WO2015096119A1 - Lorcaserin salts and crystals thereof, preparation methods and uses thereof - Google Patents

Abstract

Disclosed in the present application are the following crystals of Lorcaserin: sulfamate, stearate, cholate, 4-aminobenzene sulfonate, or terephthalate, and the preparation methods and pharmaceutical compositions thereof, and the uses thereof in the preparation of drugs for treating and/or preventing diseases associated with 5HT2c, such as obesity. The release rate index in water of sustained release tablets of the crystals has improved properties.

Description

 Chlorocyanine salt and crystal thereof, preparation method and use thereof

 Technical field

 This application relates to the field of medicinal chemical crystallization technology. Specifically, it relates to lorcaserin salt and a body thereof, and to a method for preparing the salt and crystal thereof, a pharmaceutical composition thereof and use thereof. Background technique

 The chemical name of lorcaserin is (R)-8-chloro-1-indolyl-2,3,4,5-tetrahydro-1H-3-benzazepine, the name is Lorcaserin, aka APD356 , its structural formula is as follows:

 Chloracillin is a new type of dietetic drug developed by Arena Pharmaceuticals of the United States. It is a selective serotonin (5-HT) 2C receptor agonist. The 5-HT2C receptor is highly expressed in the central nervous system, and the physiological effects involve the production of hydrocephalus, the pathophysiology of anxiety, the eating behavior, and the energy balance of the body. By modulating the activity of 5HT2C receptors, lorcaserin can help obese patients to induce satiety, reduce food intake, and promote weight loss. The US Food and Drug Administration (FDA) approved the listing of lorcaserin on June 27, 2012, becoming the first new weight-loss prescription drug approved for sale in the United States in 13 years. The marketed dosage form is an oral immediate release tablet of lorcaserin hydrochloride hemihydrate, the dosage is 10 mg, the trade name is Belviq, suitable for overweight people with adult body mass index BMI>30, or BMI≥27 and at least one weight-related disease. Obese patients (such as hypertension, hyperlipidemia or type 2 diabetes). Chlorocycline is also indicated for the treatment or prevention of other central nervous system diseases mediated by 5-HT.

 Patent Document US 6,953,787 discloses racemic lorcaserin and a process for its preparation.

 Patent document WO2005/019179 discloses hydrochloride and L-(+)-tartrate of lorcaserin and a process for its preparation.

 Patent document WO2006/069363 discloses clocaserin hydrochloride hemihydrate (referred to as Form III), two anhydrates (referred to as Form I and Form II) and methods for their preparation, and discloses Form I and Form II are hygroscopic, and are easily hygroscopically converted to stable Form III; Form III has a moisture absorption of less than 0.5% and the crystal form is most stable.

The XRPD pattern of chlorocartosine hydrochloride hemihydrate crystal form III shows that it is a crystalline solid; the PLM diagram shows that the particles are small and irregular; the TGA pattern shows 3.68% weight loss, and begins to decompose above 170 °C; The DSC chart shows that there is an endothermic peak between 70-90 °C, which is caused by the removal of crystallization water. After dehydration, it is converted into crystal form I, which melts and decomposes at 200.1 °C. The solubility of crystal form III in water is 4艮, At 25 ° C 200mg/ml; crystalline bismuth is released faster in sustained-release materials, does not reach the release index of sustained-release tablets, and is not suitable for the preparation of sustained-release preparations.

 Patent document WO2011/153206 discloses chlorocarbazone hydrochloride anhydrate form IV and a process for its preparation, which is believed to be most stable at room temperature in known chlorhexidine hydrochloride anhydrate. . Form IV can be converted to hemihydrate form III or anhydrate form II.

 Patent document WO 2012/030951 discloses hydrogen sulphate, hemisulfate, sulfonium sulfonate, hydrobromide, nitrate, sesquioxalate eutectic, adipate, malonate of lorcaserin , semi-malonate, glycolate and its preparation method, and its characterization data is disclosed. The patent document states that the above chlorocarbazone salt is very water-soluble and is suitable for preparing an immediate release dosage form.

 Patent document WO 2012/030957 discloses solvates of lorcaserin phosphate, hemi-ethanedisulfonate, citrate, heptanoate, succinate, ketoglutarate, ketoglutarate and Its preparation method and its characterization data are disclosed. The patent document states that the crystal of the above chlorhexidine salt is stable to moisture and is suitable for solid preparation applications.

 In order to meet the strict requirements of different pharmaceutical preparations for the form of active substances, there is still a need in the art to develop a clocaserin solid salt and a crystal thereof which can prolong the efficacy and are suitable for sustained release preparations, so as to ensure that the medicine can be used for a long time in a patient. Play a role, reduce the number of medications and improve the clinical efficacy of patients. Summary of the invention

 In view of the deficiencies of the prior art, it is an object of the present application to provide novel solid chlorocalyxine salts and crystals or crystal forms thereof. Compared with the prior art, the lorcaserin salt of the present application and its crystal or crystal form should have one or more improved properties, particularly in improving hygroscopicity, improving thermal stability, improving solubility, and being more suitable. The application of sustained release preparations and the like. Another object of the present application is to provide a process for the preparation of the chlorocalyxin salt and its crystal or crystal form, a pharmaceutical composition comprising the lorcaserin salt and crystal or crystal form thereof, and a preparation thereof for use in the preparation of a treatment And/or use in the prevention of 5-HT mediated disorders such as obesity, other central nervous system disorders.

 Accordingly, one of the contents of the present application is to provide lorcaserin sulfamate and crystals thereof, and processes for their preparation.

 The lorcaserin sulfamate is a compound formed by chlorocartosine and sulfamic acid in a molar ratio of about 1:1, and the structural formula is as follows:

The preparation method of the cyclaline sulfamate comprises the following steps: mixing a solution of lorcaserin in a soluble solvent with an amino acid, reacting, filtering after completion of the reaction, and concentrating the filtrate. The lorcaserin sulfamate is obtained.

Preferably, said soluble solvent is selected from alcohols, esters, ketones or mixtures thereof, more preferably Cr ^^ alcohols, C ₃ ~C ₅ esters, C ₃ ~C _5-one or mixtures thereof; the alcohol may be CH ^ It is decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol. The C ₃ ～ C ₅ ester can be ethyl decanoate, decyl acetate, ethyl acetate, propyl acetate, isopropyl acetate. Ester, ethyl propionate or ethyl isopropylate, the C ₃ -C ₅ ketone may be acetone, butanone, 2-pentanone or 3-pentanone.

 Preferably, the molar ratio of lorcaserin to sulfamic acid is 1:1 to 1:3.

 Preferably, the filtrate is concentrated to dryness by spin-drying.

 The crystal of cyclaline sulfamate (hereinafter referred to as "sulfamate crystal") is irradiated with Cu-Κα, and the X-ray powder diffraction pattern of the sulfamate crystal is at a diffraction angle of 2 Θ of 5.9. Division 0.2. 6.1 士 0.2. , 1 1.8 ± 0.2. 12.1 ± 0.2. 15.9 士 0.2. And 21.2 ± 0.2. There are characteristic peaks.

 Preferably, the X-ray powder diffraction pattern of the sulfamate crystal is at a diffraction angle of 2 Θ of 5.9 ± 0.2 °, 6.1 ± 0.2 °, 11.8 ± 0.2 °, 12.1 ± 0.2 °, 15.9 ± 0.2 °, 18.2 ± 0.2 ° , 19.9 ± 0.2 °, 21.2 ± 0.2. 22.6 ± 0.2. 23.7 ± 0.2. 24.2 ± 0.2. And 26.1 ± 0.2. There are characteristic peaks.

 Further, the X-ray powder diffraction pattern of the sulfamate crystal has characteristic peaks and relative intensities at the following diffraction angles 2Θ:

 Diffraction angle 2Θ relative intensity%

 5.9 ± 0.2 ° 23.0

 6.1 ± 0.2 ° 25.0

 11.8 ± 0.2 ° 36.5

 12.1 ± 0.2. 44.2

 15.9 ± 0.2. 24.0

 18.2 ± 0.2. 14.2

 19.9 ± 0.2. 17.3

 20.5 ± 0.2 ° 21.6

 21.2 ± 0.2. 100.0

 22.6 ± 0.2° 38.3

 23.7 ± 0.2° 30.0

 24.2 ± 0.2 ° 41.5

 26.1 ± 0.2. 28.8

 26.9 ± 0.2. 14.1

 27.4 ± 0.2. 18.1

 27.9 ± 0.2. 18.6

30.0 ± 0.2. 33.1 31.7 ± 0.2 ° 19.9.

 Without limitation, a typical example of the sulfamate crystal has an X-ray powder diffraction pattern as shown in Fig. 4.

 The Fourier infrared pattern of the sulfamate crystal has characteristic peaks at wavenumbers of 3332, 3014, 2864, 1619, 1454, 1254, 1186, 1164, 1042, 823, and 765 cm.

 The actual content of lorcaserin in the crystals of lorcaserin sulfonate was 66.5%, which was equivalent to the theoretical content of 66.8%, indicating that the ratio of lorcaserin to sulfamic acid was about 1:1. .

 The thermogravimetric analysis of the sulfamate crystals showed a decomposition temperature of 241.8 ° C, which is higher than the decomposition temperature of known lorcaserin hydrochloride hemihydrate at 170 ° C.

 The differential thermal analysis of the sulfamate crystals showed a melting point of 128.8 to 136.2 °C. The DVS isotherm adsorption curve of the sulfamate crystal showed a weight change of 2.67% in the range of 20% to 80% relative humidity.

 The sulfamate crystals have a solubility in water at 25 ° C of 29.4 mg/ml, which is lower than the solubility of the known chlorhexidine hydrochloride hemihydrate.

 The above test results show that the chlorocalyxin sulfamate crystal of the present application has better thermal stability than the known chlorhexidine hydrochloride hemihydrate, and is better able to resist pharmaceutical preparations and / or storage, etc. caused by external factors such as ambient temperature, such as uneven content and reduced purity, is more conducive to accurate quantification in the preparation of unit preparations and later transport and storage, and reduce the instability of active substances And the risk of decreased efficacy due to increased levels of impurities. Moreover, the clopidogrel sulfamate crystal of the present application is more suitable for preparing a sustained-release preparation, and the sustained-release preparation can function for a long time in a patient, thereby reducing the number of administrations and improving the clinical efficacy of the patient.

 The preparation method of the chlorocartosamine sulfamate crystal comprises the following steps: mixing an alcohol solution of lorcaserin with sulfamic acid to carry out a reaction, filtering after completion of the reaction, concentrating the filtrate, and adding acetone to crystallize, The cyclaline sulfamate crystals are obtained.

 Preferably, the alcohol is C^CA alcohol, and the Cr^C alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.

 Preferably, the molar ratio of lorcaserin to sulfamic acid is from 1:1 to 1:3, more preferably from 1:1 to 1:1.5.

 Preferably, the temperature of the reaction is -10 to 50 ° C, more preferably 10 to 30 ° C; and the reaction time is 0.5 to 48 hours, more preferably 2 to 8 hours.

 Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; and the crystallization time is 2 to 24 hours, more preferably 16 to 24 hours.

 Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.

Preferably, the ratio of the amount of lorcaserin to acetone is 5 to 200 mg: 1 ml, more preferably For 10~50 mg: 1 ml.

 The sulfamic acid may be added in a solid form, or may be formulated into a suspension or a solution by using the same alcohol solvent as the lorcaserin solution; the ratio of sulfamic acid to alcohol in the system is 5 to 200 mg: 1 ml, Preferably 10~50 mg: 1 ml „

 The filtrate is preferably concentrated to dryness to give an oil.

 The "crystallization" can be carried out by conventional beating or recrystallization in the art. The beating is to stir the suspension to precipitate crystals, and the recrystallization is to stir the solution to crystallize and/or to cool the crystal.

 A second aspect of the present application is to provide lorcaserin stearate and crystals thereof, and a process for their preparation.

 The lorcaserin stearate is a compound formed by a ratio of lorcaserin and stearic acid in a molar ratio of about 1:1, and its structural formula

 The preparation method of the lorcaseolin stearate comprises the following steps: mixing a solution of lorcaserin in a soluble solvent with stearic acid to carry out a reaction, and after the reaction is completed, concentrating the system to obtain the chlorine Carsonine stearate.

Preferably, the soluble solvent is selected from the group consisting of a nitrile, an alcohol, an ester, a ketone, an ether, an alkane or a mixture thereof, more preferably a C ₂ -C ₄ nitrile, a C-C ₄ alcohol, a C ₃ -c ₅ ketone, a c ₃ ~ c ₅ ester, c ₆ ~ c ₇ alkane, c ₄ ~ c ₆ ether or a mixture thereof; the C ₂ ~ C ₄ nitrile may be acetonitrile, propionitrile or butyronitrile, and the C ^ C alcohol may be decyl alcohol or ethanol , n-propanol, isopropanol, n-butanol or isobutanol, c ₃ ~ c ₅ ketone may be acetone, butanone, 2-pentanone or 3-pentanone, C ₃ ~ C ₅ ester may be tannic acid Ethyl ester, decyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl propionate or ethyl isopropylate, C ₆ ~ C ₇ alkane may be n-hexane or n-heptane, c ₄ ~ c _{The 6} ether may be diethyl ether, mercapto tert-butyl ether, mercaptoisobutyl ether, ethyl tert-butyl ether, or propyl ether.

 Preferably, the molar ratio of lorcaserin to stearic acid is 1:1 to 1:3.

 Preferably, the system is concentrated to dryness by spin-drying.

 The crystal of lorcaserin stearate (hereinafter referred to as "stearate crystal"), used

The Cu-Κα radiation, the X-ray powder diffraction pattern of the stearate crystal is 5.6 ± 0.2 at a diffraction angle of 2 。. , 9.8 ± 0.2. 13.8 士 0.2. , 19.5 ± 0.2. 24.1 ± 0.2. And 27.8 ± 0.2. There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the stearate crystals is 5.6 ± 0.2°, 8.5 ± 0.2°, 9.8 ± 0.2°, 12.6 ± 0.2°, 13.8 ± 0.2°, 14.1 ± 0.2° at diffraction angles 2Θ 19.5 ± 0.2 °, 21.1 ± 0.2 °, 24.1 ± 0.2. And 27.8 ± 0.2. There are characteristic peaks. Further, the X-ray powder diffraction pattern of the stearate crystal has characteristic peaks and relative intensities at the following diffraction angles 2Θ:

 Diffraction angle 2Θ relative intensity%

 5.6 士 0.2° 100.0

 8.5±0.2° 4.3

 9.8 ± 0.2° 25.2

 12.6 ± 0.2° 5.1

 13.8 ± 0.2 ° 20.6

 14.1 ± 0.2. 4.9

 19.5 ± 0.2 ° 6.5

 21.1 ± 0.2. 6.4

 24.1 ± 0.2. 14.9

 27.8 ± 0.2 ° 19.9.

 Without limitation, a typical example of the stearate crystal has an X-ray powder diffraction pattern as shown in FIG.

 The Fourier infrared spectrum of the stearate crystal is at a wave number of 2912, 2849, 1681, 1641,

There are characteristic peaks at 1472, 1261, 1104, 1030, 943, 824, 715 and 673 cm.

 The actual content of lorcaserin in lorcaserin crystals was 41.1% by HPLC, which was equivalent to 40.7% of its theoretical content, indicating that the molar ratio of lorcaserin to stearic acid was about 1:1. salt.

 Thermogravimetric analysis of the stearate crystals showed a decomposition temperature of 88.9 °C.

 The differential thermal analysis of the stearate crystals showed a melting point of 53.4 to 54.8 °C.

 The DVS isotherm adsorption curve of the stearate crystal shows: a weight change of 0.03% in the range of 20% to 80% relative humidity, which has lower hygroscopicity than the known chlorhexidine hydrochloride hemihydrate. .

 The stearate crystals have a low solubility in water at 25 ° C and are 2.5 g/ml, so that it is suitable for preparing a sustained release preparation.

 The above test results show that the chlorocalyxate stearate crystal of the present application has lower hygroscopicity than the known chlorhexidine hydrochloride hemihydrate, and is better able to combat pharmaceutical preparations and/or Or the problem of uneven content and low purity caused by external factors such as environmental humidity during storage or the like, which is more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and reduces unstable and impurity content of active substances. The risk of decreased efficacy due to increased content. Further, the lorcaserin stearate crystal of the present application is more suitable for the preparation of a sustained release preparation which can be used for a long period of time in a patient, which can reduce the number of administrations and improve the clinical efficacy of the patient.

The preparation method of the chlorocalyxate stearate crystal comprises the following steps: mixing an alcohol solution of lorcaserin with stearic acid to carry out a reaction, and after the reaction is completed, the system is concentrated, and acetone is added to crystallize to obtain chlorine. Carsonine stearate crystals. Preferably, the alcohol is a CC alcohol, and the C-C ₄ alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.

 Preferably, the molar ratio of lorcaserin to stearic acid is from 1:1 to 1:3, more preferably from 1:1 to 1:1.5.

 Preferably, the temperature of the reaction is -10 to 50 ° C, more preferably 10 to 30 ° C; and the reaction time is 0.5 to 48 hours, more preferably 2 to 8 hours.

 Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; and the crystallization time is 2 to 24 hours, more preferably 16 to 24 hours.

 Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.

 Preferably, the ratio of the amount of lorcaserin to acetone is 5 to 200 mg: 1 ml, more preferably 10 to 50 mg: 1 ml.

 The stearic acid may be added in a solid form, or may be added as a solution by using the same alcohol solvent as the lorcaserin solution; the concentration of the stearic acid alcohol solution is 5 to 200 mg/ml, more preferably 10~ 50 mg/ml.

 The system is preferably concentrated to dryness to give an oil.

 The "crystallization" can be carried out by conventional beating or recrystallization in the art. Among them, the beating is to stir the suspension to precipitate crystals, and the recrystallization is to stir the solution to crystallize and/or to cool and crystallize.

 A third aspect of the present application is to provide lorcaserin cholate and crystals thereof, and a process for their preparation.

 The chromocyanine cholate is a compound formed by the chlorocalyxin and the bile acid in a molar ratio of about 1:1, which is a monohydrate, and its structural formula is as follows:

所述氯卡色林胆酸盐的制备方法， 包括以下步骤： 形成氯卡色林在有机 溶剂和水的混合溶剂中的溶液， 与胆酸混合， 进行反应， 反应完成后将体系 浓缩， 得到所述氯卡色林胆酸盐， 其中所述有机溶剂选自醇、 酯、 酮或其混 合物。

The preparation method of the chromocyanine cholate comprises the steps of: forming a solution of lorcaserin in a mixed solvent of an organic solvent and water, mixing with bile acid, performing a reaction, and concentrating the system after the reaction is completed, thereby obtaining The chromocyanine cholate, wherein the organic solvent is selected from the group consisting of alcohols, esters, ketones, or mixtures thereof.

Preferably, the organic solvent is selected from the group consisting of CH alcohol, C ₃ -C ₅ ester, C ₃ -C ₅ ketone or a mixture thereof; the CH ^ alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, N-butanol or isobutanol, C-C ₅ The ester may be ethyl decanoate, decyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl propionate or ethyl isopropylate, and the C ₃ ～C ₅ ketone may be acetone, butanone, 2 - Pentanone or 3-pentanone.

 Preferably, the volume percentage of water in the mixed solvent is 0.5 to 5% (v/v);

 Preferably, the molar ratio of lorcaserin to cholic acid is 1:1 to 1:3.

 Preferably, the system is concentrated to dryness by spin-drying.

 The crystal of chromocyanine cholate (hereinafter referred to as "cholate crystal") is irradiated with Cu-Κα, and the X-ray powder diffraction pattern of the cholate crystal is 6.7 ± 0.2 at a diffraction angle of 2 。. , 7.3 ± 0.2. , 10.0 ± 0.2. 11.1 ± 0.2. , 12.7 ± 0.2. And 13.4 ± 0.2. There are characteristic peaks.

 Preferably, the X-ray powder diffraction pattern of the cholate crystal is at a diffraction angle of 2 Θ of 6.7 ± 0.2 °, 7.3 ± 0.2 °, 10.0 ± 0.2 °, 11.1 ± 0.2 °, 12.7 ± 0.2 °, 13.4 ± 0.2 °, 13.6 ± 0.2 °, 14.7 ± 0.2 °, 16.0 ± 0.2. , 17.3 ± 0.2. , 17.9 ± 0.2. And 19.9 ± 0.2. There are characteristic peaks.

 Further, the X-ray powder diffraction pattern of the cholate crystal has characteristic peaks and relative intensities at the following diffraction angles 2Θ:

 Diffraction angle 2Θ relative intensity%

 6.7 ± 0.2° 44.7

 7.3±0.2° 32.6

 10.0 ± 0.2. 74.8

 11.1 ± 0.2. 93.0

 12.7 ± 0.2. 94.9

 13.4 ± 0.2. 83.1

 13.6 ± 0.2. 58.6

 14.7 ± 0.2. 63.3

 15.2 ± 0.2. 35.7

 16.0 ± 0.2. 94.6

 17.3士 0.2° 79.5

 17.9 ± 0.2. 100.0

 18.7 ± 0.2 ° 19.2

 19.9 ± 0.2. 99.7

 21.2 ± 0.2. 26.6

 23.1 ± 0.2° 50.4

 24.2 ± 0.2 ° 14.5

 25.1 ± 0.2. 20.8

 25.7 ± 0.2 ° 32.0

 27.5 ± 0.2 ° 23.6

29.2 ± 0.2. 24.3 29.7 ± 0.2 ° 15.8.

 Without limitation, a typical example of the cholate crystal has an X-ray powder diffraction pattern as shown in Fig. 14.

 The Fourier infrared pattern of the cholate crystal has characteristic peaks at wave numbers 2928, 2849, 1569, 1467, 1401, 1375, 1261, 1079, 1045, 948, 816, and 693 cm.

 The actual content of lorcaserin in chromocyanine cholate crystals was 32.2% by HPLC, which was equivalent to the theoretical content of 32.4%, indicating that the ratio of lorcaserin to bile acid was about 1:1. .

 Thermogravimetric analysis of the cholate crystals showed a TGA pattern of 2.98% weight loss before 150 °C and a decomposition temperature of 151.4 °C.

 The differential thermal analysis DSC spectrum of the cholate crystal shows that there is a broad endothermic peak between 32-105 ° C, which is caused by the removal of one crystal water, melting at 166.8 ° C, and turning around 172 ° C. The crystals were melted again at 186.4 °C.

 The DVS isotherm adsorption curve of the cholate crystal showed a weight change of 0.85% in the range of 20% to 80% relative humidity.

 The cholate crystals have a low solubility in water at 25 ° C and are 1.5 mg/ml, so that it is suitable for preparing a sustained release preparation.

 The above test results indicate that the chlorocalylin cholate crystal of the present application has a property more suitable for preparing a sustained-release preparation, which is in a patient, compared with the known chlorhexidine hydrochloride hemihydrate. The body can function for a long time, which can reduce the number of medications and improve the clinical efficacy of patients.

 The method for preparing the chromocyanine cholate crystal comprises the steps of: forming a solution of lorcaserin in a mixed solvent of alcohol and water, mixing with bile acid, performing a reaction, filtering after completion of the reaction, and concentrating the filtrate. Crystallization by addition of diethyl ether gave the chlorocalyptine cholate crystals.

Preferably, the alcohol is Cr ^ alcohols, the C-C ₄ alcohol may be widely Yue, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, and more preferably ethanol.

 Preferably, the volume percentage of water in the mixed solvent is from 0.5 to 5%.

 Preferably, the molar ratio of lorcaserin to cholic acid is from 1:1 to 1:3, more preferably from 1:1 to 1:1.5. Preferably, the temperature of the reaction is -10 to 50 ° C, more preferably 10 to 30 ° C; and the reaction time is 0.5 to 48 hours, more preferably 2 to 8 hours.

 Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; and the crystallization time is 2 to 24 hours, more preferably 16 to 24 hours.

 Preferably, the concentration of the lorcaserin solution is from 5 to 500 mg/ml, more preferably from 10 to 50 mg/ml.

 Preferably, the ratio of the amount of lorcaserin to diethyl ether is 5 to 200 mg: 1 ml, more preferably 10 to 50 mg: 1 ml.

The cholic acid may be added in a solid form or may be the same alcohol solvent as the lorcaserin solution. Formulated as a suspension or solution; the ratio of cholic acid to alcohol in the system is 5~200 mg: 1 ml, preferably 10~50 mg: 1 ml.

 The filtrate is preferably concentrated to dryness to give an oil.

 The "crystallization" can be carried out by conventional beating or recrystallization in the art. Among them, the beating is to stir the suspension to precipitate crystals, and the recrystallization is to stir the solution to crystallize and/or to cool and crystallize.

 The fourth content of the present application is to provide lorcaserin 4-aminobenzenesulfonate and crystals thereof, and a process for the preparation thereof.

 The lorcaserin 4-aminobenzenesulfonate is a compound formed by chlorocartosine and 4-aminobenzenesulfonic acid at a molar ratio of about 1:1, and the structural formula is as follows:

 The preparation method of the chlorokacillin 4-aminobenzenesulfonate comprises the following steps: mixing a solution of lorcaserin in a soluble solvent with 4-aminobenzenesulfonic acid, and stirring the obtained system for 5 to 120 minutes. After filtration, the filtrate was concentrated to obtain the chlorokacillin 4-aminobenzenesulfonate.

Preferably, said soluble solvent is selected from alcohols, esters, ketones, or mixtures thereof, preferably C ^ C alcohols, C ₃ ~C ₅ esters, C ₃ ~C _5-one or mixtures thereof; the alcohol may be C ^ CA It is decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol. The C ₃ ～C ₅ ester can be ethyl decanoate, decyl acetate, ethyl acetate, propyl acetate, isopropyl acetate. Ester, ethyl propionate or ethyl isopropylate, c ₃ ~ c ₅ ketone may be acetone, butanone, 2-pentanone or 3-pentanone.

 Preferably, the molar ratio of lorcaserin to 4-aminobenzenesulfonic acid is 1:1 to 1:3.

 Preferably, the filtrate is concentrated to dryness by spin-drying.

 The crystal of cyclaline 4-aminobenzenesulfonate (hereinafter referred to as "4-aminobenzenesulfonate crystal"), using Cu-Κα radiation, X-ray of the 4-aminobenzenesulfonate crystal The powder diffraction pattern was at a diffraction angle of 2 Θ of 11.4 ± 0.2. , 12.0 ± 0.2. 13.3 ± 0.2. , 16.9 ± 0.2. 20.4 ± 0.2. And 20.7 ± 0.2. There are characteristic peaks.

 Preferably, the X-ray powder diffraction pattern of the 4-aminobenzenesulfonate crystal has a diffraction angle of 2 Θ of 11.4 ± 0.2. , 12.0 ± 0.2. 13.3 ± 0.2. , 13.7 ± 0.2. , 16.9 ± 0.2. 20.4 ± 0.2. 20.7 ± 0.2. 21.0 ± 0.2. 21.6 ± 0.2. 22.5 ± 0.2. 23.2 ± 0.2. And 24.8 ± 0.2. There are characteristic peaks.

 Further, the X-ray powder diffraction pattern of the 4-aminobenzenesulfonate crystal has characteristic peaks and relative intensities at the following diffraction angles 2Θ:

 Diffraction angle 2Θ relative intensity%

11.4 ± 0.2. 13.1 12.0 ± 0.2. 35.3

 13.3±0.2° 21.5

 13.7 ± 0.2° 12.3

 16.9 ± 0.2. 76.7

 20.0 ± 0.2. 11.9

 20.4 ± 0.2. 100.0

 20.7 ± 0.2. 32.4

 21.0 ± 0.2. 28.5

 21.6 ± 0.2. 22.2

 21.8 ± 0.2 ° 22.0

 22.5 ± 0.2. 16.7

 23.2 ± 0.2. 25.7

 24.0 ± 0.2. 17.8

 24.8 ± 0.2 ° 21.2

 25.2 ± 0.2. 16.9

 25.5 ± 0.2. 16.5

 26.6 ± 0.2. 16.9

 Without limitation, a typical example of the crystal of the 4-aminobenzenesulfonate has an X-ray powder diffraction pattern as shown in Fig. 19.

 The Fourier red pattern of the yellow S-salt crystal has characteristic peaks at wave numbers of 3427, 3349, 1641, 1599, 1186, 1171, 1120, 1025, 1003, 934, 896, 829, and 692 cm.

 The actual content of lorcaserin in the crystal of 4-aminobenzenesulfonate of lorcaserin was 52.9%, which was equivalent to the theoretical content of 53.0%, indicating the molar ratio of lorcaserin to 4-aminobenzenesulfonic acid. Approximately 1:1 salt.

 Thermogravimetric analysis of the xanthate crystals showed a decomposition temperature of 214.9 ° C, which is higher than the decomposition temperature of known lorcaserin hydrochloride hemihydrate of 170 ° C.

 The differential thermal analysis DSC pattern of the 4-tt3⁄4S^Jk crystal showed a melting point of 221.8-222.6 °C, which is higher than the melting point of the known chlorocalylin hydrochloride hemihydrate 200.1 °C.

 The DVS isotherm adsorption curve of the 4-aminobenzenesulfonate crystal shows: a weight change of 0.01% in the range of 20% to 80% relative humidity, which is lower than the known chlorocalyptine hydrochloride hemihydrate. Hygroscopicity.

 The 4-aminobenzenesulfonate crystals have a solubility of 9 mg/ml in water at 25 ° C, which is lower than the solubility of the known chlorhexidine hydrochloride hemihydrate.

The above test results show that the chlorocalyx 4-aminobenzenesulfonate crystal of the present application has lower hygroscopicity and better stability than the known chlorhexidine hydrochloride hemihydrate. Can be better The problem of uneven content and reduced purity caused by external factors such as ambient temperature and humidity during the anti-drug preparation and/or storage process is more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and lowering The risk of a decrease in efficacy due to unstable active substance content and increased levels of impurities. Moreover, the chlorocalyx 4-aminobenzenesulfonate crystal of the present application is more suitable for preparing a sustained-release preparation, and the sustained-release preparation can function for a long time in a patient, which can reduce the number of administrations and improve the clinical efficacy of the patient.

 The preparation method of the chlorokacillin 4-aminobenzenesulfonate crystal comprises the following steps: mixing an alcohol solution of lorcaserin with 4-aminobenzenesulfonic acid, filtering the obtained system, and crystallization of the filtrate to obtain The cyclaline 4-aminobenzenesulfonate crystal.

 Preferably, the alcohol is a Cr^C alcohol, and the Cr^C alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.

 Preferably, the molar ratio of lorcaserin to 4-aminobenzenesulfonic acid is 1:1 to 1:3, more preferably 1:1 to 1:1.5.

 Preferably, the resulting system is stirred for 5 to 120 minutes and then filtered, more preferably 10 to 120 minutes; the temperature of the stirring is preferably 10 to 50 ° C, more preferably 10 to 30 ° C.

 Preferably, the temperature of the crystallization is -10 to 10 ° C, more preferably -10 to 0 ° C; and the crystallization time is 0.5 to 48 hours, more preferably 0.5 to 2 hours.

 Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.

 The 4-aminobenzenesulfonic acid may be added in a solid form, or may be formulated into a suspension or a solution by using the same alcohol solvent as the lorcaserin solution; the ratio of 4-aminobenzenesulfonic acid to alcohol in the system is 5 ~200 mg: 1 ml, preferably 10-50 mg: 1 ml.

 The fifth aspect of the present application is to provide lorcaserin terephthalate and crystals thereof, and a process for the preparation thereof.

 The chlorocalyxate terephthalate is a compound formed by a ratio of chlorocamellin and terephthalic acid in a molar ratio of about 1: 1 and has the following structural formula:

 The preparation method of the chlorokacillin terephthalate comprises the following steps: mixing a solution of lorcaserin in a soluble solvent with terephthalic acid, and stirring the obtained system for 0.5-120 minutes, and then filtering The filtrate was concentrated to obtain the chlorocalyxate terephthalate.

 Preferably, the soluble solvent is selected from the group consisting of an alcohol, an ester, a ketone or a mixture thereof, preferably a Cr^C alcohol,

a C ₃ -C ₅ ester, a C ₃ -C ₅ ketone or a mixture thereof; the CH ^ alcohol may be decyl alcohol, ethanol, n-propanol, Isopropanol, n-butanol or isobutanol, c ₃ ~ c ₅ ester may be ethyl decanoate, decyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl propionate or isopropyl acid Ethyl ester, c ₃ ~ c ₅ ketone may be acetone, butanone,

2-pentanone or 3-pentanone.

 Preferably, the molar ratio of lorcaserin to terephthalic acid is 1:1 to 1:3.

 Preferably, the filtrate is concentrated to dryness by spin-drying.

 The crystal of the chlorocalyxate terephthalate (hereinafter referred to as "terephthalate crystal"), using Cu-Κα radiation, the X-ray powder diffraction pattern of the terephthalate crystal The diffraction angle 2Θ is 7.9 ± 0.2. , 12.7 ± 0.2. 13.5 ± 0.2. , 17.3 ± 0.2. 19.6 ± 0.2. And 22.9 ± 0.2. There are characteristic peaks.

 Preferably, the X-ray powder diffraction pattern of the terephthalate crystal is at a diffraction angle of 2 Θ of 7.9 ± 0.2 °, 12.7 ± 0.2 °, 13.5 ± 0.2 °, 17.3 ± 0.2 °, 18.5 ± 0.2 °, 19.6 ± 0.2°, 21.1 ± 0.2. 22.9 ± 0.2. 25.2 ± 0.2. 26.8 ± 0.2. 27.2 ± 0.2. And 27.8 ± 0.2. There are characteristic peaks.

 Further, the X-ray powder diffraction pattern of the terephthalate crystal has a characteristic peak and its relative intensity at the following diffraction angle 2Θ:

 Diffraction angle 2Θ relative intensity%

 7.9 ± 0.2° 45.2

 12.7 ± 0.2. 32.1

 13.5 ± 0.2° 100.0

 17.3 ± 0.2° 53.1

 18.5 ± 0.2. 44.5

 19.6 ± 0.2 ° 62.7

 21.1 ± 0.2. 20.1

 22.9 ± 0.2. 63.6

 25.2 ± 0.2 ° 22.1

 26.8 ± 0.2. 35.2

 27.2 ± 0.2° 35.7

 27.8 ± 0.2 ° 44.5.

 Without limitation, a typical example of the terephthalate crystal has the structure shown in FIG.

X-ray powder diffraction pattern.

 The Fourier infrared spectrum of the terephthalate crystals has characteristic peaks at wavenumbers of 1678, 1424, 1398, 1286, 1011, 933, 881, 814, 740 and 647 cm.

 The actual content of lorcaserin in the crystal of chlorhexidine in the benzoate crystal was 54.2%, which was equivalent to the theoretical content of 54.1%, indicating that the molar ratio of lorcaserin to terephthalic acid was about 1 : 1 into salt.

The thermogravimetric analysis TGA spectrum of the terephthalate crystal shows: the decomposition temperature is 181.8 ° C, It has a decomposition temperature higher than 170 ° C than the known chlorocartosine hydrochloride hemihydrate.

 The differential thermal analysis DSC pattern of the terephthalate crystals showed a melting point of 251.2 ° C, which is higher than the melting point of known lorcaserin hydrochloride hemihydrate 200.1 ° C.

 The DVS isotherm adsorption curve of the terephthalate crystal shows: the weight change is 0.06% in the range of 20%~80% relative humidity, which has lower moisture absorption than the known chlorhexidine hydrochloride hemihydrate. Sex.

 The terephthalate crystals have a low solubility in water at 25 ° C of 11.5 g/ml, and thus are more suitable for the preparation of sustained release preparations.

 The above test results show that the chlorocalyx of the present application has lower hygroscopicity and better stability than the known chlorhexidine hydrochloride hemihydrate, and can It is better to deal with problems such as uneven content and low purity caused by external factors such as ambient temperature and humidity during the preparation and/or storage of pharmaceutical preparations, and is more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations. And reduce the risk of decreased efficacy caused by unstable active substance content and increased impurity content. Moreover, the lorcaserin crystal of the present application is more suitable for preparing a sustained-release preparation, and the sustained-release preparation can function for a long time in a patient, thereby reducing the number of administrations and improving the clinical efficacy of the patient.

 The preparation method of the chromocyanine terephthalate crystal comprises the following steps: mixing an alcohol solution of lorcaserin with terephthalic acid, filtering the obtained system, and crystallization of the filtrate to obtain the Chlorosylin p-benzoate crystals.

 Preferably, the alcohol is a Cr^C alcohol, and the Cr^C alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.

 Preferably, the molar ratio of lorcaserin to terephthalic acid is from 1:1 to 1:3, more preferably from 1:1 to 1.5.

 Preferably, the resulting system is stirred for 5 to 120 minutes, followed by filtration, more preferably for 10 to 120 minutes; and the stirring temperature is preferably -10 to 50, more preferably 10 to 30 °C.

 Preferably, the crystallization temperature is -10 to 20 ° C, more preferably -10 to 0 ° C; and the crystallization time is 0.5 to 24 hours, more preferably 16 to 24 hours.

 Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.

 The terephthalic acid may be added in a solid form, or may be formulated into a suspension or a solution by using the same alcohol solvent as the chlorocalyxin solution; the ratio of the terephthalic acid to the alcohol in the system is 5 to 200. Mg: 1 ml, preferably 10 to 50 mg: 1 ml.

 The sixth content of the present application is to provide chlorocartosine hydrochloride anhydrous crystal form VI (hereinafter referred to as "hydrochloride salt-free type VI") and a preparation method thereof.

The hydrochloride salt is free of crystalline form VI, which is a combination of lorcaserin and hydrochloric acid in a molar ratio of about 1:1. The X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form VI was 11.5 ± 0.2 at a diffraction angle of 2 Å, using Cu-Κα radiation. , 13.9 ± 0.2. , 16.0 ± 0.2. 22.5 ± 0.2. , 23.1 ± 0.2. 23.4 ± 0.2. And 25.5 ± 0.2. There are characteristic peaks.

 Preferably, the X-ray powder diffraction pattern of the hydrochloride salt-free crystal form VI is 11.5 ± 0.2 at a diffraction angle of 2 。. , 13.9 ± 0.2. , 16.0 ± 0.2. 18.3 ± 0.2. 22.5 ± 0.2. 23.1 ± 0.2. 23.4 ± 0.2. 23.6 ± 0.2. 23.9 ± 0.2. 25.3 ± 0.2. , 25.5 ± 0.2. And 27.9 ± 0.2. There are characteristic peaks.

 Further, the X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form VI has characteristic peaks and relative intensities at the following diffraction angles 2Θ:

 Diffraction angle 2Θ relative intensity%

 11.5 ± 0.2. 100.0

 13.9 ± 0.2° 31.2

 16.0 ± 0.2 ° 21.3

 18.3 ± 0.2. 11.5

 22.5 ± 0.2 ° 47.9

 23.1 ± 0.2° 38.7

 23.4 ± 0.2° 50.7

 23.6 ± 0.2 ° 26.2

 23.9 ± 0.2° 22.3

 25.3 ± 0.2 ° 16.0

 25.5 ± 0.2° 39.8

 27.7 ± 0.2° 14.1

 27.9 ± 0.2° 36.8

 29.9 ± 0.2 ° 21.2.

 Without limitation, a typical example of the hydrochloride salt-free type VI has an X-ray powder diffraction pattern as shown in FIG.

 Thermogravimetric analysis of the hydrochloride salt-free VI The TGA pattern shows that the sample is anhydrate and begins to decompose above 170 °C.

 The differential thermal analysis DSC pattern of the hydrochloride anhydrous crystal type VI shows that the sample has a crystal transformation peak between 140 ° C and 157 ° C, and is converted to chlorocalyx hydrochloride anhydrate crystal form I. Melt decomposition at 200 ° C.

 The DVS isotherm adsorption curve of the hydrochloride anhydrous crystal type VI shows that the sample can be stably existed under the relative humidity of 30% or less, and starts to change to the chlorocalyxine hydrochloride hemihydrate crystal form III at a relative humidity of 30% or more. After forming Form III, it is no longer possible to switch back to Form VI.

The preparation method of the hydrochloride salt-free crystal type VI comprises the following steps: forming a slurry of lorcaserin hydrochloride hemihydrate crystal form III in a mixed solvent of anhydrous anthracene cyclohexane and absolute ethanol, Crystallization gave the chlorocalyxine hydrochloride anhydrous crystalline form VI. Preferably, the volume ratio of the anhydrous nonylcyclohexane to absolute ethanol is from 30:1 to 50:1, more preferably from 40:1 to 50:1.

 Preferably, the ratio of the crystalline form III of lorcaserin hydrochloride to the total amount of solvent is 1 mg: 4 ml to 1 mg: 20 ml, more preferably 1 mg: 10 ml to 1 mg: 20 ml.

 Preferably, the crystallization temperature is -10 to 50 ° C, more preferably 10 to 30 ° C; and the crystallization time is 0.5 to 72 hours, more preferably 10 to 72 hours.

 Seventh aspect of the present application is to provide chlorocartosine hydrochloride anhydrous crystal form V (hereinafter referred to as "hydrochloride salt-free type V") and a preparation method thereof.

 The hydrochloride salt crystal free form V is a compound formed by chlorocalyx and hydrochloric acid in a molar ratio of about 1:1, using Cu-Κα radiation, and the X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form V is The diffraction angle 2 Θ was 14.2 ± 0.2. 14.9 ± 0.2. 15.4 士 0.2. , 16.6 ± 0.2. , 19.4 ± 0.2. And 20.2 ± 0.2. There are characteristic peaks.

 Preferably, the X-ray powder diffraction pattern of the hydrochloride salt-free crystal form V is at a diffraction angle of 2 Θ of 14.2 ± 0.2 °, 14.9 ± 0.2 °, 15.4 ± 0.2 °, 16.6 ± 0.2 °, 17.7 ± 0.2 °, 18.8 ± 0.2°, 19.4 ± 0.2°, 20.2 ± 0.2. 21.7 ± 0.2. , 23.3 ± 0.2. 24.9 ± 0.2. And 26.2 ± 0.2. There are characteristic peaks.

 Further, the X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form V has characteristic peaks and relative intensities at the following diffraction angles 2Θ:

 Diffraction angle 2Θ relative intensity%

 14.2 ± 0.2. 27.1

 14.9 ± 0.2. 13.8

 15.4 ± 0.2° 16.9

 16.6 ± 0.2° 18.8

 17.7 士 0.2° 11.7

 18.8 ± 0.2° 15.8

 19.4 ± 0.2° 100.0

 20.2 ± 0.2 ° 53.6

 21.7 ± 0.2° 17.1

 22.5 ± 0.2 ° 14.3

 23.3 ± 0.2° 30.0

 24.1 ± 0.2° 17.8

 24.9 ± 0.2 ° 23.9

 26.2 ± 0.2 ° 23.6

 28.4 ± 0.2 ° 12.7

 34.8 ± 0.2. 14.7.

Without limitation, a typical example of the hydrochloride salt-free crystal form V has the structure shown in FIG. X-ray powder diffraction pattern.

 Thermogravimetric analysis of the hydrochloride salt-free V-TGA spectrum shows that the sample is anhydrate and begins to decompose above 170 °C.

 The differential thermal analysis DSC pattern of the hydrochloride anhydrous crystal form V shows: the sample has a crystal transformation peak between 140-155 ° C, and is converted to chlorocalyx hydrochloride anhydrate crystal form I at 200 ° C melt decomposition.

 The DVS isotherm adsorption curve of the hydrochloride anhydrous crystal V shows that the sample can be stably existed under the relative humidity of 40% or less, and starts to transform into the chlorocalyxine hydrochloride hemihydrate crystal form III at a relative humidity of 40% or more. After the formation of the crystal form III, it is impossible to switch back to the form V.

 The preparation method of the chlorokacillin hydrochloride anhydrous crystal form V comprises the following steps: forming a mixture of chlorocalyxine hydrochloride hemihydrate crystal form III in anhydrous decylcyclohexane and anhydrous decyl alcohol The slurry in the solvent was subjected to crystallization to obtain the chloro-calylin hydrochloride anhydrous crystal form V.

 Preferably, the volume of anhydrous nonylcyclohexane and anhydrous decyl alcohol in the mixed solvent is

30:1-50:1 , more preferably 40:1 to 50:1.

 Preferably, the ratio of the crystalline form III of lorcaserin hydrochloride to the total amount of solvent is 1 mg: 4 to 20 ml, more preferably 1 mg: 10 to 20 ml.

 Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; and the crystallization time is 0.5 to 70 hours, more preferably 10 to 72 hours.

 The various chlorocarbazone salts prepared in the present application, as well as their crystals or crystal forms, are isolated and dried by methods conventional in the art. The "separation" method, such as filtration or centrifugation; the specific operation of the filtration is: placing the sample to be separated on the filter paper and vacuum filtration; the specific operation of the centrifugation is: placing the centrifuge tube containing the sample to be separated In the centrifuge, rotate at high speed until the solids all sink to the bottom of the centrifuge tube at a rate of, for example, 6000 rpm. The "drying" method, for example, blast drying, reduced pressure drying, etc.; drying may be carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09 MPa; drying temperature is 30 to 50 ° C; drying time is 10 to 72 hours, Preferably, it is 10 to 48 hours, more preferably 10 to 24 hours; and the drying equipment is equipped with a fume hood, a blast oven or a vacuum oven.

 Compared with the prior art chlorhexacillin salt and its crystal form, especially the chlorhexacillin salt of the present application and its crystal or crystal form, compared to the known chlorhexidine hydrochloride hemihydrate. It has one or more improved properties, particularly in terms of improving stability, improving hygroscopicity, improving solubility, and being more suitable for sustained release formulation applications. In addition, the preparation method of the chlorocarbazone salt and the crystal or crystal form thereof of the present application is simple, and is carried out at room temperature or low temperature by a conventional operation, and is suitable for industrial application.

In the present application, "crystal" or "crystalline" means confirmed by the X-ray powder diffraction pattern representation. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity. The map will usually change with the instrument conditions. The relative intensity of the peaks may vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor; experimental errors of peak angles should also be taken into account, typically ±0.2. Error; the influence of experimental factors such as sample height will cause The peak angle is offset overall and usually allows a certain offset. Thus, it will be understood by those skilled in the art that any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present application is within the scope of the present application. The "single crystal form" means a single crystal form as detected by X-ray powder diffraction.

 The crystal or crystalline form of the lorcaserin salt described herein is pure, unitary, and substantially free of any other crystal, crystalline or amorphous form. In the present application, "substantially free" when used to refer to a new crystal or a new crystal form, means that the other crystal, crystal form or amorphous state contained therein is less than 20% by weight, more preferably less than 10% by weight. In particular, it means less than 5% by weight, especially less than 1% by weight.

 In the present application, "room temperature" means about 10 to 25 °C.

 The preparation method of the present application is usually carried out under stirring unless otherwise specified. The "stirring" may be carried out by a conventional method known in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm.

 In the present application, the "crystal slurry" means that the sample is stirred in a supersaturated solution (in the presence of insoluble solids) at different temperatures in different solvent systems.

 In the present application, the "concentration to dry" is a way of removing the solvent, and may be carried out by a method conventional in the art, such as spin drying, evaporation, nitrogen drying; preferably "spinning", the specific operation is: The sample solution or suspension is placed on a rotary evaporator and spun at 20 to 60 °C. In the present application, the "water-free substance" means that the sample contains not more than 1.5% by weight, or not more than 1.0% by weight, of water as measured by TGA.

 In the present application, lorcaserin can be obtained by referring to Example 1-5 of the patent document WO2005/019179 or commercially available, and chlorocartosine hydrochloride crystal form III can be referred to the example 1 of the patent document WO2006/069363. 2, made.

 Further, the present application provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more chlorokacillin salts selected from the present application, and crystals or crystal forms thereof, or by the present application a chlorocarbazone salt obtained by the preparation method, and a crystal or crystal form thereof, and at least one pharmaceutically acceptable carrier, wherein the chlorokacillin salt of the present application and the crystal or crystal form thereof include lorcaserin amino Sulfonate and its crystals, lorcaserin and its crystals, lorcaserin and its crystals, lorcaserin 4-aminobenzenesulfonate and its crystals, lorcaserin Benzoate and its crystals, lorcaserin hydrochloride anhydrous crystalline form VI or lorcaserin hydrochloride no crystalline form V. Furthermore, the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms, amorphous forms or salts of lorcaserin. Optionally, the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.

The pharmaceutically acceptable carriers described herein include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbus Alcohol, sugar, etc.; binders such as acacia, guar, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, etc.; disintegrants, such as starch, Sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, Colloidal silica or the like; a lubricant such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; a glidant such as colloidal silica; a complex forming agent, for example Various grades of cyclodextrin and resin; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl fluorenyl cellulose, ethyl cellulose, fluorenyl cellulose, bismuth methacrylate Ester, wax, etc. Other pharmaceutically acceptable carriers that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.

 The pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including solutions, syrups, suspensions, dispersions, and emulsions. Injectable preparations, including solutions, dispersions, and lyophilizates. The formulation may be suitable for immediate release, sustained release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation. Routes of administration include oral, intravenous, subcutaneous, transdermal, rectal, nasal, and the like. Ready. Preparation The chromophyllin salt of the present application and its crystal or form are mixed with one or more pharmaceutically acceptable carriers, optionally one or more other active ingredients. The solid preparation can be prepared by a process such as direct mixing, granulation, or the like.

Further, the present application provides the use of the lorcaserin salt of the present application and its crystal or crystal form for the preparation of a medicament for the treatment and/or prevention of a disease associated with 5HT _2e .

Further, the present application provides a method of treating and/or preventing a condition associated with 5HT _2c , the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more chlorine species selected from the present application. The chromophore salt and its crystal or crystal form or the above pharmaceutical composition comprising the lorcaserin salt of the present application and its crystal or crystal form; the patient refers to a mammal including a human. The chlorokacillin salt of the present application and its crystal or crystal form include lorcaserin sulfamate and crystals thereof, lorcaserin stearate and crystals thereof, chlorhexidine cholate and crystals thereof , lorcaserin 4-aminobenzenesulfonate and its crystals, lorcaserin p-benzoate and its crystals, lorcaserin hydrochloride anhydrous crystalline form VI or lorcaserin hydrochloride Crystal type V.

The above conditions associated with 5HT _2c include, but are not limited to, obesity, central nervous system disorders, central nervous system damage, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, sleep apnea, depression, atypical depression, biphasic Disorders, anxiety disorders, obsessive-compulsive disorder, social phobia or panic disorder, sleep disorders, sexual dysfunction, psychosis, schizophrenia, migraine and conditions associated with head pain or other pain, increased intracranial pressure, epilepsy , personality disorder, 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. DRAWINGS

Figure 1 is an XRPD pattern of lorcaserin hydrochloride hemihydrate prepared in Comparative Example 1. Figure 2 is a TGA diagram of lorcaserin hydrochloride hemihydrate prepared in Comparative Example 1. Figure 3 is a DSC chart of chlorhexidine hydrochloride hemihydrate prepared in Comparative Example 1. Figure 4 is an XRPD pattern of the cyclaline sulfamate crystal of the present invention.

Figure 5 is a TGA diagram of the cyclaline sulfamate crystal of the present invention.

Figure 6 is a DSC chart of the cyclaline sulfamate crystal of the present invention.

Figure 7 is a DVS diagram of the cyclaline sulfamate crystal of the present invention.

Figure 8 is an IR chart of the cyclaline sulfamate crystal of the present invention.

Figure 9 is an XRPD pattern of the lorcaserin stearate crystal of the present invention.

Figure 10 is a TGA diagram of the crystal form of lorcaserin hydrochloride of the present invention.

Figure 11 is a DSC chart of the lorcaserin stearate crystal of the present invention.

Figure 12 is a DVS diagram of the lorcaserin stearate crystal of the present invention.

Figure 13 is a IR image of the lorcaserin stearate crystal of the present invention.

Figure 14 is an XRPD pattern of the chromocyanine cholate crystal of the present invention.

Figure 15 is a TGA diagram of the chromocyanine cholate crystal of the present invention.

Figure 16 is a DSC chart of the chromocyanine cholate crystal of the present invention.

Figure 17 is a DVS diagram of the chromocyanine cholate crystal of the present invention.

Figure 18 is an IR chart of the chromocyanine cholate crystal of the present invention.

Figure 19 is an XRPD pattern of the chlorokacillin 4-aminobenzenesulfonate crystal of the present invention. Figure 20 is a TGA diagram of the chlorokacillin 4-aminobenzenesulfonate crystal of the present invention.

Figure 21 is a DSC chart of the chlorokacillin 4-aminobenzenesulfonate crystal of the present invention.

Figure 22 is a DVS diagram of the chlorokacillin 4-aminobenzenesulfonate crystal of the present invention.

Figure 23 is an IR chart of crystals of lorcaserin 4-aminobenzenesulfonate of the present invention.

Figure 24 is an XRPD pattern of chlorhexidine phthalate crystal of the present invention.

Figure 25 is a TGA diagram of the chromocyanine terephthalate crystal of the present invention.

Figure 26 is a DSC chart of the chromocyanine terephthalate crystal of the present invention.

Figure 27 is a DVS diagram of the chromocyanine terephthalate crystal of the present invention.

Figure 28 is an IR chart of the chromocyanine terephthalate crystal of the present invention.

Figure 29 is an XRPD pattern of the chlorokacillin hydrochloride form VI of the present invention.

Figure 30 is a TGA diagram of the chlorocarbazone hydrochloride Form VI of the present invention.

Figure 31 is a DSC chart of the chlorokacillin hydrochloride Form VI of the present invention.

Figure 32 is a DVS diagram of the chlorocarbazone hydrochloride Form VI of the present invention.

Figure 33 is an XRPD pattern of the crystal form V of lorcaserin hydrochloride of the present invention.

Figure 34 is a TGA diagram of the crystalline form V of lorcaserin hydrochloride of the present invention. Figure 35 is a DSC chart of the crystalline form V of lorcaserin hydrochloride of the present invention.

 Figure 36 is a DVS diagram of the crystalline form V of lorcaserin hydrochloride of the present invention. detailed description

 The present application further refers to the following examples which describe in detail the compounds of the present application and their crystals or crystal forms, their preparation and use. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the application.

 Testing equipment and methods:

 The X-ray powder diffraction (XPRD) instrument used was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a 40 kV and 40 mA operating condition, a Θ-2Θ goniometer, Mo Monochromator, Lynxeye detector. Before using the instrument, correct the peak position with the standard sample that comes with the instrument. The software is Diffrac Plus XRD Commander and the analysis software is MDI Jade 5.0. The sample is tested at room temperature and the sample to be tested is placed on an organic slide. The detailed detection conditions are as follows: Angle range: 3 to 40 ° 2 Θ; Step: 0.02 ° 2 Θ; Speed: 0.2 sec / step. Samples were not ground prior to testing unless otherwise stated.

The differential thermal analysis (DSC) data is from the TA Instruments Q200 MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually take 1~10 mg of sample and place it in aluminum crucible with capping (unless otherwise specified). Raise the sample from room temperature under the protection of 40 mL/min dry N ₂ at a heating rate of 10 °C/min. To 200 ° C or 300 ° C, the TA software records the change in heat during the temperature rise of the sample.

The thermogravimetric analysis (TGA) data is from the TA Instruments Q500 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually take 5~15 mg of the sample in platinum crucible, and use the method of segmented high-resolution detection to raise the sample from room temperature under the protection of 40 mL/min dry N ₂ at a heating rate of 10 °C/min. At 300 ° C, the TA software records the change in weight of the sample during the heating process.

 The dynamic moisture adsorption analysis (DVS) data is from the TA Instruments Q5000 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually 1 to 10 mg of the sample is placed in a platinum crucible. Usually, the TA software records the change in weight of the sample during the relative humidity change from 0% to 80% to 0%. Depending on the sample, different adsorption and desorption steps are also applied to the sample.

Infrared spectroscopy (IR) data is available from Bruker Tensor 27, instrument control software and data analysis software are OPUS. The ATR device is usually used, and the infrared absorption spectrum is collected in the range of 600-4000 cm-l. The scanning time of the sample and the blank background is 16 seconds, and the resolution of the instrument is 4 cm ^-1 .

The cumulative release test of sustained-release tablets was carried out using the RC-806 dissolution tester, and the dissolution method was used. Basket method (refer to the Chinese Pharmacopoeia 2010 edition of the second part of Appendix X, the first method of dissolution assay). Instrument parameters; speed 100 rpm, temperature 37 ° C, dissolution medium is water, 500 ml.

 High performance liquid chromatography (HPLC) data from Waters Model 2695, column VP - ODS 150x4.6mm, 5μιη; column temperature 25 °C, injection volume 5 μl, flow rate l.Oml/min, mobile phase A As a 0.05% aqueous solution of trifluoroacetic acid, the mobile phase B was acetonitrile, and the gradient was eluted with a gradient. The gradient elution table is shown in Table 1. The absorbance at a wavelength of 220 nm was measured using an ultraviolet-visible spectrophotometer.

 Table 1 HPLC gradient elution table

 The examples were operated at room temperature unless otherwise noted.

 "Overnight" as used in the examples means that the step spans the night, which may be 8 to 22 hours, or 10 to 18 hours, usually 16 hours. Comparative example 1

 The lorcaserin hydrochloride hemihydrate is obtained according to Examples 1 and 2 of the patent document WO2006/069363, and the specific operation is as follows:

 3 L of dichloromethane was added to 220 g of lorcaserin, and 1.74 L of lmol/L of a solution of HCl in diethyl ether was added thereto, and the mixture was stirred at room temperature for 2 hours, and the solvent was evaporated to give chlorochrome hydrochloride.

 To 16 g of lorcaserin hydrochloride, 36 g of isopropanol was added and heated to 60 ° C to dissolve. After adding 1.24 g of water, 96 g of cyclohexane was added, and then the system was cooled to 20 ° C over 2 hours with gentle stirring. After solids were produced, the system was cooled to 0 ° C and stirred at 0 ° C for 3 hours, filtered, and the filter cake was washed with 16 g of cyclohexane and dried under vacuum at 40 ° C to give 15.1 g of white crystal chlorocartosamine hydrochloride. Hydrate.

 The XRPD graphic is shown in Figure 1, which shows that the sample conforms to Form III in WO2006/069363.

 The TGA spectrum is shown in Figure 2, which shows that the sample has 3.68% weight loss and begins to decompose above 170 °C.

 The DSC spectrum is shown in Figure 3. It shows that the sample has an endothermic peak between 70-90 °C, which is caused by decrystallization water and melt decomposition at 200.1 °C.

Example 1

Take 169 mg of lorcaserin and dissolve it in 5 mL of ethanol. Add 92 mg of sulfamic acid to 80. Dissolve in mL ethanol, add the sulfamic acid solution in ethanol to the ethanol solution of lorcaserin, stir for 2 hours, filter, and spin the filtrate at 40 °C to obtain 228 mg of lorcaserin sulfamate. The yield was 90.2%.

Example 2

 Take 16.9 mg of lorcaserin and dissolve it in 0.5 mL of ethanol, and add 9.2 mg of sulfamic acid.

0.5 mL ethanol was stirred to obtain a suspension, and the ethanol solution of lorcaserin was added dropwise to an ethanol suspension of sulfamic acid to form a slurry, which was stirred at 10 ° C for 8 hours, filtered, and the filtrate was spun dry at 40 ° C and then added. Acetone 1 ml was stirred at 10 ° C for 16 hours to precipitate a solid, which was filtered and dried under vacuum at 40 ° C overnight to yield 23.6 mg of chlorocarbalin sulfamate crystals, yield 93.0%.

 The XRPD pattern is shown in Figure 4 and is shown as a crystalline material.

 The TGA map is shown in Figure 5. It shows: The decomposition temperature is 241.8 ° C, which is better than the known chlorcarbine hydrochloride hemihydrate at 170 ° C decomposition temperature.

 The DSC graphics are shown in Figure 6. It shows a small endothermic peak between 114.3-122.2 °C and a melting point of 128.8-136.2 °C.

 The DVS isotherm adsorption curve is shown in Figure 7. Display: The weight change in the 20%-80% relative humidity range is 2.67%.

 The infrared spectrum is shown in Figure 8.

 The actual content of lorcaserin in the crystals of lorcaserin sulfamate was 66.5%, which was equivalent to the theoretical content of 66.8%, indicating that the molar ratio of lorcaserin to sulfamic acid was about 1:1. A salt.

Example 3

 Take 16.9 mg of lorcaserin and add 3.38 mL of sterol to dissolve. Add 27.6 mg of sulfamic acid to 5 mL of sterol and stir to obtain a suspension. Add the sterol solution of lorcaserin to the sterol mixture of sulfamic acid. The slurry was slurried in the suspension, stirred at -10 ° C for 0.5 hours, filtered, and the filtrate was spun dry at 40 ° C, then 3.38 ml of acetone was added, and the mixture was stirred at -10 ° C for 2 hours to precipitate a solid, which was filtered and dried under vacuum at 40 ° C overnight to obtain chlorine. Calylin sulfamate crystals 19.8 mg, yield 78.0%.

Example 4

 Take 16.9 g of lorcaserin and add 33.8 mL of isopropanol to dissolve. Add 9.2 g of sulfamic acid to 46 mL of isopropanol and stir to obtain a suspension. Add the isopropyl alcohol solution of lorcaserin to sulfamic acid. A slurry was formed in the isopropanol suspension, stirred at 50 ° C for 48 hours, filtered, and the filtrate was spun dry at 40 ° C, then 84.5 ml of acetone was added, and the mixture was stirred at 50 ° C for 24 hours to precipitate a solid, which was filtered and dried under vacuum at 40 ° C overnight. The crystal of cyclaline sulfamate was 22.9 g, and the yield was 90.3%.

Example 5

Take 16.9 mg of lorcaserin and add 1.69 mL of butanol to dissolve, take 13.8 mg of sulfamic acid, add sulfamic acid to the butanol solution of lorcaserin to form a slurry, stir at 30 ° C for 2 hours, and filter. The filtrate was spun dry at 40 ° C, and then acetone 1.69 1111, 30 ° was added (the solid was precipitated by stirring for 2 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 21.4 mg of chlorocarbalin sulfamate crystals, yield 84.3%.

Example 6

 Take 16.9 mg of lorcaserin and add 0.34 mL of ethanol to dissolve, take 9.2 mg of sulfamic acid, add sulfamic acid to the ethanol solution of lorcaserin to form a slurry, stir at 10 ° C for 8 hours, filter, and filtrate 40 ° C After spin-drying, 0.34 ml of acetone was added, and the solid was precipitated by stirring at 10 ° C for 16 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 20.8 mg of chlorocarbazone sulfamate crystals, yield 82.0%.

 The samples prepared in Examples 3 to 6 had the same or similar XRPD patterns, DSC patterns, TGA patterns, infrared patterns, and HPLC detection results (not shown), and Examples 3 to 6 samples were prepared. The same sample as the sample of Example 2.

Example 7

 Take 169 mg of lorcaserin, add 5 mL of acetonitrile to dissolve, take 269 mg of stearic acid, add 5 mL of acetonitrile, stir to dissolve, add chlorhexidine acetonitrile solution to stearic acid in acetonitrile solution, stir 2 After an hour, the system was spun dry at 40 ° C, and dried under vacuum at 40 ° C overnight to obtain chlorochrome stearate 356 mg, yield 85.8%.

Example 8

 Take 16.9 mg of lorcaserin and dissolve it in 0.5 mL of ethanol, dissolve 26.9 mg of stearic acid into 0.5 mL of ethanol, add the stearic acid ethanol solution to the ethanol solution of lorcaserin, and stir at 10 ° C for 8 hours. After the system was spun dry at 40 ° C, 1 ml of acetone was added, and the solid was precipitated by stirring at 10 ° C for 16 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 36.4 mg of chlorocarbazone stearate crystals, yield 87.7%.

 The XRPD pattern is shown in Figure 9, which shows: It is a crystalline material.

 The TGA map is shown in Figure 10. Display: The decomposition temperature is 88.9 °C.

 The DSC graphic is shown in Figure 11. Display: Melting point 53.4-54.8 °C.

 The DVS isotherm adsorption curve is shown in Figure 12. It shows: The weight change is 0.03% in the range of 20%-80% relative humidity, and it has lower hygroscopicity than the known lorcaserin hydrochloride hemihydrate.

 The infrared spectrum is shown in Figure 13.

 The actual content of lorcaserin in lorcaserin crystals was 41.1% by HPLC, which was equivalent to 40.7% of its theoretical content, indicating that the molar ratio of lorcaserin to stearic acid was about 1:1. A salt.

Example 9

Take 16.9 mg of lorcaserin and add 3.38 mL of sterol to dissolve. Take 26.9 mg of stearic acid and add 5.38 mL of sterol to dissolve. Add the sterol solution of stearic acid to the sterol solution of lorcaserin, -10 Stir at °C for 0.5 hours, spin the system at 40 ° C, add 3.38 ml of acetone, stir at -10 ° C for 2 hours. The solid was precipitated, filtered, and dried under vacuum at 40 ° C overnight to yield 34.0 mg of chlorocarbazone stearate crystals, yield 81.9%.

Example 10

 Take 16.9 g of lorcaserin and add 33.8 mL of isopropanol to dissolve. Add 80.7 g of stearic acid to 400 mL of isopropanol, and add the stearic acid isopropanol solution to the isopropyl alcohol solution of lorcaserin. Stir at 50 ° C for 48 hours, spin the system at 40 ° C, add 84.5 ml of acetone, stir at 50 ° C for 24 hours, precipitate, filter, and vacuum dry at 40 ° C overnight to obtain chlorhexaline stearate crystals 36.0 g, yield 86.8%.

Example 11

 Take 16.9 mg of lorcaserin and add 1.69 mL of butanol to dissolve. Add 40.4 mg of stearic acid solids to the butanol solution of lorcaserin, stir at 30 ° C for 2 hours, spin the system at 40 ° C and add acetone. 1.69 ml, stirred at 30 ° C for 16 hours, solidified, filtered, and dried under vacuum at 40 ° C overnight to obtain 35.2 mg of chlorocarbazone stearate crystals, yield 84.8%.

Example 12

 16.9 mg of lorcaserin was added to 1.69 mL of ethanol to dissolve. 26.9 mg of stearic acid solid was added to the ethanol solution of lorcaserin, stirred at 30 ° C for 8 hours, and the system was spun dry at 40 ° C and then added with acetone 0.34 ml. The solid was precipitated by stirring at 10 ° C for 16 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 34.9 mg of chlorocarbazone stearate crystals, yield 8.41%.

 The samples prepared in Examples 9 to 12 have the same or similar XRPD patterns, DSC patterns, TGA patterns, infrared patterns, and HPLC detection results (not shown), and the samples of Examples 9 to 12 are illustrated. The same material as the sample of Example 8.

Example 13

 Take 16.9 g of lorcaserin, add 0.5 L of ethyl acetate solution containing 1% (v/v) water, stir to dissolve, add 35.2 g of cholic acid thereto, form a slurry and stir for 2 hours, and concentrate the system to dryness. The chlorhexidine choline salt was 40.5 g, and the yield was 77.6%.

Example 14

 Take 16.9 mg of lorcaserin, add 0.5 mL of ethanol solution containing 2% (v/v) water, and dissolve by stirring. Take 35.2 mg of cholic acid and add 1 mL of ethanol solution containing 2% (v/v) water to form a suspension. The ethanol solution of lorcaserin was added dropwise to the ethanol suspension of bile acid to form a slurry, and stirred at 10 ° C for 16 hours. After the system was spun dry at 40 ° C, 1 ml of diethyl ether was added, and the mixture was stirred at 10 ° C for 16 hours. The solid was precipitated, filtered, and dried under vacuum at 40 ° C overnight to yield 44.8 mg of chlorocarbazone crystals, yield 85.5%.

 The XRPD pattern is shown in Figure 14, which shows: It is a crystalline material.

The TGA map is shown in Figure 15. Display: 2.98% weight loss before 150 ° C, decomposition temperature is 151.4 ° C. The DSC spectrum is shown in Figure 16. It shows: There is a wide endothermic peak between 32-105 °C, which is caused by removing one crystal water, melting at 166.8 °C, crystallizing at around 172 °C, and melting at 186.4 °C.

 The DVS isotherm adsorption curve is shown in Figure 17. Display: The weight change in the range of 20%-80% relative humidity is 0.85%.

 The infrared spectrum is shown in Figure 18.

 The actual content of lorcaserin in chromocyanine cholate crystals was 32.2% by HPLC, which was equivalent to the theoretical content of 32.4%, indicating that the ratio of lorcaserin to bile acid was about 1:1. .

Example 15

 Take 16.9 mg of lorcaserin, add 3.38 mL of a methanol solution containing 0.5% (v/v) water, and stir to dissolve. Take 105.6 mg of cholic acid and add 25 mL of a sterol solution containing 0.5% (v/v) water to form a suspension. The sterol solution of lorcaserin was added dropwise to a sterol suspension of cholic acid to form a slurry, which was stirred at -10 ° C for 0.5 hours, filtered, and the filtrate was spun dry at 40 ° C, and 3.38 ml of diethyl ether was added, -10 ° After stirring for 2 hours, a solid precipitated, and the mixture was filtered and dried under vacuum at 40 ° C overnight to obtain 42.5 mg of chlorocarbazone crystals in a yield of 81.4%.

Example 16

 Take 16.9 g of lorcaserin, add 33.8 mL of 3% (v/v) water in isopropanol solution, and stir to dissolve. Take 52.8 g of cholic acid and add 176 mL of isopropyl alcohol containing 3% (v/v) water to form a suspension. The isopropyl alcohol solution of lorcaserin was added dropwise to a suspension of bile acid in isopropanol to form a slurry, which was stirred at 50 ° C for 48 hours, filtered, and the filtrate was spun dry at 40 ° C, and diethyl ether 84.5 ml, 50 ° was added. C was stirred for 24 hours, and solids were precipitated, filtered, and dried under vacuum at 40 ° C overnight to obtain 43.8 g of chlorocarbazone crystals, yield 83.9%.

Example 17

 Take 16.9 mg of lorcaserin and add 1.69 mL of butanol solution containing 4% (v/v) water and stir to dissolve. 35.2 mg of cholic acid solid was added to the butanol solution of lorcaserin to form a slurry, which was stirred at 30 ° C for 2 hours, and the system was spun dry at 40 ° C, and 1.69 ml of diethyl ether was added thereto. After stirring at 30 ° C for 16 hours, a solid precipitated. The filtrate was dried under vacuum at 40 ° C overnight to give crystals of chlorocarbazone choline salt 43. l mg, yield 82.5%.

Example 18

 Take 16.9 mg of lorcaserin, add 2 mL of ethanol solution containing 5% (v/v) water, and dissolve by stirring. 35.2 mg of bile acid solid was added to the ethanol of lorcaserin to form a slurry. The mixture was stirred at 10 ° C for 8 hours, the system was spun dry at 40 ° C, and 0.34 ml of diethyl ether was added. After stirring at 10 ° C for 16 hours, a solid precipitated and filtered. After drying overnight at 40 ° C under vacuum, the crystals of chlorocarbazone cholate were 44.2 mg, yield 84.7%.

Examples 15 to 18 The prepared samples have the same or similar XRPD patterns, DSC patterns, TGA patterns, infrared patterns, and HPLC results (not shown) as the samples of Example 14. The samples of Examples 15 to 18 were identical to the samples of Example 14.

Example 19

 Take 84.3 mg of lorcaserin and dissolve it in lmL of ethanol, add 76.4 mg of 4-aminobenzenesulfonic acid to 1 mL of ethanol to prepare a suspension and stir. Add the ethanol solution of lorcaserin to 4-aminobenzenesulfonic acid. A slurry was formed in the ethanol suspension, stirred for 0.5 hours, filtered, and the filtrate was spun dry at 40 ° C, and dried under vacuum at 40 ° C overnight to obtain chlorocarbazone 4-aminobenzenesulfonate 1 14.7 mg, yield 72.2%. .

Example 20

 Take 84.3 mg of lorcaserin and add 2 mL of ethanol to dissolve. Take 76.4 mg of 4-aminobenzenesulfonic acid and add 2 mL of ethanol to prepare a suspension and stir. Add the ethanol suspension of 4-aminobenzenesulfonic acid to the chlorine. The slurry was formed in the ethanol solution of karserin and stirred at 10 ° C for 10 minutes. After filtration, the filtrate was cooled to -10 ° C and stirred for 2 hours. Filtered and dried under vacuum at 40 ° C overnight to obtain 4-amino chlorocartosine. The benzsulfonate crystals were 142.4 mg, and the yield was 89.6%.

 The XRPD pattern is shown in Figure 19 and shows: It is a crystalline material.

 The TGA map is shown in Figure 20. Display: The decomposition temperature is 214.9 °C.

 The DSC graphics are shown in Figure 21. Display: Melting point is 221.8-222.6 °C.

 The DVS isotherm adsorption curve is shown in Figure 22. It shows: The weight change is 0.01% in the range of 20%-80% relative humidity, and it has lower hygroscopicity than the known lorcaserin hydrochloride hemihydrate.

 The infrared spectrum is shown in Figure 23.

 The actual content of lorcaserin in the crystals of 4-aminobenzenesulfonate of lorcaserin was 52.9%, which was equivalent to the theoretical content of 53.0%, indicating that cyclacillin and 4-aminobenzenesulfonic acid were in molar. The ratio is about 1:1 salt.

Example 21

 Take 84.3 mg of lorcaserin and add 16.86 mL of sterol to dissolve. Take 229.2 mg of 4-aminobenzenesulfonic acid and add 50 mL of sterol to form a suspension and stir to suspend the sterol of 4-aminobenzenesulfonic acid. Adding to the sterol solution of lorcaserin to form a slurry, stirring at 50 ° C for 5 minutes, filtering, taking the filtrate to cool to -10 ° C, stirring and crystallization for 0.5 hours, filtering, filter cake 40 ° C vacuum drying overnight, chlorine The crystal of kassin 4-aminobenzenesulfonate was 137.2 mg, and the yield was 86.3%.

Example 22

 Take 84.3 g of lorcaserin and add 168.6 mL of isopropanol to dissolve. Take 14.6 g of 4-aminobenzenesulfonic acid and add 382 mL of isopropanol to prepare a suspension and stir. Isopropanol of 4-aminobenzenesulfonic acid. The suspension was added to the isopropyl alcohol solution of lorcaserin to form a slurry, stirred at 50 ° C for 120 minutes, filtered, and the filtrate was cooled to 10 ° C and stirred for 48 hours, filtered, and the filter cake was vacuum dried at 40 ° C. Over the night, the crystals of 4-aminobenzenesulfonate of lorcaserin were 135.3 g, and the yield was 85.1%.

Example 23 Take 84.3 mg of lorcaserin and add 8.43 mL of butanol to dissolve. Add 76.4 mg of 4-aminobenzenesulfonic acid solid to the butanol solution of lorcaserin to form a slurry, stir at 30 ° C for 30 minutes, filter, and take the filtrate to cool. The crystal was stirred and stirred at -10 ° C for 0.5 hour, filtered, and the filter cake was dried under vacuum at 40 ° C overnight to obtain 140.0 mg of chlorocarbazone 4-aminobenzenesulfonate crystals, yield 88.7%.

Example 24

 84.3 mg of lorcaserin was added to 1.69 mL of ethanol to dissolve, and 76.4 mg of 4-aminobenzenesulfonic acid solid was added to the ethanol solution of lorcaserin to form a slurry, which was stirred at 10 ° C for 60 minutes, filtered, and the filtrate was cooled to 0. The crystal was stirred for 2 hours at ° C, filtered, and the filter cake was dried under vacuum at 40 ° C overnight to obtain 140.9 mg of chlorocarbazone 4-aminobenzenesulfonate crystals, yield 88.7%.

 Examples 21 to 24 The prepared samples were identical or similar to the samples of Example 20.

XRPD graphics, DSC graphics, TGA graphics, infrared spectra, and HPLC detection results (not shown), indicating that the samples of Examples 21 to 24 were the same as the samples of Example 20.

Example 25

 16.9 mg of lorcaserin was added to 0.5 mL of acetone to dissolve, 14.3 mg of terephthalic acid was added to 40 mL of acetone to dissolve, and the acetone solution of lorcaserin was added dropwise to the acetone solution of terephthalic acid to form a slurry. After stirring for 30 minutes, the mixture was filtered, and the filtrate was spun at 40 ° C, and dried under vacuum at 40 ° C overnight to obtain chlorhexidine phthalic acid 24.1 mg, yield 77.1%.

Example 26

 Take 16.9 mg of lorcaserin and dissolve it in 0.5 mL of ethanol. Add 14.3 mg of terephthalic acid to 0.5 mL of ethanol to prepare a suspension and stir. Add the ethanol suspension of p-benzoic acid to the chlorochrome. The slurry was formed in the ethanol solution of the forest, stirred at 10 ° C for 120 minutes, filtered, and the filtrate was subjected to crystallization at -10 ° C for 16 hours, filtered, and the filter cake was dried under vacuum at 40 ° C overnight to obtain chlorocarbazone terephthalate. The crystals were 26.8 mg, and the yield was 85.8%.

 The XRPD analysis is shown in Figure 24, which shows that the salt is a crystalline material.

 The TGA map is shown in Figure 25. Display: The decomposition temperature of this salt is 181.8 °C.

 The DSC spectrum is shown in Figure 26. Show: The salt has a melting point of 251.2 °C.

 The DVS isotherm adsorption curve is shown in Figure 27. It shows that the salt has a weight change of 0.06% in the range of 20%-80% relative humidity, which has lower hygroscopicity than the moisture absorption of the prior art hydrochloride half-hydrate.

 The infrared analysis is shown in Figure 28.

 The actual content of lorcaserin in the crystals of lorcaserin was 54.2% by HPLC, which was equivalent to the theoretical content of 54.1%, indicating that the molar ratio of lorcaserin to terephthalic acid was about It is 1:1 salt.

Example 27

Take 16.9 mg of lorcaserin and add 3.38 mL of sterol to dissolve and take 42.9 mg of terephthalic acid. Add 8.5 mL of sterol to form a suspension and stir. Add the sterol suspension of terephthalic acid to the sterol solution of lorcaserin to form a slurry, stir at -10 ° C for 5 minutes, and filter. The filtrate was subjected to crystallization at -10 ° C for 0.5 hour, filtered, and the filter cake was dried under vacuum at 40 ° C overnight to obtain 24.2 mg of chlorocarbazone terephthalate crystals, yield 77.4%.

Example 28

 Take 16.9 g of lorcaserin and add 33.8 mL of isopropanol to dissolve. Add 21.2 g of terephthalic acid to 28.6 mL of isopropanol to form a suspension and stir to add isopropanol suspension of terephthalic acid. Add dropwise to the isopropyl alcohol solution of lorcaserin to form a slurry, stir at 50 ° C for 120 minutes, filter, take the filtrate and crystallize at 20 ° C for 24 hours, filter, filter cake 40 ° C vacuum dry overnight, get chlorochrome The crystal of terephthalate crystals was 25.7 g, and the yield was 82.2%.

Example 29

 Take 16.9 mg of lorcaserin and add 1.69 mL of butanol to dissolve. Add 14.3 mg of terephthalic acid to 1.43 mL of butanol to form a suspension and stir. Add the butanol suspension of terephthalic acid to the suspension. A slurry was formed in the butanol solution of lorcaserin, stirred at 30 ° C for 10 minutes, filtered, and the filtrate was subjected to crystallization at 0 ° C for 16 hours, filtered, and the filter cake was vacuum dried at 40 ° C overnight to obtain chlorhexidine benzene. The citrate crystals were 25.1 mg, and the yield was 80.3%.

Example 30

 16.9 mg of lorcaserin was added to 0.34 mL of ethanol to dissolve. 14.3 mg of terephthalic acid solid was added to the ethanol solution of lorcaserin to form a slurry. The mixture was stirred at 10 ° C for 60 minutes, filtered, and the filtrate was analyzed by 0 ° C. After crystallizing for 24 hours, it was filtered, and the filter cake was dried under vacuum at 40 ° C overnight to obtain 23.9 mg of chromocyanine terephthalate crystals, yield 76.5%.

 Examples 27 to 30 The prepared samples have the same or similar XRPD patterns, DSC patterns, TGA patterns, infrared patterns, and HPLC detection results (not shown) as the samples of Example 26, illustrating Examples 27 to 30. The sample was the same as the sample of Example 26.

Example 31

 Weigh 40 g of lorcaserin hydrochloride hemihydrate Form III, add to a 5 L flask, add 3 L of anhydrous decylcyclohexane and 0.1 L of absolute ethanol, seal, and crystallize at room temperature for 10 hours. . The slurry was concentrated to dryness at 30 ° C to obtain 37.2 g of chlorocarbin hydrochloride anhydrate crystal form VI, yield 96.6%.

 The XRPD graphics are shown in Figure 29.

 The TGA spectrum is shown in Figure 30, which shows that the sample is anhydrate and begins to decompose above 170 °C.

The DSC spectrum is shown in Fig. 31. It shows that the sample has a crystal transition peak between 140 °C and 157 °C, and is converted to chlorocadherin hydrochloride anhydrate crystal form I, which melts and decomposes at 200 °C.

The DVS isotherm adsorption curve is shown in Figure 32. It shows that the sample can be stably present below 30% relative humidity. Starting from 30% relative humidity, it begins to transform into chlorocalyxine hydrochloride hemihydrate crystal form III, after forming crystal form III. It is no longer possible to switch back to Form VI. Example 32

 Weigh 40 mg of lorcaserin hydrochloride hemihydrate Form III, add it to a 5 mL glass vial, add 4 mL of anhydrous decylcyclohexane and 0.08 mL of absolute ethanol, seal, and crystallize at room temperature for 72 hours. . The slurry was concentrated to dryness at 30 ° C to obtain chlorocarbazone hydrochloride anhydrate crystal form VI 35.5 mg, yield 92.2%.

 The sample prepared in Example 32 had the same or similar XRPD pattern, DSC graphic, TGA graphic, infrared spectrum and HPLC detection result (not shown) as the sample of Example 31, indicating Example 32 sample and Example 31. The sample is the same substance.

Example 33

 Weigh 40 g of lorcaserin hydrochloride hemihydrate Form III, add it to a 5 L glass vial, add 1.25 L of anhydrous decylcyclohexane and 0.025 L of anhydrous decyl alcohol, seal, and crystallize at room temperature. 10 hours. The slurry was concentrated to dryness at 30 ° C to obtain a crystal form of chlorocarbyl hydrochloride anhydrate, V 36.9 g, yield 95.8%.

 The XRPD graphics are shown in Figure 33.

 The TGA spectrum is shown in Figure 34, showing that the sample is anhydrate and begins to decompose above 170 °C.

The DSC spectrum is shown in Fig. 35, which shows that the sample has a crystal transformation peak between 140 and 155 ° C, and is converted to chlorocarbazone hydrochloride anhydrate crystal form I, which melts and decomposes at 200 ° C.

 The DVS isotherm adsorption curve is shown in Figure 36, which shows that the sample can be stably present below 40% humidity. It starts to change to the chlorocalyxine hydrochloride hemihydrate crystal form in 40% humidity, and can not be formed after forming the crystal form m. Turn back to Form V.

Example 34

 Weigh 40 mg of lorcaserin hydrochloride hemihydrate Form III, add it to a 5 mL glass vial, add 1.5 mL of anhydrous decylcyclohexane and 0.05 mL of anhydrous decyl alcohol, seal, and crystallize at room temperature. 72 hours. The slurry was concentrated to dryness at 30 ° C to obtain chlorocarbazone hydrochloride anhydrous crystal form V 34.7 mg, yield 90.1%.

 The sample prepared in Example 34 had the same or similar XRPD pattern, DSC graphic, TGA graphic, infrared spectrum and HPLC detection result (not shown) as the sample of Example 33, indicating Example 34 sample and Example 33. The sample is the same substance.

Example 35

 The solubility test of the lorcaserin salt crystal of the present application was carried out, and the control sample was a known chlorocalyptine hydrochloride hemihydrate crystal form III.

The specific operation is as follows: take about 5 mg of lorcaserin salt crystals as a sample, and gradually add pure water to the sample at 25 °C until the sample is completely dissolved, and calculate the solubility of the sample according to the actual weight of the sample and the amount of water. The results are shown in Table 2. Parallel tests showed that the sample did not undergo crystallisation during the test. Solubility of lorcaserin salt crystals

表 2的溶解度测试结果显示， 本申请氯卡色林盐晶体的溶解度均低于 已知氯卡色林盐酸盐半水合物晶型 III的溶解度，说明本申请的氯卡色林盐 晶体更适合制备緩释制剂。

The solubility test results in Table 2 show that the solubility of the chlorocalylin salt crystals of the present application is lower than the solubility of the known chlorocalylin hydrochloride hemihydrate crystal form III, indicating that the crystal of the lorcaserin salt of the present application is more It is suitable for the preparation of sustained release preparations.

Example 36

 The cyclaline sulfamate crystal of the present application, the chlorocapsin 4-aminobenzenesulfonate crystal, the chlorocalyxate stearate crystal, the chlorhexidine cholate crystal, and the lorcaserin The p-benzoate crystals were prepared as sustained-release tablets, and the control was a known chlorocalylin hydrochloride hemihydrate crystal form III; and the dissolution test of the sustained-release tablets was carried out.

 The specific operation is as follows: According to the prescription of Table 3, a sustained release tablet containing crystals of chlorhexidine forest is pressed, and then the cumulative release percentage of the sustained release tablets dissolved in water is examined. The results are shown in Table 4.

 Table 3 prescription for sustained release tablets

 Prescription one prescription two prescription three prescription four prescription five prescription six original accessories name

 (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) lorcaserin hydrochloride hemihydrate

 25

Form III (known)

Chlorosyl

 38

Crystal (this application)

Chlorosyl sulfonate crystal

 30

 (this application)

 Chlorine color ^^之^ it crystal

 49

 (this application)

 Chlorocolor biliary ^ it crystal

 62

 (this application)

Chlorine color ^wood to ^^甲^ it crystal

37 body (this application) Hydroxypropylmethylcellulose

 110 110 110

 ( K15M )

 Hydroxypropyl methylcellulose ( E5 ) 50 65 60 pregelatinized starch 135.5 148.5 143.5

 Microcrystalline cellulose 85 70 75 a 7j field 15 15 15 114.5 101.5 126.5

 1.5 1.5 1.5 1.5 1.5 1.5 Total 300 300 300 300 300 300 Remarks: The API is equivalent to 20 mg of chlorocalyx free ^^. Table 4 Percentage of cumulative release of sustained release tablets of lorcaserin salt crystals in water

 The test results in Table 4 show that the sustained-release tablets of chlorocarserine hydrochloride hemihydrate crystal form III are released quickly in water, and the release index of sustained-release tablets is not reached (the release index of sustained-release tablets is: The cumulative release percentage at 1, 4, 8, 12, and 24 hours is 15-25%, 35-45%, 50-60%, 70-80%, and greater than 90%, respectively, and is not suitable for the preparation of sustained-release preparations; Chlorocinin 4-aminobenzenesulfonate crystals, lorcaserin sulfamate crystals, lorcaserin stearate crystals, chlorhexidine cholate crystals, and lorcaserin pairs of the present application The cumulative release of phthalate crystals in water is moderate, and it is more suitable for the preparation of sustained release preparations.

 The above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change without thinking of creative work or within the technical scope of the present invention. Alternatives are intended to be covered by the scope of the present invention.

Claims

 Claim 1. A crystal of chlorocartosamine sulfamate having the structural formula shown below,

 It is characterized in that, using Cu-Κα radiation, the X-ray powder diffraction pattern of the chlorocalyx sulfamate crystal is 5.9 ± 0.2 at a diffraction angle of 2 。. 6.1 士 0.2. , 1 1.8 ± 0.2. 12.1 ± 0.2. 15.9 士 0.2. And 21.2 ± 0.2. There are characteristic peaks.  The chlorocacillin sulfamate crystal according to claim 1, wherein the X-ray powder diffraction pattern of the cyclaline sulfamate crystal has a diffraction angle of 2 Θ of 5.9 ± 0.2°. 6.1 ± 0.2 °, 1 1.8 ± 0.2. 12.1 ± 0.2°, 15.9 ± 0.2. 18.2 ± 0.2. , 19.9 ± 0.2 °, 21.2 ± 0.2. 22.6 ± 0.2. 23.7 ± 0.2. 24.2 ± 0.2. And 26.1 ± 0.2. There are characteristic peaks.  The chlorocalycine sulfamate crystal according to claim 2, wherein the X-ray powder diffraction pattern of the cyclaline sulfamate crystal has a characteristic peak at a diffraction angle of 2 以下And its relative strength:  Diffraction angle 2Θ relative intensity%  5.9 ± 0.2 ° 23.0  6.1 ± 0.2 ° 25.0  11.8 ± 0.2 ° 36.5  12.1 ± 0.2. 44.2  15.9 ± 0.2. 24.0  18.2 ± 0.2. 14.2  19.9 ± 0.2. 17.3  20.5 ± 0.2 ° 21.6  21.2 ± 0.2. 100.0  22.6 ± 0.2° 38.3  23.7 ± 0.2° 30.0  24.2 ± 0.2 ° 41.5  26.1 ± 0.2. 28.8  26.9 ± 0.2. 14.1  27.4 ± 0.2. 18.1 27.9 ± 0.2. 18.6 30.0 ± 0.2° 33.1  31.7 ± 0.2 ° 19.9. The chlorocalyxine sulfamate crystal according to any one of claims 1 to 3, wherein the Fourier infrared spectrum of the cyclaline sulfamate crystal has a wave number of 3332 , 3014, 2864, 1619, 1454, 1254, 1186, 1 164, 1042, 823 and 765 cm ^-1 have characteristic peaks.  The method for preparing clocaserin sulfamate crystal according to any one of claims 1 to 4, comprising the steps of: mixing an alcohol solution of lorcaserin with sulfamic acid to carry out a reaction, and the reaction is completed. After filtration, the filtrate is concentrated, and acetone is added to crystallize to obtain the cyclaline sulfamate crystal;  Preferably, the alcohol is a C ^ CA alcohol, more preferably ethanol;  Preferably, the molar ratio of lorcaserin to sulfamic acid is 1: 1 to 1: 3, more preferably 1: 1 to 1: 1.5;  Preferably, the temperature of the reaction is -10 to 50 ° C, more preferably 10 to 30 ° C; the reaction time is 0.5 to 48 hours, more preferably 2 to 8 hours;  Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; the crystallization time is 2 to 24 hours, more preferably 16 to 24 hours;  Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml;  Preferably, the ratio of the amount of lorcaserin to acetone is 5 to 200 mg: 1 ml, more preferably 10 to 50 mg: 1 ml.  6, a structural body,

 It is characterized in that the X-ray powder diffraction pattern of the chlorocalyxate stearate crystal is 5.6 ± 0.2 at a diffraction angle of 2 Å using Cu-Κα radiation. , 9.8 ± 0.2. 13.8 士 0.2. , 19.5 ± 0.2. , 24.1 ± 0.2. And 27.8 ± 0.2. There are characteristic peaks. The lorcaseolin stearate crystal according to claim 6, wherein the X-ray powder diffraction pattern of the chlorocalyxate stearate crystal has a diffraction angle of 2 Θ of 5.6 ± 0.2 °, 8.5 ± 0.2 ^ο , 9.8 ± 0.2 ^ο , 12.6 ± 0.2 ^ο , 13.8 ± 0.2 ^ο , 14.1 ± 0.2 ^ο , 19.5 ± 0.2 ^ο , 21.1 ± 0.2 ^ο , 24.1 ± 0.2 . And 27.8 ± 0.2. There are characteristic peaks. The lorcaseolin stearate crystal according to claim 7, wherein the X-ray powder diffraction pattern of the chlorocalyxate stearate crystal has characteristics at the following diffraction angle 2Θ Peak and its relative intensity:  Diffraction angle 2Θ relative intensity%  5.6 士 0.2° 100.0  8.5±0.2° 4.3  9.8 ± 0.2° 25.2  12.6 ± 0.2° 5.1  13.8 ± 0.2 ° 20.6  14.1 ± 0.2. 4.9  19.5 ± 0.2 ° 6.5  21.1 ± 0.2. 6.4  24.1 ± 0.2. 14.9  27.8 ± 0.2 ° 19.9.  The lorcaseolin stearate crystal according to any one of claims 6-8, wherein the Fourier infrared spectrum of the chlorocalyxate stearate crystal has a wave number of 2912 , 2849, 1681, 1641, 1472, 1261, 1 104, 1030, 943, 824, 715, and 673 cm have characteristic peaks.  The method for preparing clocaserin stearate crystal according to any one of claims 6-9, comprising the steps of: mixing an alcohol solution of lorcaserin with stearic acid to carry out a reaction, and the reaction is completed. After the system is concentrated, and acetone is added to crystallize to obtain the chlorocalyxate stearate crystal;  Preferably, the alcohol is a C?CA alcohol, more preferably ethanol;  Preferably, the molar ratio of lorcaserin to stearic acid is 1:1 to 1:3, more preferably 1 : 1~1 : 1.5;  Preferably, the temperature of the reaction is -10 to 50 ° C, more preferably 10 to 30 ° C; the reaction time is 0.5 to 48 hours, more preferably 2 to 8 hours;  Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; the crystallization time is 2 to 24 hours, more preferably 16 to 24 hours;  Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml;  Preferably, the ratio of the amount of lorcaserin to acetone is 5 to 200 mg: 1 ml, more preferably 10 to 50 mg: 1 ml. 1 1. A crystal of chlorocartoline cholate as shown below;

It is characterized in that, using Cu-Κα radiation, the X-ray powder 4 stain pattern of the chlorochrome cholate crystal is at 6.7 ± 0.2 at 4 stain angles. , 7.3 ± 0.2. , 10.0 ± 0.2. , 1 1.1 ± 0.2. , 12.7 ± 0.2. And 13.4 ± 0.2. There are characteristic peaks.  The chlorocalyptine cholate crystal according to claim 11, wherein the X-ray powder diffraction pattern of the chromocyanine cholate crystal has a diffraction angle of 2 Θ of 6.7 ± 0.2°, 7.3. ±0.2°, 10.0 ± 0.2°, 1 1.1 ± 0.2°, 12.7 ± 0.2°, 13.4 ± 0.2°, 13.6 ± 0.2°, 14.7 ± 0.2. , 16.0 ± 0.2. , 17.3 ± 0.2. , 17.9 ± 0.2. And 19.9 ± 0.2. There are characteristic peaks.  The chromocyanine cholate crystal according to claim 12, wherein the X-ray powder diffraction pattern of the chlorocalylin cholate crystal has a characteristic peak at a diffraction angle of 2 以下 and Relative Strength:  Diffraction angle 2Θ relative intensity%  6.7 ± 0.2° 44.7  7.3±0.2° 32.6  10.0 ± 0.2. 74.8  11.1 ± 0.2. 93.0  12.7 ± 0.2. 94.9  13.4 ± 0.2. 83.1  13.6 ± 0.2. 58.6  14.7 ± 0.2. 63.3  15.2 ± 0.2. 35.7  16.0 ± 0.2. 94.6  17.3士 0.2° 79.5  17.9 ± 0.2. 100.0  18.7 ± 0.2 ° 19.2  19.9 ± 0.2. 99.7  21.2 ± 0.2. 26.6  23.1 ± 0.2° 50.4  24.2 ± 0.2 ° 14.5 25.1 ± 0.2. 20.8 32.0  23.6  24.3  15.8  The chlorocalyptine cholate crystal according to any one of claims 1 to 13, characterized in that the Fourier infrared spectrum of the chromocyanine cholate crystal has a wave number of 2928, There are characteristic peaks at 2849, 1569, 1467, 1401, 1375, 1261, 1079, 1045, 948, 816, and 693 cm.  The method for producing a chromocyanine cholate crystal according to any one of claims 11 to 14, comprising the steps of: forming a solution of lorcaserin in a mixed solvent of an alcohol and water, and mixing it with cholic acid; The reaction is carried out, and after the reaction is completed, the filtrate is concentrated, and the filtrate is concentrated, and diethyl ether is added to crystallize to obtain the chlorocalyptine cholate crystal;  Preferably, the alcohol is a C?CA alcohol, more preferably ethanol;  Preferably, the volume percentage of water in the mixed solvent is 0.5 to 5%;  Preferably, the molar ratio of lorcaserin to cholic acid is 1:1 to 1:3, more preferably 1:1 to 1:1.5; preferably, the temperature of the reaction is -10 to 50 °C, More preferably, it is 10 to 30 ° C; the reaction time is 0.5 to 48 hours, more preferably 2 to 8 hours;  Preferably, the temperature of the crystallization is -10 to 50 ° C, more preferably 10 to 30 ° C; the crystallization time is 2 to 24 hours, more preferably 16 to 24 hours;  Preferably, the concentration of the lorcaserin solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml;  Preferably, the ratio of the amount of lorcaserin to diethyl ether is 5 to 200 mg: 1 ml, more preferably 10 to 50 mg: 1 ml.  16. A crystal of a structural formula such as besylate,

 It is characterized in that the X-ray powder diffraction pattern of the chlorokacillin 4-aminobenzenesulfonate crystal is 11.4 ± 0.2 at a diffraction angle of 2 使用 using Cu-Κα radiation. , 12.0 ± 0.2. 13.3 ± 0.2. , 16.9 ± 0.2. , 20.4 ± 0.2. And 20.7 ± 0.2. There are characteristic peaks. The chlorocalyx 4-aminobenzenesulfonate crystal according to claim 16, wherein the X-ray powder diffraction pattern of the chlorokacillin 4-aminobenzenesulfonate crystal is at a diffraction angle of 2Θ. 11.4 ± 0.2 °, 12.0 ± 0.2 °, 13.3 ± 0.2 °, 13.7 ± 0.2 °, 16.9 ± 0.2 °, 20.4 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 21.6 ± 0.2 °, 22.5 ± 0.2 ° , 23.2 ± 0.2 ° and 24.8 ± 0.2 ° Characteristic peaks.  The chlorocalyx 4-aminobenzenesulfonate crystal according to claim 17, wherein the X-ray powder diffraction pattern of the chlorokacillin 4-aminobenzenesulfonate crystal is diffracted below There are characteristic peaks and their relative intensities at angle 2:  Diffraction angle 2Θ relative intensity%  11.4 ± 0.2. 13.1  12.0 ± 0.2. 35.3  13.3 ± 0.2. 21.5  13.7 ± 0.2. 12.3  16.9 士 0.2° 76.7  20.0 ± 0.2. 11.9  20.4 ± 0.2. 100.0  20.7 ± 0.2. 32.4  21.0 ± 0.2 ° 28.5  21.6 ± 0.2 ° 22.2  21.8 ± 0.2. 22.0  22.5 ± 0.2. 16.7  23.2 ± 0.2. 25.7  24.0 ± 0.2. 17.8  24.8 ± 0.2 ° 21.2  25.2 ± 0.2° 16.9  25.5 ± 0.2° 16.5  26.6 ± 0.2 ° 16.9. The cyclaline 4-aminobenzenesulfonate crystal according to any one of claims 16 to 18, wherein the chlorocalyx 4-aminobenzenesulfonate crystal has a Fourier IR spectra in the wave number 3427, 3349, 1641, 1599, 1186, 1171, 1120, 1025, 1003, 934, 896, 829, and 692 cm ^"1 with characteristic peaks at.  The method for preparing cyclaline 4-aminobenzenesulfonate crystal according to any one of claims 16 to 19, comprising the steps of: mixing an alcohol solution of lorcaserin with 4-aminobenzenesulfonic acid The obtained system is filtered, and the filtrate is subjected to crystallizing to obtain the chlorokacillin 4-aminobenzenesulfonate crystal; preferably, the alcohol is C?CA alcohol, more preferably ethanol;  Preferably, the molar ratio of lorcaserin to 4-aminobenzenesulfonic acid is 1: 1 to 1: 3, more preferably 1: 1 to 1: 1.5; Preferably, the obtained system is stirred for 5 to 120 minutes and then filtered, more preferably stirred for 10 to 120 minutes; the temperature of the stirring is preferably 10 to 50 ° C, more preferably 10 to 30 ° C; Preferably, the temperature of the crystallization is -10 to 10 ° C, more preferably -10 to 0 ° C; the crystallization time is 0.5 to 48 hours, more preferably 0.5 to 2 hours;  Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.  21. A crystal of the chlorhexidine-terephthalate salt having the structural formula shown below,

 The method is characterized in that, by using Cu-Κα radiation, the X-ray powder of the chlorhexidine phthalate crystal is in the range of 7.9 ± 0.2°, 12.7 ± 0.2°, 13.5 士. 0.2°, 17.3 ± 0.2. , 19.6 ± 0.2. And 22.9 ± 0.2. There are characteristic peaks.  The lorcaserin terephthalate crystal according to claim 21, wherein the X-ray powder diffraction pattern of the chlorocalyxate terephthalate crystal is at a diffraction angle of 2 Θ of 7.9. ± 0.2 °, 12.7 ± 0.2 °, 13.5 ± 0.2 °, 17.3 ± 0.2 °, 18.5 ± 0.2 °, 19.6 ± 0.2 °, 21.1 ± 0.2. 22.9 ± 0.2. 25.2 ± 0.2. 26.8 ± 0.2. , 27.2 ± 0.2. And 27.8 ± 0.2. There are characteristic peaks.  The chromocyanine terephthalate crystal according to claim 22, wherein the X-ray powder diffraction pattern of the chlorocalyxate terephthalate crystal is at the following diffraction angle 2Θ There are characteristic peaks and their relative strengths:  Diffraction angle 2Θ relative intensity%  7.9 ± 0.2° 45.2  12.7 ± 0.2° 32.1  13.5 ± 0.2° 100.0  17.3 ± 0.2° 53.1  18.5 ± 0.2. 44.5  19.6 ± 0.2 ° 62.7  21.1 ± 0.2. 20.1  22.9 ± 0.2. 63.6  25.2 ± 0.2 ° 22.1  26.8 ± 0.2° 35.2  27.2 ± 0.2° 35.7  27.8 ± 0.2 ° 44.5. The chromocyanine terephthalate crystal according to any one of claims 21-23, wherein the florulaline phenanthrenate crystal has a Fourier transform infrared spectrum The wave number is There are characteristic peaks at 1678, 1424, 1398, 1286, 101 1, 933, 881, 814, 740 and 647 cm.  The method for preparing chlorocalyxate terephthalate crystal according to any one of claims 21-24, comprising the steps of: mixing an alcohol solution of lorcaserin with terephthalic acid, The obtained system is filtered, and the filtrate is subjected to crystallization to obtain the chlorocalyxate terephthalate crystal;  Preferably, the alcohol is a Cr^C alcohol, more preferably ethanol;  Preferably, the molar ratio of lorcaserin to terephthalic acid is 1: 1 to 1: 3, more preferably 1: 1 to 1: 1.5;  Preferably, the obtained system is stirred for 5 to 120 minutes and then filtered, more preferably stirred for 10 to 120 minutes; the stirring temperature is preferably -10 to 50, more preferably 10 to 30 ° C;  Preferably, the temperature of the crystallization is -10 to 20 ° C, more preferably -10 to 0 ° C; the crystallization time is 0.5 to 24 hours, more preferably 16 to 24 hours;  Preferably, the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.  26. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more crystals selected from the group consisting of crystals of chlorinerazine sulfamate according to any one of claims 1 to 4, claims 6-9 The chlorocalyxate stearate crystal according to any one of claims 11 to 14, wherein the chlorochrome crystal according to any one of claims 11 to 19, A pharmaceutically active ingredient of a crystalline 4-aminobenzenesulfonate crystal or a chlorocalyxate terephthalate crystal according to any one of claims 21-24, and at least one pharmaceutically acceptable carrier.  27. The chlorocalyxin sulfamate crystal according to any one of claims 1 to 4, the chlorocalyxate stearate crystal according to any one of claims 6 to 9, claim 1-14 The chromocyanine cholate crystal according to any one of claims 16 to 19, wherein the chlorokacillin 4-aminobenzenesulfonate crystal according to any one of claims 21 to 19, Use of lorcaserin crystals of lorcaserin or a pharmaceutical composition according to claim 26 for the preparation of a medicament for the treatment and/or prophylaxis of a disorder associated with 5HT2c; the disorder associated with 5HT2c is selected from the group consisting of obesity , central nervous system disorders, central nervous system damage, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, sleep apnea, depression, atypical depression, bipolar disorder, anxiety disorder, obsessive-compulsive disorder, social phobia or panic Status, sleep disorders, sexual dysfunction, psychosis, schizophrenia, migraine and conditions associated with head pain or other pain, increased intracranial pressure, epilepsy, personality disorder, age-related behavioral disorder, and idiot Related behavioral disorders, organic mental disorders, childhood mental disorders, aggression, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexia nervosa or premenstrual tension .