CRYSTAL FORM A OF 2-(2, 5-DIOXOPYRROLIDIN-1YL) ETHYL METHYL FUMARATE, PREPARATION METHOD THEREFOR AND USE THEREOF
A crystal form A of 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate has a good light irradiation stability, high-temperature stability and high-humidity stability.
1 . A crystal form A of 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate, wherein the X-ray powder diffraction thereof using Cu-Kα radiation has characteristic peaks at 2θ diffraction angles of 13.5±0.2°, 17.9±0.2°, 23.0±0.2° and 27.3±0.2°.
2 . The crystal form A of claim 1 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 13.3±0.2°, and 18.2±0.2°.
3 . The crystal form A of claim 2 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 19.3±0.2°, and 19.6±0.2°.
4 . The crystal form A of claim 3 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 16.6±0.2°, 20.9±0.2°, 22.0±0.2°, 24.3±0.2°, 25.3±0.2°, and 30.6±0.2°.
5 . The crystal form A of claim 4 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 6.92±0.2°, 11.5±0.2°, 16.1±0.2°, 23.7±0.2°, 26.9±0.2°, and 31.1±0.2°.
6 . The crystal form A of claim 1 , wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No. of Peaks
2θ (°)
I %
1
13.3
72.3
2
13.54
19.8
3
17.878
82.2
4
22.962
100
5
27.34
97.2
7 . The crystal form A of claim 1 , wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No. of Peaks
2θ (°)
I %
1
6.92
12.8
2
11.481
6.1
3
13.3
72.3
4
13.54
19.8
5
16.562
14.5
6
17.878
82.2
7
18.24
5.1
8
19.282
2.5
9
19.644
2.9
10
20.901
53
11
21.98
18.4
12
22.962
100
13
24.26
25.7
14
26.858
13.5
15
27.34
97.2
8 . The crystal form A of claim 1 , wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No. of Peaks
2-Theta
I %
d (Å)
1
6.92
12.8
12.764
2
11.481
6.1
7.7013
3
13.3
72.3
6.6517
4
13.54
19.8
6.5344
5
16.562
14.5
5.3481
6
17.878
82.2
4.9572
7
18.24
5.1
4.8597
8
19.282
2.5
4.5995
9
19.644
2.9
4.5155
10
20.901
53
4.2467
11
21.98
18.4
4.0405
12
22.962
100
3.87
13
23.681
7.3
3.754
14
24.26
25.7
3.6657
15
25.34
8.2
3.5119
16
26.858
13.5
3.3167
17
27.34
97.2
3.2593
18
30.621
14.4
2.9171
19
31.099
11.6
2.8734
9 . The crystal form A of claim 1 , wherein the crystal form A has an X-ray powder refraction pattern substantially as shown in FIG. 4 .
10 . The crystal form A of claim 1 , wherein the crystal form A has a characteristic endothermic peak in a temperature range of 96.0° C.-107.0° C. measured by differential scanning calorimetry.
11 . The crystal form A of claim 1 , wherein the crystal form A has a differential scanning calorimetry curve substantially as shown in FIG. 5 .
12 . The crystal form A of claim 1 , wherein the crystal form A has a weight loss of less than 0.01% before a temperature of 125° C. in its thermo gravimetric analysis curve.
13 . The crystal form A of claim 1 , wherein the crystal form A has a thermo gravimetric analysis curve substantially as shown in FIG. 6 .
14 . A method for preparing the crystal form A of claim 1 , comprising the following steps of: dissolving 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate by adding a good solvent thereto, evaporating the solvent or cooling to give a solid, and drying the solid to obtain the crystal form A as a powder.
15 . The method of claim 14 , wherein said dissolving is performed by adding the good solvent at a temperature of 50° C. to 65° C., and said cooling is performed at a temperature of −18° C. to 4° C. to give a solid.
16 . A method for preparing the crystal form A of claim 1 , comprising the following steps of: dissolving 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate by adding a good solvent thereto, then adding a poor solvent, separating a solid and drying to obtain the crystal form A as a powder.
17 . The method of claim 16 , wherein the good solvent is added at a temperature of 15° C. to 35° C. for dissolving, and the poor solvent is added at a temperature of 15° C. to 35° C. to obtain a solid.
18 . The method of claim 14 , wherein the good solvent is an organic solvent selected from the group consisting of a lower alcohol, a lower ketone, a lower ester, a lower nitrile, and a lower ether;
preferably, the lower alcohol is selected from the group consisting of methanol, ethanol, isopropanol or n-butanol, the lower ketone is acetone or 4-methyl-2-pentanone, the lower ester is ethyl acetate, the lower ether is tetrahydrofuran or dioxane, and the lower nitrile is acetonitrile.
19 . The method of claim 14 , wherein a ratio of 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate to the good solvent is (10-40) mg:(0.1-5) mL.
20 . The method of claim 16 , wherein the poor solvent is select from n-heptane, n-hexane, or absolute ethyl ether.
21 . A pharmaceutical composition, comprising the crystal form A of claim 1 and a pharmaceutically acceptable excipient.
22 . A method for treating a neurological disease, comprising administering a pharmaceutically effective amount of the crystal form A of claim 1 or a pharmaceutical composition comprising the same.
23 . The method of claim 22 , wherein the neurological disease is multiple sclerosis or psoriasis.
24 . The method of claim 22 , wherein the medicament is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually rectally, as a topical, inhalation, intranasal, or transdermally.