SOLUTION COMPRISING NICOTINE IN UNPROTONATED FORM AND PROTONATED FORM

Abstract

There is provided a nicotine solution comprising a carrier; nicotine in unprotonated form and in protonated form; and one or more acids, wherein at least benzoic acid, levulinic acid or a mixture thereof is present; and wherein the total content of acid present in the solution is no greater than 0.6 mole equivalents based on the nicotine.

Claims

1. A nicotine solution comprising: (i) a carrier; (ii) nicotine in unprotonated form and in protonated form; and (iii) one or more acids, wherein at least benzoic acid is present; and wherein the total content of acid present in the solution is no greater than 0.6 mole equivalents based on the nicotine.

2. A nicotine solution according to claim 1 further comprising water.

3. A nicotine solution according to claim 1 containing acid selected from the group consisting of benzoic acid.

4. A nicotine solution according to claim 1 wherein the total content of acid present in the solution is no greater than 0.5 mole equivalents based on the nicotine.

5. A nicotine solution according to claim 1 wherein the total content of acid present in the solution is no less than 0.2 mole equivalents based on the nicotine.

6. A nicotine solution according to claim 1 wherein the amount of benzoic acid present in the solution is no less than 0.2 mole equivalents based on the nicotine.

7. A nicotine solution according to claim 1 wherein the amount of benzoic acid present in the solution is from 0.2 to 0.4 mole equivalents based on the nicotine.

8. A nicotine solution according to claim 1 comprising nicotine in an amount of no greater than 2 wt % based on the total weight of the solution.

9. A nicotine solution according to claim 1 comprising nicotine in an amount of no greater than 1.8 wt % based on the total weight of the solution.

10. A nicotine solution according to claim 1 containing a second acid selected from the group consisting of levulinic acid and comprising nicotine in an amount of no greater than 1.8 wt % based on the total weight of the solution.

11. A nicotine solution according to claim 1 wherein the carrier is a solvent.

12. A nicotine solution according to claim 11 wherein the solvent is selected from glycerol, propylene glycol and mixtures thereof

13. A contained nicotine solution comprising: (a) a container; and (b) a nicotine solution comprising (i) a carrier, (ii) nicotine in unprotonated form and in protonated form, and (iii) one or more acids, wherein at least benzoic acid is present; and wherein the total content of acid present in the solution is no greater than 0.6 mole equivalents based on the nicotine.

14. A contained nicotine solution according to claim 13 wherein the nicotine solution further comprises water.

15. A contained nicotine solution according to claim 14 wherein the container is configured for engagement with an electronic vapor provision system.

16. A contained nicotine solution according to claim 13 wherein the nicotine solution contains acid selected from the group consisting of benzoic acid.

17. An electronic vapor provision system comprising: a vaporizer for vaporizing liquid for inhalation by a user of the electronic vapor provision system; a power supply comprising a cell or battery for supplying power to the vaporizer; a nicotine solution comprising: (i) a carrier, (ii) nicotine in unprotonated form and in protonated form, and (iii) one or more acids, wherein at least benzoic acid is present; and wherein the total content of acid present in the solution is no greater than 0.6 mole equivalents based on the nicotine.

18. An electronic vapor provision system according to claim 17 wherein the nicotine solution further comprises water.

19. A process for improving the sensory properties of a vaporized nicotine solution, the process comprising: (a) providing a nicotine solution comprising: (i) a carrier, (ii) nicotine in unprotonated form and in protonated form, and (iii) one or more acids, wherein at least benzoic acid is present; and wherein the total content of acid present in the solution is no greater than 0.6 mole equivalents based on the nicotine; and (b) vaporizing the nicotine solution.

20. A process according to claim 19 wherein the nicotine solution further comprises water.

21. Use of one or more acids for improving sensory properties of a vaporized nicotine solution, wherein the nicotine solution comprises: (i) a carrier; (ii) nicotine in unprotonated form and in protonated form; and (iii) one or more acids, wherein at least benzoic acid is present; and wherein the acid present in the solution is combined with the nicotine such that the total content of the acid is no greater than 0.6 mole equivalents based on the nicotine.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0071] The present disclosure will now be described in further detail by way of example only with reference to the accompanying figure in which:

[0072] FIG. 1 shows a graph illustrating variation of p.sub.sK.sub.a2 with nicotine concentration.

DETAILED DESCRIPTION

[0073] The invention will now be described with reference to the following non-limiting example.

EXAMPLES

Determination of pKa Values

[0074] The determination of pKa values of nicotine in glycerol/water systems was carried out using the basic approach described in “Spectroscopic investigations into the acid-base properties of nicotine at different temperatures”, Peter M. Clayton, Carl A. Vas, Tam T. T. Bui, Alex F. Drake and Kevin McAdam, Anal. Methods, 2013,5, 81-88, and summarized below. Because the system is predominately non-aqueous the parameter p.sub.sK.sub.a2 was measured, where subscript s refers to the solvent composition in this largely non-aqueous system, and subscript 2 refers to the pK.sub.a value of the pyrrolidyl nitrogen.

[0075] Further information on the determination of pKa values of nicotine is provided in “Use of chiroptical spectroscopy to determine the ionisation status of (S)-nicotine in e-cigarette formulations and snus”, Clayton et al, ST 49, CORESTA Congress, Québec City, Canada, 12-Oct. 2014 (available at http://www.bat-science.com /groupms/sites/BAT_9GVJXS.nsf/vwPagesWebLive/DO9PVC3G/$FILE/CORE STA_PC_2014.pdf).

[0076] A range of glycerol/water/nicotine solutions were prepared, with the water concentration fixed at 9%, the nicotine concentration varying from 30 μg/ml to 3 mg/ml; and the glycerol content comprising the remainder of the solutions.

[0077] Simultaneous UV & CD spectra of glycerol/s-nicotine/water solutions were measured on the Applied Photophysics Ltd (Leatherhead, UK) Chiracsan Plus spectrometer. The UV absorbance & CD spectra were measured between 300-200 nm region, with various pathlengths depending upon the nicotine concentration of the solution −10 mm, 5 mm, 2 mm, 1 mm, 0.5 mm, 0.1 mm and 0.01 mm pathlengths. The instrument was flushed continuously with pure evaporated nitrogen throughout the measurements. Throughout measurements spectra were recorded with a 0.5 nm step size, a 1s measurement time-per-point and a spectral bandwidth of 2 nm. Where possible, all CD spectra were smoothed with a window factor of 4 using the Savitzky-Golay method for better presentation.

[0078] Solutions of S-Nicotine in glycerol/water were pH titrated at 23° C. The pH of these solutions was raised towards alkaline by adding small aliquots of NaOH (˜pH10) and then lowered to pH2 by adding small aliquots of HCl. A series of 0.1M, 0.5M, 1M, 5M and 10M of HCl and NaOH solutions were used during the pH titration. pHs were measured at 23° C. using a Corning pH105 pH meter with a RMS pH electrode. The p.sub.sK.sub.a2 values changed systematically with nicotine concentration (FIG. 1) and therefore values for p.sub.sK.sub.a2 were calculated at each nicotine concentration level (Table 1). Due to the viscosity of the solutions, and the optical density in the CD spectra of the high nicotine concentration solutions, very small path-length cells were required for nicotine concentrations above 3 mg/ml. Satisfactory sample preparation and spectroscopy could not be achieved with the necessary small cells at these concentrations, and therefore the p.sub.sK.sub.a2 at higher concentrations were calculated from a regression fit to FIG. 1.

TABLE-US-00001 TABLE 1 p.sub.sK.sub.a2 values measured at various nicotine concentrations in a 9% water, nicotine/glycerol system. p.sub.sK.sub.a2 conc (g/L) conc (mM) log.sub.10 [conc] 7.49 0.03 0.185 −0.732 7.34 0.06 0.370 −0.431 7.30 0.3 1.85 0.268 7.27 0.6 3.70 0.569 7.25 3 18.53 1.268

[0079] Curve fitting, using the equation y=0.0233e.sup.(-(log10[nicotine])/0.325)+7.26 provided a p.sub.sK.sub.a2 value of 7.26 at 30 mg/ml nicotine concentration. Use of this p.sub.sK.sub.a2 value with the Henderson-Hasselbalch equation allows calculation of the degree of nicotine protonation at any pH value.

Example 1

[0080] A series of tests were conducted using Vype E-pen electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 1.86% (w/w) nicotine, 25% propylene glycol containing tobacco flavor “A”, 25% water and 48.1% glycerol. A pH of 8.7 was measured for this solution, indicating 4% protonation of nicotine.

[0081] A similar set of devices were prepared wherein 0.55% w/w (0.4 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 47.6% (w/w). A pH of 7.4 was measured for this solution, indicating 43% protonation of nicotine.

[0082] A third set of devices were prepared wherein 0.25% w/w (0.2 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately adjusted to 47.9% (w/w). A pH of 7.8 was measured for this solution, indicating 24% protonation of nicotine.

[0083] One each of these e-cigarettes was presented to 15 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0084] 7 panelists preferred the unprotonated control e-cigarette, and 8 people preferred the acidified samples—4 preferred the 0.2 Meq device and 4 preferred the 0.4 Meq device.

Example 2

[0085] A series of tests were conducted using Vype E-pen electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 1.86% (w/w) nicotine, 35.3% propylene glycol containing mint flavor, 25% water and 37.9 glycerol. This solution had a pH of 9.7 indicating <1% nicotine protonation.

[0086] A similar set of devices were prepared wherein 0.55% w/w (0.4 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 37.3% (w/w). This solution had a pH of 7.4 indicating nicotine protonation of 43%.

[0087] A third set of devices were prepared wherein 0.25% w/w (0.2 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately adjusted to 37.6% (w/w). This solution had a pH of 7.8 indicating nicotine protonation of 22%.

[0088] One each of these e-cigarettes was presented to 15 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0089] 4 panelists preferred the unprotonated control e-cigarette, and 11 people preferred the acidified samples—2 preferred the 0.2 Meq device and 9 preferred the 0.4 Meq device.

Example 3

[0090] A series of tests were conducted using Vype E-pen electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 1.86% (w/w) nicotine, 25% propylene glycol containing a cherry flavor, 25% water and 48.1% glycerol. This solution had a pH of 8.4 indicating nicotine protonation at a level of 7%.

[0091] A similar set of devices were prepared wherein 0.55% w/w (0.4 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 47.6% (w/w). This solution had a pH of 7.4 indicating nicotine protonation at a level of 43%.

[0092] A third set of devices were prepared wherein 0.25% w/w (0.2 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately adjusted to 47.9% (w/w). This solution had a pH of 7.8 indicating nicotine protonation at a level of 24%

[0093] One each of these e-cigarettes was presented to 15 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0094] 3 panelists preferred the unprotonated control e-cigarette, and 12 people preferred the acidified samples—8 preferred the 0.2 Meq device and 4 preferred the 0.4 Meq device.

Example 4

[0095] A series of tests were conducted using Vype E-pen electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 1.86% (w/w) nicotine, 25% propylene glycol containing tobacco flavor “A”, 25% water and 48.1% glycerol. This solution had a pH of 8.6 indicating nicotine protonation at a level of 4%.

[0096] A similar set of devices were prepared wherein 0.41% w/w (0.3 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 47.7% (w/w). This solution had a pH of 7.7 indicating nicotine protonation at a level of 26%.

[0097] A third set of devices were prepared wherein 0.39% w/w (0.3 Meq to nicotine) levulinic acid was added to the formulation, with the glycerol content was commensurately adjusted to 47.8% (w/w). This solution had a pH of 7.26 indicating nicotine protonation at a level of 50%.

[0098] One each of these e-cigarettes was presented to 14 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0099] 3 panelists preferred the unprotonated control e-cigarette, and 11 people preferred the acidified samples—7 preferred the 0.3 Meq benzoic acid device and 4 preferred the 0.3 Meq levulinic acid device.

Example 5

[0100] A series of tests were conducted using Vype E-pen electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 1.8% (w/w) nicotine, 25% propylene glycol containing tobacco flavor “B”, 25% water and 48.1% glycerol. This solution had a pH of 9.3 indicating nicotine protonation at a level of 1%.

[0101] A similar set of devices were prepared wherein 0.41% w/w (0.3 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 47.7% (w/w). This solution had a pH of 7.7 indicating nicotine protonation at a level of 28%.

[0102] A third set of devices were prepared wherein 0.39% w/w (0.3 Meq to nicotine) levulinic acid was added to the formulation, with the glycerol content was commensurately adjusted to 47.8% (w/w). This solution had a pH of 7.4 indicating nicotine protonation at a level of 41%.

[0103] One each of these e-cigarettes was presented to 11 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0104] 4 panelists preferred the unprotonated control e-cigarette, and 7 people preferred the acidified samples—4 preferred the 0.3Meq benzoic acid device and 3 preferred the 0.3 Meq levulinic acid device.

Example 6

[0105] A series of tests were conducted using Vype E-stick electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 4% (w/w) nicotine, 25% propylene glycol containing a cherry flavor, 9% water and 62% glycerol. This solution had a pH of 8.3 indicating nicotine protonation at a level of 7%.

[0106] A similar set of devices were prepared wherein 1.2% w/w (0.4 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 60.8% (w/w). This solution had a pH of 7.4 indicating nicotine protonation at a level of 41%.

[0107] A third set of devices were prepared wherein 1.15% w/w (0.4 Meq to nicotine) levulinic acid was added to the formulation, with the glycerol content was commensurately adjusted to 60.9% (w/w). This solution had a pH of 6.9 indicating nicotine protonation at a level of 68%.

[0108] One each of these e-cigarettes was presented to 11 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0109] 1 panelist preferred the unprotonated control e-cigarette, and 10 people preferred the acidified samples—6 preferred the 0.4 Meq benzoic acid device and 4 preferred the 0.4 Meq levulinic acid device.

Example 7

[0110] A series of tests were conducted using Vype E-stick electronic cigarettes. The “unprotonated nicotine control” devices were loaded with solution containing 4% (w/w) nicotine, 36.5% propylene glycol containing a mint flavor, 9% water and 50.5% glycerol. This solution had a pH of 9.6 indicating nicotine protonation at a level of <1%.

[0111] A similar set of devices were prepared wherein 1.2% w/w (0.4 Meq to nicotine) benzoic acid was added to the formulation, with the glycerol content was commensurately reduced to 49.3% (w/w). This solution had a pH of 7.3 indicating nicotine protonation at a level of 51%.

[0112] A third set of devices were prepared wherein 1.15% w/w (0.4 Meq to nicotine) levulinic acid was added to the formulation, with the glycerol content was commensurately adjusted to 49.35% (w/w). This solution had a pH of 6.8 indicating nicotine protonation at a level of 73%.

[0113] One each of these e-cigarettes was presented to 11 panelists comprising e-cigarette users, and the panelists were asked to puff on the e-cigarettes in a sequential monadic fashion for 10 puffs on each device. They were asked to identify the preferred e-cigarette from the three offered to them.

[0114] 2 panelists preferred the unprotonated control e-cigarette, and 9 people preferred the acidified samples—5 preferred the 0.4 Meq benzoic acid device and 4 preferred the 0.4 Meq levulinic acid device.

Example 8

[0115] A series of tests were conducted using Vype E-pen electronic cigarettes. The devices were loaded with the following solutions:

[0116] A—1.86% w/w nicotine, 0.42% w/w benzoic acid (˜0.3 Meq to nicotine), 47.72% w/w glycerol, 25% w/w water, 19.5% w/w propylene glycol and 5.5% w/w flavor

[0117] B—1.86% w/w nicotine, 0.42% w/w benzoic acid (˜0.3 Meq to nicotine), 47.72% w/w glycerol, 25% w/w water, 13% w/w propylene glycol and 12% w/w flavor

[0118] C—1.86% w/w nicotine, 0.42% w/w benzoic acid (˜0.3 Meq to nicotine), 37.22% w/w glycerol, 25% w/w water, 30% w/w propylene glycol and 5.5% w/w flavor

[0119] Various modifications and variations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.