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 pharmaceutical tablet comprising:
(a) 15 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 (Compound 1);
(b) an acidic pH modifier;
(c) a release control polymer; and
(d) at least one filler.
2. The tablet of claim 1 , wherein the extended release pharmaceutical tablet provides for the release of Compound 1 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.
3. The extended release pharmaceutical tablet of claim 1 , wherein:
a single administration of the tablet to healthy adult subjects results in a mean AUC inf from about 220 ng hours/mL to about 450 ng hours/mL of Compound 1; and
a single administration of the tablet to healthy adult subjects results in a mean C max from about 25 ng/ml to about 40 ng/ml of Compound 1.
4. The extended release pharmaceutical tablet of claim 2 , wherein:
a single administration of the tablet to healthy adult subjects results in a mean AUC inf from about 220 ng hours/mL to about 450 ng hours/mL of Compound 1; and
a single administration of the tablet to healthy adult subjects results in a mean C max from about 25 ng/ml to about 40 ng/ml of Compound 1.
5. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose and sorbitol.
6. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, and sorbitol.
7. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of lactose and sucrose.
8. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises at least one lubricant selected from the group consisting of polyethylene glycol, magnesium stearate, calcium stearate, sodium stearate, sodium stearyl fumarate and talc.
9. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises at least one lubricant selected from the group consisting of magnesium stearate, calcium stearate and sodium stearate.
10. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises at least one lubricant selected from the group consisting of calcium stearate and sodium stearate.
11. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises at least one glidant selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, and talc.
12. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises at least one glidant selected from the group consisting of colloidal silicon dioxide and calcium silicate.
13. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises at least one glidant which is colloidal silicon dioxide.
14. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose and sorbitol; and
the tablet further comprises at least one lubricant selected from the group consisting of polyethylene glycol, magnesium stearate, calcium stearate, sodium stearate, sodium stearyl fumarate and talc.
15. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose and sorbitol; and
the tablet further comprises at least one lubricant selected from the group consisting of magnesium stearate.
16. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose and sorbitol; and
the tablet further comprises at least one glidant selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, and talc.
17. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, and sorbitol; and
the tablet further comprises at least one glidant which is colloidal silicon dioxide.
18. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises:
at least one lubricant selected from the group consisting of magnesium stearate, calcium stearate and sodium stearate; and
at least one glidant selected from the group consisting of colloidal silicon dioxide and calcium silicate.
19. The extended release pharmaceutical tablet of claim 4 , wherein the tablet further comprises:
at least one lubricant which is magnesium stearate; and
at least one glidant which is colloidal silicon dioxide.
20. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose and sorbitol; and
the tablet further comprises:
at least one lubricant selected from the group consisting of magnesium stearate, calcium stearate and sodium stearate; and
at least one glidant selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, and talc.
21. The extended release pharmaceutical tablet of claim 4 , wherein the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, and sorbitol; and
the tablet further comprises:
at least one lubricant which is magnesium stearate; and
at least one glidant which is colloidal silicon dioxide.
22. The extended release pharmaceutical tablet of claim 1 , wherein the release control polymer is hydroxypropyl methylcellulose.
23. The extended release pharmaceutical tablet of claim 2 , wherein the release control polymer is hydroxypropyl methylcellulose.
24. The extended release pharmaceutical tablet of claim 3 , wherein the release control polymer is hydroxypropyl methylcellulose.
25. The extended release pharmaceutical tablet of claim 4 , wherein the release control polymer is hydroxypropyl methylcellulose.
26. The extended release pharmaceutical tablet of claim 1 , wherein the acidic pH modifier is tartaric acid.
27. The extended release pharmaceutical tablet of claim 2 , wherein the acidic pH modifier is tartaric acid.
28. The extended release pharmaceutical tablet of claim 3 , wherein the acidic pH modifier is tartaric acid.
29. The extended release pharmaceutical tablet of claim 4 , wherein the acidic pH modifier is tartaric acid.
30. The extended release tablet of claim 1 , wherein the release control polymer is selected from the group consisting of a cellulose derivative, copolymers of acrylic acid crosslinked with a polyalkenyl polyether, non-ionic homopolymers of ethylene oxide, water-soluble natural gums of polysaccharides, starch, polyvinyl acetate and polyvinylpyrrolidone.
31. The extended release pharmaceutical tablet of claim 1 , wherein:
the at least one filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose and sorbitol; and
the release control polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, copolymers of acrylic acid, crosslinked with a polyalkenyl polyether, non-ionic homopolymers of ethylene oxide, water soluble natural gums of polysaccharides, starch, polyvinyl acetate and polyvinylpyrrolidone.
32. The extended release pharmaceutical tablet of claim 31 , wherein the tablet further comprises at least one lubricant selected from the group consisting of polyethylene glycol, magnesium stearate, calcium stearate, sodium stearate, sodium stearyl fumarate and talc.
33. The extended release pharmaceutical tablet of claim 32 , wherein the acidic pH modifier is selected from the group consisting of citric acid, succinic acid, malic acid, fumaric acid and tartaric acid.
34. The extended release pharmaceutical tablet of claim 33 , wherein the tablet further comprises at least one glidant selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, and talc.
35. The tablet of claim 34 , wherein the extended release pharmaceutical tablet provides for the release of Compound 1 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.
36. The extended release pharmaceutical tablet of claim 35 , wherein:
a single administration of the tablet to healthy adult subjects results in a mean AUC inf from about 220 ng hours/mL to about 450 ng hours/mL of Compound 1; and
a single administration of the tablet to healthy adult subjects results in a mean C max from about 25 ng/ml to about 40 ng/ml of Compound 1.