COCRYSTAL OF LORCASERIN, PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS AND USE THEREOF (AS AMENDED)

Abstract

The present invention relates to a new type of eutectic crystal of lorcaserin hydrochloride and benzoic acid. Compared with the prior art, the eutectic crystal has the improved properties of good stability, low solubility, and being suitable for the application of controlled-release preparation. The present invention also relates to a method for preparing the eutectic crystal, a pharmaceutical composition thereof and the use thereof in the manufacture of drugs for treating and/or preventing diseases associated with 5HT.sub.2C.

Claims

1. Cocrystal of lorcaserin hydrochloride and benzoic acid with the structural formula shown below ##STR00003##

2. The cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 1, wherein measured using Cu—Kα radiation, the X-ray powder diffraction pattern of the cocrystal, expressed as 2θ angles, has the following characteristic peaks: 4.5±0.2°, 9.0±0.2°, 12.3±0.2°, 18.0±0.2°, 19.4±0.2° and 23.0±0.2°.

3. The cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 2, wherein the X-ray powder diffraction pattern of the cocrystal, expressed as 2θ angles, has the following characteristic peaks: 4.5±0.2°, 9.0±0.2°, 11.7±0.2°, 12.3±0.2°, 13.5±0.2°, 16.9±0.2°, 18.0±0.2°, 19.4±0.2°, 20.4±0.2°, 22.6±0.2°, 23.0±0.2° and 23.5±0.2°.

4. The cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 3, wherein the X-ray powder diffraction pattern of the cocrystal, expressed as 2θ angles, has the following characteristic peaks with their relative intensities: TABLE-US-00008 Diffraction angel 2θ Relative intensity %  4.5 ± 0.2° 7.3  9.0 ± 0.2° 53.9 11.7 ± 0.2° 6.0 12.3 ± 0.2° 6.9 13.5 ± 0.2° 6.7 16.9 ± 0.2° 7.9 18.0 ± 0.2° 22.9 18.2 ± 0.2° 16.0 19.4 ± 0.2° 18.9 20.4 ± 0.2° 11.4 22.6 ± 0.2° 58.1 23.0 ± 0.2° 100.0 23.5 ± 0.2° 38.1 24.1 ± 0.2° 28.4 25.7 ± 0.2° 13.0 26.8 ± 0.2° 16.5 28.0 ± 0.2° 9.1 29.4 ± 0.2° 11.9 30.9 ± 0.2° 7.5.

5. The cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 1, wherein measured at 100K in temperature, has the following single-crystal unit cell parameters: axial length: a=6.1734(6) Å, b=7.6376(5) Å, c=39.233(4) Å; dihedral angle: α=90°, β=90°, γ=90°; space group: P 1 1 2.sub.1.

6. The cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 2, wherein the Fourier transform infrared spectrum of the cocrystal has characteristic peaks at wave numbers of 3384, 2971, 2861, 2524, 2362, 1700, 1595, 1315, 1270, 1119, 946, 818 and 710 cm.sup.−1.

7. A preparation method of the cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 1, comprises: (1) Forming a solution of benzoic acid in an organic solvent, wherein the organic solvent is selected from the group consisting of alcohols, ketones and esters, adding lorcaserin hydrochloride hemihydrate, the molar ratio of lorcaserin hydrochloride hemihydrate to benzoic acid is from 1:1 to 1.5:1, after the adding step, stirring the mixture for crystallization, and obtaining the cocrystal; or (2) Forming a solution of lorcaserin hydrochloride hemihydrate in an organic solvent, wherein the organic solvent is selected from the group consisting of alcohols, ketones and esters, adding benzoic acid to the solution, the molar ratio of lorcaserin hydrochloride hemihydrate to benzoic acid is from 1:1 to 1:3, after the adding step, stirring for crystallization, and obtaining the cocrystal; or (3) Forming a mixed system of lorcaserin, hydrochloric acid and benzoic acid in an organic solvent, wherein the organic solvent is selected from the group consisting of alcohols, ketones, esters and halo alkanes, the molar ratio of lorcaserin, hydrochloric acid and benzoic acid is from 1:1:1 to 1:2:3, stirring the mixture for crystallization, and obtaining the cocrystal; or (4) Adding a solvent to a mixture of lorcaserin hydrochloride hemihydrate and benzoic acid in which lorcaserin hydrochloride hemihydrate has equal molar ratio to benzoic acid, keeping the mixture wetted completely with the solvent, grinding the mixture to dryness, and obtaining the cocrystal, wherein the solvent is selected from the group consisting of water and organic solvents.

8. A pharmaceutical composition comprises a therapeutically and/or preventively effective amount of the cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 1, and at least one pharmaceutical acceptable carrier or additive.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is in the solid oral dosage form selected from the group consisting of tablets, capsules, granules, pills and powders.

10. A method of treating and/or preventing diseases associated with 5HT.sub.2C comprising administering an effective amount of the cocrystal of lorcaserin hydrochloride and benzoic acid according to claim 1; wherein the diseases associated with 5HT.sub.2C are obesity, central nervous system diseases, central nervous system injury, cardiovascular diseases, gastrointestinal disorders, diabetes insipidus, sleep apnea, depression, atypical depression, bipolar disorder, anxiety disorders, obsessive compulsive disorder, social phobia or panic state, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and symptoms associated with head pain or other pains, increased intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, childhood mental disorders, aggression, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexia nervosa or premenstrual tension.

11. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is in a sustained-release or controlled-release solid oral dosage form.

12. A pharmaceutical composition comprises a therapeutically and/or preventively effective amount of the cocrystal of lorcaserin hydrochloride and benzoic acid obtained according to the preparation method of claim 7, and at least one pharmaceutical acceptable carrier or additive.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is in a sustained-release or controlled-release solid oral dosage form.

14. The preparation method according to claim 7, wherein (1) the organic solvent is selected from the group consisting of C.sub.1 to C.sub.4 alcohols, ethyl acetate and acetone; (2) the organic solvent is selected from the group consisting of C.sub.1 to C.sub.4 alcohols, ethyl acetate and acetone; (3) the organic solvent is selected from the group consisting of C.sub.1 to C.sub.4 alcohols, ethyl acetate, acetone and dichloromethane; or (4) the solvent is selected from the group consisting of acetone, acetonitrile and water.

15. The preparation method according to claim 14, wherein the organic solvent in (1), (2) and (3) is isopropanol.

16. The preparation method according to claim 7, wherein (1) the concentration of the solution of benzoic acid in the organic solvent is from 75 to 120 mg/mL; (2) the concentration of the solution of lorcaserin hydrochloride hemihydrate in the organic solvent is from 50 to 100 mg/mL; (3) the weight volume ratio of lorcaserin to the organic solvent in the mixed system is from 100 mg:1 mL to 200 mg: 1 mL; or (4) the weight volume ratio of the mixture to the solvent is from 150 mg:1 mL to 240 mg:1 mL.

17. The preparation method according to claim 7, wherein (1) lorcaserin hydrochloride hemihydrate is added in 2 to 6 equal parts, and the mixture is stirred for 10 to 15 minutes after each addition; or (2) benzoic acid is added in 2 to 6 equal parts, and the mixture is stirred for 10 to 15 minutes after each addition.

18. The preparation method according to claim 7, wherein the operation temperature of the preparation method is from 10° C. to 40° C.

19. The preparation method according to claim 7, wherein (1) the crystallization time is from 8 to 48 hours; (2) the crystallization time is from 8 to 48 hours; or (3) the crystallization time is from 10 to 24 hours.

20. A method of treating and/or preventing diseases associated with 5HT.sub.2C, comprising administering an effective amount of the cocrystal of lorcaserin hydrochloride and benzoic acid obtained according to the preparation method of claim 7; wherein the diseases associated with 5HT.sub.2C are obesity, central nervous system diseases, central nervous system injury, cardiovascular diseases, gastrointestinal disorders, diabetes insipidus, sleep apnea, depression, atypical depression, bipolar disorder, anxiety disorders, obsessive compulsive disorder, social phobia or panic state, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and symptoms associated with head pain or other pains, increased intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, childhood mental disorders, aggression, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexia nervosa or premenstrual tension.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIG. 1 is the XRPD pattern of the crystalline Form III of lorcaserin hydrochloride hemihydrate prepared according to preparation example 1.

[0076] FIG. 2 is the XRPD pattern of the cocrystal in the present invention.

[0077] FIG. 3 is the molecular structure diagram of the cocrystal in the present invention.

[0078] FIG. 4 is the IR spectrum of the cocrystal in the present invention.

[0079] FIG. 5 is the XRPD pattern of the cocrystal in the present invention (top) and the simulated XRD pattern from single-crystal data (bottom).

EXAMPLES

[0080] The present invention refers further to the following examples. Those examples describe the cocrystal of the present invention, its preparations and applications in detail. It will be apparent to those skilled in the art that various modifications can be made to materials and methods without departing from the scope of the present invention.

Instruments and Characterization Methods:

[0081] X-ray powder diffraction (XRPD): performed on Bruker D8 Advance diffractometer equipped with θ-2θ goniometer, Mo monochrotneter and Lynxeye detector by using Cu—Kα X-rays with the wavelength 1.54 nm at 40 kV and 40 mA. Before testing, the instrument is performance checked using corundum. The collection software is Diffrac Plus XRPD Commander. Place the testing sample on a non-reflective plate at room temperature. The detailed testing conditions: 2θ scan range, 3-40°, step size, 0.02°, speed, 0.2 s/step.

[0082] Single-crystal diffractometer: Eos CCD detector, four-circle Kappa tester, enhanced Mo and enhanced Cu light sources. Detection parameters: ambient temperature 100K, enhanced Cu light source, graphite monochromator, the wavelength 1.54 Å. Data analysis software is CrysAlisPro. The data was further analyzed by Shelxtl software, and then the molecular structure diagram can be obtained.

[0083] Infrared spectrometry (IR) data are collected on Bruker Tensor 27 equipped with an attenuated total reflection (ATR). OPUS is used both for instrument control software and data analysis software. Usually, the infrared spectra are collected over 600-4000 cm.sup.−1. Both samples and the blank background are scanned for 16 s. The instrument resolution is 4 cm.sup.−1.

[0084] .sup.1H Nuclear magnetic resonance spectrum (.sup.1H-NNTR) data are collected on Bruker Ascene™ 500. Usually, the .sup.1H-NMR. spectra are collected using full-frequency excitation, spectral width 30 ppm, mono pulse, 30° angle excitation, scanning 16 times, digital quadrature detection, and temperature 298K.

[0085] High performance liquid chromatography (HPLC) data are collected on Waters 2695 under the following conditions: column, VP-ODS 150×4.6 mm, 5 μm; column temperature, 2.5° C.; injection volume, 5 μL; flow rate, 1.0 mL/min, mobile phase A is 0.05% trifluoroacetic acid aqueous solution, mobile phase B is acetonitrile, gradient elution of mobile phases is shown in table 1. Absorption spectra are recorded on UV-visible spectrophotometer at the detection wavelength of 220 nm.

TABLE-US-00002 TABLE 1 Gradient elution of mobile phases in HPLC Time (min) Mobile phase A (%) Mobile phase B (%) 0 90 10 8 20 80 13 20 80 13.1 90 10 15 90 10

[0086] Unless particularly specified, all examples were conducted at room temperature.

[0087] Unless particularly specified, all reagents used in the examples were commercially purchased.

[0088] “Overnight” in the examples means that the experiment step took place over the night time, such as from 8 to 22 hours or from 10 to 18 hours, usually 16 hours.

Preparation Example 1

[0089] Lorcaserin hydrochloride hemihydrate (crystalline Form III) was prepared by referencing the processes described in example 1 and example 2 of WO2006/069363A2. The operating procedures are detailed as follows:

[0090] To 220 g of lorcaserin, 3 L of dichloromethane was added, and then 1.74 L 1 mol/L solution of HCl in ether was added, the mixture was stirred for 2 hours at room temperature. The solvent was removed by rotary evaporation, and 190 g of lorcaserin hydrochloride was obtained.

[0091] To 16 g of lorcaserin hydrochloride, 36 g of isopropanol was added, the mixture was heated to 60° C. to obtain a clear solution. To the solution 96 g of cyclohexane was added followed by 12.4 g of water, then the system was cooled to 20° C. in 2 hours with slow stirring. After solids were observed, the suspension was cooled to 0° C. and stirred for 3 hours at 0° C. The suspension was filtered and the filter cake was washed with 16 g of cyclohexane. Dried at 40° C. under vacuum, 15 of lorcaserin hydrochloride hemihydrate was obtained as white crystalline solids.

[0092] The .sup.1H-NMR(CDCl.sub.3) data is shown below: 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14(dd,1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3H), 1.5 (d, 3H. J=7 Hz).

[0093] The X-ray powder diffraction pattern was shown in FIG. 1, indicating that its crystalline form is the same as the crystalline Form III in the prior art disclosed in WO2006/069363A2.

Example 1

[0094] To the mixture of 160 mg of lorcaserin hydrochloride hemihydrate and 80 mg of benzoic acid, 1 mL of acetone was added. Kept the mixture completely wetted with acetone, then ground it to dryness to obtain 234mg of the cocrystal, the molar yield was 94.7%.

[0095] The XRPD pattern of cocrystal was shown in FIG. 2, indicating it is a crystalline substance.

[0096] The IR spectrum of the cocrystal was shown in FIG. 4, indicating that it has characteristic peaks at the wave numbers of 3384 2971, 2861, 2524, 2362, 1700, 1595, 1315, 1270, 1119, 946 818 and 710 cm.sup.−1.

Example 2

[0097] Formed an acetone solution of the cocrystal prepared in Example 1, the acetone solution was injected into a 5 ml glass vial at room temperature, covered to seal the vial, then opened a small hole about 1 mm diameter in the cap for volatilization, the solution was volatilized to dryness, and the single-crystal for detection was obtained.

[0098] The single-crystal's lattice parameters were shown in Table 2.

TABLE-US-00003 TABLE 2 The single-crystal lattice parameters of the cocrystal Lattice parameters Structural formula Lorcaserin-HCl—H.sub.2O—ArCOOH molecular formula C.sub.18H.sub.23Cl.sub.2NO.sub.3 molecular weight (g/mol) 372.29 Crystal system monoclinic system Space groups P 1 1 2.sub.1 Temperature/K 100 a/Å 6.1734(6) b/Å 7.6376(5) c/Å 39.233(4) α/° 90.00 β/° 90.00 γ/° 90.00 Z 4 V/Å.sup.3 1849.83(30) D.sub.calc/g cm.sup.−3 1.33662

[0099] In table 2, a, b, and c represent axial lengths of the unit cell, α, β, and γ represent dihedral angles, Z represents the number of molecules of Lorcaserin-HCl—H.sub.2O—ArCOOH (Ar represents a phenyl group) in each unit cell, V represents cell volume, D.sub.calc represents cell density.

[0100] Single-crystal analytical parameters: residual factor R1=0.0442, weighted R value wR2=0.1194, goodness of fit GooF (S)=1.040. When R1 value is less than 0.05, wR2 value is less than 0.15, S value is almost 1; it indicates that the single-crystal data is reasonable.

[0101] Molecular structure diagram of the monocrystal is shown in FIG. 3, indicating that one cocrystal molecule consists of one lorcaserin molecule, one hydrogen chloride molecule, one benzoic acid molecule and one water molecule.

[0102] The XRPD comparison diagram shown in FIG. 5 contains the simulated XRD patterns based on single-crystal dada (bottom) and the actual measured XRPD pattern of the cocrystal (top), showing that both are essentially identical.

Example 3

[0103] To the mixture of 100 mg of lorcaserin hydrochloride hemihydrate and 50 mg of benzoic acid, 1 mL of acetonitrile was added. Kept the mixture completely wetted with acetonitrile at 40° C., then ground it to dryness to obtain 136 mg of the cocrystal, the molar yield was 88.1%

Example 4

[0104] To the mixture of 100 mg of lorcaserin hydrochloride hemihydrate and 50 mg of benzoic acid, 1 mL of water was added. Kept the mixture completely wetted with water at 40° C., then ground it to dryness to obtain136 mg of the cocrystal, the molar yield was 70.0%.

Example 5

[0105] To 120 mg of benzoic acid, 1 mL of methanol was added to produce a methanol solution of benzoic acid by sonication. 240 mg of lorcaserin hydrochloride hemihydrate was equally divided into 6 parts with each part of 40 mg, and then the parts were added into the methanol solution of benzoic acid, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the adding step, the mixture was stirred at room temperature for 8 hours, filtered, dried at room temperature for 1 hour, 55 mg of the cocrystal was obtained; the molar yield was 15.0%.

Example 6

[0106] To 240 mg of benzoic acid, 2 mL of n-butanol was added to produce a n-butanol solution of benzoic acid by sonication. 480 mg of lorcaserin hydrochloride hemihydrate was equally divided into 4 parts with each part of 120 mg, and then the parts were added into the n-butanol solution of benzoic acid, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred at room temperature for 8 hours, filtered, dried at room temperature for 1 hour, 120 mg of the cocrystal was obtained, and the molar yield was 16.4%.

Example 7

[0107] To 1.2 g of benzoic acid, 10 mL of isopropanol was added to produce an isopropanol solution of benzoic acid by sonication. 2.4 g of lorcaserin hydrochloride hemihydrate was divided into 6 parts in average with each part of 0.4 g, and then the parts were added into the isopropanol solution of benzoic acid, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred overnight at room temperature, filtered, dried at 40° C. for 2 hours, 1.63 g of the cocrystal was obtained, the molar yield was 44.6%.

Example 8

[0108] To 450 mg of benzoic acid, 4 mL of ethyl acetate was added to produce an ethyl acetate solution of benzoic acid by sonication at 40° C. 1.35 g of lorcaserin hydrochloride hemihydrate was equally divided into 6 parts, each part of 225 mg, and then the parts were added into the ethyl acetate solution of benzoic acid, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred for 48 hours, filtered, dried at 10° C. for 10 hours, 226 mg of the cocrystal was obtained, the molar yield was 16.5%.

Example 9

[0109] To 300 mg of benzoic acid, 4 mL of acetone was added to produce an acetone solution of benzoic acid by sonication, 900 mg of lorcaserin hydrochloride hemihydrate was equally divided into 2 parts with each part of 450 mg, and then the parts were added into the acetone solution of benzoic acid, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred at room temperature for 8 hours, filtered, dried at room temperature for 1 hour, 140 mg of the cocrystal was obtained; the molar yield was 15.3%.

Example 10

[0110] To 250 mg of lorcaserin hydrochloride hemihydrate, 5 mL of acetone was added to produce an acetone solution of lorcaserin hydrochloride hemihydrate by sonication. 375 mg of benzoic acid was equally divided into 3 parts with each part of 125 mg, then, the parts were added into the acetone solution of Lorcaserin hydrochloride hemihydrate, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred at room temperature for 8 hours, filtered, dried at room temperature for 2 hours, 48 mg of the cocrystal was obtained; the molar yield was 12.4%,

Example 11

[0111] To 200 mg of lorcaserin hydrochloride hemihydrate, 3 mL of ethyl acetate was added to produce an ethyl acetate solution of lorcaserin hydrochloride hemihydrate by sonication at 40° C. 300 mg of benzoic acid was equally divided into 2 parts with each part of 150 mg, then, the parts were added into the ethyl acetate solution of lorcaserin hydrochloride hemihydrate, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred overnight at room temperature, filtered, dried at 10° C. for 10 hours, 47 mg of the cocrystal was obtained, the molar yield was 15.2%.

Example 12

[0112] To 200 mg of lorcaserin hydrochloride hemihydrate, 4 mL of isopropanol was added to produce an isopropanol solution of lorcaserin hydrochloride hemihydrate by sonication. 100 mg of benzoic acid was equally divided into 2 parts with each part of 50 mg, then, the parts were added into the isopropanol solution of lorcaserin hydrochloride hemihydrate, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred overnight at room temperature, filtered, dried at 10° C. for 10 hours, 134 mg of the cocrystal was obtained, the molar yield was 43.4%.

Example 13

[0113] To 200 mg of lorcaserin hydrochloride hemihydrate, 2 mL of methanol was added to produce a methanol solution of lorcaserin hydrochloride hemihydrate by sonication at 40° C. 150 mg of benzoic acid was equally divided into 3 parts with each part of 50 mg, then, the parts were added into the methanol solution of lorcaserin hydrochloride hemihydrate, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred for 48 hours, cooled to room temperature, filtered, dried at 40° C. for 1 hour, 42 mg of the cocrystal was obtained, the molar yield was 13.6%.

Example 14

[0114] To 200 mg of lorcaserin hydrochloride hemihydrate, 2 mL of n-butanol was added to produce an n-butanol solution of lorcaserin hydrochloride hemihydrate by sonication. 300 mg of benzoic acid was equally divided into 6 parts with each part of 50 mg; the parts were added into the n-butanol solution of Lorcaserin hydrochloride hemihydrate, respectively. After each addition, the mixture was stirred for 10˜15 minutes. After the additions, the mixture was stirred for 48 hours, cooled to room temperature, filtered, dried at 40° C. for 1 hour, 45 mg of the cocrystal was obtained, the molar yield was 14.6%.

Example 15

[0115] To 200 mg of lorcaserin, 1.02 mL of 1 mol/L HCl and 124 mg of benzoic acid, 1 mL of isopropanol was added to form a mixed system, the mixed system was stirred overnight, filtered, dried at 40 ° C. for 1 hour, 87 mg of the cocrystal was obtained, the molar yield was 23.0%.

Example 16

[0116] To 200 mg of lorcaserin, 1.02 mL of 1 mol/L HCl and 248 mg of benzoic acid, 1mL of n-butanol was added to form a mixed system, the mixed system was stirred for 24 hours, filtered, dried at 40° C. for 4 hours, 62 mg of the cocrystal was obtained, the molar yield was 16.4%.

Example 17

[0117] To 200 mg of lorcaserin, 1.02 mL of 1 mol/L HCl and 248 mg of benzoic acid, 2 mL of ethanol was added to form a mixed system, the mixed system was stirred for 20 hours, filtered, dried at 40° C. for 4 hours, 65 mg of the cocrystal was obtained, the molar yield was 17.2%.

Example 18

[0118] To 200 mg of lorcaserin, 0.51 mL of 4 mol/L HCl and 248 mg of benzoic acid, 2 mL of ethyl acetate was added to form a mixed system, the mixed system was stirred for 20 hours, filtered, dried at 40° C. for 2 hours, 65 mg of the cocrystal was obtained, the molar yield was 17.2%.

Example 19

[0119] To 200 mg of lorcaserin, 1.02 mL of 1 mol/L HCl and 372 mg of benzoic acid, 1 mL of acetone was added to form a mixed system, the mixed system was stirred for 10 hours, filtered, dried at 40° C. for 2 hours, 48 mg of the cocrystal was obtained, the molar yield was 12.7%.

Example 20

[0120] To 200 mg of lorcaserin, 1.02 mL of 1 mol/L HCl and 372 mg of benzoic acid, 2 mL of dichloromethane was added to form a mixed system, the mixed system was stirred for 24 hours, filtered, dried at 40° C. for 1 hours, 54 mg of the cocrystal was obtained, the molar yield was 14.3%,

[0121] XRPD patterns and IR patterns (not shown) of the samples prepared in Examples 3˜20 were the same as or similar to those of the sample cocrystal prepared in Example 1, indicating the crystalline forms obtained in examples 3˜20 were the same as that of Example 1.

Test Example 1

[0122] Compared with lorcaserin hydrochloride hemihydrate prepared in the preparation example 1, the solubility of the cocrystal in the present invention was tested.

[0123] The operating procedures were detailed as follows:

[0124] Respectively, take 10 mg of the known lorcaserin hydrochloride hemihydrate or the cocrystal in the present invention as the sample, pure water was gradually added into each sample at 25° C. until the sample was completely dissolved, then solubility of the sample was calculated according to weights of the sample and water. The results were shown in Table 3.

TABLE-US-00004 TABLE 3 Results of the solubility Samples Solubility (mg/mL) Cocrystal (the present invention) 8~9 mg/ml Lorcaserin hydrochloride hemihydrate (the known) >200 mg/ml

[0125] The results of the solubility in Table 3 showed the solubility of the cocrystal in the present invention (8˜9 mg/m1) is obviously lower than that of the known lorcaserin hydrochloride hemihydrate (>200 mg/ml), indicating that the cocrystal in the present invention is more suitable for preparing sustained-release formulations.

Test Example 2

[0126] Compared with tablets of lorcaserin hydrochloride hemihydrate prepared in the preparation example 1, tablets of the cocrystal in the present invention were prepared, tablet formulas were shown in Table 4; dissolution rate of the tables were tested.

TABLE-US-00005 TABLE 4 Tablet Formulas Prescription Prescription No. 1 No. 2 Starting materials (mg/tablet) (mg/tablet) Core Crystalline Form III (the known) 25 — Cocrystal (the present invention) — 39 Mannitol 81.2 74.2 HPMC K4M 180 180 Avicel PH102 72 65 Magnesium stearate 1.8 1.8 Total of core 360 360 Coating Surelease ®/Opadry ®75/25 18 18 Total 378 378 Note: API is equivalent to 20 mg of lorcaserin hydrochloride free base.

[0127] The tablets were prepared by the following procedures: based on formulas of Table 4, prescribed API (either the known crystalline Form III or the cocrystal in the present invention), mannitol, HPMC K4M and Avicel PH102 were well mixed, magnesium stearate was added and mixed well; and then the mixture was compressed into tablet cores in a tablet machine. The tablet cores were coated by 5% weight in a coating machine, the coating liquid was Sureleaseg/Opadry®75/25 with 12% (w/v) of solid content.

[0128] The dissolution test of tablets was conducted according to USP dissolution test apparatus I (basket method) in 900mL of 0.1N HCl solution at 37° C. and the stirring rate of 100 rpm. Samples were withdrawn at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 14 hours, the concentration of the dissolution liquid of tablets was determined by HPLC, the cumulative release percentage was calculated. The results were shown in Table 5.

TABLE-US-00006 TABLE 5 Cumulative release percentage of tablets Cumulative release percentage of tablets (%) Formulation No. 1 (the known Formulation No. 2 (the Time lorcaserin hydrochloride cocrystal in the present (hours) hemihydrate crystalline Form III) invention) 1 10.2 3.5 2 26.1 13.8 3 38.7 17.6 4 50.5 37.7 6 66.8 56.4 8 80.2 70.2 10 89.1 82.8 12 93.6 90.1 14 97.5 95.7

[0129] The results shown in Table 5 indicated that, under the same formulation, the release rate of tablets of the known lorcaserin hydrochloride hemihydrates in pH=1.0 aqueous hydrochloric acid was faster than that of the cocrystal in the present invention, so the cocrystal in the present invention is more suitable for preparing sustained-release formulations. On the other hand, compared with the coating-controlled release rate, the release rate of the cocrystal formulation in the present invention has less dependence on the coating due to its own slower dissolution, so that influences on the release rate caused by coating processes (such as coating thickness, coating continuity) and different batches of coating material may be avoided.

Test Example 3

[0130] The lorcaserin hydrochloride hemihydrate crystalline Form III prepared in preparation example 1 and the cocrystal in the present invention were compared in stability test for 10 days under conditions of high temperature and light exposure. The high temperature is 80° C., the lighting condition is 60001 lx illumination. Purities and the maximum individual impurity contents of samples before and after the stability test were detected by HPLC. The results were shown in Table 6.

TABLE-US-00007 TABLE 6 The stability testing under conditions of high temperature and light exposure 10 days under conditions of high 0 day temperature and light exposure changed value The maximum Increase in maximum individual maximum individual impurity Decrease in individual HPLC purity impurity value HPLC purity content HPLC purity impurity value Compounds (A %) (A %) (A %) (A %) (A %) (A %) Lorcaserin 99.4 0.1 90.1 9.4 9.3 9.3 hydrochloride hemihydrate crystalline Form III Cocrystal in Lorcaserin 67.5 0.1 Lorcaserin 62.8 4.9 Lorcaserin 4.7 4.8 the present Benzoic 32.0 Benzoic 31.7 Benzoic 0.3 invention acid acid acid

[0131] The stability data shown in Table 6 indicated that, under conditions of high temperature and light exposure, the purity of lorcaserin hydrochloride hemihydrate crystalline Form III was decreased by 9.3%, its maximum individual impurity content was increased by 9.3%; while the purity of lorcaserin in the cocrystal of the present invention was decreased by 4.7%, benzoic acid in the cocrystal thereof was decreased by 0.3%, its maximum individual impurity was increased by 4.8%. Therefore, the stability of the cocrystal in present invention under conditions of high temperature and light exposure is much better than that of the known lorcaserin hydrochloride hemihydrate crystalline Form III.

[0132] The described above are only specific embodiments for illustrating the present invention, but without limiting it thereto. Any changes or alternations, without creative work, made by those skilled in the art within the technical scope disclosed by the present invention, should fall within the scope of the present invention.