Polymorph of flibanserin and preparation method thereof and use of same

Abstract

The present invention discloses novel polymorphs I, II, and V of a [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one and a preparation method and application thereof. The polymorph I is a trihydrate crystal, the polymorph II is an anhydrous crystal, and the polymorph V is an anhydrous crystal. When compared with an existing crystal form, the novel polymorphs provides significant advantages in terms of solubility and preparation techniques.

Claims

1. A crystalline form of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one designated as Form V, having an X-ray powder diffraction pattern comprising the following 2θ values measured using CuKα radiation: 13.9±0.2, 11.9±0.2, 17.9±0.2, 23.9±0.2, and 21.6±0.2, wherein the X-ray powder diffraction pattern further comprises the following 20 values measured using CuKα radiation: 22.7±0.2, 23.5±0.2, 19.4±0.2, 25.7±0.2, and 14.8±0.2 and the following 2θ values measured using CuKα radiation 14.4±0.2, 17.0±0.2, 23.0±0.2, and 11.5±0.2, 15.3±0.2, 20.0±0.2, 24.5±0.2, 40.4±0.2, and 41.9±0.2.

2. A pharmaceutical composition comprising the crystal in Form V according to claim 1 as an active ingredient.

3. A process for the preparation of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form V according to claim 1 comprising: (i) dropwise adding a solution of 2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzene imidazolidin-2-one in 2-methyltetrahydrofuran to a poor solvent to precipitate a solid; and (ii) obtaining crystal form V after filtration.

4. A method of treating or delaying hypoactive sexual desire disorder (HSDD) in premenopausal women, comprising administering to a subject in need thereof a pharmaceutical composition comprising crystalline [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-Methyl]-2,3-dihydro-1H-benzimidazol-2-one in Form V of claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 XPRD pattern of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I;

(2) FIG. 2 XPRD pattern of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form II;

(3) FIG. 3 XPRD pattern of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form V;

(4) FIG. 4 DSC plot of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I;

(5) FIG. 5 DSC plot of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form II;

(6) FIG. 6 DSC plot of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form V;

(7) FIG. 7 TGA plot of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I;

(8) FIG. 8 TGA plot of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form II;

(9) FIG. 9 TGA plot of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form V;

(10) FIG. 10 Crystal structure of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I refined by single crystal X-ray diffraction; and

(11) FIG. 11 standard XRPD pattern of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I (simulated by single crystal data).

DETAILED DESCRIPTION

(12) The specific embodiments of the present invention are further described in detail below with reference to the drawings and embodiments. The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.

Example 1

(13) 1.0 g of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one hydrochloride is dissolved in 400 mL of water, and added 2 mg/ml sodium carbonate solution till the solid was precipitated and then filtered the precipitation to obtain [2-(4-(3-trifluoromethyl-benzyl) piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

(14) The X-ray powder diffraction operation and analysis steps in this patent are as follows:

(15) The Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-Kα (40 kV, 40 mA) at room temperature using a D/tex Ultra detector. The scanning range is from 3° to 45° in the 20 interval, and the scanning speed is 20°/min.

(16) Measurement differences associated with X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (eg, sample height), (b) instrument error, (c) calibration differences, (d) operator error (including errors that occur when determining peak position), and (e) properties of the substance (eg, preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. When using a flat sampler, small differences in sample height will result in large displacements of the XRPD peak position. Systematic studies have shown that a 1 mm sample height difference can result in a 20 peak shift of up to 1°. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacement (using a system calibration factor for all peak position values) or recalibrating the instrument. As described above, the measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.

(17) [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one designated as Form I, has an X-ray powder diffraction pattern comprising the following 20 values measured using CuKα radiation: 6.3±0.2, 8.7±0.2, 12.6±0.2, 13.3±0.2, 14.4±0.2, 14.8±0.2, 15.3±0.2, 15.8±0.2, 16.4±0.2 17.4±0.2, 18.1±0.2, 18.9±0.2, 19.7±0.2, 20.3±0.2, 21.7±0.2, 22.3±0.2, 23.1±0.2, 23.6±0.2, 24.2±0.2, 24.6±0.2, 25.0±0.2, 25.4±0.2, 26.2±0.2, 27.2±0.2, 27.7±0.2, 28.1±0.2, 29.5±0.2, 30.9±0.2, 32.9±0.2, 34.6±0.2, 35.1±0.2 and 37.4±0.2. The XRPD patterns is shown in FIG. 1 and the diffraction peaks of the XRPD pattern of Form I are listed in the following table:

(18) TABLE-US-00002 2-Theta d(A) I(Height)% 6.339 13.9316 32.1 8.698 10.1574 31.7 12.639 6.9978 16.6 13.281 6.6612 13.1 14.44 6.1289 30.4 14.816 5.9741 26.1 15.339 5.7719 25 15.804 5.603 6.1 16.42 5.3939 39.2 17.361 5.1038 22.3 18.12 4.8917 13.2 18.86 4.7014 37.8 19.699 4.503 42.3 20.34 4.3625 52.2 21.72 4.0883 57.3 22.34 3.9763 6 23.061 3.8535 100 23.637 3.7609 5.8 24.2 3.6747 15 24.579 3.6188 29.3 24.961 3.5644 7 25.399 3.5038 6.8 26.219 3.396 55.1 27.178 3.2784 16.3 27.679 3.2202 25.1 28.059 3.1774 6.8 29.518 3.0236 8.4 29.92 2.9839 4.8 30.94 2.8878 14.8 32.938 2.7171 9.7 34.581 2.5917 9.5 35.078 2.556 8.3 35.799 2.5062 2.6 36.267 2.475 1.6 36.84 2.4378 2.2 37.361 2.4049 6 39.274 2.2921 2 39.921 2.2564 2.2 41.124 2.1932 2.8 42.038 2.1476 5.5 43.259 2.0897 6.4 44.381 2.0395 4.6

(19) A differential scanning calorimetry (DSC) analysis was performed on the crystal form I in Example 1, using a TA Q2000 differential scanning calorimeter using an N2 atmosphere at a temperature rising rate of 10° C./min.

(20) The DSC plot of Form I is shown in FIG. 4, in which the first stage is the dehydration process and the second stage is the melting process after the water loss.

(21) The thermogravimetric (TGA) analysis of the crystal form I in Example 1 was carried out using a TA Q500 thermogravimetric analyzer using a N.sub.2 atmosphere at a heating rate of 10° C./min.

(22) The TGA plot of Form I is shown in FIG. 7. The weight loss of 11.8% before 60° C. is the heating and dehydration process.

Example 2

(23) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 0.5 mL ethanol, 2 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 3

(24) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL n-propanol, 2 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H benzimidazol-2-one Form I.

Example 4

(25) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL isopropanol, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 5

(26) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL acetonitrile, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 6

(27) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL methanol, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 7

(28) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL trifluoroethanol, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 8

(29) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL acetone, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 9

(30) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL ethylene glycol dimethyl ether, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 10

(31) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihyrdo-1H-benzimidazol-2-one was dissolved in 1 mL N,N-dimethylformamide, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 11

(32) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL, 4-dioxane, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 12

(33) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL tetrahydrofuran, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 13

(34) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 mL pyridine, 4 ml of water was added thereto, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 14

(35) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 0.5 ml ethanol, this solution was added dropwise to 2 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 15

(36) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 0.5 ml n-propanol, this solution was added dropwise to 2 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 16

(37) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml isopanol, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 17

(38) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml acetonitrile, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 18

(39) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 0.5 ml methanol, this solution was added dropwise to 2 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 19

(40) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml trifluoroethanol, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 20

(41) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml acetone, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 21

(42) 50 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml ethylene glycol dimethyl ether, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 22

(43) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml N,N-dimethylformamide, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 23

(44) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml 1,4-dioxane, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 24

(45) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml tetrahydrofuran, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 25

(46) 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml pyridine, this solution was added dropwise to 4 ml of 4° C. water, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 26

(47) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml 50° C. ethanol/water (2:1, v/v), this solution was cooled to 0° C., and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one-one Form I.

Example 27

(48) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml 50° C. n-propanol/water (2:1, v/v), this solution was cooled to 0° C., and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 28

(49) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml 50° C. isopanol/water (2:1, v/v), this solution was cooled to 0° C., and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 29

(50) 20 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one was dissolved in 1 ml 50° C. acetonitrilel/water (2:1, v/v), this solution was cooled to 0° C., and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form I.

Example 30

(51) [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one form I prepared in Example 1 crystal was dried under vacuum at room temperature to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one crystal form II.

(52) [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one designated as Form II, has an X-ray powder diffraction pattern comprising the following 20 values measured using CuKα radiation: 8.3±0.2, 10.4±0.2, 12.6±0.2, 13.3±0.2, 14.0±0.2, 15.2±0.2, 15.6±0.2, 15.9±0.2, 16.8±0.2 17.2±0.2, 18.0±0.2, 18.6±0.2, 19.1±0.2, 19.7±0.2, 20.5±0.2, 21.1±0.2, 21.7±0.2, 22.1±0.2, 22.7±0.2, 22.9±0.2, 23.5±0.2, 23.9±0.2, 24.7±0.2, 25.3±0.2, 28.4±0.2, 29.1±0.2, 30.4±0.2, 31.9±0.2, 32.6±0.2, 32.9±0.2, 36.3±0.2, and 38.4±0.2. The XRPD patterns is shown in FIG. 2 and the diffraction peaks of the XRPD pattern of Form II are listed in the following table:

(53) TABLE-US-00003 2-Theta d(A) I(Height)% 8.337 10.5971 2.1 10.402 8.497 4.6 12.561 7.0412 5.6 13.259 6.6718 29.6 14.045 6.3004 5.3 15.16 5.8395 43.1 15.559 5.6907 44.9 15.981 5.5413 12.5 16.822 5.2661 9.8 17.199 5.1513 23.9 17.999 4.9243 16 18.599 4.7668 34.2 19.097 4.6435 40.2 19.659 4.512 72.1 20.477 4.3337 25.6 21.141 4.199 27.7 21.741 4.0845 73.7 22.081 4.0223 80.4 22.661 3.9207 21.2 22.92 3.8768 14.3 23.495 3.7833 4.3 23.878 3.7235 5.9 24.74 3.5957 100 25.261 3.5227 58.4 28.362 3.1442 26.1 29.082 3.0679 10.2 30.36 2.9416 7.1 31.879 2.8049 12.7 32.557 2.748 4.5 32.942 2.7168 8.4 35 2.5616 3.2 35.542 2.5237 3.7 36.26 2.4754 7.3 38.382 2.3433 7.7 39.286 2.2914 3.3 40.18 2.2425 1.7 41.541 2.1721 2.3 42.22 2.1387 5 43.342 2.0859 6

(54) Differential scanning calorimetry (DSC) analysis was performed on the crystal form II in Example 2. The DSC pattern of the crystal form II is shown in FIG. 5, wherein the first stage is a crystal form II crystal transformation process by heating, and the second stage is the melting process after the crystal transformation.

(55) The thermogravimetric (TGA) analysis was carried out on the crystal form II in Example 2, using a TA Q500 thermogravimetric analyzer using a N2 atmosphere at a heating rate of 10° C./min.

(56) The TGA plot of Form II is shown in FIG. 8. There is no obvious weight loss before 200° C.

Example 31

(57) Dissolving 100 mg of [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one in 1 ml 2-methyltetrahydrofuran, this solution was added dropwise to 4 ml of 0° C. n-heptane, and the solid was precipitated and filtered to give [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one Form V.

(58) [2-(4-(3-trifluoromethyl-benzyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one designated as Form I, has an X-ray powder diffraction pattern comprising the following 20 values measured using CuKα radiation: 13.9±0.2, 11.9±0.2, 17.9±0.2, 23.9±0.2, 21.6±0.2, 22.7±0.2, 23.5±0.2, 19.4±0.2, 25.7±0.21, 4.8±0.2, 14.4±0.2, 17.0±0.2, 23.0±0.2, 11.5±0.2. The XRPD patterns is shown in FIG. 3 and the diffraction peaks of the XRPD pattern of Form V are listed in the following table:

(59) TABLE-US-00004 2-Theta d(A) I(Height)% 5.9 14.9674 5.7 9.579 9.2255 8.1 11.481 7.7013 21.5 11.858 7.4568 66.4 13.92 6.3566 100 14.439 6.1293 19 14.84 5.9645 34.9 15.302 5.7854 8.6 16.98 5.2175 34.1 17.861 4.962 55.8 19.382 4.5759 38.1 20.01 4.4337 2.5 20.542 4.3201 8.7 21.599 4.111 47 22.721 3.9105 46.7 23.021 3.8602 23.4 23.54 3.7761 41 23.919 3.7173 54.4 24.521 3.6272 3.5 25.52 3.4875 25.8 25.701 3.4634 37 26.58 3.3508 11.1 27.416 3.2504 7.7 28.64 3.1143 13.2 29.02 3.0743 12.4 32.122 2.7842 10.2 35.119 2.5531 5.4 36.261 2.4753 8.9 39.343 2.2882 6.9 40.4 2.2308 7.5 41.864 2.1561 3.8

(60) The Form V in Example 31 was subjected to differential scanning calorimetry (DSC) analysis. The DSC plot of Form V is shown in FIG. 6, and a melting peak was obtained at about 161° C.

(61) The crystal form V in Example 31 was subjected to thermogravimetric (TGA) analysis using a TA Q500 thermogravimetric analyzer using a N2 atmosphere at a heating rate of 10° C./min.

(62) The TGA plot of Form V is shown in FIG. 9, and there is no obvious weight loss before 200° C.

Example 32

(63) The solubility of several new crystal forms prepared in the above examples and Form A (prepared according to the method of WO2003/014079) in a pH buffer solution (pH 6.8) was determined. Precisely weigh 20 mg Form I, Form II, Form V and Form A in a 2-mL glass vial, add 1 mL of pH 6.8 buffer, seal with cap, and mix on a rotating mixer. After the suspension was equilibrated for 1 hour, the mixture was filtered through a 0.45 μm needle filter, and the concentration of flibanserin in the filtrate was analyzed by HPLC to obtain the solubility of different crystal forms. The solubility of the polymorphs of Flibanserin is shown in the following table:

(64) TABLE-US-00005 Polymorphs Form I Form II Form V Form A Solubility in 0.004 0.008 0.010 0.002 pH 6.8 buffer (mg/mL)

Example 33

(65) Crystalline Form I single crystal culture process is described as following; weigh about 15 mg of flibanserin in 4-mL clean glass vial, then add 0.4 mL of n-propanol/water mixture solution (1:2, v/v). The mixture was dissolved by heating, filtered by a hot needle filter (tetrafluoroethylene membrane having a pore size of 0.2 μm), and then naturally cooled and then stored at 4° C. to precipitate a single crystal.