Salt of abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them
View Patent ↗Abexinostat tosylate of formula (II): and its crystalline form I characterized by its X-Ray powder diffraction diagram, its Raman spectrum and its solid-state 13 C CP/MAS NMR spectrum. Medicinal products containing the same which are useful in the treatment of cancer.
1. A crystalline form I of abexinostat tosylate of formula (II):
having an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.50, 9.94, 11.35, 12.33, 14.08, 18.95, 21.08, and 27.05.
2. The crystalline form according to claim 1 , wherein the crystalline form has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.50, 9.94, 11.35, 12.33, 14.08, 18.95, 19.61, 19.96, 21.08, 22.82, 23.61, and 27.05.
3. The crystalline form according to claim 1 , wherein the crystalline form has the following X-ray powder diffraction diagram:
Angle 2-theta
Interplanar
Line no.
(degrees)
distance (Å)
1
6.50
13.581
2
9.94
8.894
3
11.35
7.789
4
12.33
7.173
5
14.08
6.285
6
18.95
4.683
7
19.61
4.526
8
19.96
4.449
9
21.08
4.215
10
22.82
3.897
11
23.61
3.768
12
27.05
3.296.
4. The crystalline form according to claim 1 , having a Raman spectrum having peaks at 940 cm −1 , 1088 cm −1 , 1132 cm −1 , 1242 cm −1 , 1360 cm −1 , and 1608 cm −1 .
5. A crystalline form I of abexinostat tosylate of formula (II):
having a Raman spectrum having peaks at the positions 940 cm −1 , 1088 cm −1 , 1132 cm −1 , 1242 cm −1 , 1360 cm −1 , and 1608 cm −1 .
6. The crystalline form according to claim 1 , having a solid-state 13 C CP/MAS NMR spectrum having the following peaks (expressed in ppm ±0.2 ppm): 121.2 ppm, 122.1 ppm, 123.5 ppm, 126.0 ppm, 126.8 ppm, 128.2 ppm, 128.9 ppm, 143.4 ppm, 144.6 ppm, 153.8 ppm, 159 ppm, 161.2 ppm, and 162.1 ppm.
7. The crystalline form according to claim 6 , wherein the crystalline form has a solid-state 13 C CP/MAS NMR spectrum having the following peaks (expressed in ppm ±0.2 ppm):
Chemical shift
Peak no.
(ppm)
1
162.1
2
161.2
3
159.0
4
153.8
5
144.6
6
143.4
7
128.9
8
128.2
9
126.8
10
126.0
11
123.5
12
122.1
13
121.3
14
65.9
15
50.6
16
46.9
17
45.0
18
21.9.
8. A pharmaceutical composition comprising as active ingredient the crystalline form I of abexinostat tosylate according to claim 1 , in combination with one or more pharmaceutically acceptable excipients.
9. A method of treating cancer in a subject in need thereof, comprising administration of an effective amount of the pharmaceutical composition according to claim 8 , wherein the cancer is a lymphoma, a melanoma, or a sarcoma.
10. A process for the preparation of crystalline form I of abexinostat tosylate according to claim 1 , wherein the abexinostat is crystallised in the presence of para-toluenesulphonic acid in a polar medium.
11. The process according to claim 10 , wherein the polar medium is composed of one or more solvents selected from water, alcohols, ketones and esters.
12. The process according to claim 11 , wherein the polar medium is a binary mixture, one of the constituents of which is water.
13. The process according to claim 12 , wherein the polar medium is a binary mixture selected from: acetone/water, ethanol/water, isopropanol/water and methyl ethyl ketone/water.