Salt or 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 process for preparing crystalline form I of abexinostat tosylate, comprising crystallizing abexinostat in the presence of para-toluenesulfonic acid in a polar medium, wherein the polar medium is a binary mixture of isopropanol and water, wherein crystalline form I of abexinostat tosylate is characterized in that it 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, 14.08, 18.95, 21.08, and 27.05.
2. The process of claim 1 , wherein the polar medium is a 50/50 weight/weight mixture of isopropanol and water.
3. The process of claim 1 , wherein the polar medium is a 45/54 weight/weight mixture of isopropanol and water.
4. The process of claim 1 , further comprising seeding the crystallization with crystalline form I of abexinostat tosylate.
5. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it 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, 19.96, 21.08, 22.82, 23.61, and 27.05.
6. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has the following X-ray powder diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°) and interreticular distance d (expressed in Å):
Line
Angle 2 theta
Interreticular Distance
No.
(degrees)
(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.
7. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a Raman spectrum having a peak at position 1608 cm −1 .
8. The process of claim 7 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a Raman spectrum having peaks at positions 940 cm −1 , 1088 cm −1 , 1132 cm −1 , 1242 cm −1 , 1360 cm −1 , and 1608 cm −1 .
9. The process of claim 1 , wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has 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.
10. The process of claim 9 , wherein the crystallizing step results in forming Crystalline form I of abexinostat tosylate, characterized in that it has a solid-state 13 C CP/MAS NMR spectrum having the following peaks (expressed in ppm±0.2 ppm):
Peak
Chemical Shift
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.
11. A pharmaceutical composition comprising crystalline form I of abexinostat tosylate, lactose monohydrate, and maize starch, wherein crystalline form I of abexinostat tosylate is characterized in that it 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, 14.08, 18.95, 21.08, and 27.05.
12. The pharmaceutical composition of claim 11 , wherein the crystalline form I of abexinostat tosylate is characterized in that it 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, 19.96, 21.08, 22.82, 23.61, and 27.05.
13. The pharmaceutical composition of claim 12 , wherein crystalline form I of abexinostat tosylate is characterized in that it has the following X-ray powder diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°) and interreticular distance d (expressed in Å):
Line
Angle 2 theta
Interreticular Distance
No.
(degrees)
(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.
14. The pharmaceutical composition of claim 11 , wherein crystalline form I of abexinostat tosylate is characterized in that it has a Raman spectrum having a peak at position 1608 cm −1 .
15. The pharmaceutical composition of claim 14 , wherein crystalline form I of abexinostat tosylate is characterized in that it has a Raman spectrum having peaks at positions 940 cm −1 , 1088 cm −1 , 1132 cm −1 , 1242 cm −1 , 1360 cm −1 , and 1608 cm −1 .
16. The pharmaceutical composition of claim 11 , wherein crystalline form I of abexinostat tosylate is characterized in that it has 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.
17. The pharmaceutical composition of claim 16 , wherein crystalline form I of abexinostat tosylate is characterized in that it has a solid-state 13 C CP/MAS NMR spectrum having the following peaks (expressed in ppm±0.2 ppm):
Peak
Chemical Shift
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.