# US 10,865,192 B2 · Nicotine salts, co-crystals, and salt co-crystal complexes

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- Number: US 10,865,192 B2
- Document ID: US10865192B2
- Status: Granted
- Kind: B2
- Application number: 16/598,417
- Filed: 2019-10-10
- Published: 2020-02-06
- Granted: 2020-12-15
- Earliest claimed: 2014-05-27
- Assignees: R.J. Reynolds Tobacco Company
- Applicants: R.J. Reynolds Tobacco Company
- Inventors: Gary M. Dull; Andrew Carr; Emma Sharp
- Web page: https://patentgrep.com/patent/US10865192B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A24B 13/00: Tobacco for pipes, for cigars, e.g. cigar inserts, or for cigarettes; Chewing tobacco; Snuff (reconstituted tobacco products A24B3/14)
- A24B 15/243: {Nicotine}
- A24F 40/20: Devices using solid inhalable precursors
- C07C 57/15: Fumaric acid
- C07D 239/52: Two oxygen atoms
- A24F 40/10: Devices using liquid inhalable precursors
- A24F 40/40: Constructional details, e.g. connection of cartridges and battery parts
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- A61M 11/042: {electrical}
- A61M 15/06: Inhaling appliances shaped like cigars, cigarettes or pipes
- A61M 2205/8206: battery-operated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A24B: MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24F: SMOKERS' REQUISITES; MATCH BOXES; SIMULATED SMOKING DEVICES (inhaling appliances for medical purposes, shaped like cigars, cigarettes or pipes A61M15/06)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}

## Abstract

The invention provides certain nicotine salts, co-crystals, and salt co-crystals and provides novel polymorphic forms of certain nicotine salts. In particular, nicotine salts with orotic acid are described. The invention further provides methods of preparation and characterization of such nicotine salts. In addition, tobacco products, including smoking articles, smokeless tobacco products, and electronic smoking articles comprising nicotine salts, co-crystals, and/or salt co-crystals are also provided.

## Claims

### Claim 1

A salt of nicotine and fumaric acid, wherein the salt is a non-solvated mono-salt, characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 14.9, 18.4, 19.9, and 22.4.

### Claim 2 (depends on 1)

A metastable polymorph of the salt of claim 1, characterized by a different X-ray powder diffraction pattern that converts to the X-ray powder diffraction having peaks at one or more of the following 2-theta diffraction angles: 14.9, 18.4, 19.9, and 22.4 upon drying.

### Claim 3 (depends on 1)

The salt of claim 1, wherein at least about 50% of the salt is in crystalline form.

### Claim 4 (depends on 1)

A method of preparing the salt of claim 1, comprising combining nicotine and fumaric acid to form a solid and isolating the solid.

### Claim 5 (depends on 4)

The method of claim 4, wherein the combining comprises:
grinding the nicotine and fumaric acid;
mixing the nicotine and fumaric acid in ethyl acetate; or
mixing the fumaric acid in neat nicotine and using an anti-solvent selected from the group consisting of TBME, heptane, hexane, THF, DCM, ethyl acetate, MEK, IPA, or combinations thereof.

### Claim 6 (depends on 1)

A method of preparing the metastable polymorph of claim 1, comprising mixing fumaric acid in neat nicotine to form a solid, and isolating the solid.

### Claim 7 (depends on 1)

The salt of claim 1, wherein at least about 70% of the salt is in crystalline form.

### Claim 8 (depends on 1)

The salt of claim 1, wherein at least about 80% of the salt is in crystalline form.

### Claim 9 (depends on 1)

The salt of claim 1, wherein at least about 90% of the salt is in crystalline form.

### Claim 10 (depends on 1)

The salt of claim 1, characterized by an X-ray powder diffraction pattern having peaks at two or more of the following 2-theta diffraction angles: 14.9, 18.4, 19.9, and 22.4.

### Claim 11 (depends on 1)

The salt of claim 1, characterized by an X-ray powder diffraction pattern having peaks at three or more of the following 2-theta diffraction angles: 14.9, 18.4, 19.9, and 22.4.

### Claim 12 (depends on 1)

The salt of claim 1, characterized by an X-ray powder diffraction pattern having peaks at all of the following 2-theta diffraction angles: 14.9, 18.4, 19.9, and 22.4.

### Claim 13 (depends on 1)

The salt of claim 1, in a form comprising a white solid.

### Claim 14 (depends on 1)

The salt of claim 1, having a nicotine:fumaric acid ratio as measured by 1H NMR of about 1:1.1.

### Claim 15 (depends on 1)

The salt of claim 1, having a nicotine:fumaric acid ratio as measured by 1H NMR of about 1:1.2.

### Claim 16 (depends on 1)

The salt of claim 1, having a nicotine:fumaric acid ratio as measured by NMR of 1:1.4.

### Claim 17 (depends on 1)

The salt of claim 1, having a nicotine:fumaric acid ratio as measured by NMR of 1:1.0.

### Claim 18 (depends on 1)

The salt of claim 1, exhibiting an endotherm onset at 89° C.

### Claim 19 (depends on 1)

The salt of claim 1, wherein the X-ray powder diffraction pattern further comprises peaks at one or more of the following 2-theta diffraction angles: 17.5, 22.6, and 24.4.