Crystalline salts of (4S,4AS,5AR,12AS)-4-dimethylamino-3,10,12,12A-tetrahydroxy-7-[methoxy(methyl)amino)-methyl] acid amide and methods of using the same
A crystalline mono hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide is disclosed having improved stability. In addition, a crystalline mono mesylate salt and crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide are also disclosed having improved stability. A pharmaceutical composition containing the crystalline salts and methods of treating inflammatory skin disorders and bacterial infections comprising administering the crystalline salts are also disclosed.
1. A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate, and wherein the crystalline salt has a crystal-like internal structural arrangement.
2. The crystalline salt of claim 1 , wherein the salt is substantially pure.
3. The crystalline salt of claim 1 , wherein the salt is mono hydrochloride.
4. The crystalline salt of claim 3 , having an XRPD pattern substantially as illustrated in FIG. 1 after synthesis of the crystalline salt.
5. The crystalline salt of claim 3 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 13.4, about 20.5 and about 23.3, as measured by XRPD.
6. The crystalline salt of claim 3 , having a DSC curve substantially as illustrated in FIG. 2 after synthesis of the crystalline salt.
7. The crystalline salt of claim 3 , having a TGA curve substantially as illustrated in FIG. 3 after synthesis of the crystalline salt.
8. The crystalline salt of claim 3 , wherein the salt has a β-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC.
9. The crystalline salt of claim 1 , wherein the salt is mono mesylate.
10. The crystalline salt of claim 9 , having an XRPD pattern substantially as illustrated in FIG. 4 after synthesis of the crystalline salt.
11. The crystalline salt of claim 9 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 9, about 15 and about 23.8, as measured by XRPD.
12. The crystalline salt of claim 9 , having a DSC curve substantially as illustrated in FIG. 5 after synthesis of the crystalline salt.
13. The crystalline salt of claim 9 , having a TGA curve substantially as illustrated in FIG. 6 after synthesis of the crystalline salt.
14. The crystalline salt of claim 9 , wherein the salt has a β-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC.
15. The crystalline salt of claim 1 , wherein the salt is mono sulfate.
16. The crystalline salt of claim 15 , having an XRPD pattern substantially as illustrated in FIG. 7 after synthesis of the crystalline salt.
17. The crystalline salt of claim 15 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 15, about 17.8 and about 23.5, as measured by XRPD.
18. The crystalline salt of claim 15 , having a DSC curve substantially as illustrated in FIG. 8 after synthesis of the crystalline salt.
19. The crystalline salt of claim 15 , having a TGA curve substantially as illustrated in FIG. 9 after synthesis of the crystalline salt.
20. The crystalline salt of claim 15 , wherein the salt has a β-isomer content at 0 days of about 3.0% peak area to about 26.0% peak area, as measured by HPLC.
21. A pharmaceutical composition comprising the crystalline salt of claim 1 and a pharmaceutically acceptable excipient.
22. The pharmaceutical composition of claim 21 , wherein the salt is mono hydrochloride.
23. The pharmaceutical composition of claim 21 , wherein the salt is mono mesylate.
24. The pharmaceutical composition of claim 21 , wherein the salt is mono sulfate.
25. A method for treating acne comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1 .
26. The method of claim 25 , wherein the salt is mono hydrochloride.
27. The method of claim 25 , wherein the salt is mono mesylate.
28. The method of claim 25 , wherein the salt is mono sulfate.
29. A method for treating rosacea comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1 .
30. The method of claim 29 , wherein the salt is mono hydrochloride.
31. The method of claim 29 , wherein the salt is mono mesylate.
32. The method of claim 29 , wherein the salt is mono sulfate.
33. A method for treating a gram positive bacterial infection, wherein the gram positive bacteria is selected from the group consisting of Propionibacterium acnes, Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes , and Clostridium difficile , comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1 .
34. The method of claim 33 , wherein the salt is mono hydrochloride.
35. The method of claim 33 , wherein the salt is mono mesylate.
36. The method of claim 33 , wherein the salt is mono sulfate.
37. A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate, and wherein the crystalline salt is substantially free of an amorphous salt.
38. The crystalline salt of claim 37 , wherein the salt is substantially pure.
39. The crystalline salt of claim 37 , wherein the salt is mono hydrochloride.
40. The crystalline salt of claim 39 , having an XRPD pattern substantially as illustrated in FIG. 1 after synthesis of the crystalline salt.
41. The crystalline salt of claim 39 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 13.4, about 20.5 and about 23.3, as measured by XRPD.
42. The crystalline salt of claim 39 , having a DSC curve substantially as illustrated in FIG. 2 after synthesis of the crystalline salt.
43. The crystalline salt of claim 39 , having a TGA curve substantially as illustrated in FIG. 3 after synthesis of the crystalline salt.
44. The crystalline salt of claim 39 , wherein the salt has a β-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC.
45. The crystalline salt of claim 37 , wherein the salt is mono mesylate.
46. The crystalline salt of claim 45 , having an XRPD pattern substantially as illustrated in FIG. 4 after synthesis of the crystalline salt.
47. The crystalline salt of claim 45 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 48, about 15 and about 23.8, as measured by XRPD.
48. The crystalline salt of claim 45 , having a DSC curve substantially as illustrated in FIG. 5 after synthesis of the crystalline salt.
49. The crystalline salt of claim 45 , having a TGA curve substantially as illustrated in FIG. 6 after synthesis of the crystalline salt.
50. The crystalline salt of claim 45 , wherein the salt has a β-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC.
51. The crystalline salt of claim 37 , wherein the salt is mono sulfate.
52. The crystalline salt of claim 51 , having an XRPD pattern substantially as illustrated in FIG. 7 after synthesis of the crystalline salt.
53. The crystalline salt of claim 51 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 15, about 17.8 and about 23.5, as measured by XRPD.
54. The crystalline salt of claim 51 , having a DSC curve substantially as illustrated in FIG. 8 after synthesis of the crystalline salt.
55. The crystalline salt of claim 51 , having a TGA curve substantially as illustrated in FIG. 9 after synthesis of the crystalline salt.
56. The crystalline salt of claim 51 , wherein the salt has a β-isomer content at 0 days of about 3.0% peak area to about 26.0% peak area, as measured by HPLC.
57. A pharmaceutical composition comprising the crystalline salt of claim 37 and a pharmaceutically acceptable excipient.
58. The pharmaceutical composition of claim 57 , wherein the salt is mono hydrochloride.
59. The pharmaceutical composition of claim 57 , wherein the salt is mono mesylate.
60. The pharmaceutical composition of claim 57 , wherein the salt is mono sulfate.
61. A method for treating acne comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 37 .
62. The method of claim 61 , wherein the salt is mono hydrochloride.
63. The method of claim 61 , wherein the salt is mono mesylate.
64. The method of claim 61 , wherein the salt is mono sulfate.
65. A method for treating rosacea comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 37 .
66. The method of claim 65 , wherein the salt is mono hydrochloride.
67. The method of claim 65 , wherein the salt is mono mesylate.
68. The method of claim 65 , wherein the salt is mono sulfate.
69. A method for treating a gram positive bacterial infection, wherein the gram positive bacteria is selected from the group consisting of Propionibacterium acnes, Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes , and Clostridium difficile , comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 37 .
70. The method of claim 69 , wherein the salt is mono hydrochloride.
71. The method of claim 69 , wherein the salt is mono mesylate.
72. The method of claim 69 , wherein the salt is mono sulfate.