Hemi-citrate and crystalline form of GABA-A positive allosteric modifier

Abstract

The present invention provides a formulation of a salt of a synthetic neuroactive steroid compound that possesses both desirable therapeutic utility and physicochemical properties. [Solution] A substantially pure hemi-citrate of compound 1 (3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one) having the following formula is provided. TIFF2026097871000045.tif48165

Claims

1. A substantially pure hemy citrate of compound 1 having the following formula. 【Chemistry 1】

2. The hemy citrate according to claim 1, wherein the hemy citrate contains less than about 5% by weight of the mono-citrate of compound 1.

3. The hemy citrate according to claim 2, wherein the hemy citrate substantially does not contain the mono-citrate of compound 1.

4. The hemi-citrate according to any one of claims 1 to 3, wherein the hemi-citrate is a hydrate.

5. The hemi-citrate according to any one of claims 1 to 4, wherein the hemi-citrate has a water content of about 0% to about 5% by weight.

6. The hemi-citrate according to any one of claims 1 to 5, wherein the hemi-citrate is a sesquihydrate.

7. The hemy citrate according to any one of claims 1 to 6, wherein the hemy citrate is in crystalline form I.

8. The hemy citrate according to claim 7, wherein the crystalline form I has a water content of about 4.4% by weight and exhibits a differential scanning calorimetry (DSC) thermogram having a first peak value of about 65.2 ± 2.0°C and a second peak value of about 126.3 ± 2.0°C.

9. The hemy citrate according to claim 7 or 8, wherein the crystalline form I exhibits a thermogravimetric analysis (TGA) thermogram having a weight loss of approximately 0.0% to 4.4% in a temperature range of 25 to 125°C.

10. The hemy citrate according to any one of claims 1 to 9, wherein the hemy citrate is crystalline form IA of compound 1.

11. The hemy citrate according to claim 10, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta including at least one of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 21.0±0.2, and 25.5±0.

2.

12. The aforementioned crystal morphology IA exhibits the following peaks at the diffraction angle 2-theta: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, and 17.6±0. The hemy citrate according to claim 10 or 11, exhibiting an X-ray powder diffraction (XRPD) pattern comprising at least three of the following values: 2, 20.5 ± 0.2, 21.0 ± 0.2, and 25.5 ± 0.

2.

13. The hemy citrate according to any one of claims 10 to 12, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern including the following peaks at the diffraction angle 2-theta: 5.3±0.2, 14.5±0.2, and 25.5±0.

2.

14. The hemy citrate according to any one of claims 10 to 13, wherein the crystal morphology IA exhibits an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 1.

15. The hemy citrate according to any one of claims 1 to 7, wherein the hemy citrate is the crystalline form IB of compound 1.

16. The hemy citrate according to claim 15, wherein the crystalline form IB exhibits an XRPD pattern at the diffraction angle 2-theta including at least one of the following peaks: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 21.0±0.2, and 25.5±0.

2.

17. The hemy citrate according to claim 15 or 16, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern at the diffraction angle 2-theta including at least three of the following peaks: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 20.3±0.2, 21.0±0.2, and 25.5±0.

2.

18. The hemy citrate according to any one of claims 15 to 17, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern including the following peaks at the diffraction angle 2-theta: 5.4±0.2, 14.5±0.2, and 25.5±0.

2.

19. The hemy citrate according to any one of claims 15 to 18, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 2.

20. The above-mentioned form I is as follows: a = 34.7 Å, b = 8.3 Å, c = 31.7 Å, α＝９０°、 β＝１０８．５°、 γ = 90°, Space group C2, and Defined by unit cell parameters substantially similar to those of molecular / asymmetric unit 2, The hemy citrate according to claim 7, wherein the crystalline form is at approximately 173 K.

21. A pharmaceutical composition comprising a hemi-citrate according to any one of claims 1 to 20 and at least one pharmaceutically acceptable excipient.

22. The pharmaceutical composition according to claim 21, wherein after the composition is stored at approximately 40°C and 75% relative humidity for approximately 6 months, the chemical purity of compound 1 in the composition is at least approximately 98%.

23. The pharmaceutical composition according to claim 21 or 22, wherein, after the composition is stored at approximately 40°C and 75% relative humidity for approximately 6 months, the composition contains approximately 0.5% by weight or less of the C-17 epimer of compound 1, based on the total weight of compound 1 in the composition.

24. The pharmaceutical composition according to any one of claims 21 to 23, further comprising a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 4% by weight.

25. The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 3% by weight.

26. The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 2.5% by weight.

27. The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 2% by weight.

28. The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is about 1% by weight to about 2% by weight.

29. The pharmaceutical composition according to any one of claims 24 to 28, wherein the lubricant is magnesium stearate.

30. A pharmaceutical composition according to any one of claims 21 to 29, further comprising crospovidone.

31. The pharmaceutical composition according to claim 30, wherein the proportion of crospovidone in the pharmaceutical composition is about 3% by weight to about 8% by weight.

32. Approximately 25% by weight of the hemi-citrate of compound 1, Approximately 2% by weight of magnesium stearate, and A pharmaceutical composition according to any one of claims 21 to 31, comprising approximately 7% by weight of crospovidone.

33. The pharmaceutical composition according to claim 32, wherein the composition contains less than 5% by weight of a mono-citrate of compound 1.

34. A pharmaceutical composition according to any one of claims 21 to 33, formulated for oral delivery.

35. The pharmaceutical composition according to claim 34, which is in the form of a tablet.

36. The pharmaceutical composition according to claim 35, wherein the tensile strength of the tablet is at least 1.7 megapascals (MPa).

37. The pharmaceutical composition according to claim 35, wherein the tensile strength of the tablet is approximately 1.7 MPa to approximately 4.5 MPa.

38. The pharmaceutical composition according to any one of claims 35 to 37, wherein the tablet has a disintegration time of less than approximately 2.5 minutes.

39. A method for preparing the hemy citrate of compound 1 having the following formula, 【Chemistry 2】 The method described above is (a) The mono-citrate of compound 1 is C １ -C ２ Dissolving in alcohol to obtain a solution, and (b) A method comprising adding the solution to water to obtain the hemy citrate of compound 1.

40. The method according to claim 39, further comprising isolating and drying the hemy citrate of compound 1.

41. A method for preparing the hemy citrate of compound 1 having the following formula, 【Transformation 3】 The method described above is (a) Suspending the mono-citrate of compound 1 in water, and (b) A method comprising isolating the hemy citrate of compound 1.

42. The method according to claim 41, further comprising drying the hemy-citrate of compound 1.

43. A hemy citrate of compound 1, prepared according to the process described in any one of claims 39 to 42.

44. A method for treating a disease or condition, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of claims 21 to 38, wherein the disease or condition is selected from depression, epilepsy, bipolar disorder, or anxiety.

45. The method according to claim 44, wherein the depression is selected from major depressive disorder, postpartum depression, or treatment-resistant depression.

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