BR122012029907B1 - CRYSTAL POLYMORPHINE (FORM) OF FLIBANSERIN 1, ITS USE, PROCESS FOR PREPARATION OF FLIBANSERIN 1, AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

Report of the Invention Patent for "FLIBANSERIN 1 CRYSTALLINE POLYMORPH (FORM A), ITS USE, PROCESS FOR TECHNICAL PREPARATION OF FLIBANSERIN 1, AND PHARMACEUTICAL COMPOSITIONS".

Split application for PI0211601-4, filed July 7, 2002. The present invention relates to flibanserin polymorph A, a technical process for the preparation thereof, as well as the use thereof for the preparation of medicaments.

Background of the Invention Compound 1 - [2- (4- (3-trifluoromethyl-phenyl) piperazin-1-yl) ethyl] -2,3-dihydro-1H-benzimidazol-2-one (flibanserine) is described in hydrochloride form thereof in European Patent Application EP-A-526434, and has the following chemical structure: Flibanserine shows an affinity for the 5-HT 1a and 5-HT 2 receptors. It is therefore a promising therapeutic agent for the treatment of a variety of diseases, for example depression, schizophrenia, Parkinson's, anxiety, sleep disorders, mental and sexual disorders and age-related memory difficulties.

Certain pharmaceutical activity is, of course, the basic prerequisite to be fulfilled by a pharmaceutically active agent before it is approved as a commercially available drug. However, there are a variety of additional requirements with which an active pharmaceutical agent has to adjust. These requirements are based on several parameters that are linked with the nature of the active substance itself. Without being restrictive, examples of such parameters are stability of the active agent under various environmental conditions, stability thereof during production of the pharmaceutical formulation and stability of the active agent in the final compositions of the medicament. The pharmaceutically active substance used for the preparation of the pharmaceutical compositions should be as pure as possible and their stability in long term storage should be ensured under various environmental conditions. This is absolutely essential in order to prevent the use of pharmaceutical compositions containing, in addition to the actual active substance, products of deterioration thereof, for example. In such cases the content of the active substance in the medicine may be lower than that specified. The uniform distribution of the drug in the formulation is an important factor specifically when the drug has to be administered in low doses. To ensure uniform distribution, the particle size of the active substance may be reduced to an appropriate level, for example by grinding. Since degradation of the pharmaceutically active substance as a side effect of grinding (or micronising) has to be avoided as much as possible, despite the harsh conditions required during the process, it is absolutely essential that the active substance must be highly stable. through the whole shredding process. Only if the active substance is sufficiently stable during the grinding process can a homogeneous pharmaceutical formulation always containing the specified amount of active substance be produced in a reproducible manner.

Another problem that may arise in the milling process for the preparation of the desired pharmaceutical formulation is the energy input caused by this process and the stress on the surface of the crystals. This may under certain circumstances lead to polymorphic changes, a change in the amorphous configuration or a change in the crystal lattice. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance must always have the same crystalline morphology, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well. The stability of a pharmaceutically active substance is also important in pharmaceutical compositions for determining the shelf life of the specific drug; The expiry date is the amount of time that the medicine can be administered without any risk. The high stability of a medicament in the above pharmaceutical compositions under various storage conditions is therefore an additional advantage for both the patient and the manufacturer.

In addition to the above requirements, it should be borne in mind generally that any change in the solid state of the pharmaceutical composition that is capable of increasing the physical and chemical stability of the pharmaceutical composition offers a significant advantage over the less stable forms of the same medicament.

Therefore, the aim of the invention is to provide a new, stable crystalline form of the flibanserin compound that meets the stringent requirements imposed on pharmaceutically active substances as mentioned above.

Detailed Description of the Invention It has been surprisingly found that flibanserin free base in a specific polymorphic form meets the requirements mentioned above in this report.

Furthermore, it has been found that, depending on the choice of conditions that can be applied during flibanserin synthesis, the free base occurs in different crystalline modifications, polymorphs A and B.

It has been found that these different modifications can be deliberately produced through an appropriate choice of process conditions used in the manufacturing process.

It has been further surprisingly found that polymorph A, which can be obtained in crystalline form by the specific choice of reaction conditions, meets the stringent requirements mentioned above and thus solves the problem upon which the present invention is based. Accordingly the present invention relates to the flibanserin polymorph A. Flibanserin polymorph A is characterized by a melting point of about 161 ° C (determined by DSC; with a heating rate of 10 K / min). Polymorph B, the less stable modification of flibanserin exhibits a melting point of about 120 ° C (determined by DSC; with a heating rate of 10 K / min). While polymorph B exhibits poor stability under the effects of, for example, the mechanical stress produced by grinding, polymorph A appears to meet the aforementioned stability requirements.

In another aspect, the present invention relates to a process for manufacturing flibanserin polymorph A on a technical scale. The process according to the invention is illustrated in diagram 1.

Diagram 1: Benzimidazolone 2 is reacted with the pipe razin derivative 3 under basic reaction conditions in a suitable solvent to lead to 1_. In 2 the group R indicates an amino protecting group. The protecting group used may be any of the groups commonly used for amino function protection. Examples include groups selected from alkyl, substituted alkyl, heterosubstituted alkyl, unsaturated alkyl, alkyl substituted heteroatoms, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, alkyloxycarbonyl groups and aryloxycarbonyl groups . Preferred protecting groups are selected from butyl, 1,1-diphenylmethyl, methoxymethyl, benzyloxymethyl, trichloroethoxymethyl, pyrrolidinomethyl, cyanomethyl, pivaloyloxymethyl, allyl, 2-propenyl, t-butyldimethylsilyl, methoxy, thiomethyl, 4-methoxyphenyl , benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 4-chloro-phenoxycarbonyl, 4-nitro-phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl. Among these, the preferred protecting groups are selected from t-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl and 2-propenyl, the latter being most preferred. X in 3 is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or para-toluenesulfonate. Preferably X indicates chlorine, bromine or iodine, most preferably chlorine. Suitable solvents are selected from water, alcohols and mixtures of water with alcohols, polar aprotic solvents and mixtures thereof with water. Preferably the solvents are selected from the group consisting of dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol and mixtures of one or more of the aforementioned solvents with water. Preferably the solvents are those that can be easily miscible with water. Preferably a mixture of water with one of the methanol, ethanol or propanol alcohols is used as the solvent. In a preferred embodiment a mixture of water with isopropanol is used as the solvent. The base used may be an alkali metal or alkaline earth metal carbonate of lithium, sodium, potassium, calcium, such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use lithium, sodium and potassium hydrogen carbonates. Preferably the alkali metal or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohols or water may also be used. The most preferred base is sodium hydroxide. The base is preferably added in the form of aqueous solution thereof, preferably in the form of concentrated aqueous solutions, for example in concentrations of 30 to 50% weight / volume. In a preferred embodiment, an aqueous sodium hydroxide solution is used at a concentration of about 45% by weight / volume.

Compounds 2 and 3 are introduced into the reaction at a molar ratio of from 1: 1 to 1: 2, preferably from a molar ratio of from 1: 1,1 to 1: 1,5.

As mentioned earlier in this report a mixture of water and isopropanol is used as a solvent mixture preferably for conducting the process according to the invention. In this solvent mixture the weight ratio of water to isopropanol in the solvent mixture is preferably from 10: 1 to 1: 1, more preferably from 8: 1 to 3: 1, preferably specifically from 7: 1 to 5: 1. Per mol of compound 2 about 2 to 10 kg, preferably 3 to 8 kg, more preferably 4 to 7 kg of the above-mentioned solvent mixture is used. In a preferred embodiment the reaction is performed using an aqueous sodium hydroxide solution at a concentration of about 45% w / v as the base. Per mol of 2 about 0.1 to 1.5 kg, preferably 0.2 to 1.0 kg, preferably 0.3 to 0.6 kg of the above-mentioned sodium hydroxide solution is used. The reaction mixture containing 2 and 3 and the base in the above-mentioned suitable solvent is preferably heated to at least 50 ° C. In a preferred embodiment the reaction temperature is in the range of 60 ° C to the boiling point of the solvent. Preferably a temperature of from 70 to 90 ° C is specific. The reaction mixture is heated at the above temperature for about 10 minutes to about 12 hours, preferably for about 15 minutes to about 6 hours, more preferably for about 30 minutes to about 3 hours. The reaction mixture is preferably heated at the above temperature for about 45 to 60 minutes.

Then the protection group R is cleaved. Diving conditions depend on the choice of the R group. If R indicates, for example, benzylate it, the dividing is performed by hydrogenation into acetic acid in the presence of an appropriate catalyst (such as Pd on charcoal) or it may be. cleaved in aqueous HBr. Where R is methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitro phenoxycarbonyl they may be cleaved for example by the use of alkaline aqueous solutions such as NaOH (aqu.) Or KOH (aqu.). Where R is t-butoxycarbonyl it may be cleaved, for example into HCl or aqueous HBr. In the case where R indicates 2-propenyl, the specifically preferred protecting group according to the invention, the R splitting is effected through acidic reaction conditions. In a specific preference process according to the invention, the 2-propenyl group is cleaved by use of a strong mineral acid, preferably an acid selected from the group consisting of hydrobromic acid, hydrochloric acid and sulfuric acid, more preferably hydrochloric acid. Hydrochloric acid may be added in gaseous form or in the form of its aqueous solutions, preferably with the addition of aqueous solutions. It is preferably specifically the addition of hydrochloric acid as its concentrated solutions (about 36 wt% / volume). For each mol of 2, at least one mol of hydrochloric acid should be added. Preferably the amount of concentrated hydrochloric acid added (36% weight / volume) per mol of 2 is between 50 and 500 g, more preferably between 80 and 250 g. Specifically preferably about 120 to 160 g of concentrated aqueous hydrochloric acid (36% weight / volume) per mol of 2 used is added. Additional water may be optionally added. At a temperature of about 70 to 90 ° C, about 30 to 70%, preferably about 35 to 60% of the solvent is distilled off. At a temperature of about 60 to 80 ° C the pH of the remaining residue is adjusted to 5 to 9, preferably to about 6 to 8 by the addition of aqueous sodium hydroxide (45% w / v). At a temperature of about 40 to 55 ° C the pH is adjusted to about 8 to 9 by the addition of aqueous sodium hydroxide (45% w / v). The mixture is then cooled to about 20 to 40 ° C, preferably to about 30 to 35 ° C and centrifuged. The residue thus obtained is washed with about 100 to 750 ml of water per mol of 2 introduced, preferably about 200 to 500, preferably specific with about 300 to 400 ml of water per mol of introduced 2 and isopropanol. (about 50 to 250 g per mol of 2, preferably bristle from 100 to 200 g per mol of 2) and then with water until the chloride is removed. Optionally the product thus obtained may be subjected to another purification step. Preferably said purification is carried out by crystallization of 1 from, for example, acetone.

One aspect of the present invention relates to flibanserin polymorph A which can be obtained by the method described above. The following synthetic example is for an illustration of a method for preparing flibanserin polymorph A. It should be observed only as a possible method described by way of example, without restricting the invention to its contents.

Example: 375 kg of 1 - [(3-trifluoromethyl) phenyl] -4- (2-chloroethyl) piperazine are loaded into a reactor with 2500 kg of water and 200 kg of 45% aqueous sodium hydroxide. Under stirring, 169.2 kg of 1- (2-propenyl) -1,3-dihydro-benzinidazole-2H-one, 780 kg of isopropanol, 2000 kg of water and 220 kg of aqueous sodium hydroxide are added at 45 ° C. %. The reaction mixture is heated to 75 to 85 ° C and 160 kg of concentrated hydrochloric acid and 200 kg of water are added. The reaction mixture is stirred at constant temperature for about 45 minutes. After distillation of a mixture of water and isopropanol (about 3000 kg), the remaining residue is cooled to about 65 to 75 ° C and the pH adjusted to 6.5 to 7.5 by the addition of 125 kg. of 45% aqueous sodium hydroxide. After cooling to a temperature of 45 to 50 ° C the pH value is adjusted to 8 to 9 by the addition of about 4 kg of 45% aqueous sodium hydroxide. Then the mixture is cooled to 30 to 35 ° C and centrifuged. The residue thus obtained is washed with 340 liters of water and 126 liters of isopropanol and then with water until the chloride is removed. The wet product is vacuum dried at a temperature of about 45 to 55 ° C which leads to 358 kg of crude flibanserin polymorph A. The crude product thus obtained is charged to a 1750 kg acetone reactor and the resulting mixture is heated under stirring to reflux. The obtained solution is filtered and the filtered material is concentrated by distillation. The temperature is maintained for about one hour at 0 to 5 ° C and then the solid precipitate is isolated by filtration and dried at 55 ° C for at least 12 hours. The final yield is 280 kg of pure flibanserin polymorph A.

As mentioned earlier in this report, flibanserin polymorph A was characterized by DSC (Differential Scanning Calorimetry). The peak temperature determined for polymorph A is about 161 ° C. For characterization through DSC a Mettler TA 3000 System equipped with a TC 10-A processor was applied and the DSC 20 cell was applied. The heating rate was 10 K / min. Flibanserin polymorph A was further characterized by powder X-ray diffractometry. The powder X-ray diffraction pattern for polymorph A was obtained according to the following conditions: Equipment: Phillips PW 1800/10 diffractometer equipped with a 2000 digital micro-wax.

Adjustment Parameters: X-rays

Tube Type: Cu (Long Fine Focus) Wavelengths (λ) Κα -ι = 1.54060 Ka2 = 1.54439 Intensity Ratio (α2 / α1): 0.500 Starting Angle [° 2Θ]: 2000 Angle Final [° 2Θ]: 60,000 Slope Size [° 2Θ]: 0.020 Maximum Intensity (s): 7310,250 Scan Type: Continuous Minimum Peak Tip Width: 0.00 Maximum Peak Tip Width: 1.00 Peak Base Width: 2.00 Minimum Significant: 0.75 Number of Peaks: 69 Generator: High Voltage: 50 KV

Tube current: 30 mA The powder X-ray diffraction pattern obtained for polymorph A is shown in figure 1. Appropriate values are listed in table 1.

Table 1: Angle d-value d-value Width Int. Retro Intens. Signi- [° 2Θ] α1 [A] α2 [Â] peak peak intens. relative stay [° 2Θ] [cont.] [cont.] [%] 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 9.1 9.1 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 5.0922 0.100 1204 135 16.5 4.71 18.140 4.8863 4.8984 0.180 1043 139 14.3 13.1 18.650 4.7538 4.656 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 Table 1: Continuation Angle d-value D-value Width Intens. Retro Intens. Signi- [° 2Θ] α1 [A] α2 [A] from peak to peak intens. relative stay [° 2Θ] [cont.] [cont.] [%] 20,080 4,4184 4,4294 0.140 5402 149 73.9 21.06 20.385 4.3530 4.3638 0.16 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 3.9257 3.9357 0.280 4277 161 58.5 74.66 23.210 3, 8291 3.8386 0.120 484 164 6.6 3.33 24.3516 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 2.9251 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 .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 Table 1: Continuation Angle D-value Width Int. Retro Intens. Signi- [° 2Θ] α1 [Â] a.2 [Â] of the peak peak intens. relative stay [° 2Θ] [cont.] [cont.] [%] 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 0.162 428 262 5.9 1.45 43.145 2.0950 2.1002 0.120 433 266 5.9 1.50 44.190 2.0478 2.0529 0.1660 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 48.308 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 , 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 1 21 331 1.7 0.87 56.770 1.6203 1.6243 0.240 142 335 1.9 1.59 57.401 1.6079 1.6079 0.240 112 339 1.5 1.19 58.500 1.5764 1.5804 0.240 67 342 0.9 1.57 In light of the pharmaceutical efficacy of flibanserin, the present invention further relates to the use of flibanserin polymorph A as a medicament.

Another aspect of the present invention relates to the use of flibanserin polymorph A for the preparation of a pharmaceutical composition for the treatment of diseases in which the use of compounds exhibiting an affinity for 5-HT 1A and 5-HT 2 receptors may have a pharmaceutical benefit.

Another aspect of the present invention relates to the use of flibanserin polymorph A for the preparation of a pharmaceutical composition for the treatment of a disease selected from depression, schizophrenia, Parkinson's, anxiety, sleep disorders, mental and sexual disorders and memory difficulties associated with age.

Specifically, the present invention relates to the use of flibanserin polymorph A for the preparation of a medicament for the treatment of sexual desire disorders.

In a preferred embodiment, the invention relates to the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders selected from the group consisting of Hypoactive Sexual Desire Disorder, loss of sexual desire, lack of sexual desire, diminished sexual desire, inhibited sexual desire, loss of libido and disorder of libido and frigidity. Specifically according to the invention is the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders selected from the group consisting of Hypoactive Sexual Desire Disorder, loss of sexual desire, lack of sexual desire , decreased sexual desire, inhibited sexual desire.

In a specific preferred embodiment the invention relates to the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders selected from the group of Hypoactive Sexual Desire Disorder, and loss of sexual desire.

The aforementioned therapeutic effects of flibanserin polymorph A can be achieved in men and women. However, according to a further aspect of the invention is preferably the use of flibanserin polymorph A for the preparation of a medicament for the treatment of female sexual dysfunction.

The beneficial effects of flibanserin polymorph A can be observed without regard to whether the disorder exists for a lifetime or if it has been acquired, and regardless of the etiological origin (organic - physically as well as drug-induced), psychogenic, a combination (as physically as drug-induced, and psychogenic, or unknown).

As a further feature of the present invention there are provided pharmaceutical compositions comprising as an active ingredient flibanserin polymorph A with one or more pharmaceutical carriers, diluents or excipients. For pharmaceutical administration flibanserin polymorph A may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form. The composition may, for example, be presented in a form suitable for oral, rectal, parenteral or nasal inhalation administration: forms preferably include, for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray. The active ingredient may be incorporated into excipients or vehicles conventionally used in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, gelatin, magnesium stearate, cornstarch, aqueous or non-aqueous vehicles, polyvinyl pyrrine. -lidone, semi-synthetic fatty acid glycerides, benzalkonium 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. . Each dosage unit may conveniently contain from 0.01 mg to 100 mg, preferably from 0.1 to 50 mg.

Claims (5)

1. Crystalline polymorph A (Form A), characterized in that it is the crystalline polymorph A of flibanserin 1, having an endothermic maximum at 1610, which occurs during thermal analysis using DSC and is defined by the following diffraction pattern. X-ray image on powder: Angle d-value d-value Width Int. Retro Intens. Signi- [° 2 Θ] a1 [Â] a2 [Â] from peak to peak intens. relative [2 0] [cont.] [cont.] [%] 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 9.1 9.1 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 5.0922 0.100 1204 135 16.5 4.71 18.140 4.8863 4.8984 0.180 1043 139 14.3 13.1 18.650 4.7538 4.656 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 4.4864 0.1494 5402 149 73 , 9 21.06 20.385 4.3530 4.3638 0.16 2652 149 36.3 23.25 21.215 4.1845 4.1949 0.16 369 154 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 24.356 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 27.1555 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 2.9251 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 .6 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 2.823 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 0.162 279 279 3.8 0.86 46.510 1.9509 1.9558 0.240 310 282 4.2 0.87 48.308 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 57.401 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 Process for the technical preparation of flibanserin 1 as defined in claim 1, characterized in that in a first reaction step a benzimidazolone 2 in which R denotes an amino protecting group is reacted with a piperazine 3 wherein X is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate in a suitable solvent selected from water, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol and mixtures of one or more of the aforementioned solvents with water in the presence of a suitable selected base of sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide lithium hydroxide and calcium hydroxide in alcohols, and that, in a second reaction step, the amino protecting group R is cleaved under suitable divider conditions, with the 2 to 3 reaction being carried out at a temperature of 50 °, and heating being performed from 10 minutes to 12 hours. Flibanserin polymorph A according to claim 1, characterized in that it is used as a medicament. Use of flibanserin 1 polymorph A as defined in claim 1, characterized in that it is for the preparation of a medicament for the treatment of a disease selected from depression, schizophrenia, Parkinson's, anxiety, sleep disorders. , mental and sexual disorders, and age-associated memory difficulties, in which sexual disorders are selected from the group consisting of Hypoactive Sexual Desire Disorder, loss of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, and libido and frigidity disorder. Pharmaceutical compositions, characterized in that they comprise, as active ingredient, flibanserin 1 polymorph A as defined in claim 1, optionally in admixture with one or more pharmaceutical carriers, diluents or excipients.