WO2010146595A2

WO2010146595A2 - Novel polymorphs of flibanserin hydrochloride

Info

Publication number: WO2010146595A2
Application number: PCT/IN2009/000347
Authority: WO
Inventors: Dodda Mohan Rao; Pingili Krishna Reddy; Buthukuri Venkat Reddy
Original assignee: Symed Labs Limited
Priority date: 2009-06-16
Filing date: 2009-06-16
Publication date: 2010-12-23
Also published as: WO2010146595A3

Abstract

The present invention provides novel crystalline anhydrous form II, hemihydrate form III, anhydrous form IV, anhydrous form V, anhydrous form VI, hemihydrate form VII, hemihydrate form VIII, hemihydrate form IX and amorphous form of flibanserin hydrochloride, processes for its preparation and to pharmaceutical compositions containing them.

Description

NOVEL POLYMORPHS OF FL1BANSERIN HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention provides novel crystalline forms of flibanserin hydrochloride, processes for their preparation and pharmaceutical compositions comprising them. The present invention also provides a novel amorphous form of flibanserin hydrochloride, process for the preparation and pharmaceutical compositions comprising it.

BACKGROUND OF THE INVENTION Flibanserin shows affinity for the 5-HT_1A serotonin receptor agonist, a 5-

HT_2A serotonin receptor antagonist, and a dopamine D₄ receptor partial agonist that had initially been developed as an anti-depressant. 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. It is currently being investigated as a drug for women diagnosed with decreased sexual desire.

Flibanserin, chemically 1-[2-(4-(3-trifluoromethylphenyl)piperazin-1- yl)ethyl]-2,3-dihydro-1 H-benzimidazole-2-one was disclosed in form of its hydrochloride in U.S. Patent No. 5,576,318 and has the following chemical structure:

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.

It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction

(XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.

Processes for the preparations of flibanserin hydrochloride were disclosed in the U.S. Patent No. 5,576,318. According to Patent No. US 5,576,318, crystalline solid of flibanserin hydrochloride was obtained by condensing 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-one with m- trifluoromethyl phenyl piperazine and obtained product is recrystalized from isopropanol to obtain the free base. The flibanserin hydrochloride is prepared in isopropanol and isolated as crystalline solid. The crystalline flibanserin hydrochloride obtained by the process of the prior art is herein after designated as flibanserin hydrochloride crystalline form I. The powdered x-ray diffractogram (PXRD) of crystalline form I is shown in figure 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.6, 12.0, 17.3, 17.7, 21.1 and 22.3 + 0.2 degrees.

U.S. Application Publication No. 2007/0032655 disclosed two crystalline forms (Polymorph A and Polymorph B) of Flibanserin. Thus there is a need for stable and reproducible crystalline forms of flibanserin hydrochloride and its hydrates.

We have discovered one amorphous form of flibanserin hydrochloride and eight novel crystalline forms of flibanserin hydrochloride and its hydrates. The novel forms have been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.

One object of the present invention is to provide a novel crystalline hemihydrate forms of flibanserin hydrochloride, process for their preparation and pharmaceutical compositions comprising them. Another object of the present invention is to provide a novel crystalline anhydrous forms of flibanserin hydrochloride, process for their preparation and pharmaceutical compositions comprising them.

Still another object of the present invention is to provide a novel amorphous form of flibanserin hydrochloride, process for their preparation and pharmaceutical compositions comprising them.

SUMMARY OF THE INVENTION

In one aspect, the present invention provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form Il characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.6, 11.9, 12.8, 13.1 , 16.4, 16.9, 18.7 and 23.4 ± 0.2 degrees.

In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline anhydrous form II, which comprises: a) suspending flibanserin hydrochloride in an organic solvent; b) maintaining the contents in step (a) at elevated temperature above 50⁰C; and c) isolating flibanserin hydrochloride crystalline anhydrous form II. In another aspect, the present invention provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form III characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 9.4, 11.0, 12.6, 15.5, 18.1 , 18.9, 24.0 and 25.2 ± 0.2 degrees.

In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline hemihydrate form III, which comprises: a) dissolving flibanserin in a chlorinated solvent to obtain a solution; b) adding the solution obtained in step (a) to hydrochloric acid; and c) isolating flibanserin hydrochloride crystalline hemihydrate form III.

In another aspect, the present invention provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form IV characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 13.4, 16.8, 17.2, 17.7, 18.1 , 20.6, 23.1 and 24.5 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline anhydrous form IV, which comprises heating flibanserin hydrochloride at above 120 deg C.

In another aspect, the present invention provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form V characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 6.4, 13.0, 13.3, 16.7, 18.0, 20.2, 21.3, 21.6, 23.6, 23.9 and 26.2 ± 0.2 degrees.

In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline anhydrous form V, which comprises: a) dissolving flibanserin hydrochloride in an alcohol solvent to obtain a solution. b) distilling off the solvent from a solution obtained in step (a); and c) isolating flibanserin hydrochloride crystalline anhydrous form V. In another aspect, the present invention provided a novel crystalline^* anhydrous form of flibanserin hydrochloride designated as form Vl characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 11.9, 12.9, 13.7, 15.6, 16.5, 17.2, 18.7, 20.5, 21.3, 22.0 and 25.4 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline anhydrous form Vl, which comprises: a) dissolving flibanserin hydrochloride in a chlorinated solvent to obtain a solution; b) distilling off the solvent from a solution obtained in step (a); and c) isolating flibanserin hydrochloride crystalline anhydrous form Vl.

In another aspect, the present invention provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form VII characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 11.0, 15.6, 17.3, 18.1 and 18.9 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline hemihydrate form VII, which comprises: a) dissolving flibanserin in concentrated hydrochloric acid; b) diluting the solution with water; c) optionally, the contents obtained in step (b) may be maintained at above 25⁰C; and d) isolating flibanserin hydrochloride crystalline hemihydrate form VII.

In another aspect, the present invention provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form VIII characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 12.4, 14.5, 17.8, 19.7 and 20.7 ± 0.2 degrees.

In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline hemihydrate form VIII, which comprises: a) suspending flibanserin in methanol; b) adding aqueous hydrochloric acid dropwise to the suspension obtained in step (a); c) stirring the reaction mass obtained in step (b); and d) isolating flibanserin hydrochloride crystalline hemihydrate form VIII. In another aspect, the present invention provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form IX characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 11.0, 12.3, 15.6, 18.0, 18.8, 19.1 , 20.7 and 24.0 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing flibanserin hydrochloride crystalline hemihydrate form IX, which comprises: a) suspending flibanserin in methanol; b) adding aqueous hydrochloric acid at once to the suspension obtained in step (a); c) stirring the reaction mass obtained in step (b); and d) isolating flibanserin hydrochloride crystalline hemihydrate form IX.

In another aspect, the present invention provided novel amorphous form of flibanserin hydrochloride.

In another aspect, the present invention provides a process for preparing flibanserin hydrochloride amorphous form, which comprises: a) dissolving flibanserin hydrochloride crystalline anhydrous form Il in an alcohol solvent to obtain a solution; b) distilling off the solvent to the solution obtained in step (a); and c) dried at 80 to 85⁰C to obtain flibanserin hydrochloride amorphous form. In yet another aspect, the present invention provides a pharmaceutical composition comprising a polymorphic form of flibanserin hydrochloride selected from anhydrous form II, hemihydrate form III, anhydrous form IV₁ anhydrous form V, anhydrous form Vl, hemihydrate form VII, hemihydrate form VIII, hemihydrate form IX and amorphous form or a mixture thereof; and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline form I.

Figure 2 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline anhydrous form II.

Figure 3 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline hemihydrate form III. Figure 4 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline anhydrous form IV.

Figure 5 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline anhydrous form V.

Figure 6 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline anhydrous form Vl.

Figure 7 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline hemihydrate form VII.

Figure 8 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline hemihydrate form VIII. Figure 9 is X-ray powder diffraction spectrum of flibanserin hydrochloride crystalline hemihydrate form IX.

Figure 10 is X-ray powder diffraction spectrum of flibanserin hydrochloride amorphous form.

Figure 11 is FTIR spectrum of flibanserin hydrochloride crystalline form I. Figure 12 is FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form II.

Figure 13 is FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form III. Figure 14 is FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form IV.

Figure 15 is FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form V. Figure 16 is FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form Vl.

Figure 17 is FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form VII.

Figure 18 is FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form VIII.

Figure 19 is FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form IX.

Figure 20 is FTIR spectrum of flibanserin hydrochloride amorphous form.

Figure 21 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline form I.

Figure 22 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline anhydrous form II.

Figure 23 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline hemihydrate form III. Figure 24 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline anhydrous form IV.

Figure 25 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline anhydrous form V.

Figure 26 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline anhydrous form Vl.

Figure 27 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline hemihydrate form VII.

Figure 28 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline hemihydrate form VIII. Figure 29 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride crystalline hemihydrate form IX.

Figure 30 is Differential scanning calorimetry (DSC) thermogram of flibanserin hydrochloride amorphous form. X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-Kα radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

FTIR (Fourier Transform Infrared Spectroscopy) spectrum was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm^"1 to 650 cm^"

DSC (Differential Scanning Calorimetry) measurements were performed with a DSC Q200 (TA Instruments, Inc.). About 1 to 1.3 mg of the powder was placed in an open aluminum pan and it was crimped with an aluminum lid. The crimped sample was then placed in the DSC cell opposite to empty aluminum pan (as reference) and the sample was scanned at 10 deg C/min from 40 deg C to 250 deg C.

DETAILED DESCRIPTION OF THE INVENTION In accordance with one aspect of the present invention there is provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form Il characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.6, 11.9, 12.8, 13.1 , 16.4, 16.9, 18.7 and 23.4 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline anhydrous form Il is shown in figure 2.

Flibanserin hydrochloride crystalline anhydrous form Il is further characterized by IR spectrum having main bands at about 3140, 2536, 2465, 1695, 1495, 1440, 1311 , 1113, and 948 crτϊ¹. FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form Il is shown in figure 12. Flibanserin hydrochloride crystalline anhydrous form Il of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 22. In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline anhydrous form II, which comprises: a) suspending flibanserin hydrochloride in an organic solvent; b) maintaining the contents in step (a) at elevated temperature above 50⁰C; and c) isolating flibanserin hydrochloride crystalline anhydrous form II.

Flibanserin hydrochloride used in the process of the present invention may be in the form flibanserin hydrochloride crystalline form I₁ flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form IV, flibanserin hydrochloride crystalline anhydrous form V, flibanserin hydrochloride crystalline anhydrous form Vl and flibanserin hydrochloride crystalline hemihydrate form VII.

The organic solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of acetone, ethyl acetate, toluene, xylene, n-heptane, cyclohexane and hexane. Preferable organic solvent is selected from acetone, ethyl acetate and toluene.

Preferably, the contents are maintained at 50 to 150⁰C and more preferably the contents are maintained at reflux. The isolation of flibanserin hydrochloride crystalline anhydrous form Il may be performed by conventional techniques such as centrifugation and filtration.

In accordance with one aspect of the present invention there is provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form III characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 9.4, 1 1.0, 12.6, 15.5, 18.1 , 18.9, 24.0 and 25.2 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline hemihydrate form III is shown in figure 3.

Flibanserin hydrochloride crystalline hemihydrate form III is further characterized by IR spectrum having main bands at about 3374, 1686, 1491 , 1451 , 1311 , 1111 , 946 and 693 cm^"1. FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form III is shown in figure 13. Flibanserin hydrochloride crystalline hemihydrate form III of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 23.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline hemihydrate form III, which comprises: a) dissolving flibanserin in a chlorinated solvent to obtain a solution; b) adding the solution obtained in step (a) to hydrochloric acid; and c) isolating flibanserin hydrochloride crystalline hemihydrate form III. The chlorinated solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methylene dichloride, ethylene dichloride and chloroform. Preferably chlorinated solvent is methylene dichloride.

Preferably, the addition of step (b) is at about 0 to 35⁰C and more preferably the addition of step (b) is at about room temperature.

The isolation of flibanserin hydrochloride crystalline hemihydrate form III may be performed by conventional techniques such as centrifugation and filtration.

In accordance with one aspect of the present invention there is provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form IV characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 13.4, 16.8, 17.2, 17.7, 18.1 , 20.6, 23.1 and 24.5 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline anhydrous form IV is shown in figure 4. Flibanserin hydrochloride crystalline anhydrous form IV is further characterized by IR spectrum having main bands at about 3226, 1734, 1492, 1448, 1312, 1155, 1100, 945, and 730 cm^"1. FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form IV is shown in figure 14.

Flibanserin hydrochloride crystalline anhydrous form IV of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 24.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline anhydrous form IV, which comprises heating flibanserin hydrochloride at above 120 deg C. Preferably heating may be performed at 140 deg C to 150 deg C. The heating may be carried out until flibanserin hydrochloride is completely converted into flibanserin hydrochloride crystalline anhydrous form IV.

Flibanserin hydrochloride used in the process of the present invention may be in the form flibanserin hydrochloride crystalline form I, flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form V, flibanserin hydrochloride crystalline anhydrous form Vl, flibanserin hydrochloride crystalline hemihydrate form VII, flibanserin hydrochloride crystalline hemihydrate form VIII and flibanserin hydrochloride crystalline hemihydrate form IX.

In accordance with one aspect of the present invention there is provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form V characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 6.4, 13.0, 13.3, 16.7, 18.0, 20.2, 21.3, 21.6, 23.6, 23.9 and 26.2 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline anhydrous form V is shown in figure 5.

Flibanserin hydrochloride crystalline anhydrous form V is further characterized by IR spectrum having main bands at about 3403, 1712, 1494, 1349, 1313, 1167, 1125, 951 and 757 cm^"1. FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form V is shown in figure 15.

Flibanserin hydrochloride crystalline anhydrous form V of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 25.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline anhydrous form V₁ which comprises: a) dissolving flibanserin hydrochloride in an alcohol solvent to obtain a solution. b) distilling off the solvent from a solution obtained in step (a); and c) isolating flibanserin hydrochloride crystalline anhydrous form V.

Provided flibanserin hydrochloride used in step (a) is not flibanserin hydrochloride crystalline anhydrous form II.

Flibanserin hydrochloride used in the process of the present invention may be in the form flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form IV₁ flibanserin hydrochloride crystalline hemihydrate form VII and flibanserin hydrochloride crystalline hemihydrate form VIII.

The alcohol solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methanol, ethanol, tert-butyl alcohol and n-butyl alcohol. Preferable alcohol solvent is methanol.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off. The isolation of flibanserin hydrochloride crystalline anhydrous form V, if required may be performed by conventional techniques such as centrifugation and filtration.

In accordance with one aspect of the present invention there is provided a novel crystalline anhydrous form of flibanserin hydrochloride designated as form Vl characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 11.9, 12.9, 13.7, 15.6, 16.5, 17.2, 18.7, 20.5, 21.3, 22.0 and 25.4 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline anhydrous form Vl is shown in figure 6.

Flibanserin hydrochloride crystalline anhydrous form Vl is further characterized by IR spectrum having main bands at about 3127, 2535, 2450, 1690, 1495, 1310, 11 13, 1 105, 947 and 752 cm ¹. FTIR spectrum of flibanserin hydrochloride crystalline anhydrous form Vl is shown in figure 16.

Flibanserin hydrochloride crystalline anhydrous form Vl of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 26.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline anhydrous form Vl, which comprises: a) dissolving flibanserin hydrochloride in a chlorinated solvent to obtain a solution; b) distilling off the solvent from a solution obtained in step (a); and c) isolating flibanserin hydrochloride. crystalline anhydrous form Vl. Provided flibanserin hydrochloride used in step (a) is not flibanserin hydrochloride crystalline anhydrous form II. Flibanserin hydrochloride used in the process of the present invention may be in the form flibanserin hydrochloride crystalline form I₁ flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form IV₁ flibanserin hydrochloride crystalline hemihydrate form VII and flibanserin hydrochloride crystalline hemihydrate form VIII.

The chlorinated solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methylene dichloride, ethylene dichloride and chloroform. Preferably chlorinated solvent is methylene dichloride. The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

The isolation of flibanserin hydrochloride crystalline anhydrous form Vl, if required may be performed by conventional techniques such as centrifugation and filtration.

In accordance with one aspect of the present invention there is provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form VII characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 11.0, 15.6, 17.3, 18.1 and 18.9 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline hemihydrate form VII is shown in figure 7.

Flibanserin hydrochloride crystalline hemihydrate form VII is further characterized by IR spectrum having main bands at about 3388, 1691, 1491 , 1450, 1314, 1168, 1114, 945 and 694 cm^"1. FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form VII is shown in figure 17.

Flibanserin hydrochloride crystalline hemihydrate form VII of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 27.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline hemihydrate form VII, which comprises: a) dissolving flibanserin in concentrated hydrochloric acid; b) diluting the solution with water; c) optionally, the contents obtained in step (b) may be maintained at above 25⁰C; and d) isolating flibanserin hydrochloride crystalline hemihydrate form VII. Preferably, the contents are maintained at reflux. In accordance with one aspect of the present invention there is provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form VIII characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 12.4, 14.5, 17.8, 19.7 and 20.7 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline hemihydrate form VIII is shown in figure 8.

Flibanserin hydrochloride crystalline hemihydrate form VIII is further characterized by IR spectrum having main bands at about 3411 , 1676, 1489, 1447, 1314, 1130, 947 and 730 cm^"1. FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form VIII is shown in figure 18. Flibanserin hydrochloride crystalline hemihydrate form VIII of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 28.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline hemihydrate form VIII, which comprises: a) suspending flibanserin in methanol; b) adding aqueous hydrochloric acid dropwise to the suspension obtained in step (a); c) stirring the reaction mass obtained in step (b); and d) isolating flibanserin hydrochloride crystalline hemihydrate form VIII.

Preferably, the stirring may be carried out at room temperature.

The isolation of flibanserin hydrochloride crystalline hemihydrate form VIII may be performed by conventional techniques such as centrifugation and filtration.

In accordance with one aspect of the present invention there is provided a novel crystalline hemihydrate form of flibanserin hydrochloride designated as form IX characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 11.0, 12.3, 15.6, 18.0, 18.8, 19.1 , 20.7 and 24.0 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride crystalline hemihydrate form IX is shown in figure 9.

Flibanserin hydrochloride crystalline hemihydrate form IX is further characterized by IR spectrum having main bands at about 1695, 1491 , 1449, 1314, 1167, 1119, 946 and 695 cm^"1. FTIR spectrum of flibanserin hydrochloride crystalline hemihydrate form IX is shown in figure 19.

Flibanserin hydrochloride crystalline hemihydrate form IX of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 29.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride crystalline hemihydrate form IX, which comprises: a) suspending flibanserin in methanol; b) adding aqueous hydrochloric acid at once to the suspension obtained in step (a); c) stirring the reaction mass obtained in step (b); and d) isolating flibanserin hydrochloride crystalline hemihydrate form IX. Preferably, the addition of step (b) is at about 0 to 35⁰C and more preferably the addition of step (b) is at about room temperature.

Preferably, the stirring may be carried out at room temperature. The isolation of flibanserin hydrochloride crystalline hemihydrate form IX may be performed by conventional techniques such as centrifugation and filtration. In accordance with one aspect of the present invention, there is provided novel amorphous form of flibanserin hydrochloride. The powdered x-ray diffractogram (PXRD) of flibanserin hydrochloride amorphous form is shown in figure 10.

Flibanserin hydrochloride amorphous form is further characterized by IR spectrum having main bands at about 3404, 1702, 1491 , 1450, 1314, 1166, 1119, 946, 754 and 695 cm^"1. FTIR spectrum of flibanserin hydrochloride amorphous form is shown in figure 20. Flibanserin hydrochloride amorphous form of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 30.

In accordance with another aspect of the present invention, there is provided a process for preparing flibanserin hydrochloride amorphous form, which comprises: a) dissolving flibanserin hydrochloride crystalline anhydrous form Il in an alcohol solvent to obtain a solution; b) distilling off the solvent to the solution obtained in step (a); and c) dried at 80 to 85⁰C to obtain flibanserin hydrochloride amorphous form.

The alcohol solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methanol, ethanol and butanol. Preferably organic solvent is methanol.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a polymorphic form of flibanserin hydrochloride selected from anhydrous form II, hemihydrate form III, anhydrous form IV, anhydrous form V, anhydrous form Vl, hemihydrate form VII, hemihydrate form VIII₁ hemihydrate form IX and amorphous form or a mixture thereof; and a pharmaceutically acceptable excipient.

The pharmaceutical dosage forms may preferably be in solid, liquid or spray form and more preferable in a form of oral, rectal, parenteral administration or for nasal inhalation. Still more preferable forms capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

EXAMPLES

Preparation of flibanserin hydrochloride crystalline form I Example 1

To a mixture of flibanserin (10 gm) and isopropanol (200 ml), concentrated hydrochloric acid (50 ml) was added dropwise under stirring at room temperature. The reaction mass was stirred for 2 hours at room temperature and filtered, washed with water and dried at 80 to 85⁰C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline form I.

Example 2

To a mixture of flibanserin (10 gm) and isopropanol (50 ml), adjusted pH to 2 with isopropanolic hydrochloric acid solution (12 ml) at room temperature.

The reaction mass was stirred for 2 hours at room temperature and filtered, washed with isopropanol and dried at 80 to 85⁰C for 2 hours to obtain 9 gm of flibanserin hydrochloride crystalline form I.

Preparation of flibanserin hydrochloride crystalline anhydrous form Il Example 3

Flibanserin hydrochloride crystalline form I (10 gm) was added to acetone (100 ml) and heated to reflux for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour at room temperature, filtered.

The solid obtained was washed with acetone and dried at 80 to 85 deg C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline anhydrous form II.

Example 4

Example 3 was repeated using flibanserin hydrochloride crystalline hemihydrate form III instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form II.

Example 5

Example 3 was repeated using flibanserin hydrochloride crystalline anhydrous form IV instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form II.

Example 6

Example 3 was repeated using flibanserin hydrochloride crystalline anhydrous form V instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form II. Example 7

Example 3 was repeated using flibanserin hydrochloride crystalline anhydrous form Vl instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form II.

Example 8

Example 3 was repeated using flibanserin hydrochloride crystalline hemihydrate form VII instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form II.

Example 9

Flibanserin hydrochloride crystalline form I (10 gm) was added to ethyl acetate (100 ml) and heated to reflux for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour at room temperature, filtered. The solid obtained was washed with acetone and dried at 80 to 85 deg C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline anhydrous form II.

Example 10

Flibanserin hydrochloride crystalline form I (10 gm) was added to toluene (100 ml) and heated to reflux for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour at room temperature, filtered. The solid obtained was washed with acetone and dried at 80 to 85 deg C for 2 hours to obtain 8.5 gm of flibanserin hydrochloride crystalline anhydrous form II.

Preparation of flibanserin hydrochloride crystalline hemihydrate form III Example 11

A mixture of flibanserin (10 gm, chromatographic purity: 99.5%) and methylene dichloride (50 ml) was added to hydrochloric acid (10%, 100 ml) under stirring at room temperature. The reaction mass was stirred for 2 hours at room temperature and filtered. The solid obtained was washed with methylene dichloride followed by water and dried at 80 to 85⁰C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline hemihydrate form III (chromatographic purity: 99.95%). Preparation of flibanserin hydrochloride crystalline anhydrous form IV Example 12

Flibanserin hydrochloride crystalline form I (5 gm) was heated at 140 to 145⁰C for 1 hour and the solid was cooled to room temperature to obtain 5 gm of flibanserin hydrochloride crystalline anhydrous form IV.

Example 13

Example 12 was repeated using flibanserin hydrochloride crystalline hemihydrate form III instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form IV.

Example 14

Example 12 was repeated using flibanserin hydrochloride crystalline anhydrous form V instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form IV.

Example 15

Example 12 was repeated using flibanserin hydrochloride crystalline anhydrous form Vl instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form IV.

Example 16

Example 12 was repeated using flibanserin hydrochloride crystalline hemihydrate form VII instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form IV.

Example 17

Example 12 was repeated using flibanserin hydrochloride crystalline hemihydrate form VIII instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form IV.

Example 18 Example 12_was repeated using flibanserin hydrochloride crystalline hemihydrate form IX instead of flibanserin hydrochloride crystalline form I to obtain flibanserin hydrochloride crystalline anhydrous form IV.

Preparation of flibanserin hydrochloride crystalline anhydrous form V Example 19

Flibanserin hydrochloride crystalline hemihydrate form III (5.0 gm) was dissolved in methanol (100 ml). The solution was completely distilled off the solvent under reduced pressure at 50 to 60⁰C and dried the solid at 80 to 85⁰C for 2 hours to obtain 5 gm of flibanserin hydrochloride crystalline anhydrous form

V.

Example 20

Example 19 was repeated using flibanserin hydrochloride crystalline anhydrous form IV instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form V.

Example 21

Example 19 was repeated using flibanserin hydrochloride crystalline hemihydrate form VII instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form V.

Example 22

Example 19 was repeated using flibanserin hydrochloride crystalline hemihydrate form VIII instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form V.

Preparation of flibanserin hydrochloride crystalline anhydrous form Vl Example 23

Flibanserin hydrochloride crystalline hemihydrate form III (5 gm) was added to methylene dichloride (100 ml). The reaction mass was distilled off the solvent at atmospheric pressure and dried the solid at 80 to 85⁰C for 2 hours to obtain 5 gm of flibanserin hydrochloride crystalline anhydrous form Vl. Example 24

Example 23 was repeated using flibanserin hydrochloride crystalline form I instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form Vl.

Example 25

Example 23 was repeated using flibanserin hydrochloride crystalline anhydrous form IV instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form Vl.

Example 26

Example 23 was repeated using flibanserin hydrochloride crystalline hemihydrate form VII instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form Vl.

Example 27

Example 23 was repeated using flibanserin hydrochloride crystalline hemihydrate form VIII instead of flibanserin hydrochloride crystalline hemihydrate form III to obtain flibanserin hydrochloride crystalline anhydrous form Vl.

Preparation of flibanserin hydrochloride crystalline hemihvdrate form VII Example 28 Flibanserin (10 gm) was added to concentrated hydrochloric acid (30 ml) in portion wise. The reaction mass was stirred for 15 minutes at room temperature and water (60 ml) added to the reaction mass. The reaction mass was heated to reflux for 30 minutes and cooled to room temperature, stirred for 1 hour at room temperature. The solid obtained was collected by filtration, washed with water and dried at 80 to 85⁰C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline hemihydrate form VII.

Preparation of flibanserin hydrochloride crystalline hemihvdrate form VIII Example 29 To a suspension of filbanserin (10 gm) and methanol (50 ml), added hydrochloric acid (10%, 100 ml) under stirring at room temperature. The reaction mass was stirred for 2 hours at room temperature, filtered. The solid obtained was washed with water and dried at 80 to 85⁰C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline hemihydrate form VIII.

Preparation of flibanserin hydrochloride crystalline hemihvdrate form IX Example 30

To a suspension of filbanserin (10 gm) and methanol (50 ml), added hydrochloric acid (10%, 100 ml) at once under stirring at room temperature. The reaction mass was stirred for 2 hours at room temperature, filtered. The solid obtained was washed with water and dried at 80 to 85⁰C for 2 hours to obtain 8 gm of flibanserin hydrochloride crystalline hemihydrate form IX.

Preparation of flibanserin hydrochloride amorphous form Example 31

Flibanserin hydrochloride crystalline anhydrous form Il (5 gm) was dissolved in methanol (100 ml). The solution was completely distilled off the solvent under reduced pressure at 50 to 60⁰C and dried the solid at 80 to 85⁰C for 2 hours to obtain 5 gm of flibanserin hydrochloride amorphous form.

Claims

We claim:

1. A flibanserin hydrochloride crystalline anhydrous form II, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.6, 11.9, 12.8, 13.1 , 16.4, 16.9, 18.7 and 23.4 ± 0.2 degrees.

2. A flibanserin hydrochloride crystalline anhydrous form II, characterized by an x-ray powder diffractogram as shown in figure 2.

3. The flibanserin hydrochloride crystalline anhydrous form Il as defined in claim 1 , further characterized by FTIR spectrum having main bands at about 3140, 2536, 2465, 1695, 1495, 1440, 1311 , 1113, and 948 cm^"1.

4. The flibanserin hydrochloride crystalline anhydrous form Il as defined in claim 1 , characterized by an FTIR spectrum as shown in figure 12.

5. The flibanserin hydrochloride crystalline anhydrous form Il as claimed in claim 1 , wherein the flibanserin hydrochloride crystalline anhydrous form Il is further characterized by a differential scanning calorimetry thermogram as shown in figure 22.

6. A process for the preparation of flibanserin hydrochloride crystalline anhydrous form Il as defined in claim 1 , which comprises: a. suspending flibanserin hydrochloride in an organic solvent; b. maintaining the contents in step (a) at elevated temperature above 50⁰C; c. isolating flibanserin hydrochloride crystalline anhydrous form II.

7. The process as claimed in claim 6, wherein the flibanserin hydrochloride used is in the form of flibanserin hydrochloride crystalline form I, flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form IV, flibanserin hydrochloride crystalline anhydrous form V, flibanserin hydrochloride crystalline anhydrous form Vl and flibanserin hydrochloride crystalline hemihydrate form VII.

8. The process as claimed in claim 6, wherein the organic solvent used in step (a) is a solvent or mixture of solvents selected from acetone, ethyl acetate, toluene, xylene, n-heptane, cyclohexane and hexane.

9. The process as claimed in claim 8, wherein the organic solvent used in step (a) is selected from acetone, ethyl acetate and toluene.

10. The process as claimed in claim 6, wherein the contents are maintained at 50 to 150⁰C.

11. The process as claimed in claim 10, wherein the contents are maintained at reflux.

12. A flibanserin hydrochloride crystalline hemihydrate form III, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 9.4, 1 1.0, 12.6, 15.5, 18.1 , 18.9, 24.0 and 25.2 ± 0.2 degrees.

13. A flibanserin hydrochloride crystalline hemihydrate form III, characterized by an x-ray powder diffractogram as shown in figure 3.

14. The flibanserin hydrochloride crystalline hemihydrate form III as defined in claim 12, further characterized by FTIR spectrum having main bands at about 3374, 1686, 1491 , 1451 , 131 1 , 1 1 1 1 , 946 and 693 cm^"1.

15. The flibanserin hydrochloride crystalline hemihydrate form III as defined in claim 12, characterized by an FTIR spectrum as shown in figure 13.

16. The flibanserin hydrochloride crystalline hemihydrate form III as claimed in claim 12, wherein the flibanserin hydrochloride crystalline hemihydrate form III is further characterized by a differential scanning calorimetry thermogram as shown in figure 23.

17. A process for the preparation of flibanserin hydrochloride crystalline hemihydrate form III as defined in claim 12, which comprises: a. dissolving flibanserin in a chlorinated solvent to obtain a solution; b. adding the solution obtained in step (a) to hydrochloric acid; and c. isolating flibanserin hydrochloride crystalline hemihydrate form III.

18. The process as claimed in claim 17, wherein the chlorinated solvent used in step (a) is a solvent or mixture of solvents selected from methylene dichloride, ethylene dichloride and chloroform.

19. The process as claimed in claim 18, wherein the chlorinated solvent used in step (a) is methylene dichloride.

20. The process as claimed in claim 17, wherein the addition in step (b) is at 0 to 35⁰C.

21 . The process as claimed in claim 20, wherein the addition in step (b) is at room temperature.

22. A flibanserin hydrochloride crystalline anhydrous form IV, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 13.4, 16.8, 17.2, 17.7, 18.1 , 20.6, 23.1 and 24.5 ± 0.2 degrees.

23. A flibanserin hydrochloride crystalline anhydrous form IV, characterized by an x-ray powder diffractogram as shown in figure 4.

24. The flibanserin hydrochloride crystalline anhydrous form IV as defined in claim 22, further characterized by FTIR spectrum having main bands at about 3226, 1734, 1492, 1448, 1312, 1155, 1100, 945, and 730 cm^"1.

25. The flibanserin hydrochloride crystalline anhydrous form IV as defined in claim 22, characterized by an FTIR spectrum as shown in figure 14.

26. The flibanserin hydrochloride crystalline anhydrous form IV as claimed in claim 22, wherein the flibanserin hydrochloride crystalline anhydrous form IV is further characterized by a differential scanning calorimetry thermogram as shown in figure 24.

27. A process for the preparation of flibanserin hydrochloride crystalline anhydrous form IV as defined in claim 22, which comprises heating flibanserin hydrochloride at above 120 deg C.

28. The process as claimed in claim 27, wherein the heating is carried out at about 140 deg C to 150 deg C.

29. The process as claimed in claim 27, wherein the flibanserin hydrochloride used is in the form of flibanserin . hydrochloride crystalline form I, flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form V, flibanserin hydrochloride crystalline anhydrous form Vl, flibanserin hydrochloride crystalline hemihydrate form VII, flibanserin hydrochloride crystalline hemihydrate form VIII and flibanserin hydrochloride crystalline hemihydrate form IX.

30. A flibanserin hydrochloride crystalline anhydrous form V, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 6.4, 13.0, 13.3, 16.7, 18.0, 20.2, 21.3, 21.6, 23.6, 23.9 and 26.2 ± 0.2 degrees.

31. A flibanserin hydrochloride crystalline anhydrous form V, characterized by an x-ray powder diffractogram as shown in figure 5.

32. The flibanserin hydrochloride crystalline anhydrous form V as defined in claim 30, further characterized by FTIR spectrum having main bands at about 3403, 1712, 1494, 1349, 1313, 1167, 1125, 951 and 757 cm^"1.

33. The flibanserin hydrochloride crystalline anhydrous form V as defined in claim 30, characterized by an FTIR spectrum as shown in figure 15.

34. The flibanserin hydrochloride crystalline anhydrous form V as claimed in claim 30, wherein the flibanserin hydrochloride crystalline anhydrous form V is further characterized by a differential scanning calorimetry thermogram as shown in figure 25.

35. A process for the preparation of flibanserin hydrochloride crystalline anhydrous form V as defined in claim 30, which comprises: a. dissolving flibanserin hydrochloride in an alcohol solvent to obtain a solution. b. distilling off the solvent from a solution obtained in step (a); and c. isolating flibanserin hydrochloride crystalline anhydrous form V.

36. The process as claimed in claim 35, wherein the flibanserin hydrochloride used is in the form of flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form IV, flibanserin hydrochloride crystalline hemihydrate form VII and flibanserin hydrochloride crystalline hemihydrate form VIII.

37. The process as claimed in claim 35, wherein the alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, tert- butyl alcohol and n-butyl alcohol.

38. The process as claimed in claim 37, wherein the alcohol solvent used in step (a) is methanol.

39. A flibanserin hydrochloride crystalline anhydrous form Vl, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.8, 1 1.9, 12.9, 13.7, 15.6, 16.5, 17.2, 18.7, 20.5, 21.3, 22.0 and 25.4 ± 0.2 degrees.

40. A flibanserin hydrochloride crystalline anhydrous form Vl, characterized by an x-ray powder diffractogram as shown in figure 6.

41. The flibanserin hydrochloride crystalline anhydrous form Vl as defined in claim 39, further characterized by FTIR spectrum having main bands at about 3127, 2535, 2450, 1690, 1495, 1310, 1 1 13, 1 105, 947 and 752 cm^"1.

42. The flibanserin hydrochloride crystalline anhydrous form Vl as defined in claim 39, characterized by an FTIR spectrum as shown in figure 16.

43. The flibanserin hydrochloride crystalline anhydrous form Vl as claimed in claim 39, wherein the flibanserin hydrochloride crystalline anhydrous form Vl is further characterized by a differential scanning calorimetry thermogram as shown in figure 26.

44. A process for the preparation of flibanserin hydrochloride crystalline anhydrous form Vl as defined in claim 39, which comprises: a. dissolving flibanserin hydrochloride in a chlorinated solvent to obtain a solution; b. distilling off the solvent from a solution obtained in step (a); and c. isolating flibanserin hydrochloride crystalline anhydrous form Vl.

45. The process as claimed in claim 44, wherein the flibanserin hydrochloride used is in the form of flibanserin hydrochloride crystalline form I, flibanserin hydrochloride crystalline hemihydrate form III, flibanserin hydrochloride crystalline anhydrous form IV, flibanserin hydrochloride crystalline hemihydrate form VII and flibanserin hydrochloride crystalline hemihydrate form VIII.

46. The process as claimed in claim 44, wherein the chlorinated solvent used in step (a) is a solvent or mixture of solvents selected from methylene dichloride, ethylene dichloride and chloroform.

47. The process as claimed in claim 37, wherein the chlorinated solvent used in step (a) is methylene dichloride.

48. A flibanserin hydrochloride crystalline hemihydrate form VII, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 11.0, 15.6, 17.3, 18.1 and 18.9 ± 0.2 degrees.

49. A flibanserin hydrochloride crystalline hemihydrate form VII, characterized by an x-ray powder diffractogram as shown in figure 7.

50. The flibanserin hydrochloride crystalline hemihydrate form VII as defined in claim 48, further characterized by FTIR spectrum having main bands at about 3388, 1691 , 1491 , 1450, 1314, 1168, 1114, 945 and 694 cm^"1.

51. The flibanserin hydrochloride crystalline hemihydrate form VII as defined in claim 48, characterized by an FTIR spectrum as shown in figure 17.

52. The flibanserin hydrochloride crystalline hemihydrate form VII as claimed in claim 48, wherein the flibanserin hydrochloride crystalline anhydrous form VII is further characterized by a differential scanning calorimetry thermogram as shown in figure 27.

53. A process for the preparation of flibanserin hydrochloride crystalline hemihydrate form VII as defined in claim 48, which comprises: a. dissolving flibanserin in concentrated hydrochloric acid; b. diluting the solution with water; c. optionally, the contents obtained in step (b) may be maintained at above 25⁰C; and d. isolating flibanserin hydrochloride crystalline hemihydrate form VII.

54. The process as claimed in claim 53, wherein the contents are maintained at reflux.

55. A flibanserin hydrochloride crystalline hemihydrate form VIII, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.8, 12.4, 14.5, 17.8, 19.7 and 20.7 ± 0.2 degrees.

56. A flibanserin hydrochloride crystalline hemihydrate form VIII, characterized by an x-ray powder diffractogram as shown in figure 8.

57. The flibanserin hydrochloride crystalline hemihydrate form VIII as defined in claim 55, further characterized by FTIR spectrum having main bands at about 3411 , 1676, 1489, 1447, 1314, 1130, 947 and 730 cm^"1.

58. The flibanserin hydrochloride crystalline hemihydrate form VIII as defined in claim 55, characterized by an FTIR spectrum as shown in figure 18.

59. The flibanserin hydrochloride crystalline hemihydrate form VIII as claimed in claim 55, wherein the flibanserin hydrochloride crystalline anhydrous form VIII is further characterized by a differential scanning calorimetry thermogram as shown in figure 28.

60. A process for the preparation of flibanserin hydrochloride crystalline hemihydrate form VIII as defined in claim 55, which comprises: a. suspending flibanserin in methanol; b. adding aqueous hydrochloric acid dropwise to the suspension obtained in step (a); c. stirring the reaction mass obtained in step (b); and d. isolating flibanserin hydrochloride crystalline hemihydrate form VIII.

61. A flibanserin hydrochloride crystalline hemihydrate form IX, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.8, 11.0, 12.3, 15.6, 18.0, 18.8, 19.1 , 20.7 and 24.0 ± 0.2 degrees.

62. A flibanserin hydrochloride crystalline hemihydrate form IX, characterized by an x-ray powder diffractogram as shown in figure 9.

63. The flibanserin hydrochloride crystalline hemihydrate form IX as defined in claim 61 , further characterized by FTIR spectrum having main bands at about 1695, 1491 , 1449, 1314, 1167, 1119, 946 and 695 cm ¹.

64. The flibanserin hydrochloride crystalline hemihydrate form IX as defined in claim 61 , characterized by an FTIR spectrum as shown in figure 19.

65. The flibanserin hydrochloride crystalline hemihydrate form IX as claimed in claim 61 , wherein the flibanserin hydrochloride crystalline anhydrous form VIII is further characterized by a differential scanning calorimetry thermogram as shown in figure 29.

66. A process for the preparation of flibanserin hydrochloride crystalline hemihydrate form IX as defined in claim 61 , which comprises: a. suspending flibanserin in methanol; b. adding aqueous hydrochloric acid at once to the suspension obtained in step (a); c. stirring the reaction mass obtained in step (b); and d. isolating flibanserin hydrochloride crystalline hemihydrate form IX.

67. A flibanserin hydrochloride amorphous form, characterized by an x-ray powder diffractogram as shown in figure 10.

68. The flibanserin hydrochloride amorphous form as defined in claim 67, further characterized by FTIR spectrum having main bands at about 3404, 1702, 1491 , 1450, 1314, 1166, 1119, 946, 754 and 695 cm^"1.

69. The flibanserin hydrochloride amorphous form as defined in claim 67, characterized by an FTIR spectrum as shown in figure 20.

70. The flibanserin hydrochloride amorphous form as claimed in claim 67, wherein the flibanserin hydrochloride amorphous form is further characterized by a differential scanning calorimetry thermogram as shown in figure 30.

71. A process for the preparation of flibanserin hydrochloride amorphous form as defined in claim 67, which comprises: a. dissolving flibanserin hydrochloride crystalline anhydrous form Il in an alcohol solvent to obtain a solution; b. distilling off the solvent to the solution obtained in step (a); and c. dried at 80 to 85⁰C to obtain flibanserin hydrochloride amorphous form.

72. The process as claimed in claim 71 , wherein the alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol and butanol.

73. The process as claimed in claim 72, wherein the alcohol solvent used in step (a) is methanol.

74. A pharmaceutical composition comprising a polymorphic form of flibanserin hydrochloride selected from anhydrous form II, hemihydrate form III, anhydrous form IV, anhydrous form V, anhydrous form Vl, hemihydrate form

VII, hemihydrate form VIII, hemihydrate form IX and amorphous form or a mixture thereof and a pharmaceutically acceptable excipient.

75. The pharmaceutical composition as claimed in claim 74, wherein the pharmaceutical composition is used in a solid, liquid or spray form.

76. The pharmaceutical compositions as claimed in claim 75, wherein the forms of oral, rectal, parenteral administration or for nasal inhalation.

77. The pharmaceutical compositions as claimed in claim 76, wherein the forms of capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.