Drug substance preparations, pharmaceutical compositions and dosage forms
The invention relates to drug substance preparations, pharmaceutical compositions and dosage forms containing (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid as the active pharmaceutical ingredient, and limited amounts of specific product-related and process-related impurities.
1. A drug substance preparation comprising (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient, and between about 0.001% and about 3%, by weight, product-related impurities, wherein said product-related impurities comprise not more than about 0.5%, by weight, 2-(4-biphenylyl) propionic acid, or a salt thereof, and not more than about 2%, by weight, of the enantiomeric impurity (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid, or a salt thereof, and not more than about 200 ppm of the process-related impurity, (R)-(+)-α-methylbenzylamine.
2. The drug substance preparation of claim 1 wherein said product-related impurities further comprise not more than about 0.1%, by weight, methyl (2-(2-fluoro-4-biphenylyl)) propionate, or a salt thereof.
3. The drug substance preparation of claim 1 , wherein said product-related impurities comprise not more than about 1%, by weight, of the enantiomeric impurity (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid, or a salt thereof.
4. The drug substance preparation of claim 1 , wherein said product-related impurities comprise not more than about 0.5%, by weight, of the enantiomeric impurity (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid, or a salt thereof.
5. A pharmaceutical composition comprising the drug substance preparation of claim 4 , and one or more excipients.
6. A drug product or dosage form comprising the pharmaceutical composition of claim 5 and one or more additional excipients.
7. The drug product or dosage form of claim 6 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 100 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
8. The drug product or dosage form of claim 6 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 200 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
9. The drug product or dosage form of claim 6 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 400 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
10. The drug product or dosage form of claim 6 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 800 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
11. The drug substance preparation of claim 1 further comprising not more than about 50 ppm of the process-related impurity, (R)-(+)-α-methylbenzylamine.
12. The drug substance preparation of claim 11 further comprising residual solvents of not more than about 890 ppm of toluene, not more than about 0.3%, by weight, methanol, and not more than about 0.3%, by weight, n-heptane.
13. The drug substance preparation of claim 12 further comprising not more than about 10 ppm lead.
14. A unit dosage form comprising 55-90%, by weight, drug substance preparation of claim 4 and 10-45% total, by weight, of one or more excipients, wherein said unit dosage form contains 100 mg or more of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
15. The unit dosage form of claim 14 having from about 200 to about 800 mg (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
16. The unit dosage form of claim 14 having from about 300 to about 500 mg (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
17. The unit dosage form of claim 16 having about 400 mg (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
18. The unit dosage form of claim 17 , wherein said unit dosage form is a tablet.
19. The unit dosage form of claim 16 , wherein the total weight of said dosage form is no more than about 800 mg.
20. The unit dosage form of claim 16 , wherein the total weight of said dosage form is no more than about 700 mg.
21. The unit dosage form of claim 14 , wherein said one or more excipients comprises microcrystalline cellulose.
22. The unit dosage form of claim 14 , wherein said (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid is the free acid form of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid.
23. The unit dosage form of claim 14 , wherein said dosage form is a tablet or a capsule.
24. The unit dosage form of claim 14 , wherein said dosage form is a tablet.
25. A drug substance preparation comprising:
(1) (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient;
(2) between about 0.001% and about 2%, by weight, product-related impurities, wherein said product-related impurities comprise:
(a) not more than about 0.5%, by weight, 2-(4-biphenylyl) propionic acid,
(b) not more than about 0.1%, by weight, methyl (2-(2-fluoro-4-biphenylyl)) propionate, and
(c) not more than about 1.0%, by weight, of the enantiomeric impurity (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid, or a salt thereof;
(3) not more than about 200 ppm of the process-related impurity, (R)-(+)-α-methylbenzylamine;
(4) not more than about 900 ppm of toluene, not more than about 0.3%, by weight, methanol, and not more than about 0.3%, by weight, n-heptane; and
(5) not more than about 10 ppm lead.
26. The drug substance preparation of claim 25 , wherein said product-related impurities comprise not more than about 0.5%, by weight, of the enantiomeric impurity (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid, or a salt thereof.
27. A pharmaceutical composition comprising the drug substance preparation of claim 26 , and one or more excipients.
28. A drug product or dosage form comprising the pharmaceutical composition of claim 27 and one or more additional excipients.
29. The drug product or dosage form of claim 28 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 100 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
30. The drug product or dosage form of claim 28 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 200 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
31. The drug product or dosage form of claim 28 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 400 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
32. The drug product or dosage form of claim 28 , wherein the drug product or dosage form is a tablet formulated to orally administer at least about 800 mg of (R)-(−)-2-(2-fluoro-4-biphenylyl) propionic acid, or the molar equivalent amount of a salt thereof.
33. The drug substance preparation of claim 25 , wherein the drug substance preparation comprises not more than about 50 ppm of the process-related impurity, (R)-(+)-α-methylbenzylamine.