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Definitions

• the present invention relates to crystalline salts of flibanserin, 1-[2-(4-(3- trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-one, to a process for their manufacture, to pharmaceutical formulations containing them and to their use as medicament.
• the aim of the invention is to provide new forms of flibanserin with advantageous properties for pharmaceutical use.
• the above mentioned pharmacologically valuable properties of flibanserin disclosed in the prior art constitutes the basic prerequisite for effective use of the compound as pharmaceutical compositions.
• an active substance must also satisfy further requirements, besides actually being effective for the desired indication. These parameters are largely to do with the physicochemical nature of the active substance.
• examples of these parameters are the stability of effect of the starting substance under various environmental conditions, the stability during production of the pharmaceutical formulation and stability in the final compositions of the drug.
• the pharmaceutically active substance used to prepare the pharmaceutical compositions should therefore have great stability which is ensured even under different environmental conditions. This is absolutely essential to prevent pharmaceutical compositions being used which contain breakdown products, for example, in addition to the active substance itself. In such a case the content of active substance present in the pharmaceutical formulation might be lower than specified.
• the absorption of moisture reduces the content of pharmaceutically active substance as a result of the increased weight caused by the uptake of water.
• Pharmaceutical compositions with a tendency to absorb moisture have to be protected from moisture during storage, e.g. by the addition of suitable drying agents or by storing the drug in an environment where it is protected from moisture.
• the uptake of moisture may reduce the content of pharmaceutically active substance during manufacture if the pharmaceutical substance is exposed to the environment without being protected from moisture in any way.
• a pharmaceutically active substance should be, if at all, only slightly hygroscopic.
• the solubility of the active substance Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. If for example pharmaceutical solutions are prepared (e.g. for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents. It is also very important for drugs which are to be taken orally that the active substance should be sufficiently soluble.
• the problem of the present invention is to provide a pharmaceutically active substance which not only is characterised by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.
• the aim of the present invention is to provide new crystalline salt forms of flibanserin, 1 -[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1 -yl)ethyl]-2,3- dihydro-1 H-benzimidazol-2-one, which are characterized by advantageous physicochemical properties, especially improved solubility in water and minimized hygroscopicity
• Another embodiment of the present invention relates to the process for manufacture of new crystalline salt forms of 1 -[2-(4-(3-trifluoro-methyl- phenyl)piperazin-1 -yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-one.
• Another embodiment of the present invention relates to pharmaceutical compositions containing the new crystalline salt forms of 1 -[2-(4-(3-trifluoro- methyl-phenyl)piperazin-1 -yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-one and to their use as medicament.
• the present invention relates to the following salts and/or crystalline forms and/or crystalline salt forms of the compound 1 -[2-(4-(3- trifluoro-methyl-phenyl)piperazin-1 -yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-one:
• d 3.99 ⁇ 0.05 A
• d 4.69 ⁇ 0.05 A
• d 4.85 ⁇ 0.05 A
• d 6.42 ⁇ 0.05 A
• Its solubility in water at room temperature is 0.1 mg/ml.
• the hygroscopiycity expressed in the uptake of water in the range of 10-90 % relative humidity is 0.15 %.
• the DSC diagram is additionally characterised in that two further weakly endothermic signals can be observed at approx. 112 0 C and 198 0 C.
• the DSC diagram is additionally characterised in that a further weakly endothermic signal can be observed at approx. 78 0 C.
• the invention relates to a process for the preparation of the new crystalline salt forms of flibansehn as specified above under I) to XXIX).
• the compounds specified above can be obtained by i) dissolving the free base of flibanserin and the acid providing the anion for salt formation in a suitable solvent (preferably TFE/water (80:20)) 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 (e.g. evaporation under reduced pressure) iv) adding a suitable crystallization solvent to the residue obtained by step iii), and heating the reaction mixture slowly up (e.g.
• the free base of the compound of formula (I) is dissolved in a suitable solvent, such as TFE/water (80:20).
• a suitable solvent such as TFE/water (80:20) (depending on the acid).
• the free base of the compound of formula (I) is then mixed with the acid at a predetermined base /acid molar ratio, which is selected from 1 :1 or 2:1 depending on the acid.
• the solvent is evaporated under reduced pressure.
• a suitable crystallization solvent is added to the reaction mixture, and the reaction mixture is slowly heated up to 50 0 C (e.g. a heating rate of about 5 °C/min).
• suitable solvents for the crystallization are ethanol, tetrahydrofuran, dichloromethane, n-mthylpyrrolidone, propyl acetate, methyl tert-butyl ether, 1 ,4 dioxane, 1 ,2-dimetoxyethane, water, 2,2,2,- trifloroethanol, chloroform, methanol, nitrobenzene, nitromethane, cyclohexanone, propionitrile, ethyl phenyl ether, diisobutyl keton, isophorone, water/ethanol (20/80), water/n-methylpyrrolidone (80/20), water/2,2,2- trifluoroethanol (20/80), water/acteone (20/80) and water/DMSO (80/20).
• the reaction mixture After staying for about 30 minutes at 50°C, the reaction mixture is slowly cooled down (e.g. at a cooling rate of 5°C/h) to a suitable crystallization temperature, which is for example between 20 0 C or 3°C. The reaction mixture stays at this temperature until enough crystals are formed, which can then be collected, for example by filtration.
• a suitable crystallization temperature which is for example between 20 0 C or 3°C.
• the reaction mixture stays at this temperature until enough crystals are formed, which can then be collected, for example by filtration.
• the salt forms of flibanserin as specified above under I) to XXIX) were investigated more thoroughly by X-ray powder diffraction and thermal analysis (DSC). The diagrams obtained are shown in Figures 1.1 to 1.23. Tables 1.1 to 1.23 contain the data obtained in the analysis. Tables 2.1 to 2.18 contain the single crystal data obtained in the analysis.
• T Temperature of data collection
• ⁇ wavelength of X-ray source
• D m calculated density
• ⁇ range Theta range of data collection
• a further object of the present invention is the use of the above salts and crystalline salt forms for the manufacture of a medicament for the treatment or prevention of the following diseases.
• the indication of the above salts and crystalline salt forms of the present invention may include all known indications for flibanserin, e.g. in the treatment of patients suffering from central nervous system disorders, in particular in affective disorders (e.g. depression like major depressive disorder, childhood depression, dysthymia, seasonal affective disorder, dysthymic disorder and minor depressive disorder; bipolar disorders), anxiety (incl.
• 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.
• 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.
• ADHD Attention Deficit Hyperactivity Disorder
• 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, postherpetic 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.
• 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 neurode
• salts and crystalline salt forms can be used for the treatment of disorders of sexual desire, more preferably for HSDD (Hypoactive Sexual Desire Disorder).
• HSDD Hydrophilic Sexual Desire Disorder
• the present invention also relates to pharmaceutical compositions comprising the above-mentioned salts or crystalline salt forms of the present invention
• compositions may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
• the active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80.
• the compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient.
• the dosis range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg.
• Each dosage unit may conveniently contain from 0,01 mg to 100 mg, preferably from 0,1 to 50 mg.
• Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• the tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
• excipients for example inert
• Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• a sweetener such as saccharine, cyclamate, glycerol or sugar
• a flavour enhancer e.g of. a flavouring such as vanilline or orange extract.
• suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
• preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid
• Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
• Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
• the harvested crystals may be characterized by X-ray powder diffraction and thermal analysis (DSC). If suitable single crystals grow, single crystal X-ray structure analysis may be performed. The following equipment was used to characterize the crystalline salts forms.
• XRPD patterns were obtained using a high throughput XRPD set-up.
• the plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector.
• the diffractometer was calibrated using Silver Behenate for the long d- spacings and corundum for the short d-spacings.
• the data collection was carried out at room temperature using monochromatic Cu Ka radiation in the region of 2 ⁇ between 1.5 and 41.5 °.
• the diffraction pattern of each well was collected with an exposure time of 3 - 4 minutes.
• Suitable single crystals were selected and glued to a glass fibre, which is mounted on a X-ray diffraction goniometer.
• X-ray diffraction data were collected for the mounted crystals at a temperature of 233 K using a KappaCCD system and MoKa radiation generated by a FR590 X-ray generator (Bruker Nonius
• IGAsorp water sorption monitor from Hiden lsochema was used for the analysis of the hygroscopical behaviour at room temperature. humidity profile: from 10 - 90 % r.h. in steps of 10 %, sorption as well as desorption profiles were registered weight-in quantity: 10 - 20 mg
• Solubility of the different crystalline salt forms in water was determined by adding approx. 5 mg of compound into 5 ml of water at room temperature. The mixture was vigorously shaken for 2 hours at room temperature. Afterwards the undissolved solid was removed by filtering through a 0.45 ⁇ m PTFE filter, in the filtrate the dissolved amount of compound was determined by UV-spectroscopy.
• TFE/water 80:20 The acids used to prepare the salts were dissolved in different solvents such that the molar ratio of the flibanserin to the respective acid was set according to the information given in Table 3 under "ratio base/acid". Fumaric acid was dissolved in THF/water 80:20, HCI in water and all other acids used were dissolved in TFE/water 80:20. However it is to mention that all other solvents which are able to dissolve the acid used could have been used. The 96 well plates were then placed in a vacuum chamber (1 kPa) at room temperature for 24 h in order to evaporate the solvent.
• the finely ground active substance, lactose and some of the corn starch are mixed together.
• the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
• the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
• the mixture is compressed to produce tablets of suitable shape and size.
• active substance 5 mg corn starch 41 .5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesium stearate 0.5 m ⁇
• the active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water.
• the moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen.
• convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine .
• the tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc.
• the finished coated tablets are polished with wax.
• the substance and corn starch are mixed and moistened with water.
• the moist mass is screened and dried.
• the dry granules are screened and mixed with magnesium stearate.
• the finished mixture is packed into size 1 hard gelatine capsules.
• the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
• the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
• the hard fat is melted.
• the ground active substance is homogeneously dispersed. It is cooled to 38°C and poured into slightly chilled suppository moulds.

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• 2009
  • 2009-11-26 CA CA 2686480 patent/CA2686480A1/en not_active Abandoned
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