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WO2015096119A1 - Sels de lorcasérine et leurs cristaux, leurs procédés de préparation et utilisations - Google Patents

Sels de lorcasérine et leurs cristaux, leurs procédés de préparation et utilisations Download PDF

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Publication number
WO2015096119A1
WO2015096119A1 PCT/CN2013/090668 CN2013090668W WO2015096119A1 WO 2015096119 A1 WO2015096119 A1 WO 2015096119A1 CN 2013090668 W CN2013090668 W CN 2013090668W WO 2015096119 A1 WO2015096119 A1 WO 2015096119A1
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Prior art keywords
crystal
lorcaserin
hours
alcohol
characteristic peaks
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PCT/CN2013/090668
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English (en)
Chinese (zh)
Inventor
任芳俊
盛晓霞
盛晓红
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杭州普晒医药科技有限公司
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Priority to CN201380069724.5A priority Critical patent/CN104936947B/zh
Priority to PCT/CN2013/090668 priority patent/WO2015096119A1/fr
Publication of WO2015096119A1 publication Critical patent/WO2015096119A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • Chlorocyanine salt and crystal thereof, preparation method and use thereof are Chlorocyanine salt and crystal thereof, preparation method and use thereof
  • 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
  • lorcaserin (R)-8-chloro-1-indolyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  • 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.
  • 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 ⁇ , 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.
  • the lorcaserin salt of the present application 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 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.
  • 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.
  • 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.
  • the molar ratio of lorcaserin to sulfamic acid is 1:1 to 1:3.
  • the filtrate is concentrated to dryness by spin-drying.
  • the crystal of cyclaline sulfamate (hereinafter referred to as "sulfamate crystal") is irradiated with Cu- ⁇ , and the X-ray powder diffraction pattern of the sulfamate crystal is at a diffraction angle of 2 ⁇ of 5.9. Division 0.2. 6.1 ⁇ 0.2. , 1 1.8 ⁇ 0.2. 12.1 ⁇ 0.2. 15.9 ⁇ 0.2. And 21.2 ⁇ 0.2. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the sulfamate crystal is at a diffraction angle of 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the sulfamate crystal has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • 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.
  • 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.
  • 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.
  • the alcohol is C ⁇ CA alcohol
  • the Cr ⁇ C alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.
  • the molar ratio of lorcaserin to sulfamic acid is from 1:1 to 1:3, more preferably from 1:1 to 1:1.5.
  • 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.
  • 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.
  • the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.
  • 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 mlappel
  • 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
  • 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.
  • 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
  • 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 tan
  • the molar ratio of lorcaserin to stearic acid is 1:1 to 1:3.
  • the system is concentrated to dryness by spin-drying.
  • stearate crystal The crystal of lorcaserin stearate (hereinafter referred to as "stearate crystal"), used
  • the Cu- ⁇ 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 ⁇ 0.2. , 19.5 ⁇ 0.2. 24.1 ⁇ 0.2. And 27.8 ⁇ 0.2. There are characteristic peaks.
  • 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 2 ⁇ 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 2 ⁇ :
  • 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,
  • 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 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 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.
  • the molar ratio of lorcaserin to stearic acid is from 1:1 to 1:3, more preferably from 1:1 to 1:1.5.
  • 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.
  • 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.
  • the concentration of the cyclamol solution is 5 to 500 mg/ml, more preferably 10 to 50 mg/ml.
  • 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.
  • the beating is to stir the suspension to precipitate crystals
  • 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:
  • 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.
  • 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
  • the C 3 ⁇ C 5 ketone may be acetone, butanone, 2 - Pentanone or 3-pentanone.
  • the volume percentage of water in the mixed solvent is 0.5 to 5% (v/v);
  • the molar ratio of lorcaserin to cholic acid is 1:1 to 1:3.
  • the system is concentrated to dryness by spin-drying.
  • cholate crystal The crystal of chromocyanine cholate (hereinafter referred to as "cholate crystal") is irradiated with Cu- ⁇ , 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.
  • the X-ray powder diffraction pattern of the cholate crystal is at a diffraction angle of 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the cholate crystal has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • 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.
  • 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.
  • 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.
  • the volume percentage of water in the mixed solvent is from 0.5 to 5%.
  • the molar ratio of lorcaserin to cholic acid is from 1:1 to 1:3, more preferably from 1:1 to 1:1.5.
  • 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.
  • 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.
  • the concentration of the lorcaserin solution is from 5 to 500 mg/ml, more preferably from 10 to 50 mg/ml.
  • 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.
  • the beating is to stir the suspension to precipitate crystals
  • 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.
  • 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.
  • the molar ratio of lorcaserin to 4-aminobenzenesulfonic acid is 1:1 to 1:3.
  • the filtrate is concentrated to dryness by spin-drying.
  • the crystal of cyclaline 4-aminobenzenesulfonate (hereinafter referred to as "4-aminobenzenesulfonate crystal"), using Cu- ⁇ radiation, X-ray of the 4-aminobenzenesulfonate crystal
  • the powder diffraction pattern was at a diffraction angle of 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the 4-aminobenzenesulfonate crystal has a diffraction angle of 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the 4-aminobenzenesulfonate crystal has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • 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.
  • 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.
  • 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.
  • the alcohol is a Cr ⁇ C alcohol
  • the Cr ⁇ C alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.
  • the molar ratio of lorcaserin to 4-aminobenzenesulfonic acid is 1:1 to 1:3, more preferably 1:1 to 1:1.5.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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,
  • the molar ratio of lorcaserin to terephthalic acid is 1:1 to 1:3.
  • the filtrate is concentrated to dryness by spin-drying.
  • terephthalate crystal The crystal of the chlorocalyxate terephthalate (hereinafter referred to as "terephthalate crystal"), using Cu- ⁇ radiation, the X-ray powder diffraction pattern of the terephthalate crystal
  • the diffraction angle 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the terephthalate crystal is at a diffraction angle of 2 ⁇ 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 X-ray powder diffraction pattern of the terephthalate crystal has a characteristic peak and its relative intensity at the following diffraction angle 2 ⁇ :
  • a typical example of the terephthalate crystal has the structure shown in FIG.
  • 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.
  • 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 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.
  • 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.
  • the alcohol is a Cr ⁇ C alcohol
  • the Cr ⁇ C alcohol may be decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, more preferably ethanol.
  • the molar ratio of lorcaserin to terephthalic acid is from 1:1 to 1:3, more preferably from 1:1 to 1.5.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ , using Cu- ⁇ 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.
  • 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.
  • the X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form VI has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • hydrochloride salt-free type VI has an X-ray powder diffraction pattern as shown in FIG.
  • Thermogravimetric analysis of the hydrochloride salt-free VI 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.
  • 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.
  • 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.
  • 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- ⁇ radiation, and the X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form V is The diffraction angle 2 ⁇ was 14.2 ⁇ 0.2. 14.9 ⁇ 0.2. 15.4 ⁇ 0.2. , 16.6 ⁇ 0.2. , 19.4 ⁇ 0.2. And 20.2 ⁇ 0.2. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the hydrochloride salt-free crystal form V is at a diffraction angle of 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the hydrochloride anhydrous crystal form V has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • 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.
  • the volume of anhydrous nonylcyclohexane and anhydrous decyl alcohol in the mixed solvent is
  • 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.
  • 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.
  • drying 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.
  • the chlorhexacillin salt of the present application 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present application provides a pharmaceutical composition
  • 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.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms, amorphous forms or salts of lorcaserin.
  • the pharmaceutical composition may also comprise one or more additional pharmaceutically active
  • 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
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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 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 ⁇ -2 ⁇ 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 ⁇ ; Step: 0.02 ° 2 ⁇ ; 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.
  • 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.
  • 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.
  • “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:
  • the XRPD graphic is shown in Figure 1, which shows that the sample conforms to Form III in WO2006/069363.
  • 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.
  • 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 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.
  • 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 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 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 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%.
  • 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.
  • 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 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 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%.
  • Examples 21 to 24 The prepared samples were identical or similar to the samples of Example 20.
  • lorcaserin 16.9 mg 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%.
  • 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.
  • lorcaserin 16.9 mg 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%.
  • Example 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.
  • 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 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.
  • 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 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.
  • 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 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 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.

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Abstract

La présente invention concerne les cristaux suivants de Lorcasérine : le sulfamate, le stéarate, le cholate, le 4-aminobenzène sulfonate ou le téréphthalate, et les procédés de préparation et les compositions pharmaceutiques de ces derniers, et leurs utilisations dans la préparation de médicaments destinés à traiter et/ou prévenir les maladies associées à 5HT2c, telles que l'obésité. L'indice du taux de libération dans l'eau de comprimés à libération prolongée des cristaux présente des propriétés améliorées.
PCT/CN2013/090668 2013-12-27 2013-12-27 Sels de lorcasérine et leurs cristaux, leurs procédés de préparation et utilisations WO2015096119A1 (fr)

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Cited By (2)

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WO2016138138A1 (fr) 2015-02-25 2016-09-01 The Regents Of The University Of California Agonistes de récepteur 5ht pour le traitement de troubles
WO2023278597A1 (fr) * 2021-06-30 2023-01-05 Apnimed, Inc. (Delaware) Agonistes de 5-ht2c destinés à être utilisés dans le traitement d'états associés à une hypoventilation centrale

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WO2011153206A1 (fr) * 2010-06-02 2011-12-08 Arena Pharmaceuticals, Inc. Procédés pour la préparation d'agonistes du récepteur 5-ht2c
WO2012030951A1 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes posologiques à dissolution rapide d'agonistes de 5-ht2c
WO2012030957A2 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Sels non hygroscopiques d'agonistes de 5-ht2c

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WO2005003096A1 (fr) * 2003-06-17 2005-01-13 Arena Pharmaceuticals, Inc. Derives de benzazepine et methodes de prophylaxie ou de traitement de maladies associees au recepteur 5ht2c

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WO2005019179A2 (fr) * 2003-06-17 2005-03-03 Arena Pharmaceuticals, Inc. Processus de preparation de 3-benzazepines
WO2006069363A2 (fr) * 2004-12-21 2006-06-29 Arena Pharmaceuticals, Inc. Formes cristallines d'hydrochlorure de (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine
WO2011153206A1 (fr) * 2010-06-02 2011-12-08 Arena Pharmaceuticals, Inc. Procédés pour la préparation d'agonistes du récepteur 5-ht2c
WO2012030951A1 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes posologiques à dissolution rapide d'agonistes de 5-ht2c
WO2012030957A2 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Sels non hygroscopiques d'agonistes de 5-ht2c

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016138138A1 (fr) 2015-02-25 2016-09-01 The Regents Of The University Of California Agonistes de récepteur 5ht pour le traitement de troubles
CN107530326A (zh) * 2015-02-25 2018-01-02 加利福尼亚大学董事会 用于治疗病症的5ht激动剂
EP3261640A4 (fr) * 2015-02-25 2018-12-19 The Regents of The University of California Agonistes de récepteur 5ht pour le traitement de troubles
US10874643B2 (en) 2015-02-25 2020-12-29 The Regents Of The University Of California 5HT agonists for treating disorders
CN107530326B (zh) * 2015-02-25 2021-09-21 加利福尼亚大学董事会 用于治疗病症的5ht激动剂
US11648237B2 (en) 2015-02-25 2023-05-16 The Regents Of The University Of California 5HT agonists for treating disorders
WO2023278597A1 (fr) * 2021-06-30 2023-01-05 Apnimed, Inc. (Delaware) Agonistes de 5-ht2c destinés à être utilisés dans le traitement d'états associés à une hypoventilation centrale

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