Processes for the preparation 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 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. An extended release solid dosage form comprising
a) (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 or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver about 30 mg 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 freebase equivalent;
b) an acidic pH modifier; and
c) a release control polymer.
2. The extended release solid dosage form of claim 1 , wherein the release control polymer is a hydrophilic polymer and wherein the acidic pH modifier is an organic acid.
3. The extended release solid dosage form of claim 2 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
4. The extended release solid dosage form of claim 3 , wherein the organic acid is tartaric acid.
5. The extended release solid dosage form of claim 2 , wherein the extended release formulation provides for the release 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 or a pharmaceutically acceptable salt thereof upon entry into a use environment at a rate substantially independent of the pH of the use environment, wherein the use environment has a pH range from about 1.2 to about 6.8.
6. The extended release solid dosage form of claim 5 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
7. The extended release solid dosage form of claim 6 , wherein the organic acid is tartaric acid.
8. The extended release solid dosage form of claim 2 , wherein the extended release solid dosage form, when added to a test medium comprising 900 mL of 50 mM pH 6.8 sodium phosphate buffer at 37° C.±0.5° C. in a standard USP rotating paddle apparatus when the paddles are rotated at 75 rpm±4%, dissolves from about 50% to about 90% 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 or a pharmaceutically acceptable salt thereof after about 8 hours.
9. The extended release solid dosage form of claim 8 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
10. The extended release solid dosage form of claim 9 , wherein the organic acid is tartaric acid.
11. An extended release solid dosage form comprising
a) (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in an amount sufficient to deliver about 30 mg of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide freebase equivalent;
b) an acidic pH modifier; and
c) a release control polymer.
12. The extended release solid dosage form of claim 11 , wherein the release control polymer is a hydrophilic polymer and wherein the acidic pH modifier is an organic acid.
13. The extended release solid dosage form of claim 12 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
14. The extended release solid dosage form of claim 13 , wherein the organic acid is tartaric acid.
15. The extended release solid dosage form of claim 12 , wherein the extended release formulation provides for the release 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 upon entry into a use environment at a rate substantially independent of the pH of the use environment, wherein the use environment has a pH range from about 1.2 to about 6.8.
16. The extended release solid dosage form of claim 15 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
17. The extended release solid dosage form of claim 16 , wherein the organic acid is tartaric acid.
18. The extended release solid dosage form of claim 12 , wherein the extended release solid dosage form, when added to a test medium comprising 900 mL of 50 mM pH 6.8 sodium phosphate buffer at 37° C.±0.5° C. in a standard USP rotating paddle apparatus when the paddles are rotated at 75 rpm±4%, dissolves from about 50% to about 90% 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 after about 8 hours.
19. The extended release solid dosage form of claim 18 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
20. The extended release solid dosage form of claim 19 , wherein the organic acid is tartaric acid.
21. An extended release solid dosage form comprising
a) a crystalline hemihydrate 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) present in an amount sufficient to deliver about 30 mg 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 freebase equivalent;
b) an acid pH modifier; and
c) a release control polymer;
wherein the crystalline hemihydrate 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 has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
22. The extended release solid dosage form of claim 21 , wherein the release control polymer is a hydrophilic polymer and wherein the acidic pH modifier is an organic acid.
23. The extended release solid dosage form of claim 22 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
24. The extended release solid dosage form of claim 23 , wherein the organic acid is tartaric acid.
25. The extended release solid dosage form of claim 22 , wherein the extended release formulation provides for the release 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 upon entry into a use environment at a rate substantially independent of the pH of the use environment, wherein the use environment has a pH range from about 1.2 to about 6.8.
26. The extended release solid dosage form of claim 25 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
27. The extended release solid dosage form of claim 26 , wherein the organic acid is tartaric acid.
28. The extended release solid dosage form of claim 22 , wherein the extended release solid dosage form, when added to a test medium comprising 900 mL of 50 mM pH 6.8 sodium phosphate buffer at 37° C.±0.5° C. in a standard USP rotating paddle apparatus when the paddles are rotated at 75 rpm±4%, dissolves from about 50% to about 90% of the crystalline hemihydrate 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 after about 8 hours.
29. The extended release solid dosage form of claim 28 , wherein the organic acid is present in an amount from about 10 w/w % to about 35 w/w %.
30. The extended release solid dosage form of claim 29 , wherein the organic acid is tartaric acid.