NEW SALTS
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.;
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.;
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 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 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 having the following characteristics:
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:
XX.
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
XXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one salicylate having the following characteristics:
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
XXII. 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.;
XXIII. 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.;
XXIV. 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.;
XXV. 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.;
XXVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one citrate, characterized by having a melting point of T fus (onset)=176±5° C.;
XXVII. 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.;
XXVIII. 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.;
XXIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one succinate having the following characteristics:
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 naphthalenesulfonate having 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;
XXXI. 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.;
XXXII. 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.;
XXXIII. 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.; and
XXXIV. 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 . (canceled)
3 . A pharmaceutical composition comprising the crystalline salt forms according to claim 1 and a pharmaceutically acceptable excipients.
4 . A process for preparing a crystalline salt according to claim 1 , comprising:
i) dissolving the free base of flibanserin and the acid providing the anion for salt formation in a suitable solvent;
ii) mixing the free base of flibanserin with the acid at a predetermined base/acid molar ratio, which is selected from 1:1 or 2:1 depending on the acid;
iii) removing the solvent;
iv) adding a suitable crystallization solvent to the residue obtained by step iii), and heating the reaction mixture slowly up to about 50° C.; and leaving it to stand for a further period of time;
v) slowly cooling down the reaction mixture to a suitable crystallization temperature and leaving it to stand until enough crystals are formed; and
vi) isolating the precipitated crystals.
5 . A method a treating a disorder in a patient in need thereof, the method comprising administering an effective amount of a compound according to claim 1 to the patient.
6 . The method according to claim 5 , wherein the disorder is Hypoactive Sexual Desire Disorder.
7 . The method according to claim 5 , wherein the disorder is selected from a central nervous system disorder, including an affective disorder (e.g., depression like major depressive disorder, childhood depression, dysthymia, seasonal affective disorder, dysthymic disorder and minor depressive disorder; bipolar disorders), anxiety (e.g., panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia (simple phobia), social phobia (social anxiety disorder), obsessive-compulsive disorder (OCD), post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder and anxiety disorder not otherwise specified), sleep and sexual disorders (e.g., Hypoactive Sexual Desire Disorder, premenstrual disorders like premenstrual dysphoria, premenstrual syndrome, premenstrual dysphoric disorder; sexual aversion disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorders like dyspareunia, vaginismus, noncoital sexual pain disorder; sexual dysfunction due to a general medical condition and substance-induced sexual dysfunction), psychosis, schizophrenia (including the disorganized type, the catatonic type, the paranoid type, the undifferentiated type, the residual type of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, and psychotic disorder not otherwise specified), personality disorders, mental organic disorders, mental disorders in childhood, aggressiveness, age associated memory impairment, for neuroprotection, the treatment and/or prevention of neurodegenerative diseases as well as cerebral ischaemia of various origins (e.g. epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotension, cardiac infarct, brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke (stroke), global cerebral ischaemia during stoppage of the heart, diabetic polyneuropathy, tinnitus, perinatal asphyxia, cardiac hypertrophia (thickening of the heart muscle) and cardiac insufficiency (weakness of the heart muscle); anorexia nervosa (incl. binge-eating/purging type of anorexia nervosa and the restricting type of anorexia nervosa), Attention Deficit Hyperactivity Disorder (ADHD) (incl. ADHD predominantly combined type, ADHD predominantly inattentive type, and ADHD predominantly hyperactive-impulsive type), obesity (incl. exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity and central obesity), urinary incontinence (incl. overactive bladder syndrome, urgency, urge urinary incontinence, stress urinary incontinence, mixed urinary incontinence), chronic pain (incl. neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, phantom limb pain, complex regional pain syndrome (CPRS), trigeminal neuralgia/trigeminus neuralgia/tic douloureux, surgical intervention (e.g. post-operative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, pain associated with menstruation, pain associated with cancer, dental pain, headache, migraine, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscular injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture bone pain due to osteoarthritis, osteoporosis, bone metastases or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndromes, upper back pain or lower back pain (wherein the back pain results from systematic, regional, or primary spine disease (radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI)-associated pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain and geriatric pain), Valvular Heart Disease (incl. valvular stenosis, valvular regurgitation, atresia of one of the valves, mitral valve prolapse), insomnia (including primary and secondary Insomnia), and vasomotor symptoms.