(R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, preparation method therefor, and application thereof
View Patent ↗The present invention provides an (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, which has diffraction peaks when 2θ is 12.423±0.2°, 16.465±0.2°, 17.344±0.2°, 21.889±0.2°, and 25.054±0.2°. The present invention can promote synthesis of phosphorylcholine and phosphoethanolamine and promote cerebral metabolism, has a stimulating effect on the specific central nervous pathway through the blood-brain barrier, and has special biological activity in the fields of sedation, anti-epilepsy, etc. The (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form in the present invention has a melting point peak temperature of 133.1±2° C. and a solubility in water of greater than or equal to 100 mg/mL, dissolves fast in water, provides high bioavailability, good stability, and good particle fluidity, is suitable for production of pharmaceutical preparations and storage and transportation. The crystal form is suitable for preparation into a variety of pharmaceutical compositions, and can be prepared into a variety of preparations, such as tablets, capsules, dripping pills, sustained-release controlled-release preparations, lyophilized powder injections, etc. The preparation method of the present invention is simple and suitable for industrial production.
1. A crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide having diffraction peaks at diffraction angles 2θ of 12.423±0.2°, 16.465±0.2°, 17.344±0.2°, 21.889±0.2°, and 25.054±0.2°.
2. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 , characterized in that the relative peak intensity at the diffraction angle 2θ of 17.344±0.2° is 100%; the relative peak intensity at the diffraction angle 2θ of 16.465±0.2° is greater than 90% and less than 100%; the relative peak intensities at the diffraction angles 2θ of 12.423±0.2°, 21.889±0.2°, and 25.054±0.2° are not less than 70%.
3. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 having diffraction peaks at diffraction angles 2θ of 12.423±0.2°, 16.285±0.2°, 16.465±0.2°, 17.344±0.2°, 20.707±0.2°, 21.889±0.2°, 25.054±0.2°, and 35.138±0.2°.
4. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 having diffraction peaks at diffraction angles 2θ of 12.423±0.2°, 14.928±0.2°, 16.285±0.2°, 16.465±0.2°, 17.344±0.2°, 19.198±0.2°, 20.459±0.2°, 20.707±0.2°, 21.548±0.2°, 21.889±0.2°, 23.203±0.2°, 25.054±0.2°, 26.117±0.2°, 29.913±0.2°, 30.49±0.2°, 35.138±0.2°, 37.569±0.2°, and 37.972±0.2°.
5. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 having a powder diffraction pattern as shown in FIG. 1 .
6. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 having the following—X-ray powder diffraction data expressed by d(Å) value and relative intensity percentage I (%) value,
d(Å)
I %
7.1193
73
5.9296
15.6
5.4386
46.2
5.3794
95.1
5.1086
100
4.6193
22.6
4.3374
28.4
4.286
43.5
4.1205
12.9
4.0572
83.1
3.8303
14.5
3.5513
73.1
3.4092
19.1
2.9846
36.7
2.9295
35.4
2.5519
44.8
2.3921
15
2.3677
18.4.
7. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 , characterized in that the unit cell of the crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide is Orthorhombic (orthorhombic crystal system), a=14.122 Å, b=5.82 Å, and c=8.704 Å.
8. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 , characterized by having a crystalline structure diagram as described in FIG. 2 .
9. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 , characterized in that the peak temperature of the melting point of the crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide is 133.1±2° C.
10. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 characterized by having a differential scanning calorimetry (DSC) pattern as shown in FIG. 3 .
11. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 , characterized in that the infrared spectrum generated by the crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide shows absorption peaks at the following wave numbers:
3413(cm −1 ), 3353(cm −1 ), 3182(cm −1 ), 2961(cm −1 ), 2880(cm −1 ), 2797(cm −1 ), 1671(cm −1 ), 1491(cm −1 ), 1452(cm −1 ), 1398(cm −1 ), 1308(cm −1 ), 1240(cm −1 ), 1199(cm −1 ), 1081(cm −1 ), 1037(cm −1 ), 1012(cm −1 ), 947(cm −1 ), 671(cm −1 ), 613(cm −1 ), 462(cm −1 ).
12. The crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 1 characterized by having an infrared spectrum as shown in FIG. 4 .
13. A method for preparing a crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide applying the following steps:
(1) Adding (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide to isopropanol or sec-butanol, stirring constantly, heating at from 30° C. to 100° C., filtering to form a supersaturated solution;
(2) Sealing and placing the supersaturated solution obtained in the step (1) in a low temperature environment of from −10° C. to −19° C. to cool and crystallize to obtain crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide.
14. The method for preparing a crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide according to claim 13 applying the following steps:
(1) Adding (R)-4-hydroxy-2-oxo-1-pyrrolidinoacetamide to isopropanol or sec-butanol at 5 mg/mL to 50 mg/mL, stirring constantly, and heating at from 40° C. to 50° C., filtering to form a supersaturated solution;
(2) Sealing and placing the supersaturated solution obtained in the step (1) in a low temperature environment of from −15° C. to −19° C. to cool and crystallize to obtain crystalline form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide.