Crystal form VII of agomelatine, preparation method and use thereof and pharmaceutical composition containing same
The present invention provides a new crystalline form VII of agomelatine, its method of preparation, application and pharmaceutical composition. This new crystalline form offers high purity, a stable crystalline structure and good reproducibility, while its method of production lends itself well to large scale production. In terms of stability and purity, it is superior to the numerous crystalline forms which have hitherto been reported. As a result, the crystalline form VII of the present invention possesses advantages in pharmaceutical preparation.
1. A crystalline form VII of agomelatine, characterized by the following X-ray diffraction diagram expressed in terms of interplanar crystal spacing d, Bragg angle 2θ and relative intensity:
Relative
2θ°
d(Å)
intensity (I %)
10.557 ± 0.2
8.3725
32.35
13.301 ± 0.2
6.6509
11.45
16.145 ± 0.2
5.4855
10.60
17.286 ± 0.2
5.1258
6.19
17.841 ± 0.2
4.9675
100.00
19.359 ± 0.2
4.5813
10.83
20.089 ± 0.2
4.4164
11.77
23.366 ± 0.2
3.8040
29.82
24.944 ± 0.2
3.5667
21.60
26.128 ± 0.2
3.4078
12.47.
2. A preparation method for the crystalline form of claim 1 , wherein an agomelatine compound of formula (II) or (III)
is dissolved in acetic acid, to which acetate is then added, followed by the addition of water dropwise to this reaction mixture, which is then agitated at a temperature of 17-23° C. in order to bring about crystallization, with the crystals then being separated from the solution.
3. The preparation method according to claim 2 , wherein the molar ratio of the agomelatine compound of formula (II) or (III) and acetate is from 1:1-1.5.
4. The preparation method according to claim 3 , wherein the molar ratio of the agomelatine compound of formula (II) or (III) and acetate is from 1:1-1.1.
5. The preparation method according to claim 2 , wherein the ratio of volume of acetic acid to water is 1:10-30.
6. The preparation method according to claim 2 , wherein the acetate is potassium acetate or ammonium acetate.
7. The preparation method according to claim 2 , wherein when the temperature of the resulting reaction mixture reaches 19-25° C., water is added dropwise in order to bring about crystallization.
8. The preparation method according to claim 7 , wherein when the temperature of the resulting reaction mixture reaches 22° C. or 23° C., water is added dropwise in order to bring about crystallization.
9. The preparation method according to claim 2 , wherein water is added dropwise to the resulting reaction mixture which is then agitated at a temperature of 20° C. in order to bring about crystallization.
10. The preparation method according to claim 2 , wherein following the addition of the acetate, the reaction mixture is heated to 30-50° C., resulting in a clear solution; the solution is then left to cool on its own, and water is added dropwise in order to bring about crystallization.
11. A pharmaceutical composition comprising the crystalline form of agomelatine according to claim 1 in combination with one or more pharmaceutically acceptable adjuvants or excipients.
12. A method of treating a condition selected from sleep disorders, stress, anxiety, seasonal affective disorder, severe depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue brought on by jet lag, schizophrenia, phobias, and depression in a subject in need thereof, comprising administration of an effective amount of the crystalline form of agomelatine according to claim 1 .