Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis), kits, methods of synthesis, and products-by-process.
1. Crystalline (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) selected from the group consisting of:
a. crystalline freebase Compound 1 having an X-ray powder diffraction pattern characterized by peaks at 7.9±0.2, 10.3±0.2, and 13.4±0.2 degrees two theta when measured at about 25° C. with monochromatic Kai radiation;
b. crystalline freebase Compound 1 having an X-ray powder diffraction pattern characterized by peaks at 9.7±0.2, 14.2±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kai radiation; and
c. crystalline tartrate Compound 1 having an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 14.1±0.2, and 15.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
2. A solid composition comprising a solid state form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1), wherein at least about 80% by weight of the solid state form is an amorphous freebase of Compound 1.
3. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier and an amorphous freebase of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1), comprising contacting a crystalline freebase of Compound 1 with the pharmaceutically acceptable carrier, wherein crystalline freebase of Compound 1 is converted into amorphous freebase of Compound 1.
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amorphous freebase of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1), prepared by the process of claim 3 .
5. The crystalline freebase Compound 1 of claim 1 , having an X-ray powder diffraction pattern characterized by peaks at 7.9±0.2, 10.3±0.2, and 13.4±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
6. The crystalline freebase Compound 1 of claim 5 , having an X-ray powder diffraction pattern characterized by peaks at 7.9±0.2, 10.3±0.2, and 13.4±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation, and further characterized by at least one additional peak selected from the group consisting of 15.1±0.2, 15.5±0.2, 17.0±0.2, 17.2±0.2, 18.3±0.2, 19.3±0.2, 20.5±0.2, 20.9±0.2, 21.7±0.2, 21.9±0.2, and 24.9±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
7. The crystalline freebase Compound 1 of claim 5 , which is a hemihydrate.
8. The crystalline freebase Compound 1 of claim 1 , having an X-ray powder diffraction pattern characterized by peaks at 9.7±0.2, 14.2±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
9. The crystalline freebase Compound 1 of claim 8 , having an X-ray powder diffraction pattern characterized by peaks at 9.7±0.2, 14.2±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation, and further characterized by at least one additional peak selected from the group consisting of 8.0±0.2, 14.5±0.2, 23.0±0.2, and 24.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
10. The crystalline freebase Compound 1 of claim 8 , which is an anhydrate.
11. The crystalline tartrate Compound 1 of claim 1 , having an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 14.1±0.2, and 15.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation, wherein the crystalline tartrate Compound 1 is a tetrahydrate.
12. The crystalline tartrate Compound 1 of claim 1 , having an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 14.1±0.2, and 15.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation, and further characterized by at least one additional peak selected from the group consisting of 6.8±0.2, 11.8±0.2, 18.0±0.2, 21.9±0.2, and 25.9±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
13. The crystalline tartrate Compound 1 of claim 12 , which is a tetrahydrate.
14. The composition of claim 2 , wherein the amorphous freebase comprises blade or irregular morphology.
15. The composition of claim 14 , wherein the blade morphology comprises hexagonal crystal faces.
16. The composition of claim 2 , further comprising tartartic acid.
17. The composition of claim 2 , wherein at least about 98% by weight of the solid state form is the amorphous freebase of Compound 1.
18. The composition of claim 2 , wherein the composition comprises the solid state form dispersed in a hydrophilic polymer.
19. The composition of claim 2 , wherein the amorphous freebase of Compound 1 in the composition exhibits no growth of degradation products after storage at 50° C. and 75% relative humidity in an open or closed glass vial for at least six weeks.
20. The process of claim 3 , wherein the contacting comprises dispersing the crystalline freebase of Compound 1 in the pharmaceutically acceptable carrier.
21. The process of claim 3 , wherein the pharmaceutically acceptable carrier is a hydrophilic polymer.
22. The process of claim 3 , wherein at least about 80% by weight of crystalline freebase of Compound 1 is converted into amorphous freebase of Compound 1.
23. The process of claim 3 , wherein at least about 98% by weight of crystalline freebase of Compound 1 is converted into amorphous freebase of Compound 1.
24. The process of claim 3 , wherein the crystalline freebase of Compound 1 is selected from the group consisting of:
a. crystalline freebase Compound 1 having an X-ray powder diffraction pattern characterized by peaks at 7.9±0.2, 10.3±0.2, and 13.4±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;
b. crystalline freebase Compound 1 having an X-ray powder diffraction pattern characterized by peaks at 9.7±0.2, 14.2±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation; and
c. crystalline tartrate Compound 1 having an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 14.1±0.2, and 15.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
25. The pharmaceutical composition of claim 4 , comprising a dispersion of the amorphous freebase of Compound 1 in the pharmaceutically acceptable carrier.
26. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable carrier is a hydrophilic polymer.
27. The pharmaceutical composition of claim 4 , wherein at least about 80% by weight of the Compound 1 present in the composition is the amorphous freebase of Compound 1.
28. The pharmaceutical composition of claim 4 , wherein at least about 98% by weight of the Compound 1 present in the composition is the amorphous freebase of Compound 1.
29. The pharmaceutical composition of claim 25 , wherein at least about 80% by weight of the Compound 1 present in the composition is the amorphous freebase of Compound 1.
30. The pharmaceutical composition of claim 25 , wherein at least about 98% by weight of the Compound 1 present in the composition is the amorphous freebase of Compound 1.