasses products containing purified nicotine isolate 24 and methods of providing products containing purified nicotine isolate 24.

[0061] In some embodiments, the purified nicotine isolate is incorporated within a pharmaceutical product in the form of a lozenge, tablet, microtab, or other tablet-type product. Nicotine-containing pharmaceutical compositions can generally incorporate, in addition to isolate 24, various pharmaceutically acceptable excipients. By pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is intended a carrier or excipient that is conventionally used in the art to facilitate the storage, administration, and/or the healing effect of an active agent (e.g., a nicotinic compound). The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. A carrier may also reduce any undesirable side effects of the agent. See, Wang et al. (1980) J. Parent. Drug Assn. 34(6):452-462, herein incorporated by reference in its entirety. Other exemplary pharmaceutical excipients and/or additives suitable for use in the compositions according to the invention are listed in Remington: The Science & Practice of Pharmacy, 21.sup.st ed., Lippincott Williams & Wilkins (2006); in the Physician's Desk Reference, 64.sup.th ed., Thomson PDR (2010); and in Handbook of Pharmaceutical Excipients, 6.sup.th ed., Eds. Raymond C. Rowe et al., Pharmaceutical Press (2009), which are incorporated herein by reference.

[0062] The various excipients can vary, and the selection and amount of each excipient can depend upon factors such as the ultimate form and function of product that is desired. See, for example, the types of ingredients, relative amounts and combinations of ingredients, nicotine-containing formulations and preparation processes for nicotine-containing products set forth in U.S. Pat. No. 5,512,306 to Carlsson et al.; U.S. Pat. No. 5,525,351 to Dam; U.S. Pat. No. 5,549,906 to Santus; U.S. Pat. No. 5,711,961 to Reiner et al.; U.S. Pat. No. 5,811,126 to Krishnamurthy; U.S. Pat. No. 5,939,100 to Albrechtsen et al.; U.S. Pat. No. 6,024,981 to Khankari et al.; U.S. Pat. No. 6,083,531 to Humbert-Droz et al.; U.S. Pat. No. 6,090,401 to Gowan, Jr. et al.; 6,110,495 to Dam; U.S. Pat. No. 6,426,090 to Ream et al.; U.S. Pat. No. 6,569,463 to Patel et al.; U.S. Pat. No. 6,583,160 to Smith et al.; U.S. Pat. No. 6,585,997 to Moro et al.; U.S. Pat. No. 6,893,654 to Pinney et al.; U.S. Pat. No. 7,025,983 to Leung et al.; and 7,163,705 Johnson et al.; US Pat. Pub. Nos. 2003/0176467 to Andersson et al.; 2003/0235617 to Martino et al.; 2004/0096501 to Vaya et al.; 2004/0191322 to Hansson; 2005/0053665 to Ek et al.; 2005/0123502 to Chan et al.; 2008/0038209 to Andersen et al.; 2008/0286341 to Andersson et al.; 2009/0023819 to Axelsson; 2009/0092573 to Andersen; and 2010/0061940 to Axelsson et al., which are incorporated herein by reference.

[0063] One particularly preferred type of a representative composition incorporating nicotine as an active ingredient, and that comprises nicotine in an orally provided form, has the form of a lozenge, tablet, microtab, or other tablet-type product. See, for example, the types of nicotine-containing lozenges, lozenge formulations, lozenge formats and configurations, lozenge characteristics and techniques for formulating or manufacturing lozenges set forth in U.S. Pat. No. 4,967,773 to Shaw; U.S. Pat. No. 5,110,605 to Acharya; U.S. Pat. No. 5,733,574 to Dam; U.S. Pat. No. 6,280,761 to Santus; U.S. Pat. No. 6,676,959 to Andersson et al.; U.S. Pat. No. 6,248,760 to Wilhelmsen; and U.S. Pat. No. 7,374,779 to Chen et al.; US Pat. Pub. Nos. 2001/0016593 to Wilhelmsen; 2004/0101543 to Liu et al.; 2006/0120974 to Mcneight; 2008/0020050 to Chau et al.; 2009/0081291 to Gin et al.; 2010/0004294 to Axelsson et al.; and 2013/0078307 to Holton, Jr. et al.; which are incorporated herein by reference. In some such embodiments, the nicotine isolate is sorbed onto a porous particulate carrier material, such as microcrystalline cellulose (MCC) prior to incorporation within a composition. See, for example, US Pat. Pub. No. 2004/0191322 to Hansson, which is incorporated by reference herein.

[0064] In some embodiments, the nicotine isolate derived from methods described herein can be incorporated into an electronic smoking article. There have been proposed numerous smoking products, flavor generators, and medicinal inhalers that utilize electrical energy to vaporize or heat a volatile material, or attempt to provide the sensations of cigarette, cigar, or pipe smoking without burning tobacco to a significant degree. See, for example, the various alternative smoking articles, aerosol delivery devices and heat generating sources set forth in the background art described in U.S. Pat. No. 7,726,320 to Robinson et al., U.S. Pat. Pub. Nos. 2013/0255702 to Griffith Jr. et al., 2014/0000638 to Sebastian et al., 2014/0060554 to Collett et al., 2014/0096781 to Sears et al., 2014/0096782 to Ampolini et al., and 2015/0059780 to Davis et al., which are incorporated herein by reference in their entirety.

[0065] An exemplary embodiment of an electronic smoking article 200 is shown in FIG. 3. As illustrated therein, a control body 202 can be formed of a control body shell 201 that can include a control component 206, a flow sensor 208, a battery 210, and an LED 212. A cartridge 204 can be formed of a cartridge shell 203 enclosing a reservoir housing 244 that is in fluid communication with a liquid transport element 236 adapted to wick or otherwise transport an aerosol precursor composition stored in the reservoir housing to a heater 234. An opening 228 may be present in the cartridge shell 203 to allow for egress of formed aerosol from the cartridge 204. Such components are representative of the components that may be present in a cartridge and are not intended to limit the scope of cartridge components that are encompassed by the present disclosure. The cartridge 204 may be adapted to engage the control body 202 through a press-fit engagement between the control body projection 224 and the cartridge receptacle 240. Such engagement can facilitate a stable connection between the control body 202 and the cartridge 204 as well as establish an electrical connection between the battery 210 and control component 206 in the control body and the heater 234 in the cartridge. The cartridge 204 also may include one or more electronic components 250, which may include an IC, a memory component, a sensor, or the like. The electronic component 250 may be adapted to communicate with the control component 206. The various components of an electronic smoking device according to the present disclosure can be chosen from components described in the art and commercially available.

[0066] In various embodiments, the aerosol precursor composition can comprise a nicotine isolate derived according to methods of the present disclosure. Exemplary formulations for aerosol precursor materials that may be used according to the present disclosure are described in U.S. Pat. No. 7,217,320 to Robinson et al.; U.S. Pat. Pub. Nos. 2013/0008457 to Zheng et al.; 2013/0213417 to Chong et al.; 2014/0060554 to Collett et al.; and 2014/0000638 to Sebastian et al., the disclosures of which are incorporated herein by reference in their entirety. Other aerosol precursors that can incorporate the nicotine isolate described herein include the aerosol precursors that have been incorporated in the VUSE product by R. J. Reynolds Vapor Company, the BLU product by Imperial Tobacco, the MISTIC MENTHOL product by Mistic Ecigs, and the VYPE product by CN Creative Ltd. Also desirable are the so-called smoke juices for electronic cigarettes that have been available from Johnson Creek Enterprises LLC.

EXPERIMENTAL

[0067] Aspects of the present disclosure are more fully illustrated by the following example, which is set forth to illustrate certain aspects of the present disclosure and is not to be construed as limiting thereof.

[0068] Multiple nicotine sulfate solutions (prepared by treating byproducts of protein isolation from tobacco with sulfuric acid) were combined as shown below in Table 1.

TABLE-US-00001 TABLE 1 Starting Materials Nicotine mass Drum # Volume (L) pH (dry basis, g) 1 195.5 4.93 196.50 2 203.0 4.91 199.00 3 199.5 4.21 476.60 4 195.0 4.31 528.60 5 198.0 5.04 442.50 6 199.0 4.96 435.60 7 146.5 4.83 266.00 8 146.0 3.08 259.70 Total 1482.5 2804.50

[0069] The combined solution was concentrated to 30% by vacuum evaporation. Specifically, the combined nicotine sulfate solution (1482.5 L) was concentrated at 27 in Hg with a temperature setpoint of 50 C. Heat was maintained with steam. After concentration, a total of 8.9 L was obtained. Of the total, 5.2 L was through processed and 3.7 L was retained for stability studies.

[0070] The concentrate was tested at 18% nicotine sulfate by mass. The nicotine sulfate was then pH adjusted from 4.60 to 12.98 with 1.55 L of 10M NaOH solution. After pH adjustment, the solution was extracted with 2.9 L of cyclohexane (>99.9%). The two solvents were allowed to mix for 60 mins. After mixing, the solution was left standing for 2.5 hours. Solid precipitant (sodium sulfate) settled to the bottom of the mixing vessel. The liquid portion was carefully decanted through filter paper and into a separatory funnel. The phase separation continued in the separatory funnel for 60 mins. The aqueous phase was collected from the bottom of the separatory funnel. 6.71 L of aqueous phase was collected, sampled, and discarded. The organic phase was collected separately in a total volume of 3070 mL.

[0071] The organic phase was then distilled using a 1 diameter spinning band fractional distillation column. Two different batch distillation methods were performed. The first method was performed to distill off cyclohexane. The second was performed under high vacuum to distill the nicotine from other organic impurities. The method parameters are P.sub.GP-2.sub.2,TI outlined in Table 2 below.

TABLE-US-00002 TABLE 2 Distillation Parameters Method 1 Method 2 Parameter (cyclohexane) (purification) Vacuum (torr) Atmospheric 3.00 Band speed (RPM) 2000 2000 Reflux (X:1)* 5 15 Equilibration (mins) 30 150 Initial Heating Rate (%) 25 25 Process Heating Rate (%) 10 10 Collection T low ( C.) 60 70 Collection T high ( C.) 100 90 Shutoff ( C.) 150 250 *Reflux (X:1) is a ratio of how much recondensed vapor is collected as distillate (product) and how much is sent back to the distillation column (reflux), e.g., for Method 1, 5 parts reflux for every 1 part distillate was used; for Method 2, 15 parts reflux for every 1 part distillate was used.

[0072] A total of 2.5 L of distilled cyclohexane was obtained from method 1, leaving 550 mL of impure nicotine to process through Method 2. A forerun fraction of 40 mL was collected and discarded. After collecting the forerun fraction, a final cut of 457 mL of purified nicotine was collected. The pure nicotine was stored in a stainless steel container under argon to preserve stability. Characterization data for the material provided by this example are provided below in Table 3, as compared against the USP and/or EP reference.

TABLE-US-00003 TABLE 3 Characterization Data USP/EP Target Test Parameters Test Method Reference Specification Result Appearance Visual Inspection N/A Colorless to Brown Colorless Liquid Liquid Identity Infrared Absorption USP <197A> Compares to Standard Compares to Standard Spectroscopy Specific Rotation Polarimeter USP <781S> 130 to 143 137.7 EP (2.2.7) 140 to 152 146.3 Water Karl Fisher/Toluene USP <921> <0.5% 0.05% distillation Residual Solvent Headspace GC/FID USP <467> <500 ppm Pass Heavy Metals ICP-MS USP <231> <20 ppm (Pb) Pass Purity Non-Aqueous USP <541> 99.0% to 101.0% 100.0% Titration Purity HPLC EP (2.2.29) Sum of impurities A = <0.05% <0.8%, no known B = <0.05% impurity (A-G) >0.4% C = <0.05% D = <0.05% E = <0.05% F = <0.05% G = <0.05% Unknown: None detected

[0073] Many modifications and other embodiments of the disclosure will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing description. Therefore, it is to be understood that the disclosure is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.