Use of a polymorph of flibanserin for treating disease   

Abstract: 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.

This application is a divisional of U.S. Ser. No. 10/210,474, filed Aug. 1, 2002, which claims, as does the present application, benefit of U.S. Provisional Application Ser. No. 60/329,435, filed on Oct. 15, 2001, European Patent Application EP 01 118 593, filed Aug. 2, 2001, and European Patent Application EP 01 130 180, filed Dec. 19, 2001, the disclosures of all of which are incorporated by reference in their entireties.

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

The compound 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one (flibanserin) is disclosed in form of its hydrochloride in European Patent Application EP-A-526434 and has the following chemical structure:

Flibanserin shows affinity for the 5-HTIA and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment of a variety of diseases, for instance depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment.

A certain pharmaceutical activity is of course the basic prerequisite to be fulfilled by a pharmaceutically active agent before same is approved as a medicament on the market. However, there are a variety of additional requirements a pharmaceutically active agent has to comply with. These requirements are based on various parameters which are connected with the nature of the active substance itself. Without being restrictive, examples of these parameters are the stability of the active agent under various environmental conditions, its stability during production of the pharmaceutical formulation and the stability of the active agent in the final medicament compositions. The pharmaceutically active substance used for preparing the pharmaceutical compositions should be as pure as possible and its stability in long-term storage must be guaranteed under various environmental conditions. This is absolutely essential to prevent the use of pharmaceutical compositions which contain, in addition to the actual active substance, breakdown products thereof, for example. In such cases the content of active substance in the medicament might be less than that specified.

Uniform distribution of the medicament in the formulation is a critical factor, particularly when the medicament has to be given in low doses. To ensure uniform distribution, the particle size of the active substance can be reduced to a suitable level, e.g. by grinding. Since breakdown of the pharmaceutically active substance as a side effect of the grinding (or micronising) has to be avoided as far as possible, in spite of the hard conditions required during the process, it is absolutely essential that the active substance should be highly stable throughout the grinding process. Only if the active substance is sufficiently stable during the grinding process is it possible to produce a homogeneous pharmaceutical formulation which always contains the specified amount of active substance in reproducible manner.

Another problem which may arise in the grinding process for preparing the desired pharmaceutical formulation is the input of energy caused by this process and the stress on the surface of the crystals. This may in certain circumstances lead to polymorphous changes, to a change in the amorphous configuration or to a change in the crystal lattice. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance should 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 particular medicament; the shelf life is the length of time during which the medicament can be administered without any risk. High stability of a medicament in the abovementioned pharmaceutical compositions under various storage conditions is therefore an additional advantage for both the patient and the manufacturer.

Apart from the requirements indicated above, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which is capable of improving its physical and chemical stability gives a significant advantage over less stable forms of the same medicament.

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

FIG. 1 shows the X-ray powder diffraction pattern of polymorph A of flibanserin.

DETAILED DESCRIPTION

Surprisingly, it has been found that the free base of flibanserin in a specific polymorphic form fulfills the requirements mentioned hereinbefore.

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

It has been found that these different modifications can be deliberately produced by a suitable choice of the process conditions used in the manufacturing process.

Surprisingly, it has been found that polymorph A, which can be obtained in crystalline form by choosing specific reaction conditions, meets the stringent requirements mentioned above and thus solves the problem on which the present invention is based. Accordingly the present invention relates to polymorph A of flibanserin.

Polymorph A of flibanserin is characterised by a melting point of about 161° C. (determined via DSC; heating rate 10 K/min). 161° C. as determined using DSC.

Polymorph B, the less stable modification of flibanserin displays a melting point of about 120° C. (determined via DSC; heating rate 10 K/min). Whereas polymorph B shows little stability under the effects of for instance mechanical stress produced by grinding, polymorph A turned out to fulfill the aforementioned stability requirements.

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

The benzimidazolone 2 is reacted with the piperazine-derivative 3 under basic reaction conditions in a suitable solvent to lead to 1. In 2 the group R denotes an amino protecting group. The protecting group used may be any of the groups commonly used to protect the amino function. 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, phenoxy carbonyl, 4-chloro-phenoxycarbonyl, 4-nitro-phenoxycarbonyl, methoxycarbonyl and ethoxycarbonyl. Among them the preferred protecting groups are selected from t-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl and 2-propenyl, the latter being most preferred. X in 3 represents a leaving group selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate or para-toluenesulphonate. Preferably X denotes chlorine, bromine or iodine, chlorine being most preferred. Suitable solvents are selected from water, alcohols and mixtures of water with alcohols, polar aprotic solvents and mixtures thereof with water. Preferred solvents are selected from the group consisting of dimethylformamid, dimethylsulfoxid, acetonitrile, tetrahydrofurane, dioxane, methanol, ethanol isopropanaol and mixtures of one or several of the aforementioned solvents with water. Preferred solvents are those being readily miscible with water. Preferably, a mixture of water with one of the alcohols methanol, ethanol or isopropanol is used as the solvent. In a preferred embodiment a mixture of water and 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 the hydrogen carbonates of lithium, sodium and potassium. 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. Most preferred base is sodium hydroxide. The base is preferably added in form of its aqueous solution, preferably in form of concentrated aqueous solutions, for example in concentrations between 30-50% weight/volume. In a preferred embodiment aqueous sodium hydroxide solution in a concentration of about 45% weight/volume is used.

The compounds 2 and 3 are introduced into the reaction in a molar ratio of between 1:1 to 1:2, preferably in a molar ratio of between 1:1.1 to 1:1.5.

As mentioned hereinbefore a mixture of water and isopropanol is used as a preferred solvent mixture for the conduction of the process according to the invention. In this solvent mixture the weight-ratio of water to isopropanol in the preferred solvent mixture is between 10:1 and 1:1, more preferred between 8:1 and 3:1, particular preferred between 7:1 and 5:1. Per mol of compound 2 about 2-10 kg, preferably

3-8 kg, more preferred 4-7 kg of the aforementioned solvent mixture are used. In a preferred embodiment the reaction is conducted using aqueous sodium hydroxide solution in a concentration of about 45% weight/volume as the base. Per mol of 2 about 0.1-1.5 kg, preferably 0.2-1.0 kg, particularly preferred 0.3-0.6 kg of the aforementioned sodium hydroxide solution are used. The reaction mixture containing 2, 3 and the base in the aforementioned suitable solvent is preferably heated to at least 50° C. In a preferred embodiment the reaction temperature is in a range of between 60° C. to the boiling point of the solvent. Particularly preferred is a temperature between 70-90° C. The reaction mixture is heated at the aforementioned 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 aforementioned temperature for about 45 to 60 minutes.

Subsequently the protective group R is cleaved. The cleaving conditions depend on the choice of group R. If R denotes for instance benzyl, cleavage is conducted via hydrogenation in acetic acid in the presence of an appropriate catalyst (e.g. Pd on charcoal) or it can be cleaved in aqueous HBr. In case R is methoxycarbonyl, ethoxycarbonyl, phenoxy carbonyl, 4-nitrophenoxycarbonyl it can be cleaved for example by using aqueous alkaline solutions such as NaOH (aq) or KOH (aq). In case R is t-butoxycarbonyl it can be cleaved for instance in aqueous HCl or HBr. In case R denotes 2-propenyl, the particularly preferred protective group according to the invention, cleavage of R is effected via acidic reaction conditions. In a particularly preferred process according to the invention the 2-propenyl group is cleaved by using 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 can be added in gaseous form or in form of its aqueous solutions, the addition of aqueous solutions being preferred. Particularly preferred is the addition of hydrochloric acid in form of its concentrated solution (about 36% weight/volume). Per mol 2 at least one mol of hydrochloric acid is to be added. Preferably the amount of added concentrated hydrochloric acid (36% weight/volume) per mol 2 is between 50-500 g, more preferred between 80-250 g. Particularly preferred about 120-160 g of concentrated (36% w/v) aqueous hydrochloric acid are added per mol 2 used. Additional water can be optionally added. At a temperature of about 70-90° C. about 30-70%, preferably about 35-60% of the solvent is removed via distillation. At a temperature of about 60-80° C. the pH of the remaining residue is adjusted to about 5-9, preferably to about 6-8 by addition of aqueous sodium hydroxide (45% w/v). At a temperature of about 40-55° C. the pH is adjusted to about 8-9 by addition of aqueous sodium hydroxide (45% w/v). Subsequently the mixture is cooled to about 20-40° C., preferably about 30-35° C. and centrifuged. The residue thus obtained is washed with about 100 to 750 ml water per mol introduced 2, preferably with about 200 to 500, particularly preferred with about 300 to 400 ml water per mol introduced 2 and isopropanol (about 50 to 250 g per mol 2, preferably about 100 to 200 g per mol 2) and then with water until chlorides elimination. Optionally the product thus obtained can be subjected to another purification step. Preferably, said purification is conducted via crystallization of 1 from for instance acetone.

One aspect of the present invention relates to flibanserin polymorph A obtainable via the method described above.

The following example of synthesis serves to illustrate a method of preparing polymorph A of flibanserin. It is to be regarded only as a possible method described by way of example, without restricting the invention to its contents.

375 kg of 1-[(3-trifluoromethyl)phenyl]-4-(2-cloroethyl)piperazin are charged in a reactor with 2500 kg of water and 200 kg of aqueous Sodium Hydroxide 45%. Under stirring 169.2 kg of 1-(2-propenyl)-1,3-dihydro-benzimidazol-2H-one, 780 kg of isopropanol, 2000 kg of water and 220 kg of aqueous Sodium Hydroxide 45% are added. The reaction mixture is heated to 75-85° 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 65-75° C. and the pH is adjusted to 6.5-7.5 by addition of 125 kg of aqueous Sodium Hydroxide 45%. After cooling to a temperature of 45-50° C., the pH value is adjusted to 8-9 by addition of about 4 kg of aqueous Sodium Hydroxide 45%. Subsequently the mixture is cooled to 30-35° C. and centrifuged. The residue thus obtained is washed with 340 l of water and 126 l of isopropanol and then with water until chlorides elimination. The wet product is dried under vacuum at a temperature of about 45-55° C. which leads to 358 kg of crude flibanserin polymorph A. The crude product thus obtained is loaded in a reactor with 1750 kg of Acetone and the resulting mixture is heated under stirring until reflux. The obtained solution is filtered and the filtrate is concentrated by distillation. The temperature is maintained for about 1 hour 0-5° C., then the precipitate solid 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 here inbefore flibanserin polymorph A was characterised by DSC (Differential Scanning calorimetry). The peak temperature (endothermic maximum) determined for polymorph A is about 161° C. For the characterization via DSC a Mettler TA 3000 System equipped with TC 10-A processor and DSC 20 cell was applied. The heating rate was 10 K/min.

The flibanserin polymorph A was additionally characterised by powder x-ray diffractometry. The x-ray powder diffraction pattern for polymorph A was obtained according to the following conditions:

Equipment: Philips PW 1800/10 diffractometer equipped with a digital microvax 2000. Setting parameters: X-ray Type tube: Cu (long fine focus) Wavelengths (λ): Kα1 = 1.54060 Å Kα2 = 1.54439 Å Intensity ratio (α2/α1): 0.500 Start angle [°2Θ]: 2.000 End angle [°2Θ]: 60.000 Step size [°2Θ]: 0.020 Maximum intensity[s]: 7310.250 Type of scan: continuous Minimum peak tip width: 0.00 Maximum peak tip width: 1.00 Peak base width: 2.00 Minimum significance: 0.75 Number of peaks: 69 Generator: high voltage: 50 KV tube current: 30 mA

The x-ray powder diffraction pattern obtained for polymorph A is illustrated in FIG. 1. The appropriate values are shown below in Table 1.

TABLE 1 Peak Back. Angle d-value d-value width Peak int int Rel. int [°2Θ] α1 [Å] α2 [Å] [°2Θ] [counts] [counts] [%] Signif. 5.195 16.9967 17.0390 0.960 8 69 0.1

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