CRYSTALLINE COMPOSITION OF TILDACERFONT AND METHODS OF USE AND PREPARATION THEREOF
Described herein are crystalline composition, methods of making such crystalline composition, pharmaceutical compositions and medicaments comprising such crystalline composition, and methods of using such crystalline composition in the treatment of conditions, diseases, or disorders that would benefit from modulation of Corticotropin-releasing hormone receptor 1 (CRF1).
1 . A pharmaceutical composition comprising a CRF1 antagonist, wherein the composition is characterized by an X-ray powder diffraction pattern comprising a peak selected from any one or more of 10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, and 24.80±0.2° 2-θ, wherein the CRF1 antagonist comprises Compound 1:
or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
2 . The pharmaceutical composition of claim 1 , wherein the composition is measured by X-ray powder diffraction using an X-ray wavelength of 0.71073 Å.
3 . The pharmaceutical composition of claim 1 , wherein the X-ray powder diffraction pattern further comprising at least one peak selected from 5.44±0.2° 2-θ, 20.78±0.2° 2-θ, 22.74±0.2° 2-θ, 23.04±0.2° 2-θ, 26.80±0.2° 2-θ, and 28.86 ±0.2° 2-θ, and as measured by X-ray powder diffraction using an X-ray wavelength of 0.71073 Å.
4 . The pharmaceutical composition of claim 1 , wherein the X-ray powder diffraction pattern further comprising at least five peaks selected from 8.82±0.2° 2-θ, 11.70±0.2° 2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ, 19.18±0.2° 2-θ, 20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ, 25.52±0.2° 2-θ, 25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, and as measured by X-ray powder diffraction using an X-ray wavelength of 0.71073 Å.
5 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is further characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 11% over a temperature range of about 25° C. to about 200° C.
6 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is further characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to the one set forth in FIG. 2 .
7 . (canceled)
8 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a crystalline pharmaceutical composition.
9 . The pharmaceutical composition of claim 8 , wherein the crystalline pharmaceutical composition further comprises oxalic acid.
10 . The pharmaceutical composition of claim 9 , wherein the crystalline pharmaceutical composition comprises Compound 1 and oxalic acid in a molar ratio of about 2:1.
11 .- 18 . (canceled)
19 . A method of preparing a crystalline composition comprising Compound 1:
wherein the method comprises:
(a) dissolving Compound 1 and an acid in a solvent;
(b) heating the solution or slurry from step (a); and
(c) crystallizing the solution or slurry obtained in step (b) to obtain the crystalline composition comprising Compound 1.
20 . The method of claim 19 , wherein the acid comprises oxalic acid.
21 . The method of claim 19 , wherein the solvent in step (a) is heptane.
22 . The method of claim 19 , wherein the solvent in step (a) is methyl tert-butyl ether or methyl ethyl ketone.
23 . The method of claim 19 , wherein the solvent in step (a) is a mixture of heptane and methyl ethyl ketone.
24 . The method of claim 19 , wherein step (b) is heated at about 50° C.
25 .- 55 . (canceled)
56 . A crystalline composition comprising Formula I:
57 . The crystalline composition of claim 56 , wherein the crystals have unit cell parameters at T=150° K of: a=34.003(4) Å, b=6.5843(13) Å, c=21.062(5) Å; R=108.703(12°), V=4466.5(15) Å 3 and a monoclinic C2/c space group.
58 . The crystalline composition of claim 56 , wherein the crystalline composition is characterized by:
(a) an X-ray powder diffraction pattern comprising peaks at 10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, and 24.80±0.2° 2-θ, and as measured by X-ray powder diffraction using an X-ray wavelength of 0.71073 Å;
(b) an X-ray powder diffraction pattern substantially the same as shown in FIG. 1 ;
(c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 160° C. to 170° C.;
(d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 164° C. and a peak of about 166° C.;
(e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 2 ;
(f) a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 11% over a temperature range of about 25° C. to about 200° C.;
(g) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in FIG. 3 ; or
(h) combinations thereof.
59 .- 68 . (canceled)
69 . A method of preparing a crystalline composition comprising Formula I:
wherein the method comprises:
(a) dissolving 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine (Compound 1) and oxalic acid in a solvent;
(b) heating the solution or slurry from step (a); and
(c) crystallizing the solution or slurry obtained in step (b) to obtain the crystalline composition comprising Formula I.
70 . The method of claim 69 , wherein the solvent in step (a) comprises acetone, heptane, water, 2-butanol, ethyl acetate, 2-propanol, methyl tert-butyl ether, ethanol, methyl ethyl ketone, 1-pentanol, or a combination thereof.
71 .- 105 . (canceled)