Crystal form of gonadotropin releasing hormone antagonist, preparation method therefor, and use thereof
Provided are a crystal form of a gonadotropin releasing hormone antagonist, a preparation method therefor, and use thereof. A crystal form C and a crystal form D have high purity, good illumination stability, high temperature stability, and high humidity stability, and have good solubility and low hygroscopicity; the saturation solubility of the crystal form C and the crystal form D is 101.75 μg/ml and 87.21 μg/ml, respectively; when the relative humidity is increased from 0 to 50% RH, the hygroscopy gain of the crystal form C and the crystal form D is not greater than 1.76% and 0.73%, respectively; and when the relative humidity is increased from 0 to 90% RH, the hygroscopy gain of the crystal form C and the crystal form D is not greater than 3.43% and 1.61%, respectively. Therefore, the control of a production condition is facilitated, the preparation process is simple, the quality is stable, and large-scale industrial production is easy.
1 . A crystal form C of a gonadotropin releasing hormone antagonist, wherein an X-ray powder diffraction of the crystal form C using Cu—Kα radiation has characteristic peaks at 2θ angles of 5.6±0.2°, 7.8±0.2°, 10.8±0.2°, 17.4±0.2° and 19.1±0.2°,
wherein the gonadotropin releasing hormone antagonist has the structure:
and wherein pattern data of the X-ray powder diffraction of the crystal form C is as follows:
2θ (±0.2°)
d (Å)
I %
5.6
15.8
100
7.8
11.4
16.2
10.8
8.2
44.9
17.4
5.1
13.4
19.1
4.6
10.4.
2 . The crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 , wherein the X-ray powder diffraction of the crystal form C using Cu-Kα radiation also has a characteristic peak at 2θ angle of 6.8±0.2°.
3 . The crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 , wherein a differential scanning calorimetry curve of the crystal form C has two endothermic peaks, wherein a first endothermic peak is at a temperature of 90±2° C., and a second endothermic peak is at a temperature of 143±2° C.
4 . The crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 , wherein, the crystal form C has a differential scanning calorimetry curve substantially as shown in FIG. 8 .
5 . The crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 , wherein the crystal form C has a thermal weight loss of less than 2.07% before 100° C. in its thermo gravimetric analysis curve.
6 . The crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 , wherein the crystal form C has a thermo gravimetric analysis curve substantially as shown in FIG. 9 .
7 . A pharmaceutical composition, comprising the crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 and a pharmaceutically acceptable excipient.
8 . A method for preparing the crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 , the method comprising: dissolving a raw drug of a compound according to formula (I) into dichloromethane, then adding water, precipitating a solid, and drying to obtain the crystal form C of the gonadotropin releasing hormone antagonist.
9 . The method according to claim 8 , wherein precipitating the solid comprises first cooling to 8-12° C., then placing in an environment of −20° C. to −5° C. for 20-28 hours, and then heating to room temperature.
10 . The method according to claim 8 , wherein a ratio of the mass of the raw drug of the compound according to formula (I) to the volume of dichloromethane to the volume of the water is (100-200 mg):(1-5 ml):(4-20 ml).
11 . A method for treating endometriosis, metrofibroma, prostate cancer, or sexual precocity in a patient in need thereof, the method comprising administering to the patient a pharmaceutically effective dose of the crystal form C of the gonadotropin releasing hormone antagonist according to claim 1 or a pharmaceutical composition comprising the crystal form C of the gonadotropin releasing hormone antagonist.