Forms of aticaprant
The disclosure provides crystalline and amorphous forms of aticaprant. Also provided by the disclosure are pharmaceutical compositions comprising the amorphous or crystalline forms, methods of treating major depressive disorder using the amorphous or crystalline forms of aticaprant, amorphous or crystalline forms of aticaprant for use in the treatment of major depressive disorder in a human patient having anhedonia, uses of the amorphous or crystalline forms of aticaprant in the manufacture of a medicament for the treatment of major depressive disorder, and packages or pharmaceutical products comprising (i) amorphous or crystalline forms of aticaprant and (ii) instructions for treating major depressive disorder. In some aspects, the human patient treated as described herein has anhedonia.
1. A method of treating major depressive disorder in a human patient, comprising administering an effective amount of crystalline aticaprant of Form I, II, or III to the human patient, wherein the patient had a previous inadequate response to other antidepressant therapy, wherein:
crystalline Form I is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°,
crystalline Form II is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 3.1°, 19.0°, 24.0°, 24.3°, and 26.2°,
crystalline Form III is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, and 21.4°,
wherein aticaprant has the following structure:
2. The method of claim 1 , wherein the crystalline aticaprant is crystalline Form I of aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°.
3. The method of claim 2 , wherein the crystalline aticaprant is crystalline Form I of aticaprant that is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 6 .
4. The method of claim 2 , wherein the crystalline Form I of aticaprant is characterized by a differential scanning calorimetry thermogram comprising one endotherm at about 92.9° C.
5. The method of claim 2 , wherein the crystalline Form I of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 7 .
6. The method of claim 1 , wherein the crystalline aticaprant is a crystalline Form II of aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 3.1°, 19.0°, 24.0°, 24.3°, and 26.2°.
7. The method of claim 6 , wherein the crystalline Form II of aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 8 .
8. The method of claim 6 , wherein the crystalline Form II of aticaprant is characterized by a differential scanning calorimetry thermogram comprising one or both endotherms at about 74.7° C. and about 96.2° C.
9. The method of claim 6 , wherein the crystalline Form II of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 9 .
10. The method of claim 1 , wherein the crystalline aticaprant is a crystalline Form III of aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, and 21.4°.
11. The method of claim 10 , wherein the crystalline Form III of aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 1 .
12. The method of claim 10 , wherein the crystalline Form III of aticaprant is characterized by a peak temperature (T m ) at about 121° C.
13. The method of claim 10 , wherein the crystalline Form III of aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 4 .
14. The method of claim 1 , wherein the crystalline form of aticaprant is anhydrous.
15. The method of claim 1 , wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, or serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
16. The method of claim 1 , further comprising adjunctive treatment with an effective amount of one or more antidepressants.
17. The method of claim 16 , wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
18. The method of claim 1 , wherein the effective amount of the crystalline Form I, II, or III of aticaprant is between about 2 mg and about 35 mg, between about 5 mg and about 10 mg, about 5 mg, or about 10 mg.
19. The method of claim 1 , wherein the crystalline Form I, II, or III of aticaprant is administered orally once daily.
20. The method of claim 1 , wherein the patient has anhedonia.
21. A method of treating major depressive disorder in a human patient, comprising administering an effective amount of crystalline S-aticaprant of Form I, II, or III to the human patient, wherein the patient had a previous inadequate response to other antidepressant therapy, wherein:
crystalline Form I of S-aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3°, 17.4°, 18.0°, and 24.0°;
crystalline Form II of S-aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 3.1°, 19.0°, 24.0°, 24.3°, and 26.2°; and
crystalline Form III of S-aticaprant is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, and 21.4°;
wherein S-aticaprant has the following structure:
22. The method of claim 21 , wherein the crystalline S-aticaprant is crystalline Form I of S-aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.6°, 17.3º, 17.4°, 18.0°, and 24.0°.
23. The method of claim 22 , wherein the crystalline S-aticaprant is crystalline Form I of S-aticaprant that is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 6 .
24. The method of claim 22 , wherein the crystalline Form I of S-aticaprant is characterized by a differential scanning calorimetry thermogram comprising one endotherm at about 92.9°C.
25. The method of claim 22 , wherein the crystalline Form I of S-aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 7 .
26. The method of claim 21 , wherein the crystalline S-aticaprant is a crystalline Form II of S-aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 3.1°, 19.0°, 24.0°, 24.3°, and 26.2°.
27. The method of claim 26 , wherein the crystalline Form II of S-aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 8 .
28. The method of claim 26 , wherein the crystalline Form II of S-aticaprant is characterized by a differential scanning calorimetry thermogram comprising one or both endotherms at about 74.7° C. and about 96.2° C.
29. The method of claim 26 , wherein the crystalline Form II of S-aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 9 .
30. The method of claim 21 , wherein the crystalline S-aticaprant is a crystalline Form III of S-aticaprant that is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, and 21.4°.
31. The method of claim 30 , wherein the crystalline Form III of S-aticaprant is characterized by an x-ray powder diffraction pattern that corresponds to FIG. 1 .
32. The method of claim 30 , wherein the crystalline Form III of S-aticaprant is characterized by a peak temperature (T m ) at about 121° C.
33. The method of claim 30 , wherein the crystalline Form III of S-aticaprant is characterized by a differential scanning calorimetry thermogram that corresponds to FIG. 4 .
34. The method of claim 21 , wherein the crystalline form of S-aticaprant is anhydrous.
35. The method of claim 21 , wherein the other antidepressant therapy is a selective serotonin reuptake inhibitor, or serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
36. The method of claim 21 , further comprising adjunctive treatment with an effective amount of one or more antidepressants.
37. The method of claim 36 , wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
38. The method of claim 21 , wherein the effective amount of the crystalline Form I, II, or III of S-aticaprant is between about 2 mg and about 35 mg, between about 5 mg and about 10mg, about 5 mg, or about 10 mg.
39. The method of claim 21 , wherein the crystalline Form I, II, or III of S-aticaprant is administered orally once daily.
40. The method of claim 21 , wherein the patient has anhedonia.
41. The method of claim 30 , wherein about 10 mg of the crystalline Form III is administered orally once daily.
42. The method of claim 41 , further comprising adjunctive treatment with an effective amount of one or more antidepressants.
43. The method of claim 42 , wherein the one or more antidepressants is a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or a combination thereof.
44. The method of claim 30 , wherein the patient has anhedonia.