The present invention relates to new crystalline salt forms of flibanserine which have valuable pharmacological properties, to a process for their manufacture, to pharmaceutical formulations containing them and to their use as medicament.
1. A salt of the compound 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one selected from the group consisting of:
I. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=215±5° C. and characteristic peaks in the x-ray powder diffractogram of d=15.99±0.05 Å, 7.44±0.05 Å, 3.98±0.05 Å, and 3.44±0.05 Å;
II. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=217±5° C. and characteristic peaks in the x-ray powder diffractogram of d=16.43±0.05 Å, 5.08±0.05 Å, 4.35±0.05 Å, 3.47±0.05 Å, and 7.66±0.05 Å;
III. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one bromide having a melting point of T fus (onset)=252±5° C. and by the peaks in the X-ray powder diffractogram which occur at d=3.48±0.05 Å, d=3.33±0.05 Å, d=4.28±0.05 Å, d=3.43±0.05 Å and d=16.03±0.05 Å;
IV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one bromide having a melting point of T fus (onset)=252±5° C. and by the peaks in the X-ray powder diffractogram which occur at d=15.52±0.05 Å, d=5.15±0.05 Å, d=4.60±0.05 Å, d=4.36±0.05 Å and d=3.94±0.05 Å;
V. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one edisylate having a melting point of T fus (onset)=144±5° C.;
VI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one tosylate having a melting point of T fus (onset)=238±5° C.;
VII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one mesylate having a melting point of T fus (onset)=207±5° C.;
VIII. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one besylate having a melting point of T fus (onset)=247±5° C.;
IX. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one oxalate having a melting point of T fus (onset)=209±5° C.;
X. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one oxalate having a melting point of T fus (onset)=254±5° C.;
XI. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one sacharinate having a melting point of T fus (onset)=90±5° C.;
XII. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one phosphate having a melting point of T fus (onset)=182±5° C.;
XIII a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one maleate having a melting point of T fus (onset)=98±5° C.;
XIV. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one maleate having a melting point of T fus (onset)=172±5° C.;
XV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one ethansulfonate having a melting point of T fus (onset)=207±5° C.;
XVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one camphorsulfonate having a melting point of T fus (onset)=217±5° C.;
XVII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate having a melting point of T fus (onset)=103±5° C.;
XVIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate the following data:
Empirical formula
C 20 H 22 F 3 N 4 O + •C 3 H 3 O 4 −2 •2 C 4 H 10 O
Fw
642.71
T [K]
120(2)
λ[Å]
0.71073
Crystal system
Monoclinic
Space group
P 2 1 /c
Unit cell dimensions
a [Å]
9.2650(3)
b [Å]
24.2380(2)
c [Å]
30.128(8)
α [°]
90
β [°]
101.620(2)
γ [°]
90
V [Å 3 ]
6627.0(4)
Z
8
D m [g/cm 3 ]
1.288
F(000)
2736
Crystal size [mm 3 ]
0.25 × 0.1 × 0.08
θ range [°]
1.5 → 24
Reflections collected
22364
Independent reflections
10286 [R int = 0.1143]
S
1.093
R [I > 2σ(I)]
R1 = 0.1070, wR2 = 0.1271
R indices (all data)
R1 = 0.2167, wR2 = 0.1563
XIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate, having the following characteristics:
Empirical formula
C 20 H 22 F 3 N 4 O + •C 3 H 3 O 4 −2 •H 2 O
Fw
530.50
T [K]
120(2)
λ[Å]
0.71073
Crystal system
Triclinic
Space group
P −1
Unit cell dimensions
a [Å]
7.8050(2)
b [Å]
8.0730(2)
c [Å]
20.1470(4)
α [°]
80.0090(8)
β [°]
87.4660(8)
γ [°]
74.5320(9)
V [Å 3 ]
1204.92(3)
Z
2
D m [g/cm 3 ]
1.462
F(000)
556
Crystal size [mm 3 ]
0.3 × 0.25 × 0.1
θ range [°]
2 → 37
Reflections collected
14593
Independent reflections
12114 [R int = 0.0408]
S
1.062
R [I > 2σ(I)]
R1 = 0.0742, wR2 = 0.1389
R indices (all data)
R1 = 0.1184, wR2 = 0.1594
XX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one salicylate the following data:
Empirical formula
C 20 H 22 F 3 N 4 O + •C 7 H 5 O 3 −
Fw
528.53
T [K]
293(2)
λ[Å]
0.71073
Crystal system
Monoclinic
Space group
P 2 1 /c
Unit cell dimensions
a [Å]
16.3790(2)
b [Å]
15.4410(4)
c [Å]
10.1810(4)
α [°]
90
β [°]
98.1820(12)
γ [°]
90
V [Å 3 ]
2548.6(2)
Z
4
D m [g/cm 3 ]
1.377
F(000)
1104
Crystal size [mm 3 ]
0.4 × 0.3 × 0.2
θ range [°]
2.5 → 26
Reflections collected
12472
Independent reflections
4948 [R int = 0.0289]
S
0.949
R [I > 2σ(I)]
R1 = 0.0565, wR2 = 0.1471
R indices (all data)
R1 = 0.0753, wR2 = 0.1647
XXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one L-tartrate having a melting point of T fus (onset)=151±5° C.;
XXII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one hemifumarate having a melting point of T fus (onset)=195±5° C.;
XXIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one fumarate having a melting point of T fus (onset)=193±5° C.;
XXIV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one glycolate (form I) (=hydrate form) having a melting point of T fus (onset)=139±5° C.;
XXV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one citrate having a melting point of T fus (onset)=176±5° C.;
XXVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one mandelate having a melting point of T fus (onset)=148±5° C.;
XXVII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one L-malate having a melting point of T fus (onset)=176±5° C.;
XXVIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one succinate the following data:
XXIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one naphthalenesulfonate peaks in the X-ray powder diffractogram which occur at d=4.92±0.05 Å, d=3.43±0.05 Å, d=4.00±0.05 Å and d=3.96±0.05 Å;
Empirical formula
2 C 20 H 22 F 3 N 4 O + •C 4 H 4 O 4 2− •2 H 2 O
Fw
934.94
T [K]
293(2)
λ[Å]
0.71073
Crystal system
Triclinic
Space group
P −1
Unit cell dimensions
a [Å]
9.5450(4)
b [Å]
10.7120(5)
c [Å]
11.7330(7)
α [°]
97.597(2)
β [°]
93.690(2)
γ [°]
110.663(3)
V [Å 3 ]
1104.6(1)
Z
1
D m [g/cm 3 ]
1.405
F(000)
490
Crystal size [mm 3 ]
0.3 × 0.3 × 0.2
θ range [°]
3.5 → 26
Reflections collected
6382
Independent reflections
4176 [R int = 0.0194]
S
1.036
R [I > 2σ(I)]
R1 = 0.0555, wR2 = 0.1386
R indices (all data)
R1 = 0.0649, wR2 = 0.1484
XXX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one tosylate (form II) (=anhydrous form) having a melting point of T fus (onset)=241±5° C.;
XXXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one fumarate (form III) (=anhydrous form) having a melting point of T fus (onset)=202±5° C.;
XXXII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one camphorsulfonate (form II) (=anhydrous form) having a melting point of T fus (onset)=231±5° C.;
XXXIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one glycolate (form II) (=hydrate form) having a melting point of T fus (onset)=231±5° C.
2. A pharmaceutical composition comprising the crystalline salt forms according to claim 1 and a pharmaceutically acceptable excipient.
3. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=215±5° C. and characteristic peaks in the x-ray powder diffractogram of d=15.99±0.05 Å, 7.44±0.05 Å, 3.98±0.05 Å, and 3.44±0.05 Å is an anhydrous form.
4. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=217±5° C. and characteristic peaks in the x-ray powder diffractogram of d=16.43±0.05 Å, 5.08±0.05 Å, 4.35±0.05 Å, 3.47±0.05 Å, and 7.66±0.05 Å is a solvate.
5. The salt of the compound of claim 3 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=215±5° C. and characteristic peaks in the x-ray powder diffractogram of d=15.99±0.05 Å, 7.44±0.05 Å, 3.98±0.05 Å, and 3.44±0.05 Å is crystallized from a mixture of water and ethanol.
6. The salt of the compound of claim 4 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=217±5° C. and characteristic peaks in the x-ray powder diffractogram of d=16.43±0.05 Å, 5.08±0.05 Å, 4.35±0.05 Å, 3.47±0.05 Å, and 7.66±0.05 Å is crystallized from a mixture of water and 1-methyl-2-pyrrolidinone.
7. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=215±5° C. and characteristic peaks in the x-ray powder diffractogram of d=15.99±0.05 Å, 7.44±0.05 Å, 3.98±0.05 Å, and 3.44±0.05 Å is further characterized by having weakly endothermic signals at approximately 122° C. and 186° C.
8. The salt of the compound of claim 1 wherein the crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of T fus (onset)=217±5° C. and characteristic peaks in the x-ray powder diffractogram of d=16.43±0.05 Å, 5.08±0.05 Å, 4.35±0.05 Å, 3.47±0.05 Å, and 7.66±0.05 Å is further characterized by having weakly endothermic signals at approximately 56° C. and 121° C.