# US 12,180,155 B2 · Crystalline forms of a cannabinoid receptor type 1 (CB1) modulator and methods of use and preparation thereof

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- Number: US 12,180,155 B2
- Document ID: US12180155B2
- Status: Granted
- Kind: B2
- Application number: 18/471,170
- Filed: 2023-09-20
- Published: 2024-01-11
- Granted: 2024-12-31
- Earliest claimed: 2021-10-11
- Assignees: Anebulo Pharmaceuticals, Inc.
- Applicants: Anebulo Pharmaceuticals, Inc.
- Inventors: Joseph Fenton Lawler; Daniel Pawel Schneeberger
- Web page: https://patentgrep.com/patent/US12180155B2

## CPC

- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Described herein are polymorphic forms of a CB1 modulator, methods of making such forms, pharmaceutical compositions and medicaments comprising such forms, and methods of using such forms in the treatment of conditions, diseases, or disorders that would benefit from modulation of the CB1 receptor.

## Claims

### Claim 1

A method of preparing a crystalline form of (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide (Compound 1):
Compound 1, wherein the method comprises: (a) dissolving the (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in a solvent to obtain a solution; and (b) crystallizing the solution obtained in step (a).

### Claim 2 (depends on 1)

The method of claim 1, wherein the (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is amorphous in 3 step (a).

### Claim 3 (depends on 1)

The method of claim 1, wherein the solvent in step (a) comprises water, heptane, methanol, acetone, or a combination thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the solvent in step (a) comprises heptane.

### Claim 5 (depends on 3)

The method of claim 3, wherein the solvent in step (a) comprises a mixture of acetone and water.

### Claim 6 (depends on 1)

The method of claim 1, wherein the concentration of the solution obtained in step (a) is 20 mg/mL to 300 mg/mL.

### Claim 7 (depends on 1)

The method of claim 1, wherein the solution temperature is 10-40° C.

### Claim 8 (depends on 1)

The method of claim 1, wherein the chemical purity of the crystalline form is greater than about 90%.

### Claim 9 (depends on 1)

The method of claim 1, wherein the crystalline form is non-solvated.

### Claim 10 (depends on 1)

The method of claim 1, wherein the crystalline form is anhydrous.

### Claim 11 (depends on 1)

The method of claim 1, wherein the method further comprises mixing the crystalline form with one or more pharmaceutically acceptable excipients.

### Claim 12 (depends on 1)

The method of claim 1, wherein the method further comprises formulating the crystalline form for oral administration.

### Claim 13 (depends on 12)

The method of claim 12, wherein the method comprises formulating the crystalline form into a tablet, powder, pill, dragee, capsule, liquid, gel, syrup, elixir, slurry, or suspension.

### Claim 14 (depends on 13)

The method of claim 13, wherein the tablet, powder, pill, dragee, capsule, liquid, gel, syrup, elixir, slurry, or suspension comprises 1-200 mg of (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide.

### Claim 15 (depends on 1)

The method of claim 1, wherein the method further comprises formulating the crystalline form into a mixture for parenteral administration.

### Claim 16 (depends on 1)

The method of claim 1, wherein the crystalline form comprises unit cell parameters at T=160° K of: a=19.371(2) Å, b=9.7283(9) Å, c=25.173(5) Å; β=111.07(1)° and a chiral monoclinic 12 space group.

### Claim 17

A method of preparing a crystalline form of (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide (Compound 1):
Compound 1, wherein the method comprises: (a) dissolving the (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in a solvent to obtain a solution; and (b) crystallizing the solution obtained in step (a),
wherein the crystalline (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is characterized by:
(a) an X-ray powder diffraction pattern comprising peaks at 10.2±0.2° 2-θ, 18.1±0.2° 2-θ, and 20.7±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å;
(b) an X-ray powder diffraction pattern substantially the same as shown in FIG. 1;
(c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 80-90° C.;
(d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 84° C. and a peak of about 86° C.;
(e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 2;
(f) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in FIG. 3;
(g) a dynamic vapor sorption (DVS) trace substantially the same as shown in FIG. 4;
(h) a substantially unchanged XPRD after storage at 25° C. and 90% relative humidity (RH);
(i) a substantially unchanged XPRD after storage at laboratory conditions for at least 5 weeks; or
(j) combinations thereof.

### Claim 18

A method of preparing a crystalline form of (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide (Compound 1):
Compound 1, wherein the method comprises: (a) dissolving the (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in a solvent to obtain a solution; and (b) crystallizing the solution obtained in step (a),
wherein the crystalline (R)—N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is characterized by:
(a) an X-ray powder diffraction pattern comprising peaks at 15.2±0.2° 2-θ, 18.2±0.2° 2−θ, and 20.8±0.2° 2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å;
(b) an X-ray powder diffraction pattern substantially the same as shown in FIG. 5;
(c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 80-90° C.;
(d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 81° C. and a peak of about 85° C.;
(e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 6;
(f) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in FIG. 7;
(g) a dynamic vapor sorption (DVS) trace substantially the same as shown in FIG. 8;
(h) a substantially unchanged XPRD after storage at 25° C. and 90% relative humidity (RH);
(i) a substantially unchanged XPRD after storage at laboratory conditions for at least 5 weeks; or
(j) combinations thereof.