In vivo studies of crystalline forms of meloxicam

1. A co-crystal comprising meloxicam and a co-crystal former selected from the group consisting of fumaric acid, succinic acid, adipic acid, benzoic acid, DL-malic acid, L-malic acid, glutaric acid, acetylsalicylic acid, salicylic acid, 1-hydroxy-2-naphthoic acid, maleic acid, 4-hydroxybenzoic acid, malonic acid, glycolic acid, 2,5-dihydroxybenzoic acid, camphoric acid, maltol, ethyl maltol, and hydrocinnamic acid.

2. A solid pharmaceutical composition comprising:

a co-crystal comprising meloxicam and a co-crystal former selected from the group consisting of fumaric acid, succinic acid, adipic acid, benzoic acid, DL-malic acid, L-malic acid, glutaric acid, acetylsalicylic acid, salicylic acid, 1-hydroxy-2-naphthoic acid, maleic acid, 4-hydroxybenzoic acid, malonic acid, glycolic acid, 2,5-dihydroxybenzoic acid, camphoric acid, maltol, ethyl maltol, and hydrocinnamic acid; and

a pharmaceutically acceptable excipient.

3. The solid pharmaceutical composition of claim 2 , wherein said co-crystal comprising meloxicam and a co-crystal former has one or more properties selected from the group consisting of a shorter time to C max in blood compared to pure meloxicam, improved aqueous solubility compared to pure meloxicam, and improved bioavailability compared to pure meloxicam.

4. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is fumaric acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 12.13, 14.75, 16.52, 18.14, 22.21, 23.53 and 26.86+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 1 .

5. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is succinic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 13.22, 14.50, 16.41, 18.30, 23.68, 26.59 and 27.67+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 3 .

6. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is adipic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 8.56, 9.38, 12.67, 17.50, 24.13, 26.77, and 27.46+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 5 .

7. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is benzoic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 9.61, 14.06, 15.00, 16.01, 17.21, 18.20 and 26.47+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 7 .

8. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is DL-malic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 13.39, 14.87, 16.55, 18.39, 23.78, 26.80 and 27.91+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 9 .

9. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is L-malic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 13.14, 14.57, 16.25, 23.51, 24.66, 26.53 and 27.66+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 11 .

10. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is glutaric acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 5.16, 13.85, 15.26, 16.13, 19.64, 26.17 and 27.58+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 13 .

11. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is acetylsalicylic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 9.57, 13.55, 14.18, 19.49, 22.51, 23.86 and 24.88+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 15 .

12. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is salicylic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 12.08, 13.85, 14.75, 16.10, 25.24, 25.87 and 27.00+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 17 .

13. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is salicylic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 6.27, 15.02, 15.47, 19.70, 25.66, 26.23 and 27.49+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 19 .

14. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is salicylic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 9.413, 12.830, 14.869, 16.368, 23.386, 25.781, and 28.875+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 41 .

15. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is 1-hydroxy-2-naphthoic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 6.67, 12.35, 14.92, 16.25, 17.75, 25.93 and 26.88+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 21 .

16. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is maleic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 8.27, 15.50, 16.35, 18.59, 21.43, 22.58 and 25.69+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 23 .

17. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is 4-hydroxybenzoic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 6.88, 7.92, 13.34, 17.87, 19.41, 25.36 and 26.86+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 25 .

18. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is malonic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 9.74, 11.88, 14.06, 15.02, 19.34, 22.27 and 26.83+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 27 .

19. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is glycolic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 10.91, 14.18, 14.87, 15.56, 19.28, 21.37 and 26.38+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 29 .

20. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is 2,5-dihydroxybenzoic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 9.77, 14.96, 18.84, 22.85, 24.43, 25.12 and 29.02+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 31 .

21. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is 2,5-dihydroxybenzoic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 9.86, 15.05, 19.07, 19.79, 22.99, 25.27 and 26.32+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 33 .

22. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is camphoric acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 7.68, 11.35, 13.64, 15.47, 26.23 and 26.83+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 35 .

23. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is camphoric acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 5.19, 9.95, 11.41, 13.50, 15.38, 16.70, 26.23 and 36.21+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 37 .

24. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is maltol and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 3.950, 7.398, 10.940, 14.451, 16.069, 26.201, and 26.950+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 39 .

25. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is ethyl maltol and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 3.758, 7.165, 10.541, 13.940, 15.262, 19.678, and 25.211+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 43 .

26. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is hydrocinnamic acid and said co-crystal is characterized by having a) a PXRD diffraction pattern with peaks at about 4.243, 8.321, 13.692, 15.798, 19.965, 23.223, and 26.471+/−0.2 degrees two-theta; or b) a PXRD diffraction pattern as depicted in FIG. 45 .

27. A suspension comprising a co-crystal which comprises meloxicam and a co-crystal former selected from the group consisting of fumaric acid, succinic acid, adipic acid, benzoic acid, DL-malic acid, L-malic acid, glutaric acid, acetylsalicylic acid, salicylic acid, 1-hydroxy-2-naphthoic acid, maleic acid, 4-hydroxybenzoic acid, malonic acid, glycolic acid, 2,5-dihydroxybenzoic acid, camphoric acid, maltol, ethyl maltol, and hydrocinnamic acid.

28. A pharmaceutical composition comprising a suspension which comprises a co-crystal comprised of meloxicam and a co-crystal former selected from the group consisting of fumaric acid, succinic acid, adipic acid, benzoic acid, DL-malic acid, L-malic acid, glutaric acid, acetylsalicylic acid, salicylic acid, 1-hydroxy-2-naphthoic acid, maleic acid, 4-hydroxybenzoic acid, malonic acid, glycolic acid, 2,5-dihydroxybenzoic acid, camphoric acid, maltol, ethyl maltol, and hydrocinnamic acid.

29. The co-crystal of claim 1 wherein said co-crystal former is 1-hydroxy-2-naphthoic acid.

30. The co-crystal of claim 1 wherein said co-crystal former is acetylsalicylic acid.

31. The co-crystal of claim 30 wherein said co-crystal is meloxicam:acetylsalicylic acid form 3 co-crystal.

32. The co-crystal of claim 1 wherein said co-crystal former is succinic acid.

33. The co-crystal of claim 1 wherein said co-crystal former is 4-hydroxybenzoic acid.

34. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is 1-hydroxy-2-naphthoic acid.

35. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is acetylsalicylic acid.

36. The solid pharmaceutical composition of claim 35 , wherein said co-crystal is meloxicam:acetylsalicylic acid form 3 co-crystal.

37. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is succinic acid.

38. The solid pharmaceutical composition of claim 2 , wherein said co-crystal former is 4-hydroxybenzoic acid.

39. The solid pharmaceutical composition of claim 34 , wherein said solid pharmaceutical composition has one or more properties selected from the group consisting of a shorter time to C max in blood compared to pure meloxicam, improved aqueous solubility compared to pure meloxicam, and improved bioavailability compared to pure meloxicam.

40. The solid pharmaceutical composition of claim 35 , wherein said solid pharmaceutical composition has one or more properties selected from the group consisting of a shorter time to C max in blood compared to pure meloxicam, improved aqueous solubility compared to pure meloxicam, and improved bioavailability compared to pure meloxicam.

41. The solid pharmaceutical composition of claim 36 , wherein said solid pharmaceutical composition has one or more properties selected from the group consisting of a shorter time to C max in blood compared to pure meloxicam, improved aqueous solubility compared to pure meloxicam, and improved bioavailability compared to pure meloxicam.

42. The solid pharmaceutical composition of claim 37 , wherein said solid pharmaceutical composition has one or more properties selected from the group consisting of a shorter time to C max in blood compared to pure meloxicam, improved aqueous solubility compared to pure meloxicam, and improved bioavailability compared to pure meloxicam.

43. The solid pharmaceutical composition of claim 38 , wherein said solid pharmaceutical composition has one or more properties selected from the group consisting of a shorter time to C max in blood compared to pure meloxicam, improved aqueous solubility compared to pure meloxicam, and improved bioavailability compared to pure meloxicam.