Stable polymorph of flibanserin
View Patent ↗The invention relates to the polymorph A of flibanserin, to a technical process for the preparation thereof, as well as to the use thereof for preparing medicaments.
1. A crystalline polymorph, designated form A, of flibanserin 1,
having an endothermic maximum at about 161° C. which occurs during thermal analysis using DSC.
2. A polymorph, designated form A, of flibanserin 1, characterized by the following X-ray powder diffraction pattern:
d-
d-
Peak
Peak
Back.
Rel.
Angle
value
value
width
int
int
int
[°2Θ]
α1 [Å]
α2 [Å]
[°2Θ]
[counts]
[counts]
[%]
Signif.
5.195
16.9967
17.0390
0.960
8
69
0.1
1.05
9.045
9.7689
9.7931
0.100
92
96
1.3
0.97
9.335
9.4660
9.4896
0.080
114
98
1.6
0.88
10.025
8.8160
8.8379
0.140
400
100
5.5
7.18
10.595
8.3430
8.3637
0.140
204
102
2.8
3.46
11.290
7.8309
7.8503
0.140
467
104
6.4
6.91
13.225
6.6891
6.7058
0.180
548
112
7.5
13.10
14.595
6.0642
6.0793
0.180
404
121
5.5
9.17
15.460
5.7268
5.7410
0.140
4186
125
57.3
23.20
16.655
5.3185
5.3317
0.200
515
130
7.0
12.38
17.085
5.1856
5.1985
0.100
1347
132
18.4
2.78
17.285
5.1260
5.1388
0.060
1399
135
19.1
2.26
17.420
5.0866
5.0992
0.100
1204
135
16.5
4.71
18.140
4.8863
4.8984
0.180
1043
139
14.3
13.14
18.650
4.7538
4.7656
0.120
1063
142
14.5
0.91
19.140
4.6332
4.6447
0.140
7310
144
100.0
32.77
19.820
4.4757
4.4869
0.160
3624
146
49.6
9.02
20.080
4.4184
4.4294
0.140
5402
149
73.9
21.06
20.385
4.3530
4.3638
0.160
2652
149
36.3
23.25
21.215
4.1845
4.1949
0.160
369
154
5.0
5.78
21.890
4.0570
4.0670
0.200
773
156
10.6
3.09
22.630
3.9259
3.9357
0.280
4277
161
58.5
74.66
23.210
3.8291
3.8386
0.120
484
164
6.6
3.33
24.355
3.6516
3.6607
0.060
2725
169
37.3
1.16
24.610
3.6144
3.6234
0.140
3540
172
48.4
17.08
24.995
3.5596
3.5684
0.100
529
174
7.2
1.01
25.260
3.5228
3.5316
0.120
557
174
7.6
3.02
26.575
3.3514
3.3597
0.240
2421
182
33.1
42.58
27.155
3.2811
3.2893
0.140
676
185
9.2
1.32
27.310
3.2629
3.2710
0.100
767
185
10.5
2.75
27.865
3.1991
3.2071
0.120
420
188
5.7
1.08
28.210
3.1608
3.1686
0.100
1467
190
20.1
0.79
28.325
3.1482
3.1560
0.140
1789
190
24.5
4.41
28.650
3.1132
3.1210
0.180
1204
190
16.5
11.65
29.520
3.0234
3.0309
0.220
1011
196
13.8
15.74
30.250
2.9521
2.9594
0.120
159
199
2.2
1.22
31.105
2.8729
2.8800
0.360
282
204
3.9
8.14
31.905
2.8026
2.8096
0.100
339
207
4.6
0.96
32.350
2.7651
2.7720
0.120
237
210
3.2
3.01
33.300
2.6884
2.6950
0.180
1347
216
18.4
14.06
33.640
2.6620
2.6686
0.100
404
216
5.5
1.45
34.880
2.5701
2.5765
0.200
202
222
2.8
1.04
35.275
2.5422
2.5486
0.240
299
225
4.1
4.84
36.055
2.4890
2.4952
0.280
202
228
2.8
3.78
36.910
2.4333
2.4393
0.320
169
234
2.3
0.90
37.160
2.4175
2.4235
0.120
216
234
3.0
2.14
37.680
2.3853
2.3912
0.240
240
237
3.3
1.58
39.435
2.2831
2.2888
0.280
449
246
6.1
2.67
39.675
2.2698
2.2755
0.080
396
246
5.4
0.82
40.325
2.2347
2.2403
0.160
520
250
7.1
0.95
40.930
2.2031
2.2086
0.120
480
253
6.6
2.66
41.445
2.1769
2.1823
0.240
372
256
5.1
2.65
41.990
2.1499
2.1552
0.120
538
259
7.4
1.31
42.670
2.1172
2.1225
0.160
428
262
5.9
1.45
43.145
2.0950
2.1002
0.120
433
266
5.9
1.50
44.190
2.0478
2.0529
0.160
376
269
5.1
0.89
46.095
1.9675
1.9724
0.160
279
279
3.8
0.86
46.510
1.9509
1.9558
0.240
310
282
4.2
0.87
48.305
1.8826
1.8872
0.200
506
292
6.9
2.06
48.900
1.8610
1.8657
0.240
615
296
8.4
1.67
50.330
1.8115
1.8160
0.160
437
303
6.0
1.73
51.035
1.7881
1.7925
0.080
416
306
5.7
0.93
53.550
1.7099
1.7141
0.480
177
317
2.4
2.84
54.500
1.6823
1.6865
0.400
130
324
1.8
1.37
55.420
1.6565
1.6606
0.320
130
328
1.8
1.72
56.220
1.6348
1.6389
0.320
121
331
1.7
0.87
56.770
1.6203
1.6243
0.240
142
335
1.9
1.59
57.405
1.6039
1.6079
0.240
112
339
1.5
1.19
58.500
1.5764
1.5804
0.240
67
342
0.9
1.57.
3. A pharmaceutical composition comprising form A according to claim 1 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.
4. A pharmaceutical composition comprising a polymorph, designated form A, of flibanserin 1 according to claim 2 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.
5. Form A of flibanserin 1
having an endothermic maximum at about 161° C. which occurs during thermal analysis using DSC, and obtained by the process comprising:
(a) reacting a benzimidazolone 2
wherein R denotes a suitable amino protecting group,
with a piperazine 3
wherein X is a leaving group selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethansulphonate and para-toluenesulphonate, in a suitable solvent selected from water, alcohols, mixtures of water with alcohols, polar aprotic solvents and mixtures of polar aprotic solvents with water, in the presence of a suitable base, and
(b) cleaving the amino protecting group R under suitable cleaving conditions.
6. A pharmaceutical composition comprising form A of flibanserin 1
having an endothermic maximum at about 161° C. which occurs during thermal analysis using DSC, and obtained by the process-comprising:
(a) reacting a benzimidazolone 2
wherein R denotes a suitable amino protecting group,
with a piperazine 3
wherein X is a leaving group selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethansulphonate and para-toluenesulphonate, in a suitable solvent selected from water, alcohols, mixtures of water with alcohols, polar aprotic solvents and mixtures of polar aprotic solvents with water, in the presence of a suitable base, and
(b) cleaving the amino protecting group R under suitable cleaving conditions.
7. A polymorph, designated form A, of flibanserin 1,
having an endothermic maximum at about 161° C. which occurs during thermal analysis using DSC, and characterized by an X-ray powder diffraction pattern comprising peaks (°2Θ) at 15.460, 19.140, 19.820, 20.080, 22.630, 24.610, 24.355, 26.575, 28.210 and 28.325.
8. A polymorph, designated form A, of flibanserin 1,
characterized by a powder X-ray diffraction patent comprising peaks (°20Θ) at 15.460, 19.140, 19.820, 20.080, 22.630, 24.610, 24.355, 26.575, 28.210 and 28.325.
9. A polymorph, designated form A, of flibanserin 1,
having an endothermic maximum at about 161° C. which occurs during thermal analysis using DSC, and characterized by an X-ray powder diffraction pattern comprising peaks(°20Θ) at 5.195, 9.045, 9.335, 10.025, 10.595, 11.290, 13.225, 14.595, 15.460, 16.655, 17.085, 17.285, 17.420, 18.140, 18.650, 19.140, 19.820, 20.080, 20.385, 21.215, 21.890, 22.630, 23.210, 24.355, 24.610, 25.995, 25.260, 26.575, 27.155, 27.310, 27.865, 28.210, 28.325, 28.650, 29.520, 30.250, 31.105, 31.905, 32.350, 33.300, 33.640, 34.880, 35.275, 36.055, 36.910, 37.160, 37.680 39.435, 39.675, 40.325, 40.930, 41.445, 41.990, 42.670, 43.145, 44.190, 46.095, 46.510, 48.305, 48.900, 50.330, 51.035, 53.550, 54.500, 55.420, 56.220, 56.770, 57.405, and 58.500.
10. A polymorph, designated form A, of flibanserin 1,
characterized by an X-ray powder diffraction pattern comprising peaks (°2Θ) at 5.195, 9.045, 9.335, 10.025, 10.595, 11.290, 13.225, 14.595, 15.460, 16.655, 17.085, 17.285, 17.420, 18.140, 18.650, 19.140, 19.820, 20.080, 20.385, 21.215, 21.890, 22.630, 23.210, 24.355, 24.610, 25.995, 25.260, 26.575, 27.155, 27.310, 27.865, 28.210, 28.325, 28.650, 29.520, 30.250, 31.105, 31.905, 32.350, 33.300, 33.640, 34.880, 35.275, 36.055, 36.910, 37.160, 37.680 39.435, 39.675, 40.325, 40.930, 41.445, 41.990, 42.670, 43.145, 44.190, 46.095, 46.510, 48.305, 48.900, 50.330, 51.035, 53.550, 54.500, 55.420, 56.220, 56.770, 57.405, and 58.500.
11. A pharmaceutical composition comprising a polymorph designated form A, of flibanserin 1 according to claim 7 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.
12. A pharmaceutical composition comprising a polymorph, designated form A, of flibanserin 1 according to claim 8 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.
13. A pharmaceutical composition comprising a polymorph, designated form A, of flibanserin 1 according to claim 9 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.
14. A pharmaceutical composition comprising a polymorph, designated form A, of flibanserin 1 according to claim 10 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.
15. A polymorph, designated form A, of flibanserin 1 characterized by having an X-ray powder diffraction pattern as shown in FIG. 1 .
16. A pharmaceutical composition comprising a polymorph, designated form A, of flibanserin 1 according to claim 15 , optionally in admixture with one or more pharmaceutical carriers, diluents or excipients, wherein the polymorph is present in crystalline form.