SOLID-STATE FORMS OF RELUGOLIX
The present invention is directed to a solid-state DMF solvate of relugolix and to solid-state anhydrous forms of relugolix designated as Form A and Form C of anhydrous relugolix. The present invention is further directed to processes for the preparation of the solid-state DMF solvate of relugolix and each of Form A, Form B, and Form C of anhydrous relugolix. The present invention also is directed to pharmaceutical compositions comprising the DMF solvate of relugolix or Form A or Form C of anhydrous relugolix, and to a method for treating disease using the DMF solvate of relugolix or Form A or Form C of anhydrous relugolix.
1 . A DMF solvate of relugolix.
2 . The DMF solvate of claim 1 which is Form A of the DMF solvate of relugolix.
3 . The DMF solvate according to claim 2 , which is characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 20.1, 24.3, and 9.0° 2θ±0.2° 2θ.
4 . The DMF solvate according to claim 2 , which is characterized by an onset of an endothermic event at about 99° C.±3° C., as measured by differential scanning calorimetry.
5 . The DMF solvate according to claim 2 , which is characterized by an endothermic event at about 149° C.±3° C., as measured by differential scanning calorimetry.
6 . A process for the preparation of the DMF solvate according to claim 2 comprising:
a) mixing a solution of relugolix in DMF with an anti-solvent; and
b) stirring the mixture of step a) to yield Form A of the DMF solvate of relugolix as a precipitate.
7 . The process according to claim 6 , wherein the ratio of relugolix to DMF in the solution of relugolix in DMF is about 1:5 weight (g relugolix ) to volume (mL DMF ).
8 . The process according to claim 6 , wherein the anti-solvent is tert-butylmethyl ether or toluene.
9 . The process according to claim 6 , wherein the ratio of relugolix in the solution of relugolix in DMF to anti-solvent is from about 1:10 to about 1:13 weight (g relugolix ) to volume (mL anti-solvent ).
10 . The process according to claim 6 , wherein the stirring occurs for about 15-18 hours.
11 . The process according to claim 6 , wherein the stirring the mixture of step a) to produce a precipitate occurs at ambient temperature.
12 . The DMF solvate according to claim 2 , which has single crystal parameters
a=11.1ű1.5%
b=12.0ű1.5%
c=14.0ű1.5%
α=112°±3°
β=110°±3°
γ=91°±3°
13 . The DMF solvate according to claim 2 , which has a cell volume of about 1609Å 3 ±3%.
14 . Form A of anhydrous relugolix.
15 . Form A of anhydrous relugolix according to claim 14 , which is characterized by having X-ray powder diffraction peaks selected from about 10.7, 20.9, and 19.2° 2θ±0.2° 2θ.
16 . Form A of anhydrous relugolix according to claim 14 , which is characterized by an onset of an endothermic event at about 158° C.±3° C., as measured by differential scanning calorimetry.
17 . Form A of anhydrous relugolix according to claim 14 , which is characterized by an endothermic event at about 183° C.±3° C., as measured by differential scanning calorimetry.
18 . A process for the preparation of Form A of anhydrous relugolix according to claim 14 comprising:
a) forming a solution of relugolix in acetone wherein the relugolix is in about 10 volumes of acetone (weight(g relugolix ):volume(mL acetone )); and
b) stirring the solution of relugolix in acetone to yield Form A of anhydrous relugolix as a precipitate.
19 . A process for the preparation of Form B of anhydrous relugolix which is characterized by having an X-ray powder diffraction peak at about 5.7°2θ±0.2° 2θ comprising:
a) forming a solution of relugolix in DCM wherein the relugolix is in about 20 volumes of DCM (weight(g relugolix ):volume(mL DCM )); and
b) evaporating the DCM to yield Form B of anhydrous relugolix.
20 . A process for the preparation of Form B of anhydrous relugolix which is characterized by having an X-ray powder diffraction peak at about 5.7°2θ±0.2°2θ comprising:
a) mixing a solution of relugolix in DCM wherein the relugolix is in at least about 20 volumes of DCM (weight(g relugolix ):volume(mL DCM ) with an anti-solvent wherein the anti-solvent is at about a 1:1 ratio of anti-solvent to DCM (volume anti-solvent :volume DCM );
b) stirring the mixture of step a) for a period of time to yield Form B of anhydrous relugolix as a precipitate.
21 . The process according to claim 20 wherein the anti-solvent is cumene, cyclohexane, TBME, heptane, or toluene.
22 . Form C of anhydrous relugolix.
23 . Form C of anhydrous relugolix according to claim 22 , which is characterized by having X-ray powder diffraction peaks selected from about 8.3, 6.8, 7.7, and 19.9° 2θ±0.2°2θ.
24 . Form C of anhydrous relugolix according to claim 22 , which is characterized by an onset of an endothermic event at about 140° C.±3° C., as measured by differential scanning calorimetry.
25 . Form C of anhydrous relugolix according to claim 22 , which is characterized by an endothermic event at about 175° C.±3° C., as measured by differential scanning calorimetry.
26 . A process for the preparation of Form C of anhydrous relugolix according to claim 22 comprising;
a) adding about 10 volumes of an organic solvent to Form B of anhydrous relugolix (weight(g relugolix ):volume(mL organic solvent ); and
b) stirring the mixture of organic solvent and Form B of anhydrous relugolix for about 16-24 hours resulting in a slurry of Form C of anhydrous relugolix.
27 . The process according to claim 26 , wherein the organic solvent is isopropyl acetate or 2-butanol.
28 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from the DMF solvate of relugolix according to claim 1 , Form A of anhydrous relugolix according to claim 14 , and Form C of anhydrous relugolix according to claim 22 , and a pharmaceutically acceptable excipient.
29 . A method of treating disease in a patient comprising administering the pharmaceutical composition according to claim 28 to a patient in need thereof.
30 . The method of treating disease according to claim 29 , wherein the disease is uterine fibroids, endometriosis, or prostate cancer.