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 oral extended-release tablet comprising (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”) in an amount sufficient to deliver 15 mg of Compound 1 free base equivalent,
wherein the tablet, when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases:
(i) not more than about 60% of Compound 1 after passage of about 4 hours;
(ii) from about 50% to about 80% of Compound 1 after passage of about 8 hours;
(iii) from about 55% to about 90% of Compound 1 after passage of about 10 hours; and
(iv) from about 70% to about 100% of Compound 1 after passage of about 20 hours.
2. The tablet of claim 1 , wherein Compound 1 is released at a steady rate.
3. The tablet of claim 1 , wherein the tablet provides for the release of Compound 1 at a rate substantially independent of the pH of the test medium.
4. An oral extended-release tablet comprising (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”) in an amount sufficient to deliver 30 mg of Compound 1 free base equivalent,
wherein the tablet, when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases:
(i) not more than about 60% of Compound 1 after passage of about 4 hours;
(ii) from about 50% to about 80% of Compound 1 after passage of about 8 hours;
(iii) from about 55% to about 90% of Compound 1 after passage of about 10 hours; and
(iv) from about 70% to about 100% of Compound 1 after passage of about 20 hours.
5. The tablet of claim 4 , wherein Compound 1 is released at a steady rate.
6. The tablet of claim 4 , wherein the tablet provides for the release of Compound 1 at a rate substantially independent of the pH of the test medium.
7. The tablet of claim 1 , wherein when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases between about 40% to about 60% after passage of about 4 hours.
8. The tablet of claim 1 , wherein when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases between about 60% to about 80% after passage of about 8 hours.
9. The tablet of claim 1 , wherein when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases between about 80% to about 100% after passage of about 20 hours.
10. The tablet of claim 4 , wherein when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases between about 40 to about 60% after passage of about 4 hours.
11. The tablet of claim 4 , wherein when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases between about 60 to about 80% after passage of about 8 hours.
12. The tablet of claim 4 , wherein when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, at a pH of 6.8±0.05, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at 75 rpm±4%, releases between about 80 to about 100% after passage of about 20 hours.
13. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases from about 10% to about 60% of Compound 1 after passage of about 1 to about 4 hours.
14. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases not less than about 70% of Compound 1 after passage of about 10 hours.
15. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases from about 60% to about 90% of Compound 1 after passage of about 4 to about 10 hours.
16. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases not less than about 90% of Compound 1 after passage of about 20 hours.
17. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases from about 90% to about 100% of Compound 1 after passage of about 10 hours to about 20 hours.
18. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases:
(i) from about 10% to about 60% of Compound 1 after passage of about 1 to about 4 hours;
(ii) not less than about 70% of Compound 1 after passage of about 10 hours; and
(iii) not less than about 90% of Compound 1 after passage of about 20 hours.
19. The tablet of claim 1 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases:
(i) from about 10% to about 60% of Compound 1 after passage of about 1 to about 4 hours;
(ii) from about 60% to about 90% of Compound 1 after passage of about 4 to about 10 hours; and
(iii) from about 90% to about 100% of Compound 1 after passage of about 10 hours to about 20 hours.
20. The tablet of claim 4 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases from about 10% to about 60% of Compound 1 after passage of about 1 to about 4 hours.
21. The tablet of claim 4 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases not less than about 70% of Compound 1 after passage of about 10 hours.
22. The tablet of claim 4 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases from about 60% to about 90% of Compound 1 after passage of about 4 to about 10 hours.
23. The tablet of claim 4 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases not less than about 90% of Compound 1 after passage of about 20 hours.
24. The tablet of claim 4 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases:
(i) from about 10% to about 60% of Compound 1 after passage of about 1 to about 4 hours;
(ii) not less than about 70% of Compound 1 after passage of about 10 hours; and
(iii) not less than about 90% of Compound 1 after passage of about 20 hours.
25. The tablet of claim 4 , wherein when added to a test medium comprising 500 mL of acidic medium at a pH of about 1.2, a temperature of 37° C.±0.5° C., in a standard USP rotating paddle apparatus, and when the paddles are rotated at ±4%, releases:
(i) from about 10% to about 60% of Compound 1 after passage of about 1 to about 4 hours;
(ii) from about 60% to about 90% of Compound 1 after passage of about 4 to about 10 hours; and
(iii) from about 90% to about 100% of Compound 1 after passage of about 10 hours to about 20 hours.