Inhibitor crystalline form and preparation method and use thereof
The present invention relates to new crystalline forms of the inhibitor, 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazoline-4-one; the present invention also relates to methods for preparing the new crystalline forms of 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one, pharmaceutical compositions containing the new crystalline forms thereof, and uses thereof for the treatment and/or prevention of diseases such as chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma.
1. A crystal Form IX of Idelalisib with the structural formula shown below,
wherein, Form IX is a hydrate with 0.7 molecule of water; and Form IX is characterized by a X-ray powder diffraction pattern measured using Cu-Kα radiation, expressed as 2θ angles, having the following characteristic peaks: 8.8±0.2°, 11.0±0.2°, 13.9±0.2°, 14.9±0.2°, 16.2±0.2° and 20.6±0.2°.
2. The Form IX of Idelalisib according to claim 1 , wherein the X-ray powder diffraction pattern of Form IX of Idelalisib, expressed as 2θ angles, has the following characteristic peaks: 8.8±0.2°, 11.0±0.2°, 12.1±0.2°, 13.9±0.2°, 14.9±0.2°, 15.4±0.2°, 16.2±0.2°, 17.1±0.2°, 17.5±0.2°, 20.6±0.2°, 23.2±0.2° and 24.1±0.2°.
3. The Form IX of Idelalisib according to claim 2 , wherein the X-ray powder diffraction pattern of Form IX of Idelalisib, expressed as 2θ angles, has the following characteristic peaks and relative intensities:
diffraction angle 2θ
relative intensity %
8.8 ± 0.2°
100.0
11.0 ± 0.2°
88.1
12.1 ± 0.2°
12.1
13.9 ± 0.2°
79.4
14.9 ± 0.2°
33.3
15.4 ± 0.2°
19.9
16.2 ± 0.2°
51.2
17.1 ± 0.2°
17.3
17.5 ± 0.2°
25.6
20.6 ± 0.2°
44.7
20.9 ± 0.2°
11.2
21.8 ± 0.2°
11.6
23.2 ± 0.2°
19.8
23.8 ± 0.2°
16.0
24.1 ± 0.2°
25.5
24.6 ± 0.2°
22.5
27.8 ± 0.2°
14.2.
4. The Form IX of Idelalisib according to claim 1 , wherein Form IX of Idelalisib is characterized by a FTIR spectrum comprising the following characteristic peaks at the wavenumbers of 1675, 1607, 1472, 1382, 1326, 1301, 1233, 1184, 1100, 1036, 946, 821, 798, 785, 718, 698 and 649 cm −1 .
5. A method of preparing the Form IX of Idelalisib according to claim 1 , comprising:
suspending Form I of Idelalisib in a solvent system of water and ethanol to form a suspension, stirring or sonicating at a crystallization temperature, and then isolating and drying precipitated solids to obtain Form IX of Idelalisib;
wherein the volume ratio of ethanol to water in the solvent system is 1:1 to 1:10,
the amount of Form I of Idelalisib is 1.5-20 times of its solubility in the corresponding solvent system at the crystallization temperature;
the stirring crystallization temperature is 0° C. to 40° C.; the duration of stirring crystallization is 1 to 14 days; and
the crystallization by sonication is carried out at room temperature, sonicating for 1 to 3 hours at the working power of 20 KHz to 40 KHz.
6. A pharmaceutical composition, comprising a therapeutically effective amount of the Form IX of Idelalisib according to claim 1 and at least one pharmaceutically acceptable excipient.
7. A method of treating the diseases of chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, hodgkin's lymphoma, multiple myeloma, acute myelocytic leukemia, or other hematological malignant tumor, comprising administering to a patient in need thereof an effective amount of the Form IX of Idelalisib according to claim 1 .
8. A crystal Form IV of Idelalisib with the structural formula shown below,
wherein, Form IV is characterized by a X-ray powder diffraction pattern measured using Cu-Kα radiation, expressed as 2θ angles, having the following characteristic peaks: 7.8±0.2°, 9.2±0.2° 14.1±0.2°, 15.7±0.2°, 17.7±0.2°, 18.9±0.2° and 20.7±0.2°.
9. The Form IV of Idelalisib according to claim 8 , wherein the X-ray powder diffraction pattern of the Form IV of Idelalisib, expressed as 2θ angles, has the following characteristic peaks: 7.8±0.2°, 9.2±0.2°, 11.5±0.2°, 13.6±0.2°, 14.1±0.2°, 15.7±0.2°, 17.7±0.2°, 18.9±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, 22.2±0.2° and 23.8±0.2°.
10. The Form IV of Idelalisib according to claim 9 , wherein the X-ray powder diffraction pattern of the Form IV of Idelalisib, expressed as 2θ angles, has the following characteristic peaks and relative intensities:
diffraction angle 2θ
relative intensity %
7.8 ± 0.2°
65.7
9.2 ± 0.2°
100.0
11.5 ± 0.2°
25.9
13.6 ± 0.2°
39.2
14.1 ± 0.2°
91.4
15.7 ± 0.2°
97.9
17.2 ± 0.2°
10.5
17.7 ± 0.2°
83.5
18.4 ± 0.2°
12.8
18.9 ± 0.2°
57.3
20.2 ± 0.2°
39.3
20.7 ± 0.2°
61.5
21.2 ± 0.2°
29.6
21.8 ± 0.2°
12.3
22.2 ± 0.2°
31.2
22.8 ± 0.2°
29.4
23.1 ± 0.2°
17.6
23.8 ± 0.2°
31.6
25.3 ± 0.2°
22.2
25.8 ± 0.2°
24.1
26.5 ± 0.2°
17.0
27.1 ± 0.2°
13.8
27.5 ± 0.2°
12.5
27.9 ± 0.2°
18.1
29.0 ± 0.2°
16.3
29.7 ± 0.2°
10.7.
11. The Form IV of Idelalisib according to claim 8 , wherein the Form IV of Idelalisib is characterized by a FTIR spectrum comprising the following characteristic peaks at the wavenumbers of 1698, 1628, 1590, 1568, 1475, 1453, 1412, 1329, 1296, 1231, 1152, 1096, 1036, 1025, 937, 901, 818, 801, 779, 755, 721, 694 and 610 cm −1 .
12. A method of preparing the Form IV of Idelalisib according to claim 8 , comprising:
heating Form IX of Idelalisib according to 100˜150° C. at a rate of 1 to 15° C./min, keeping isothermal for 1 to 5 minutes until complete form transformation, and then naturally cooling to obtain Form IV of Idelalisib.
13. A pharmaceutical composition, comprising a therapeutically effective amount of the Form IV of Idelalisib according to claim 8 and at least one pharmaceutically acceptable excipient.
14. A method of treating the diseases of chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, hodgkin's lymphoma, multiple myeloma, acute myelocytic leukemia, or other hematological malignant tumor, comprising administering to a patient in need thereof an effective amount of the Form IV of Idelalisib according to claim 8 .
15. A crystal Form VI of Idelalisib with the structural formula shown below,
wherein, Form VI is a tetrahydrate, and Form VI is characterized by a X-ray powder diffraction pattern measured using Cu-Kα radiation, expressed as 2θ angles, having the following characteristic peaks: 9.8±0.2°, 11.3±0.2°, 13.3±0.2°, 17.5±0.2°, 19.3±0.2° and 23.2±0.2°.
16. The Form VI of Idelalisib according to claim 15 , wherein the X-ray powder diffraction pattern of the Form VI of Idelalisib, expressed as 2θ angles, has the following characteristic peaks: 9.8±0.2°, 11.3±0.2°, 12.5±0.2°, 13.3±0.2°, 17.1±0.2°, 17.5±0.2°, 19.3±0.2°, 22.1±0.2°, 22.7±0.2°, 23.2±0.2°, 23.6±0.2° and 26.4±0.2°.
17. The Form VI of Idelalisib according to claim 16 , wherein the X-ray powder diffraction pattern of the Form VI of Idelalisib, expressed as 2θ angles, has the following characteristic peaks and relative intensities:
diffraction angle 2θ
relative intensity %
9.8 ± 0.2°
100.0
11.3 ± 0.2°
28.4
11.6 ± 0.2°
13.7
12.5 ± 0.2°
25.9
13.3 ± 0.2°
47.7
16.4 ± 0.2°
12.7
16.8 ± 0.2°
14.8
17.1 ± 0.2°
24.2
17.5 ± 0.2°
35.9
18.4 ± 0.2°
30.1
19.3 ± 0.2°
46.4
22.1 ± 0.2°
25.1
22.7 ± 0.2°
23.3
23.2 ± 0.2°
46.7
23.6 ± 0.2°
30.5
24.3 ± 0.2°
11.1
26.4 ± 0.2°
24.0
26.8 ± 0.2°
12.4
28.5 ± 0.2°
14.3
29.0 ± 0.2°
19.0.
18. The Form VI of Idelalisib according to claim 15 , wherein the Form VI of Idelalisib is characterized by a FTIR spectrum comprising the following characteristic peaks at the wavenumbers of 3191, 1697, 1632, 1590, 1565, 1475, 1457, 1420, 1394, 1299, 1232, 1185, 1166, 1120, 1039, 1027, 953, 900, 819, 802, 781, 712, 695, 647 and 610 cm −1 .
19. A method of preparing the Form VI of Idelalisib according to claim 15 , comprising:
suspending Form I of Idelalisib in a solvent system to form a suspension, stirring at a crystallization temperature for crystallization, and then isolating and drying precipitated solids to obtain Form VI of Idelalisib;
wherein the solvent system is a solvent mixture of water and isopropanol, or a solvent mixture of water and n-propanol;
the volume ratio of water to isopropanol in the solvent mixture of water and isopropanol is 0.5:1 to 50:1, the volume ratio of water to n-propanol in the solvent mixture of water and n-propanol is 0.5:1 to 50:1; and
the amount of Form I of Idelalisib is 1.5 to 20 times of its solubility in the corresponding solvent system at the crystallization temperature; the crystallization temperature is 0° C. to 40° C.
20. A pharmaceutical composition, comprising a therapeutically effective amount of the Form VI of Idelalisib according to claim 15 and at least one pharmaceutically acceptable excipient.
21. A method of treating the diseases of chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, hodgkin's lymphoma, multiple myeloma, acute myelocytic leukemia, or other hematological malignant tumor, comprising administering to a patient in need thereof an effective amount of the Form VI of Idelalisib according to claim 15 .
22. A crystal Form III of Idelalisib with the structural formula shown below,
wherein, Form III is characterized by a X-ray powder diffraction pattern measured using Cu-Kα radiation, expressed as 2θ angles, having the following characteristic peaks: 9.3±0.2°, 12.8±0.2°, 14.2±0.2°, 15.9±0.2°, 18.1±0.2° and 18.8±0.2°.
23. The Form III of Idelalisib according to claim 22 , wherein the X-ray powder diffraction pattern of the Form III of Idelalisib, expressed as 2θ angles, has the following characteristic peaks: 12.3±0.2°, 12.8±0.2°, 14.2±0.2°, 15.9±0.2°, 16.3±0.2°, 17.4±0.2°, 17.9±0.2°, 18.1±0.2°, 18.8±0.2°, 19.6±0.2°, 20.6±0.2° and 24.5±0.2°.
24. The Form III of Idelalisib according to claim 23 , wherein the X-ray powder diffraction pattern of Form III of Idelalisib, expressed as 2θ angles, has the following characteristic peaks and relative intensities:
diffraction angle 2θ
relative intensity %
11.9 ± 0.2°
11.1
12.3 ± 0.2°
59.3
12.8 ± 0.2°
16.6
14.2 ± 0.2°
16.9
15.9 ± 0.2°
18.2
16.3 ± 0.2°
14.3
17.4 ± 0.2°
18.4
17.9 ± 0.2°
18.1
18.1 ± 0.2°
27.0
18.8 ± 0.2°
100.0
19.6 ± 0.2°
10.6
20.6 ± 0.2°
13.5
21.4 ± 0.2°
11.2
24.2 ± 0.2°
14.8
24.5 ± 0.2°
19.1.
25. The Form III of Idelalisib according to claim 22 , wherein the Form III of Idelalisib is characterized by a FTIR spectrum comprising the following characteristic peaks at the wavenumbers of 1689, 1623, 1589, 1569, 1473, 1454, 1384, 1328, 1300, 1251, 1231, 1159, 1098, 1067, 1036, 914, 820, 780, 766, 727, 696, 668 and 618 cm −1 .
26. A method of preparing the Form III of Idelalisib according to claim 22 , which is selected from any one of the following methods, comprising:
1) suspending Form I of Idelalisib in a solvent system to form a suspension, stirring the suspension at a crystallization temperature for crystallization, and then isolating and drying precipitated solids to obtain Form III of Idelalisib;
wherein the solvent system is selected from the group consisting of acetonitrile, nitromethane, and a solvent mixture of water and acetone at a volume ratio 2:1 to 1:2; and
the amount of Form I of Idelalisib is 1.5 to 20 times of its solubility in the corresponding solvent system at the crystallization temperature; the crystallization temperature is 0 to 40° C.; the duration of crystallization is 1 to 14 days;
2) slurrying Form IV of Idelalisib in nitromethane for crystallization, and then isolating and drying precipitated solids to obtain Form III of Idelalisib;
wherein the amount of Form IV of Idelalisib is 1.5 to 20 times of its solubility in nitromethane; and
the slurry crystallization temperature is 0 to 40° C., the duration of slurry crystallization is 3 to 10 days.
27. A pharmaceutical composition, comprising a therapeutically effective amount of the Form III of Idelalisib according to claim 22 and at least one pharmaceutically acceptable excipient.
28. A method of treating the diseases of chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, hodgkin's lymphoma, multiple myeloma, acute myelocytic leukemia, or other hematological malignant tumor, comprising administering to a patient in need thereof an effective amount of the Form III of Idelalisib according to claim 22 .