CRYSTAL FORMS OF 5-[3-(2,5-DICHLORO-4, 6-DIMETHYL-1-OXY-PYRIDINE-3-YL)[1,2,4] OXADIAZOL-5-YL]-3-NITROBENZENE-1,2-DIOL

• US 20110112301A1
• Filed: 03/16/2009
• Published: 05/12/2011
• Est. Priority Date: 03/17/2008
• Status: Active Grant

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Eszenyi, Tibor, Meyer, Kevin Wayne, Kovách, Álmosné, Learmonth, David Alexander, Lorimer, Keith
• Granted Patent: US 8,975,410 B2
• Time in Patent Office: Days
• US Class Current: 546/269.4
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention relates to novel polymorphs of (HO)₂NO₂(C₆H)—(C₂N₂O)—(C₅N)(CH₃)₂Cl₂O, to processes for their preparation, and to pharmaceutical compositions containing said novel polymorphs as active pharmaceutical ingredient.

Claims

1. Crystal modification of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

6.6, 13.2, 17.9 and 23.8.

2. Crystal modification according to claim 1, further characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

23.2 and 24.3.

3. Crystal modification according to any one of claims 1 to 2, further characterized in that it exhibits an exotherm at 251°

C. in a Differential Scanning calorimetry (DSC) thermogram.

4. Crystal modification according to any preceding claim, further characterized by Raman peaks at 810, 1325, 1537, 1589, and 1628 cm⁻

1.

5. Crystal modification according to any preceding claim, further characterized by peaks at 15.7, 114.6, 148.8 and 174.0 ppm in Solid State ¹³C-NMR.

6. Crystal modification according to any preceding claim, further characterized in that it exhibits a melt onset at 238°

C. in hotstage analysis.

7. Crystal modification according to any preceding claim, further characterized in that it does not rearrange into another polymorph under conditions of 60% relative humidity and 25°

C. over a period of 3 months.

28. Pharmaceutical composition comprising a crystal modification according to any one of claims 1 to 27.

40. Process for the conversion of a crystal modification according to any one of claims 20 to 25 to the modification according to any one of claims 1 to 7, comprising the step of drying the crystal modification according to any one of claims 20 to 25 under vacuum.

41. Process according to claim 40 wherein the drying takes place at a temperature range of ambient temperatures to 60°

C.

42. Process for the conversion of a crystal form according to any one of claims 8 to 27 to a crystal form according to any one of claims 1 to 7, comprising the step of seeding a slurry of a crystal form according to any one of claims 8 to 27 with a crystal form according to any one of claims 1 to 7.

43. Polymorph according to any one of claims 1 to 27 or a pharmaceutical composition according to any one of claims 28 to 37 for treating a subject afflicted by a central or peripheral nervous system disorder.

44. Polymorph or a pharmaceutical composition according to claim 43 for treating mood disorders, Parkinson'"'"'s disease and parkinsonian disorders, gastrointestinal disturbances, edema formation states and hypertension.

45. Polymorph or a pharmaceutical composition according to claim 43 or 44 for use in L-DOPA/AADC therapy.

8. Crystal modification of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

5.7, 6.9, 13.8 and 19.6.

9. Crystal modification according to claim 8, further characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

11.9, and 16.9.

10. Crystal modification according to claim 8 or 9, further characterized by Raman peaks at 505, 1292, 1385, 1583, and 1630 cm⁻

1.

11. Crystal modification according to any one of claims 8 to 10, further characterized by peaks at 150.3, 133.9, 112.6 and 19.8 ppm in Solid State ¹³C-NMR.

12. Crystal modification according to any one of claims 8 to 11, further characterized in that it exhibits an exotherm at 237°

C. in a Differential Scanning calorimetry (DSC) thermogram.

38. Process for the conversion of a crystal modification according to any one of claims 13 to 17 to the modification according to any one of claims 8 to 12, comprising the step of drying the crystal modification according to any one of claims 13 to 17 under vacuum.

13. Crystal modification of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

4.9, 13.3, 19.1 and 24.0.

14. Crystal modification according to claim 13, further characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

7.3, 21.9 and 23.4.

15. Crystal modification according to claim 13 or 14, further characterized by Raman peaks at 1387, 1406, 1537, 1585, and 1630 cm⁻

1.

16. Crystal modification according to any one of claims 13 to 15, further characterized by peaks at 150.7, 133.5, 114.0 and 20.2 ppm in Solid State ¹³C-NMR.

17. Crystal modification according to any one of claims 13 to 16, further characterized in that it exhibits an exotherm at 203°

C. in a Differential Scanning calorimetry (DSC) thermogram.

18. Crystal modification of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

12.3, 20.0, 20.7 and 21.4.

19. Crystal modification according to claim 18, further characterised in that its X-ray powder diffractogram exhibits the following 2θ

angles;

11.6 and 24.8.

20. Crystal modification of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, characterized in that its X-ray powder diffractogram exhibits the following 2θ

angles;

9.8, 12.2, 19.8 and 24.5.

21. Crystal modification according to claim 20, further characterised in that its X-ray powder diffractogram exhibits the following 2θ

angles;

7.8, 15.6, 16.2, 17.6, 21.7 and 22.9.

22. Crystal modification according to claim 20 or 21, further characterized by Raman peaks at 1356, 1533, 1556, 1583, and 1635 cm⁻

1.

23. Crystal modification according to any one of claims 20 to 22, further characterized by peaks at 151.8, 133.6, 105.1 and 19.4 ppm in Solid State ¹³C-NMR.

24. Crystal modification according to any one of claims 20 to 23, further characterised in that it exhibits an exotherm at 243°

C. in a Differential Scanning calorimetry (DSC) thermogram.

25. Crystal modification according to any one of claims 20 to 24, further characterised in that it exhibits an endotherm at 159°

C. in a Differential Scanning calorimetry (DSC) thermogram.

27. Crystal modification according to claim 20, further characterised in that its X-ray powder diffractogram exhibits the following 2θ

angles;

8.2 and 13.5.

26. Crystal modification of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, characterized in that its X-ray powder diffractogram is exhibiting the following 2θ

angles;

10.7, 12.6, 16.4 and 25.4.

29. Pharmaceutical composition comprising 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and characterized in that its X-ray powder diffractogram exhibits at least 3 2θ

angles from the following list of 2θ

angles;

6.6, 6.9, 11.8, 13.2, 17.2, 17.9, 19.8, 22.6, 23.2, 23.8, 24.3, and 25.3; and

in that it exhibits an exotherm at 251°

C. in a Differential Scanning calorimetry (DSC) thermogram.

30. Pharmaceutical composition according to claim 29 wherein its XRPD exhibits the following peaks:

6.6, 23.2 and 24.3.

31. Pharmaceutical composition according to claim 29 or 30, further characterized in that its Raman spectrum exhibits at least 3 peaks from the following peak list [cm⁻

1];

145, 170, 216, 237, 256, 285, 339, 370, 420, 442, 465, 505, 526, 710, 810, 974, 1007, 1059, 1159, 1228, 1254, 1277, 1325, 1387, 1414, 1448, 1498, 1537, 1589, 1628, 2927.

32. Pharmaceutical composition according to any one of claims 29 to 31, further characterized in that its Solid State ¹³C-NMR spectrum (100 MHz) exhibits at least 3 peaks from the following peak list [ppm]:

174.0, 163.9, 150.4, 148.8, 144.5, 140.2, 134.8, 133.2, 129.8, 124.9, 124.0, 122.1, 114.6, 22.5, and 15.7

37. Pharmaceutical composition according to any one of claims 29 to 36, further characterized in that the variation of the time period until 80% of the active pharmaceutical ingredient has been released under test conditions according to the USP Paddle Test Method, USP, 30th Edition, The National Formulary 25th Edition, 2007, The United States Pharmacopeial Convention, Rockville, volume 1, chapter 711, is less than 10% after storage under conditions of 60% relative humidity at 25°

C. over a period of at least 3 months.

39. Process according to claim 37 wherein the drying takes place at a temperature range of ambient temperatures to 60°

C.

33. Pharmaceutical composition comprising 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and character-ized in that its X-ray powder diffractogram exhibits at least 3 2θ

angles from the following list of 2θ

angles;

5.7, 6.9, 8.0, 9.8, 11.3, 11.9, 13.8, 14.4, 16.9, 19.6, and 20.4; and

in that it exhibits an exotherm at 237°

in a Differential Scanning Calorimetry (DSC) thermogram.

34. Pharmaceutical composition according to claim 33 wherein its XRPD exhibits the following peaks:

5.7, 16.9 and 19.6.

35. Pharmaceutical composition according to claim 33 or 34, further characterized in that its Raman spectrum exhibits at least 3 peaks within from the following peak list [cm⁻

1];

141, 214, 235, 253, 280, 339, 361, 372, 399, 415, 440, 463, 505, 526, 710, 812, 887, 926, 970, 1001, 1059, 1157, 1227, 1292, 1317, 1385, 1406, 1444, 1504, 1537, 1583, 1630, and 2933.

36. Pharmaceutical composition according to any one of claims 33 to 35, further characterized in that its Solid State ¹³C-NMR spectrum (100 MHz) exhibits at least 3 peaks from the following peak list [ppm]:

174.4, 164.7, 150.3, 139.1, 133.9, 132.8, 123.5, 120.3, 114.0, 112.6, 19.8, and 16.6.