Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
View Patent ↗Disclosed herein are crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, which is a prodrug of methyl hydrogen fumarate. Crystalline form 1, Crystalline form 2, Crystalline 3, and Crystalline form 4 are disclosed.
1. A crystalline form of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate selected from: Crystalline form 1 having a purity of at least 99% by weight as measured by HPLC; Crystalline form 2; Crystalline form 3; or Crystalline form 4, wherein
the Crystalline form 1 exhibits characteristic scattering angles (2θ) at least at 14.5±0.2°, 21.7±0.2°, 12.3±0.2°, 29.0±0.2°, and 27.1±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation,
the Crystalline form 2 exhibits characteristic scattering angles (2θ) at least at 8.4±0.2°, 4.2±0.2°, 16.9±0.2°, 18.3±0.2°, and 20.0±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation,
the Crystalline form 3 which exhibits characteristic scattering angles (2θ) at least at 20.6±0.2°, 9.5±0.2°, 11.1±0.2°, 15.8±0.2°, and 18.6±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation, and
the Crystalline form 4 which exhibits characteristic scattering angles (2θ) at least at 20.4±0.2°, 8.2±0.2°, 33.2±0.2°, 26.3±0.2°, and 20.8±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation.
2. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 1 having a DSC thermogram peak of between about 57° C. and about 59° C.
3. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 1 further comprising characteristic scattering angles (2θ) at least at 21.0±0.2°, 22.8±0.2°, 19.8±0.2°, 6.8±0.2°, and 20.3±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation.
4. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 1 exhibiting characteristic scattering angles (2θ) in an X-ray powder diffraction pattern measured using Cu—K α radiation shown in FIG. 1 .
5. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 1 having a purity of at least 99.5% by weight as measured by HPLC.
6. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 11 having a purity of at least 99.9% by weight as measured by HPLC.
7. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 2 having a DSC thermogram peak of between about 49° C. and about 51° C.
8. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 2 further comprising characteristic scattering angles (2θ) at least at 26.8±0.2°, 23.5±0.2°, 29.8±0.2°, 20.7±0.2° and 24.2±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation.
9. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 2 exhibiting characteristic scattering angles (2θ) in an X-ray powder diffraction pattern measured using Cu—K α radiation shown in FIG. 4 .
10. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 3 having a DSC thermogram peak of between about 46° C. and about 48° C.
11. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 3 further comprising characteristic scattering angles (2θ) at least at 20.8±0.1°, 29.2±0.1°, 19.1±0.1°, 22.2±0.1°, and 24.3±0.1° in an X-ray powder diffraction pattern measured using Cu—K α radiation.
12. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 3 which exhibits characteristic scattering angles (2θ) in an X-ray powder diffraction pattern measured using Cu—K α radiation shown in FIG. 7 .
13. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 4 having a DSC thermogram peak of between about 37° C. and about 39° C.
14. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 4 further comprising characteristic scattering angles (2θ) at least at 8.3±0.2°, 26.2±0.2°, 13.2±0.2°, 16.4±0.2°, and 21.8±0.2° in an X-ray powder diffraction pattern measured using Cu—K α radiation.
15. The crystalline form of claim 1 , wherein the crystalline form is Crystalline form 4 which exhibits characteristic scattering angles (2θ) in an X-ray powder diffraction pattern measured using Cu—K α radiation shown in FIG. 10 .
16. A pharmaceutical composition comprising a crystalline form of claim 1 and a pharmaceutically acceptable vehicle.
17. A dosage form comprising a therapeutically effective amount of a crystalline form of claim 1 and a pharmaceutically acceptable vehicle.
18. The dosage form of claim 17 , wherein the dosage form is an oral dosage form.
19. A method of treating a disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of claim 1 , wherein the disease is selected from selected from multiple sclerosis and psoriasis.