WO2015161730A1 - 一种氯卡色林共晶及其制备方法、药物组合物和用途 - Google Patents

一种氯卡色林共晶及其制备方法、药物组合物和用途 Download PDF

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WO2015161730A1
WO2015161730A1 PCT/CN2015/075175 CN2015075175W WO2015161730A1 WO 2015161730 A1 WO2015161730 A1 WO 2015161730A1 CN 2015075175 W CN2015075175 W CN 2015075175W WO 2015161730 A1 WO2015161730 A1 WO 2015161730A1
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eutectic
benzoic acid
lorcaserin
preparation
lorcaserin hydrochloride
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PCT/CN2015/075175
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English (en)
French (fr)
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胡晨阳
盛晓霞
盛晓红
贾强
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杭州普晒医药科技有限公司
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Priority to US15/107,032 priority Critical patent/US9981912B2/en
Priority to CN201580000681.4A priority patent/CN105228986B/zh
Publication of WO2015161730A1 publication Critical patent/WO2015161730A1/zh

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    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemical crystallization.
  • it relates to a chlorocamellin co-crystal, and to a process for the preparation of the eutectic, a pharmaceutical composition thereof and use thereof.
  • the types of solid forms of drugs are mainly polymorphs, salts, hydrates or solvates and eutectic.
  • the drug eutectic is a crystal in which an active pharmaceutical ingredient (API) and a eutectic precursor (CCF) are combined by a weak interaction force at a fixed stoichiometric ratio, wherein the pure state of the component is at ambient temperature.
  • the bottom is solid.
  • Weak interactions are defined as interactions that are neither ionic nor covalent, including, for example, hydrogen bonds, van der Waals forces, ⁇ - ⁇ interactions, and halogen bonds.
  • Eutectic is a multi-component crystal that includes both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
  • Drug eutectic has a greater advantage than traditional solid forms such as polymorphs, salts, hydrates or solvates.
  • salt salt formation relies on the electrostatic attraction between the ionic API and the acid or base, so salt formation is only suitable for ionizable drugs; and between the API and CCF in the eutectic is the intermolecular force,
  • eutectic is an important means of altering the shape of solids.
  • solvates there are currently very few types of pharmaceutically acceptable solvents, especially organic solvent molecules which are easily transported in solids and have a high vapor pressure. Such solvates are prone to desolvation and conversion to amorphous substances.
  • CCF in the eutectic is rarely volatilized or sublimated, and physical changes such as phase separation rarely occur, and the crystal is more stable. It can be seen from the many advantages of eutectic, eutectic is a promising solid form, which has far-reaching effects on pre-prescription research and dosage form design of drugs.
  • 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-HT 2C receptor is highly expressed in the central nervous system, and its physiological effects involve the production of hydrocephalus, the pathophysiology of anxiety, the feeding 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 under the trade name Belviq.
  • the listed dosage form is an oral immediate release tablet of lorcaserin hydrochloride hemihydrate with a specification of 10 mg.
  • BMI ⁇ 30, or BMI ⁇ 27 at least one weight-related disease (such as hypertension, Obese patients with hyperlipidemia or type 2 diabetes.
  • Chloraxerin is also indicated for the treatment or prevention of other central nervous system diseases mediated by 5-HT 2C .
  • Patent document WO2006/069363A2 discloses a hemihydrate of lorcaserin hydrochloride (abbreviated as "Form III” in the present invention) and two anhydrates (Form I and Form II), and is referred to as crystal Type III is less hygroscopic and most stable.
  • Patent document WO 2012/030927 A2 discloses various salts, hydrates or solvates of lorcaserin such as hydroiodide, maleate, fumarate, hemi-fumarate, orotate, milk. Hydrate hydrate, cis cinnamate, hemi-naphthalate, hemi-naphthalate solvate 1, hemi-naphthalate solvate 2, mandelate hydrate, hemi-hydroxynaphthoate However, this document does not provide specific details of the formulation of these compounds.
  • Patent document WO 2012/030951 A1 discloses hydrogen sulphate, hemisulfate, methanesulfonate, hydrobromide, nitrate, adipate, malonate, hemi-malonate and ethanol of lorcaserin. Acid salt.
  • the patent document states that the above chlorocarbazone salt has good water solubility and is suitable for preparing an immediate release dosage form.
  • Patent document WO 2012/030957 A2 discloses solvates of lorcaserin phosphate, hemi-ethanedisulfonate, citrate, hemi-oxalate, succinate, ketoglutarate, ketoglutarate.
  • the patent document states that the above compounds are stable to humidity and are suitable for solid formulation applications.
  • the eutectic should have one or more improved properties, such as high stability; good solubility; fast dissolution rate; high crystallinity; not easy to absorb moisture; easy to purify and process; Low residual solvent; good particle morphology; suitable formulation processability such as fluidity, powder Plasticity, tightness and compressibility; improve the appearance of the preparation; improve the bioavailability and improve the efficacy; suitable for new dosage forms such as suitable for sustained release, controlled release preparation applications.
  • the invention also relates to a process for the preparation of said co-crystals, to pharmaceutical compositions thereof and to uses thereof.
  • the present invention provides a eutectic of lorcaserin hydrochloride and benzoic acid (referred to simply as "eutectic" in the present invention).
  • the eutectic is a compound formed by chlorocalyxine hydrochloride, benzoic acid and water in a molar ratio of 1:1:1, and its structural formula is as follows:
  • Cu-K ⁇ radiation is used, the X-ray powder diffraction pattern of the eutectic expressed in 2 ⁇ angle having characteristic peaks at: 4.5 ⁇ 0.2°, 9.0 ⁇ 0.2°, 12.3 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 19.4 ⁇ 0.2 ° and 23.0 ⁇ 0.2 °.
  • Cu-K ⁇ radiation is used, the X-ray powder diffraction pattern of the eutectic expressed in 2 ⁇ angle having characteristic peaks at: 4.5 ⁇ 0.2°, 9.0 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.9 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.4 ⁇ 0.2°, 22.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, and 23.5 ⁇ 0.2°.
  • Cu-K alpha radiation is used, the X-ray powder diffraction pattern of the eutectic represented by the 2 theta angle having characteristic peaks and their relative intensities at:
  • a typical example of the eutectic has an X-ray powder diffraction pattern as shown in FIG.
  • the eutectic single crystal is prepared.
  • the specific operation of the preparation is as follows: the eutectic acetone solution is volatilized to dryness at room temperature to obtain a single crystal.
  • the "pore volatilization" is a process in which a container containing a solution is volatilized and crystallized at a corresponding temperature through a single orifice having a diameter of 2 mm.
  • the eutectic is a twin crystal composed of two monoclinic crystal systems, and exhibits 90° at the angle of the two sides of the three unit vectors a, b, and c.
  • the eutectic Fourier infrared spectrum is at wavenumbers of 3384, 2971, 2861, 2524, 2362, 1700, 1595, 1315, 1270, 1119, 946, 818, and 710 cm -1 Has a characteristic peak.
  • the solubility of the eutectic in water at 25 ° C is 8-9 mg/ml, while the solubility of lorcaserin hydrochloride hemihydrate in water at 25 ° C is known to be greater than 200 mg/ml.
  • the eutectic of the invention has the following beneficial properties and application effects:
  • the solubility of the eutectic of the invention in water is 8-9 mg/ml, which is suitable for preparing a sustained-release preparation, which can exert a therapeutic effect for a long time in a patient, maintain an effective stable blood concentration, and meet clinical requirements. It can reduce the number of medications used by patients and significantly increase patient compliance. Under the same prescription, the known chlorhexidine hydrochloride hemihydrate may be rapidly released completely due to high solubility, resulting in a vacuum period lower than the effective concentration.
  • the dissolution release of the eutectic itself of the present invention is slower than the case of controlling the release degree by the sustained release coating, and therefore, the release degree of the eutectic preparation of the present invention is packaged.
  • the dependence of the garment is small, and the influence of the coating process (coating thickness, coating continuity) and the difference in the batch of the coating material on the release degree can be avoided.
  • the eutectic of the invention is stored at a temperature of 25 ° C and a relative humidity of 60% for 6 months, and the purity and the crystal form can remain unchanged; after the eutectic of the invention is stored under high temperature illumination of 80 ° C - 6000 l x for 10 days,
  • the decrease in purity and the increase in the maximum single impurity content are significantly lower than the known chlorhexidine hydrochloride hemihydrate
  • the data. Therefore, the eutectic of the invention has high chemical stability and crystal form stability, is suitable for the requirements of the preparation, and can better resist the uneven content and purity caused by the change of the active ingredient of the drug during the manufacture and/or storage of the drug. Problems such as decreased, reduced processability of the preparation, reduced risk and safety risks resulting from the resulting reduction, and also facilitated later transportation and storage.
  • the present invention provides a method of preparing the eutectic, comprising any one of the following methods:
  • the organic solvent is selected from C 1 ⁇ C 4 alcohols, ethyl acetate or acetone, even more preferably isopropanol.
  • the concentration of the solution of the benzoic acid in an organic solvent is 75 to 120 mg/mL.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature.
  • the crystallization time is from 8 to 48 hours, more preferably from 8 to 16 hours.
  • the lorcaserin hydrochloride hemihydrate is divided equally into 2 to 6 portions, and stirred for 10 to 15 minutes after each addition.
  • the organic solvent is selected from C 1 ⁇ C 4 alcohols, ethyl acetate or acetone, even more preferably isopropanol.
  • the molar ratio of lorcaserin hydrochloride hemihydrate to benzoic acid is from 1:1 to 1:1.5.
  • the concentration of the solution of the lorcaserin hydrochloride hemihydrate in an organic solvent is 50 to 100 mg/mL.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature.
  • the crystallization time is from 8 to 48 hours, more preferably from 8 to 16 hours.
  • the benzoic acid is divided equally into 2 to 6 parts, and the mixture is stirred for 10 to 15 minutes after each addition.
  • the organic solvent is selected from C 1 ⁇ C 4 alcohols, ethyl acetate, acetone or methylene chloride, more preferably isopropanol.
  • the molar ratio of lorcaserin, hydrochloric acid and benzoic acid is 1:1:1 to 1:2:2.
  • the weight-to-volume ratio of lorcaserin to the organic solvent in the mixed system is 100 mg: 1 mL to 200 mg: 1 mL.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature.
  • the crystallization time is 10 to 24 hours.
  • the hydrochloric acid is an aqueous solution of hydrogen chloride, and the usable concentration ranges from 1 to 4 mol/L.
  • the "C 1 -C 4 alcohol” includes methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and isobutanol.
  • the eutectic precipitated in the above production methods (1), (2) and (3) is separated and dried by a conventional method in the art.
  • the "separation” method such as filtration; the specific operation of the filtration is: placing the sample to be separated on a filter paper, and filtering under reduced pressure.
  • the "drying” method such as blast drying, vacuum drying, etc.; drying equipment using a fume hood, a blast oven or a vacuum oven; drying under reduced pressure or no reduced pressure, preferably less than 0.09 MPa; drying temperature It is 10 to 40 ° C, preferably room temperature; and the drying time is 1 to 72 hours, preferably 1 to 10 hours, more preferably 1 to 2 hours.
  • a solvent to an equimolar ratio of a mixture of lorcaserin hydrochloride hemihydrate and benzoic acid, keeping the mixture completely wetted by the solvent, and grinding to dryness to obtain the eutectic, wherein
  • the solvent is selected from water or an organic solvent.
  • the organic solvent in the production method (4) means an organic solvent which is pharmaceutically acceptable and which does not affect the biological activity of the pharmaceutically active ingredient and which can wet the mixture.
  • the solvent in the production method (4) is selected from the group consisting of acetone, acetonitrile or water.
  • the solvent is used in the production method (4) in an amount sufficient to completely wet the mixture; preferably, the mixture and the solvent have a weight-to-volume ratio of 150 mg: 1 mL to 240 mg: 1 mL.
  • the production method (4) has an operating temperature of 10 to 40 ° C, preferably room temperature.
  • the "grinding” can be carried out by a conventional method in the art, that is, grinding the sample in a mortar.
  • stirring may be carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the preparation method of the eutectic of the invention has simple steps and is easy to handle.
  • room temperature means about 10 to 30 °C.
  • lorcaserin can be obtained by a method described in Examples 1 to 5 of the patent document WO2005/019179A2 or commercially available, and clocaserin hydrochloride hemihydrate (Form III) can be referred to the patent literature.
  • WO2006/069363A2 is prepared by the methods described in Examples 1 and 2.
  • the "eutectic" crystal form is confirmed by the X-ray powder diffraction pattern characterization.
  • the structure of "eutectic” is confirmed by the structure diagram obtained by X-ray single crystal diffraction. It is well known to those skilled in the art that the experimental error of the X-ray powder diffraction pattern depends on instrument conditions, sample preparation, and sample purity.
  • the X-ray powder diffraction pattern usually changes with the instrument conditions; the relative intensity of the peak may vary with the experimental conditions, so the order of the peak intensity cannot be the sole or decisive factor; the experimental error of the peak angle should also be taken into account.
  • the eutectic of the present invention is pure, singular, and substantially free of any other crystal, crystalline or amorphous state.
  • substantially free means that the other crystals, crystal forms or amorphous forms contained therein are less than 20% by weight, more preferably less than 10% by weight, especially less than 5% by weight, especially less At 1% by weight.
  • the eutectic precursor may be not only limited to benzoic acid, but may also include malonic acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, adipic acid, benzene.
  • malonic acid succinic acid
  • maleic acid fumaric acid
  • citric acid malic acid
  • tartaric acid adipic acid
  • benzene a compound that isoctic acid
  • Formic acid p-aminobenzoic acid, fructose, aspartame, benzyl alcohol, sorbitol, dextrin, maltodextrin, saccharin, nicotinamide, urea and 2-aminopyrimidine.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the eutectic of chlorhexidine hydrochloride and benzoic acid of the present invention or The above-described eutectic obtained by the preparation method of the invention, and at least one pharmaceutically acceptable carrier or adjuvant.
  • the pharmaceutical composition generally comprises, by weight, from about 1% to about 99% by weight of the eutectic of chlorhexidine hydrochloride and benzoic acid of the present invention, and from about 99% to about 1% by weight of at least one pharmaceutically acceptable A suitable carrier or adjuvant is accepted.
  • the pharmaceutical composition may also comprise crystals or amorphous forms of other pharmaceutically acceptable salts, solvates, hydrates of clocaserin, or eutectic.
  • the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.
  • the pharmaceutical composition can be prepared in a solid, semi-solid or liquid dosage form, solid oral dosage forms including, for example, tablets, capsules, granules, pills, and powders; liquid oral dosage forms including, for example, solutions, syrups, suspensions Agents, dispersing agents and emulsions; injectable preparations, for example, including solutions, dispersions, and lyophilized powders formulated into solutions.
  • the formulations may be adapted for immediate, sustained or controlled release of the pharmaceutically active ingredient, and may be conventional, dispersible, chewable, orally dissolvable or rapidly melted formulations. Routes of administration include oral, intravenous, subcutaneous, transdermal, rectal, nasal, and the like.
  • the pharmaceutical composition of the present invention is preferably a solid oral dosage form comprising a tablet, a capsule, a granule, a pill, and a powder, more preferably a solid orally or controlled release solid orally. Dosage form.
  • the pharmaceutically acceptable carrier or adjuvant of the present invention includes, but is not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, hydrogen phosphate Calcium, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene Alcohols, etc.; disintegrating agents, such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; lubricants such as stearic acid, hard Magnesium citrate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants such as colloidal silica; complex forming agents such as various grades of cyclodiluents such as starch,
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art.
  • the eutectic of lorcaserin hydrochloride and benzoic acid of the present invention is prepared by mixing with one or more pharmaceutically acceptable carriers or adjuvants, 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 invention provides the use of the co-crystal of lorcaserin hydrochloride and benzoic acid of the present invention for the preparation of a medicament for the treatment and/or prevention of a condition associated with 5HT 2c .
  • the present invention 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 lorcaserin hydrochloride of the present invention and Eutectic of benzoic acid or a eutectic of lorcaserin hydrochloride and benzoic acid obtained according to the preparation method of the present invention or the aforementioned pharmaceutical composition of the present invention; said patient means a mammal including human.
  • the dosage may range from about 0.01 mg to about 100 mg per kilogram of body weight per day, and a convenient daily dosage regimen may be used. The dosage can be adjusted depending on the type and extent of the condition, the overall health of the patient, the characteristics of the formulation, and the route of administration.
  • 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, 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 the crystal form III of lorcaserin hydrochloride hemihydrate prepared in Preparation Example 1.
  • Figure 2 is an XRPD pattern of the eutectic of the present invention
  • Figure 3 is a schematic view showing the molecular structure of the eutectic of the present invention
  • Figure 4 is an IR diagram of the eutectic of the present invention
  • Figure 5 is a comparison of XRPD of the eutectic (top) and single crystal diffraction simulation (bottom) of the present invention.
  • X-ray powder diffraction The instrument is a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, an operating condition of 40 kV and 40 mA, a ⁇ -2 ⁇ goniometer, a Mo monochromator, and a Lynxeye. detector. The instrument is calibrated with silicon carbide before use. The acquisition software is Diffrac Plus XRD Commander. The sample was tested at room temperature and the sample was placed on a non-reflective plate. The detection conditions are: angle range: 3 - 40 ° 2 ⁇ , step size: 0.02 ° 2 ⁇ , speed: 0.2 sec / step.
  • Single crystal diffractometer Eos CCD detector, four-circle Kappa meter, enhanced Mo source and enhanced Cu source. Detection parameters: ambient temperature 100K, enhanced Cu source, graphite monochromator, wavelength
  • the data analysis software is Crysalispro. After analysis and processing by shelxtl software, a schematic diagram of the molecular structure can be obtained.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS.
  • ATR devices usually, in the range of 600 ⁇ 4000cm -1, collecting the infrared absorption spectrum, and the scanning time of the sample on a white background is 16 sec, the resolution of 4cm -1.
  • Nuclear magnetic resonance spectroscopy ( 1 H-NMR) data was taken from Bruker Ascend Tm 500. Usually use full-frequency excitation, spectrum width 30ppm, single pulse, 30° angle excitation, 16 scans, digital orthogonal detection, temperature control 298K.
  • High performance liquid chromatography (HPLC) data were obtained from Waters Model 2695.
  • the column was VP-ODS 150 ⁇ 4.6 mm, 5 ⁇ m; column temperature was 25 ° C, injection volume was 5 ⁇ L, flow rate was 1.0 ml/min, and mobile phase A was 0.05%.
  • the aqueous solution of fluoroacetic acid, mobile phase B was acetonitrile, gradient elution, and 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 means that the step spans the night, and may be 8 to 22 hours, or 10 to 18 hours, usually 16 hours.
  • Chlorhexerin hydrochloride hemihydrate (Form III) was prepared according to Examples 1 and 2 of the patent document WO2006/069363A2, the specific operation is as follows:
  • the XRPD pattern of the eutectic is shown in Figure 2. Displayed as a crystalline material.
  • the infrared spectrum of the eutectic is shown in Figure 4.
  • the acetone solution containing the eutectic obtained in Example 1 was formed, and the acetone solution was poured into a 5 ml glass bottle at room temperature, sealed, and a small hole having a diameter of about 1 mm was opened on the lid to volatilize, and the solution was evaporated to dryness.
  • the single crystal unit cell parameters are shown in Table 2.
  • a, b, and c indicate the unit cell axis length, ⁇ , ⁇ , and ⁇ represent dihedral angles, and Z indicates that each unit cell is in units of Lorcaserin-HCl-H 2 O-ArCOOH (Ar represents phenyl).
  • the eutectic molecule is composed of a chlorocarbin molecule, a hydrogen chloride molecule, a benzoic acid molecule, and a water molecule.
  • the comparison chart shown in Fig. 5 is a single crystal simulated XRPD pattern (bottom) and a measured XRPD pattern (top), showing that the two are substantially identical.
  • n-butanol solution Take 240mg of benzoic acid and add 2mL of n-butanol to dissolve ultrasonically to obtain n-butanol solution of benzoic acid.
  • the n-butanol solution was stirred for 10-15 min each time, and the mixture was stirred at room temperature for 8 hours, filtered, and dried at room temperature for 1 hour to obtain a eutectic 120 mg, yield 16.4%.
  • lorcaserin hydrochloride hemihydrate 250 mg was added to 5 mL of acetone to dissolve ultrasonically to obtain acetone solution of lorcaserin hydrochloride hemihydrate. 375 mg of benzoic acid was taken, and the average was divided into 3 parts, 125 mg each, and then added.
  • To the acetone solution of lorcaserin hydrochloride hemihydrate add one part each time, stir for 10 to 15 minutes, stir at room temperature for 8 hours after adding, filter, and dry at room temperature for 2 hours to obtain eutectic 48 mg, yield 12.4%. .
  • lorcaserin hydrochloride hemihydrate was added to 3 mL of ethyl acetate to dissolve ultrasonically to obtain ethyl acetate solution of lorcaserin hydrochloride hemihydrate, and 300 mg of benzoic acid was obtained, and the average was divided into 2 Serve, 150mg each, add to the ethyl acetate solution of lorcaserin hydrochloride hemihydrate, add one part each time, stir for 10 ⁇ 15min, stir at room temperature after adding, filter, dry at 10 °C for 10 hours , eutectic 47 mg, yield 15.2%.
  • lorcaserin hydrochloride hemihydrate was added to 2 mL of methanol for sonication to obtain a methanol solution of lorcaserin hydrochloride hemihydrate, and 150 mg of benzoic acid was taken, and the average was divided into 3 parts. 50mg, added to the methanol solution of lorcaserin hydrochloride hemihydrate in turn, each additional part, stirred for 10 ⁇ 15min, stirred for 48 hours after the addition, cooled to room temperature, filtered, drying time of 40 ° C for 1 hour , eutectic 42 mg, yield 13.6%.
  • lorcaserin hydrochloride hemihydrate 200 mg was added to 2 mL of n-butanol for sonication to obtain a n-butanol solution of lorcaserin hydrochloride hemihydrate, and 300 mg of benzoic acid was taken, and the average was divided into 6 parts. 50mg, added to the n-butanol solution of lorcaserin hydrochloride hemihydrate, add one part each time, stir for 10 ⁇ 15min, stir for 48 hours after adding, cool to room temperature, filter, dry time at 40 °C After 1 hour, a total of 45 mg of eutectic was obtained with a yield of 14.6%.
  • the samples prepared in Examples 3 to 20 had the same or similar XRPD patterns and IR patterns (not shown) as the samples of Example 1.
  • the samples of Examples 3 to 20 are identical to the samples of Example 1 in the same eutectic.
  • the specific operation is: taking about 10 mg of the known chlorocartosine hydrochloride hemihydrate and the eutectic of the invention as a sample, and gradually adding pure water to the sample at 25 ° C until the sample is completely dissolved, according to the sample. The actual weight and amount of water were used to calculate the solubility of the sample. The results are shown in Table 3.
  • Solubility Eutectic 8 ⁇ 9mg/ml Chlorosamine hydrochloride hemihydrate (known) More than 200mg/ml
  • the eutectic of the present invention was prepared into tablets, and the control was a tablet of the known chlorocalylin hydrochloride hemihydrate crystal form III prepared in Preparation Example 1.
  • the tablet prescription is shown in Table 4; Dissolution test.
  • the specific operation of preparing the tablet is: according to the prescription of Table 4, taking a prescribed amount of API (API is known crystal form III or eutectic of the invention), mannitol, HPMC K4M and Avicel PH102 are evenly mixed, and the prescription amount is added.
  • API is known crystal form III or eutectic of the invention
  • mannitol mannitol
  • HPMC K4M mannitol
  • Avicel PH102 mannitol
  • the magnesium stearate is uniformly mixed and placed in a tablet press to form a tablet core.
  • the obtained core-coated machine was coated with 5% by weight of the core, and the coating liquid was solid content of 12% (w/v). That is, tablets are available.
  • the dissolution test of the tablets was carried out using a USP apparatus I (basket method) in 900 mL of 0.1 N HCl solution at 37 ° C and 100 rpm. Samples were taken at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 14 hours. The HPLC concentration of the tablet eluate was measured, and the cumulative release percentage was calculated. The results are shown in Table 5.
  • the eutectic of the invention is more suitable for the preparation of sustained release formulations.
  • the release degree control of the sustained release preparation the dissolution release of the eutectic itself of the present invention is slower than the case of controlling the release degree by the sustained release coating, and therefore, the release degree of the eutectic preparation of the present invention is The dependence of the coating is small, and the influence of the coating process (coating thickness, coating continuity) and the difference in the batch of the coating material on the release degree can be avoided.
  • the chlorocarbazone hydrochloride hemihydrate crystal form III prepared in Preparation Example 1 and the eutectic of the present invention were subjected to a stability test under high temperature illumination for 10 days.
  • the high temperature condition is 80 ° C, and the illumination condition is 6000 lx illuminance.
  • the HPLC purity and the maximum single impurity content of the samples before and after the placement were examined. The results are shown in Table 6.

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Abstract

本发明涉及新型的盐酸氯卡色林和苯甲酸的共晶，与现有技术相比，所述共晶具有稳定性好、溶解度低、适合缓释制剂应用的改进特性。本发明还涉及所述共晶的制备方法、其药物组合物、及其用于制备治疗和/或预防与5HT2c相关疾病的药物中的用途。

Description

一种氯卡色林共晶及其制备方法、药物组合物和用途 技术领域
本发明属于药物化学结晶技术领域。具体而言，涉及一种氯卡色林共晶，还涉及所述共晶的制备方法、其药物组合物和用途。
背景技术
在药品处方前研究阶段，常常需要根据药物的性质以及目标制剂的要求来选择药物的固体形态。药物固体形态的不同会导致理化性质，如稳定性、溶解度、溶出度、吸湿性等的不同，进而影响其药效和药理毒理作用；药物的不同固体形态具有不同的颗粒性质及粉体性质，如颗粒的形貌、大小、密度、流动性等，这些都会影响制剂的工艺可开发性及质量，甚至药效。所以药物固体形态的选择是制剂研究中要考虑的重要因素。
药物固体形态的种类主要有多晶型、盐、水合物或溶剂化物以及共晶。药物共晶是活性药物成分(active pharmaceutical ingredient,API)与共晶前体(cocrystal former,CCF)以固定的化学计量比通过弱相互作用力结合而成的晶体，其中组分的纯态在环境温度下均为固体。弱相互作用被定义为既不是离子键也不是共价键的相互作用，例如包括氢键、范德华力、π-π相互作用和卤键。共晶是一种多组分晶体，既包括两种中性固体之间形成的二元共晶，也包括中性固体与盐或溶剂化物形成的多元共晶。
与多晶型、盐、水合物或溶剂化物等传统的固体形态相比，药物共晶有着更大的优势。对于盐来说，成盐依赖于离子态的API与酸或碱之间的静电引力作用，所以成盐仅仅适用于可电离的药物；而共晶中API和CCF之间是分子间作用力，对于那些非解离和弱解离的药物，共晶是一种改变固体形态的重要手段。对于溶剂化物来说，目前药学上可接受的溶剂种类很少，特别是有机溶剂分子在固体中容易迁移并具有很高的蒸气压，该类溶剂化物易于发生去溶剂化而转化成无定形物或结晶；共晶中CCF极少挥发或升华、也很少发生相分离等物理变化，晶体更加稳定。从共晶的诸多优势可以看出，共晶是一种很有潜力的固体形态，对药物的处方前研究和剂型设计有深远影响。
氯卡色林是美国Arena制药公司研制的新型减肥药，是一种选择性的5-羟色胺(5-HT2C)受体激动剂。5-HT2C受体高度表达在中枢神经系统，生理作用涉及脑积液的产生、焦虑的病理生理、进食行为以及机体的能量平衡。氯卡色林通过调节5HT2C受体活性，可以帮助肥胖患者诱导饱腹感，减少食物摄取，促进减肥。美国食品药品管理局(FDA)于2012年6月27日批准了氯卡色林上市，商品名Belviq。上市剂型为盐酸氯卡色林半水合物的口服速释片， 规格10毫克，适用于成人体质指数BMI≥30的超重者，或BMI≥27且至少有一项与体重相关疾病(如高血压、高血脂症或2型糖尿病)的肥胖患者。氯卡色林还适用于治疗或预防由5-HT2C介导的其他中枢神经系统疾病。
氯卡色林的化学名称为(R)-8-氯-1-甲基-2,3,4,5-四氢-1H-3-苯并氮杂卓，英文名称为Lorcaserin，又名APD356，其结构式如下：
Figure PCTCN2015075175-appb-000001
专利文献US6953787 B2公开了消旋氯卡色林及其制备方法。
专利文献WO2005/019179A2公开了氯卡色林的盐酸盐和L-(+)-酒石酸盐。
专利文献WO2006/069363A2公开了氯卡色林盐酸盐的半水合物(在本发明中简称为“晶型III”)和两个无水物(晶型I和晶型II)，并称晶型III不易吸湿且最稳定。
专利文献WO2012/030927A2公开了氯卡色林的多种盐、水合物或溶剂化物，例如氢碘酸盐、马来酸盐、富马酸盐、半富马酸盐、乳清酸盐、乳清酸盐水合物、顺式肉桂酸盐、半萘二甲酸盐、半萘二甲酸盐溶剂化物1、半萘二甲酸盐溶剂化物2、扁桃酸盐水合物、半双羟萘酸盐，但该文献没有提供这些化合物在制剂应用方面的具体内容。
专利文献WO2012/030951A1公开了氯卡色林的硫酸氢盐、半硫酸盐、甲磺酸盐、氢溴酸盐、硝酸盐、己二酸盐、丙二酸盐、半丙二酸盐及乙醇酸盐。该专利文献称，上述氯卡色林盐的水溶性好，适合制备速释剂型。
专利文献WO2012/030957A2公开了氯卡色林的磷酸盐、半乙二磺酸盐、柠檬酸盐、半草酸盐、琥珀酸盐、酮戊二酸盐、酮戊二酸盐的溶剂化物。该专利文献称，上述化合物对湿度稳定，适合固体制剂应用。
从文献看，针对氯卡色林固体形态的研究主要集中在其盐、水合物、溶剂化物及其晶型的开发和应用上，而本发明致力于提供氯卡色林的新的固体形态，以扩大制剂开发所选用的原料类型。此外，氯卡色林速释片虽然有溶出速度快、迅速达到有效血药浓度的优点，但是存在血药浓度不稳定、需要患者多次服药的不足，因此本领域仍需要开发氯卡色林的新的固体形态。
发明内容
针对现有技术的不足，本发明的目的是提供一种新型的氯卡色林共晶。与现有技术相比，所述共晶应具有一种或多种改进的特性，例如稳定性高；溶解性好；溶出速度快；结晶度高；不易吸湿；易于纯化和处理；纯度高；低残留溶剂；颗粒形貌佳；具有适宜的制剂可加工性例如流动性、粉体的可 塑性、紧密度和可压性；改进制剂表观；提高生物利用度、改善药效；适合新剂型应用例如适合缓释、控释制剂应用等方面。本发明还涉及所述共晶的制备方法、其药物组合物和用途。
药物共晶作为一种新型的药物固体形态，其发展刚刚起步，共晶的制备方法目前仍主要停留在反复实验阶段，不同物系之间能否形成共晶、形成的共晶能否具有改进的物化性质都是不可预知的。本发明人经过大量的实验，通过变换不同的物系和反应条件，惊喜地获得了一种具有改进特性的氯卡色林共晶。
根据本发明的目的，本发明提供盐酸氯卡色林和苯甲酸的共晶(在本发明中简称为“共晶”)。所述共晶是盐酸氯卡色林、苯甲酸和水以1:1:1摩尔比形成的化合物，其结构式如下所示：
Figure PCTCN2015075175-appb-000002
在本发明的一个实施方案中，使用Cu-Kα辐射，所述共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.5±0.2°、9.0±0.2°、12.3±0.2°、18.0±0.2°、19.4±0.2°和23.0±0.2°。
在本发明优选的一个实施方案中，使用Cu-Kα辐射，所述共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.5±0.2°、9.0±0.2°、11.7±0.2°、12.3±0.2°、13.5±0.2°、16.9±0.2°、18.0±0.2°、19.4±0.2°、20.4±0.2°、22.6±0.2°、23.0±0.2°和23.5±0.2°。
在本发明更优选的一个实施方案中，使用Cu-Kα辐射，所述共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
Figure PCTCN2015075175-appb-000003
Figure PCTCN2015075175-appb-000004
非限制性地，所述共晶的一个典型实例具有如图2所示的X-射线粉末衍射图。
在本发明的一个实施方案中，制备得到所述共晶的单晶。制备的具体操作例如：将共晶的丙酮溶液进行室温小孔挥发至干，得到单晶。所述“小孔挥发”是将装有溶液的容器在相应温度下通过直径为2毫米的单个小孔进行挥发结晶。
所述共晶的单晶，在100K的温度下进行测量，具有以下的单晶晶胞参数：轴长为
Figure PCTCN2015075175-appb-000005
二面角为α＝90°，β＝90°，γ＝90°；空间群：P 1 1 21。所述共晶是由两个单斜晶系组成的孪晶，在三个单位向量a、b、c的二面夹角上都表现为90°。
在本发明的一个实施方案中，所述共晶的傅里叶红外光谱在波数为3384、2971、2861、2524、2362、1700、1595、1315、1270、1119、946、818和710cm-1处具有特征峰。
所述共晶在25℃水中的溶解度为8～9mg/ml，而已知氯卡色林盐酸盐半水合物在25℃水中的溶解度大于200mg/ml。
与已知的氯卡色林盐酸盐半水合物相比，本发明的共晶具有以下有益性质及应用效果：
(1)本发明共晶在水中的溶解度为8～9mg/ml，较适合制备缓释制剂，其在患者体内能够长时间发挥药物治疗作用，维持有效的稳定的血药浓度，符合临床要求，可减少患者的用药次数和显著增加患者的顺应性。相同处方下，已知的氯卡色林盐酸盐半水合物因溶解度高可能会迅速释放完全，造成血药浓度低于起效浓度的真空期。
(2)关于缓释制剂的释放度控制，与依靠缓释包衣控制释放度的情况相比，因本发明共晶本身的溶出释放较慢，因此，本发明共晶制剂的释放度对包衣的依赖小，可避免包衣工序(包衣厚度、包衣连续性)以及包衣材料批次差异对释放度的影响。
(3)本发明共晶在温度25℃、相对湿度60％下保存6个月，纯度和晶型都能保持不变；本发明共晶在80℃-6000lx的高温光照条件下保存10天后，其纯度的下降和最大单杂含量的增长都明显低于已知的氯卡色林盐酸盐半水合物 的数据。因此本发明共晶具有较高的化学稳定性和晶型稳定性，适合制剂的要求，能够更好地对抗药物制造和/或存储等过程中由于药物活性成分变化所引起的含量不均匀、纯度下降、制剂可加工性降低等问题，减少由此带来的疗效下降风险和安全风险，也有利于后期的运输和储存。
根据本发明的目的，本发明提供所述共晶的制备方法，包括下述方法中的任意一种：
(1)形成苯甲酸在有机溶剂中的溶液，所述有机溶剂选自醇、酮或酯，加入氯卡色林盐酸盐半水合物，氯卡色林盐酸盐半水合物和苯甲酸的摩尔比为1:1～1.5:1，加完后搅拌析晶，得到所述的共晶。
优选地，所述有机溶剂选自C1～C4醇、乙酸乙酯或丙酮，更优选为异丙醇。
优选地，所述苯甲酸在有机溶剂中的溶液的浓度为75～120mg/mL。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温。
优选地，所述析晶的时间为8～48小时，更优选为8～16小时。
优选地，将氯卡色林盐酸盐半水合物平均分为2～6份加入，每次加入后搅拌10～15分钟。
(2)形成氯卡色林盐酸盐半水合物在有机溶剂中的溶液，所述有机溶剂选自醇、酮或酯，加入苯甲酸，氯卡色林盐酸盐半水合物和苯甲酸的摩尔比为1:1～1:3，加完后搅拌析晶，得到所述的共晶。
优选地，所述有机溶剂选自C1～C4醇、乙酸乙酯或丙酮，更优选为异丙醇。
优选地，所述氯卡色林盐酸盐半水合物和苯甲酸的摩尔比为1:1～1:1.5。
优选地，所述氯卡色林盐酸盐半水合物在有机溶剂中的溶液的浓度为50～100mg/mL。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温。
优选地，所述析晶的时间为8～48小时，更优选为8～16小时。
优选地，将苯甲酸平均分为2～6份加入，每次加入后搅拌10～15分钟。
(3)形成氯卡色林、盐酸和苯甲酸在有机溶剂中的混合体系，所述有机溶剂选自醇、酮、酯或卤代烷烃，氯卡色林、盐酸和苯甲酸的摩尔比为1:1:1～1:2:3，将混合体系搅拌析晶，得到所述的共晶。
优选地，所述有机溶剂选自C1～C4醇、乙酸乙酯、丙酮或二氯甲烷，更优选为异丙醇。
优选地，所述氯卡色林、盐酸和苯甲酸的摩尔比为1:1:1～1:2:2。
优选地，所述混合体系中氯卡色林与有机溶剂的重量体积比为100mg:1mL～200mg:1mL。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温。
优选地，所述析晶的时间为10～24小时。
所述盐酸为氯化氢的水溶液，可用的浓度范围为1～4mol/L。
上述制备方法(1)、(2)和(3)中，所述“C1～C4醇”包括甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇和异丁醇。
上述制备方法(1)、(2)和(3)中析出的共晶，采用本领域的常规方法进行分离和干燥。所述“分离”方法，例如过滤；过滤的具体操作为：将欲分离的样品置于滤纸上，减压抽滤。所述“干燥”方法，例如鼓风干燥、减压干燥等；干燥设备采用通风橱、鼓风烘箱或真空烘箱；可以在减压或不减压下进行干燥，优选压力小于0.09MPa；干燥温度为10～40℃，优选为室温；干燥时间为1～72小时，优选为1～10小时，更优选为1～2小时。
(4)将溶剂加入到等摩尔比的氯卡色林盐酸盐半水合物和苯甲酸的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述的共晶，其中所述溶剂选自水或有机溶剂。
制备方法(4)中所述有机溶剂是指药学上可接受的、不影响药物活性成分的生物活性且能将所述混合物润湿的有机溶剂。
优选地，制备方法(4)中所述溶剂选自丙酮、乙腈或水。
制备方法(4)中所述溶剂的用量以能将所述混合物完全润湿即可；优选地，所述混合物和溶剂的重量体积比为150mg:1mL～240mg:1mL。
优选地，制备方法(4)的操作温度为10～40℃，优选为室温。
所述“研磨”可以采用本领域的常规方法，即在研钵内对样品进行研磨。
本发明上述各种制备方法中，“搅拌”可以采用本领域的常规方法，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分，优选为300～900转/分。
本发明共晶的制备方法步骤简单，易于操作。
本发明中，“室温”指约10～30℃。
本发明中，氯卡色林可以参照专利文献WO2005/019179A2实施例1～5描述的方法制备得到或由商购得到，氯卡色林盐酸盐半水合物(晶型III)可以参照专利文献WO2006/069363A2实施例1、2描述的方法制备得到。
本发明中，“共晶”的晶型是被所示X射线粉末衍射图表征所证实的。“共晶”的结构是被所示X射线单晶衍射得到的结构图所证实的。本领域技术人员公知，X射线粉末衍射图的实验误差取决于仪器条件、样品准备和样品纯度。X射线粉末衍射图图谱通常会随着仪器条件而有所改变；峰的相对强度可能随实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素；峰角度的实验误差也应该被考虑进去，通常允许±0.2°的误差；样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何氯卡色林盐酸盐和苯甲酸的加成物如具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。
本发明所述共晶是纯的、单一的，基本没有混合任何其他晶体、晶型或非晶态。“基本没有”是指其中含有的其他晶体、晶型或非晶态少于20％(重量)，更指少于10％(重量)，尤其指少于5％(重量)，特别是指少于1％(重量)。
本发明人在研究中还发现，共晶前体可以不只限于苯甲酸，还可以包括丙二酸、琥珀酸、马来酸、富马酸、柠檬酸、苹果酸、酒石酸、己二酸、苯甲酸、对氨基苯甲酸、果糖、阿斯巴甜、苯甲醇、山梨醇、糊精、麦芽糊精、糖精、烟酰胺、尿素和2-氨基嘧啶等。
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的药物活性成分选自本发明的盐酸氯卡色林和苯甲酸的共晶或者由本发明制备方法得到的上述共晶，以及至少一种药学上可接受的载体或助剂。所述药物组合物通常包含，按重量计约1％～99％的本发明的盐酸氯卡色林和苯甲酸的共晶，以及按重量计约99％～1％的至少一种药学上可接受的适当的载体或助剂。此外，所述药物组合物还可以包含氯卡色林其它可药用的盐、溶剂化物、水合物的晶体或非晶态，或共晶。任选地，所述药物组合物还可以包含一种或多种其他的药物活性成分。
所述药物组合物可制备为固态、半固态或液态的剂型，固体口服剂型，例如包括片剂、胶囊剂、颗粒剂、丸剂和散剂；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，例如包括溶液剂、分散剂和复配成溶液的冻干粉。配方可适于药物活性成分的速释、缓释或控释，可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。给药途径包括口服、静脉注射、皮下注射、透皮给药、直肠给药、滴鼻给药等。为了制备时保持本发明的共晶，本发明的药物组合物优选为固体口服剂型，其包括片剂、胶囊剂、颗粒剂、丸剂和散剂，更优选为可缓释或可控释的固体口服剂型。
在固体剂型的情况下，本发明所述药学上可接受的载体或助剂包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的载体或助剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。
所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备时将本发明的盐酸氯卡色林和苯甲酸的共晶与一种或多种药学上可接受的载体或助剂，任选的一种或多种的其他活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
根据本发明的目的，本发明提供本发明的盐酸氯卡色林和苯甲酸的共晶在制备用于治疗和/或预防与5HT2c相关病症的药物中的用途。
根据本发明的目的，本发明提供一种治疗和/或预防与5HT2c相关的病症的方法，所述方法包括给予需要的患者治疗和/或预防有效量的本发明的盐酸氯卡色林和苯甲酸的共晶或者根据本发明制备方法得到的盐酸氯卡色林和苯甲酸的共晶或者本发明的前述药物组合物；所述患者是指包括人类在内的哺乳动物。在一些实施方案中，剂量范围可以是每日每千克体重约0.01毫克到约100毫克，可使用方便的每日剂量方式。剂量可视病症的类型和程度、患者的总体健康状况、配方的特性以及给药途径等而调节。
上述与5HT2c相关的病症包括但不限于肥胖症、中枢神经系统病症、中枢神经系统的损伤、心血管病症、肠胃失调、尿崩症、睡眠呼吸暂停、抑郁症、非典型抑郁症、双相障碍、焦虑症、强迫症、社交恐怖症或惊恐状态、睡眠障碍、性功能障碍、精神病、精神分裂症、偏头痛和与头部疼痛或与其他疼痛相关的病状、颅内压增高、癫痫症、人格障碍、与年龄相关的行为障碍、与痴呆相关的行为障碍、器质性精神障碍、儿童期精神障碍、攻击性、与年龄相关的记忆障碍、慢性疲劳综合症、药物与酒精成瘾、贪食症、神经性厌食症或经前期紧张症。
附图说明
图1是制备例1制备的氯卡色林盐酸盐半水合物晶型III的XRPD图
图2是本发明共晶的XRPD图
图3是本发明共晶的分子结构示意图
图4是本发明共晶的IR图
图5是本发明共晶(上)和单晶衍射模拟(下)的XRPD对比图
具体实施方式
本发明进一步参考以下实施例，所述实施例详细描述本发明的共晶、其制备方法和应用。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8Advance diffractometer，采用铜靶波长为1.54nm的Ka X-射线，在40kV和40mA的操作条件下、θ-2θ测角仪、Mo单色仪、Lynxeye探测器。仪器在使用前用金刚砂校准。采集软件是Diffrac Plus XRD Commander。样品在室温下测试，将样品放在无反射板上。 检测条件为：角度范围：3–40°2θ，步长：0.02°2θ，速度：0.2秒/步。
单晶衍射仪：Eos CCD检测器、四圆Kappa测仪、增强型Mo光源和增强型Cu光源。检测参数：环境温度100K，增强型Cu光源，石墨单色仪，波长
Figure PCTCN2015075175-appb-000006
数据分析软件是Crysalispro。再经shelxtl软件分析处理，可得分子结构示意图。
红外光谱分析(IR)数据采自于Bruker Tensor 27，仪器控制软件和数据分析软件都是OPUS。通常采用ATR设备，在600～4000cm-1范围内，采集红外吸收光谱，样品和空白背景的扫描时间均为16秒，仪器分辨率4cm-1。
核磁共振氢谱分析(1H-NMR)数据采自于Bruker Ascend Tm 500。通常使用全频激发，谱宽30ppm，单脉冲，30°角激发，扫描16次，数字化正交检测，控温298K。
高效液相色谱(HPLC)数据采自于Waters 2695型，色谱柱为VP－ODS150×4.6mm，5μm；柱温25℃，进样量5μL，流速1.0ml/min，流动相A为0.05％三氟乙酸水溶液，流动相B为乙腈，采用梯度洗脱，梯度洗脱表见表1。使用紫外-可见分光光度仪，测定波长220nm处的吸光度。
表1  HPLC梯度洗脱表
Figure PCTCN2015075175-appb-000007
除非特殊注明，实施例均在室温条件下操作。
实施例中所用的各种试剂如无特别说明均为商购获得。
实施例中，“过夜”是指该步骤跨越晚上的时间，可以为8～22小时，或者10～18小时，通常是16小时。
制备例1
根据专利文献WO2006/069363A2的实施例1、2制得氯卡色林盐酸盐半水合物(晶型III)，具体操作如下：
向220g氯卡色林中加入3L二氯甲烷，再加入1.74L 1mol/L的HCl乙醚溶液，室温下搅拌2小时，旋干除去溶剂，得到氯卡色林盐酸盐190g。
向16g氯卡色林盐酸盐中加入36g异丙醇，加热至60℃溶清。加入12.4g水，加入96g环己烷，然后将体系用2小时降温至20℃，缓慢搅拌。产生固体以后将体系冷却至0℃并在0℃搅拌3小时，过滤，滤饼用16g环己烷洗涤，40℃真空干燥，得15.1g白色晶体，为氯卡色林盐酸盐半水合物。
核磁共振氢谱数据：1H-NMR(CDCl3):10.2(br s,1H),9.8(br s,1H),7.14 (dd,1H,J＝2,8Hz),7.11(d,1H,J＝2Hz),7.03(d,1H,J＝8Hz),3.6(m,2H),3.5(m,2H),2.8-3.0(m,3H),1.5(d,3H.J＝7Hz)。
XRPD图谱如图1所示，显示该样品和WO2006/069363A2中晶型III一致。
实施例1
取160mg氯卡色林盐酸盐半水合物和80mg苯甲酸混合，加入1mL丙酮，保持混合物完全被丙酮湿润后，研磨至干，得到共晶234mg，产率94.7％。
共晶的XRPD图谱如图2所示。显示为结晶态物质。
共晶的红外图谱如图4所示。显示：在波数为3384、2971、2861、2524、2362、1700、1595、1315、1270、1119、946、818和710cm-1处具有特征峰。
实施例2
形成含实施例1所得共晶的丙酮溶液，室温下，将上述丙酮溶液注入到5ml玻璃瓶中，加盖密封，盖子上开一直径约为1mm的小孔进行挥发，挥发溶液至干，得到可供单晶检测的晶体。
单晶晶胞参数如表2所示。
表2  共晶的单晶晶胞参数
Figure PCTCN2015075175-appb-000008
表2中，a、b、c表示晶胞轴长，α、β、γ表示二面角，Z表示每个晶胞内以Lorcaserin-HCl-H2O-ArCOOH(Ar表示苯基)为单位分子的数目，V表示晶胞体积，Dcalc表示晶胞密度。
单晶解析相关参数：残差因子R1＝0.0442，加权R值wR2＝0.1194，拟合优度GooF(S)＝1.040。R1值小于0.05，wR2值小于0.15，S值接近1，说明单晶数据合理。
单晶的分子结构示意图如图3所示。显示共晶分子由一个氯卡色林分子、一个氯化氢分子、一个苯甲酸分子和一个水分子组成。
图5所示的对照图是单晶模拟的XRPD图(下)和实测的XRPD图(上)，显示两者基本一致。
实施例3
取100mg氯卡色林盐酸盐半水合物和50mg苯甲酸混合，加入1mL乙腈，40℃保持混合物完全被乙腈湿润后，研磨至干，得到共晶136mg，产率88.1％。
实施例4
取100mg氯卡色林盐酸盐半水合物和50mg苯甲酸混合，加入1mL水，40℃保持混合物完全被水湿润后，研磨至干，得到共晶108mg，产率70.0％。
实施例5
取120mg苯甲酸加入1mL甲醇超声溶解，得到苯甲酸的甲醇溶液，取240mg氯卡色林盐酸盐半水合物，平均分为6份，每份40mg，依次加入到苯甲酸的甲醇溶液中，每加一份，搅拌10～15min，加完后室温搅拌8小时，过滤，室温干燥1小时，得共晶55mg，产率15.0％。
实施例6
取240mg苯甲酸加入2mL正丁醇超声溶解，得到苯甲酸的正丁醇溶液，取480mg氯卡色林盐酸盐半水合物，平均分为4份，每份120mg，依次加入到苯甲酸的正丁醇溶液中，每加一份，搅拌10～15min，加完后室温搅拌8小时，过滤，室温干燥1小时，得共晶120mg，产率16.4％。
实施例7
取1.2g苯甲酸加入10mL异丙醇超声溶解，得到苯甲酸的异丙醇溶液，取2.4g氯卡色林盐酸盐半水合物，平均分为6份，每份0.4g，依次加入到苯甲酸的异丙醇溶液中，每加一份，搅拌10～15min，加完后室温搅拌过夜，过滤，40℃干燥2小时，得共晶1.63g，产率44.6％。
实施例8
40℃下，取450mg苯甲酸加入4mL乙酸乙酯超声溶解，得到苯甲酸的乙酸乙酯溶液，取1.35g氯卡色林盐酸盐半水合物，平均分为6份，每份225mg，依次加入到苯甲酸的乙酸乙酯溶液中，每加一份，搅拌10～15min，加完后搅拌48小时，过滤，10℃干燥10小时，得共晶226mg，产率16.5％。
实施例9
取300mg苯甲酸加入4mL丙酮超声溶解，得到苯甲酸的丙酮溶液，取900mg氯卡色林盐酸盐半水合物，平均分为2份，每份450mg，依次加入到苯甲酸的丙酮溶液中，每加一份，搅拌10～15min，加完后室温搅拌8小时，过滤，室温干燥1小时，得共晶140mg，产率15.3％。
实施例10
取250mg氯卡色林盐酸盐半水合物加入5mL丙酮超声溶解，得到氯卡色林盐酸盐半水合物的丙酮溶液，取375mg苯甲酸，平均分为3份，每份125mg，依次加入到氯卡色林盐酸盐半水合物的丙酮溶液中，每加一份，搅拌10～15min，加完后室温搅拌8小时，过滤，室温干燥2小时，得共晶48mg，产率12.4％。
实施例11
40℃下，取200mg氯卡色林盐酸盐半水合物加入3mL乙酸乙酯超声溶解，得到氯卡色林盐酸盐半水合物的乙酸乙酯溶液，取300mg苯甲酸，平均分为2份，每份150mg，依次加入到氯卡色林盐酸盐半水合物的乙酸乙酯溶液中，每加一份，搅拌10～15min，加完后室温搅拌过夜，过滤，10℃干燥10小时，得共晶47mg，产率15.2％。
实施例12
取200mg氯卡色林盐酸盐半水合物加入4mL异丙醇超声溶解，得到氯卡色林盐酸盐半水合物的异丙醇溶液，取100mg苯甲酸，平均分为2份，每份50mg，依次加入到氯卡色林盐酸盐半水合物的异丙醇溶液中，每加一份，搅拌10～15min，加完后室温搅拌过夜，过滤，10℃干燥10小时，得共晶134mg，产率43.4％。
实施例13
40℃下，取200mg氯卡色林盐酸盐半水合物加入2mL甲醇中超声溶解，得到氯卡色林盐酸盐半水合物的甲醇溶液，取150mg苯甲酸，平均分为3份，每份50mg，依次加入到氯卡色林盐酸盐半水合物的甲醇溶液中，每加一份，搅拌10～15min，加完后搅拌48小时，冷却至室温，过滤，40℃干燥时间1小时，得共晶42mg，产率13.6％。
实施例14
取200mg氯卡色林盐酸盐半水合物加入2mL正丁醇中超声溶解，得到氯卡色林盐酸盐半水合物的正丁醇溶液，取300mg苯甲酸，平均分为6份，每份50mg，依次加入到氯卡色林盐酸盐半水合物的正丁醇溶液中，每加一份，搅拌10～15min，加完后搅拌48小时，冷却至室温，过滤，40℃干燥时间1小时，得共晶45mg，产率14.6％。
实施例15
取200mg氯卡色林、1.02mL 1mol/L的盐酸和124mg苯甲酸，加入1mL异丙醇形成混合体系，将混合体系搅拌过夜，过滤，40℃干燥1小时，得共晶87mg，产率23.0％。
实施例16
取200mg氯卡色林、1.02mL 1mol/L的盐酸和248mg苯甲酸，加入1mL正丁醇形成混合体系，将混合体系搅拌24小时，过滤，40℃干燥4小时，得 共晶62mg，产率16.4％。
实施例17
取200mg氯卡色林、1.02mL 1mol/L的盐酸和248mg苯甲酸，加入2mL乙醇形成混合体系，将混合体系搅拌20小时，过滤，40℃干燥4小时，得共晶65mg，产率17.2％。
实施例18
取200mg氯卡色林、0.51mL 4mol/L的盐酸和248mg苯甲酸，加入2mL乙酸乙酯形成混合体系，将混合体系搅拌20小时，过滤，40℃干燥2小时，得共晶65mg，产率17.2％。
实施例19
取200mg氯卡色林、1.02mL 1mol/L的盐酸和372mg苯甲酸，加入1mL丙酮形成混合体系，将混合体系搅拌10小时，过滤，40℃干燥2小时，得共晶48mg，产率12.7％。
实施例20
取200mg氯卡色林、1.02mL 2mol/L的盐酸和372mg苯甲酸，加入2mL二氯甲烷形成混合体系，将混合体系搅拌24小时，过滤，40℃干燥1小时，得共晶54mg，产率14.3％。
实施例3～20制备的样品具有与实施例1样品相同或相似的XRPD图谱和IR图谱(未示出)。说明实施例3～20样品与实施例1样品是相同的共晶。
测试例1
对本发明的共晶进行溶解度测试，对照样为制备例1制备的已知的氯卡色林盐酸盐半水合物。
具体操作是:将已知的氯卡色林盐酸盐半水合物和本发明的共晶各取约10mg作为样品，25℃下向样品中逐步添加纯水直至样品全部溶清，根据样品的实际重量和水的用量计算样品的溶解度。结果见表3。
表3  溶解度测试结果
名称 溶解度
共晶(本发明) 8～9mg/ml
氯卡色林盐酸盐半水合物(已知) 大于200mg/ml
表3的溶解度测试结果显示，本发明共晶的溶解度(8～9mg/ml)明显低于已知的氯卡色林盐酸盐半水合物的溶解度(大于200mg/ml)，因而本发明的共晶更适合制备缓释制剂。
测试例2
将本发明的共晶制备成片剂，对照样为制备例1制备的已知的氯卡色林盐酸盐半水合物晶型III的片剂，片剂处方见表4；再进行片剂的溶出度检测。
表4  片剂处方
Figure PCTCN2015075175-appb-000009
制备片剂的具体操作是：根据表4处方，取处方量的API(API为已知的晶型III或本发明的共晶)、甘露醇、HPMC K4M和Avicel PH102混合均匀后，加入处方量的硬脂酸镁，混合均匀后，置于压片机中压制成片芯。取所得片芯置包衣机内以片芯重量的5％包衣，包衣液为固含量12％(w/v)的
Figure PCTCN2015075175-appb-000010
即得片剂。
片剂的溶出试验使用USP装置I(篮式方法)，在900mL的0.1N HCl溶液中、在37℃和100rpm条件下进行。于1小时、2小时、3小时、4小时、6小时、8小时、10小时、12小时和14小时取样，检测片剂溶出液的HPLC浓度，计算累积释放百分率，结果见表5。
表5  片剂的累积释放百分率
Figure PCTCN2015075175-appb-000011
表5的检测结果显示：在相同处方条件下，已知的氯卡色林盐酸盐半水合物晶型III的片剂比本发明共晶的片剂在pH＝1.0盐酸水溶液中释放快，因而本发明的共晶更适合制备缓释制剂。另一方面，关于缓释制剂的释放度控制，与依靠缓释包衣控制释放度的情况相比，因本发明共晶本身的溶出释放较慢，因此，本发明共晶制剂的释放度对包衣的依赖小，可避免包衣工序(包衣厚度、包衣连续性)以及包衣材料批次差异对释放度的影响。
测试例3
取制备例1制备的氯卡色林盐酸盐半水合物晶型III和本发明共晶，进行高温光照条件下放置10天的稳定性实验。高温条件为80℃，光照条件为6000lx照度。检测样品在放置前后的HPLC纯度和最大单杂含量，结果见表6。
表6  高温光照条件下的稳定性数据
Figure PCTCN2015075175-appb-000012
由表6的稳定性数据可知：在高温光照10天的条件下，氯卡色林盐酸盐半水合物晶型III的纯度降低了9.3％，最大单杂含量增加了9.3％；而本发明的共晶中氯卡色林的纯度降低了4.7％，苯甲酸的纯度降低了0.3％，最大单杂含量增加了4.8％。因此说明，本发明共晶在高温光照条件下的稳定性明显优于已知的氯卡色林盐酸盐半水合物晶型III。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种结构式如下所示的盐酸氯卡色林和苯甲酸的共晶：
    Figure PCTCN2015075175-appb-100001
  2. 根据权利要求1所述的盐酸氯卡色林和苯甲酸的共晶，其特征在于，使用Cu-Kα辐射，所述共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.5±0.2°、9.0±0.2°、12.3±0.2°、18.0±0.2°、19.4±0.2°和23.0±0.2°。
  3. 根据权利要求2所述的盐酸氯卡色林和苯甲酸的共晶，其特征在于，所述共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.5±0.2°、9.0±0.2°、11.7±0.2°、12.3±0.2°、13.5±0.2°、16.9±0.2°、18.0±0.2°、19.4±0.2°、20.4±0.2°、22.6±0.2°、23.0±0.2°和23.5±0.2°。
  4. 根据权利要求3所述的盐酸氯卡色林和苯甲酸的共晶，其特征在于，所述共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2015075175-appb-100002
  5. 根据权利要求1所述的盐酸氯卡色林和苯甲酸的共晶，其特征在于，所述共晶的单晶在100K的温度下进行测量，具有下列的单晶晶胞参数：轴长为
    Figure PCTCN2015075175-appb-100003
    二面角为α＝90°，β＝90°，γ＝90°；空间群：P1121。
  6. 根据权利要求2～5中任一项所述的盐酸氯卡色林和苯甲酸的共晶，其特征在于，所述共晶的傅里叶红外光谱在波数为3384、2971、2861、2524、2362、1700、1595、1315、1270、1119、946、818和710cm-1处具有特征峰。
  7. 权利要求1～6中任一项所述的盐酸氯卡色林和苯甲酸的共晶的制备方法，所述制备方法包括下述方法中的任意一种：
    (1)形成苯甲酸在有机溶剂中的溶液，所述有机溶剂选自醇、酮或酯，加入氯卡色林盐酸盐半水合物，氯卡色林盐酸盐半水合物和苯甲酸的摩尔比为1:1～1.5:1，加完后搅拌析晶，得到所述的共晶；
    优选地，所述有机溶剂选自C1～C4醇、乙酸乙酯或丙酮，更优选为异丙醇；
    优选地，所述苯甲酸在有机溶剂中的溶液的浓度为75～120mg/mL；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    优选地，所述析晶的时间为8～48小时，更优选为8～16小时；
    优选地，将氯卡色林盐酸盐半水合物平均分为2～6份加入，每次加入后搅拌10～15分钟；
    (2)形成氯卡色林盐酸盐半水合物在有机溶剂中的溶液，所述有机溶剂选自醇、酮或酯，加入苯甲酸，氯卡色林盐酸盐半水合物和苯甲酸的摩尔比为1:1～1:3，加完后搅拌析晶，得到所述的共晶；
    优选地，所述有机溶剂选自C1～C4醇、乙酸乙酯或丙酮，更优选为异丙醇；
    优选地，所述氯卡色林盐酸盐半水合物和苯甲酸的摩尔比为1:1～1:1.5；
    优选地，所述氯卡色林盐酸盐半水合物在有机溶剂中的溶液的浓度为50～100mg/mL；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    优选地，所述析晶的时间为8～48小时，更优选为8～16小时；
    优选地，将苯甲酸平均分为2～6份加入，每次加入后搅拌10～15分钟；
    (3)形成氯卡色林、盐酸和苯甲酸在有机溶剂中的混合体系，所述有机溶剂选自醇、酮、酯或卤代烷烃，氯卡色林、盐酸和苯甲酸的摩尔比为1:1:1～1:2:3，将混合体系搅拌析晶，得到所述的共晶；
    优选地，所述有机溶剂选自C1～C4醇、乙酸乙酯、丙酮或二氯甲烷，更优选为异丙醇；
    优选地，所述氯卡色林、盐酸和苯甲酸的摩尔比为1:1:1～1:2:2；
    优选地，所述混合体系中氯卡色林与有机溶剂的重量体积比为100mg:1mL～200mg:1mL；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    优选地，所述析晶的时间为10～24小时；
    (4)将溶剂加入到等摩尔比的氯卡色林盐酸盐半水合物和苯甲酸的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述的共晶，其中所述溶剂选自水或有机溶剂；
    优选地，所述溶剂选自丙酮、乙腈或水；
    优选地，所述混合物和溶剂的重量体积比为150mg：1mL～240mg：1mL；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温。
  8. 一种药物组合物，包含治疗和/或预防有效量的药物活性成分选自权利要求1～6中任一项所述的盐酸氯卡色林和苯甲酸的共晶或根据权利要求7中任一项所述制备方法得到的盐酸氯卡色林和苯甲酸的共晶，以及至少一种药学上可接受的载体或助剂。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述药物组合物的剂型为固体口服剂型，包括片剂、胶囊剂、颗粒剂、丸剂和散剂，优选为可缓释或可控释的固体口服剂型。
  10. 权利要求1～6中任一项所述的盐酸氯卡色林和苯甲酸的共晶或根据权利要求7中任一项所述制备方法得到的盐酸氯卡色林和苯甲酸的共晶在制备用于治疗和/或预防与5HT2c相关病症的药物中的用途；所述与5HT2c相关的病症选自肥胖症、中枢神经系统病症、中枢神经系统的损伤、心血管病症、肠胃失调、尿崩症、睡眠呼吸暂停、抑郁症、非典型抑郁症、双相障碍、焦虑症、强迫症、社交恐怖症或惊恐状态、睡眠障碍、性功能障碍、精神病、精神分裂症、偏头痛和与头部疼痛或与其他疼痛相关的病状、颅内压增高、癫痫症、人格障碍、与年龄相关的行为障碍、与痴呆相关的行为障碍、器质性精神障碍、儿童期精神障碍、攻击性、与年龄相关的记忆障碍、慢性疲劳综合症、药物与酒精成瘾、贪食症、神经性厌食症或经前期紧张症。
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