CN113024532A

CN113024532A - Crystal form of anti-schizophrenia drug mesylate

Info

Publication number: CN113024532A
Application number: CN201911348254.1A
Authority: CN
Inventors: 江华; 陈寅; 金牮; 张桂森
Original assignee: Jiangsu Tieqi Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Tieqi Pharmaceutical Technology Co ltd
Priority date: 2019-12-24
Filing date: 2019-12-24
Publication date: 2021-06-25
Anticipated expiration: 2039-12-24
Also published as: CN113024532B

Abstract

The invention discloses a crystal form of an anti-schizophrenia drug mesylate, which is prepared by reacting 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one with methanesulfonic acid, further dissolving a solid product of the mesylate in a mixed solvent containing alcohol for recrystallization to prepare two novel crystal forms I and II, and determining the crystal forms by an X-ray powder diffraction characteristic absorption peak, a differential scanning calorimeter characteristic peak and a Fourier infrared spectrum. The novel crystal form prepared by the invention has high purity, high solubility, good stability and simple preparation process, and can be applied to preparation and large-scale production of medicaments for resisting mental diseases such as schizophrenia and the like.

Description

Crystal form of anti-schizophrenia drug mesylate

Technical Field

The invention relates to the technical field of medicinal chemistry, relates to a crystal form of a mesylate of an anti-schizophrenia medicament, and particularly relates to novel crystal forms I and II of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydrogen-benzopyran-2-one mesylate, and a preparation method and application thereof.

Background

Schizophrenia is a disease characterized by deep cognitive and emotional divisions that manifest as the most basic human behavior, such as language, thought, perception, and self-perception. The symptoms of the disease are included in a wide range, most commonly mental disorders such as hallucinations, delusions, and delusions.

Schizophrenia is the most serious psychological disorder, with about 1% of people worldwide suffering from schizophrenia, and only 5% of all treated patients eventually recovering completely. In addition, since schizophrenia often causes complications such as anxiety disorder, depression, or psychotropic substance abuse, a research study by Datamonitor has shown that schizophrenia patients exceeding 1/3 suffer from at least one or more concurrent mental diseases or cognitive disorders.

Antipsychotics that exert pharmacological effects by blocking dopamine D2 receptors have traditionally been referred to as the first generation antipsychotics, the "typical" antipsychotics (e.g., haloperidol), which are breakthrough in treating the positive symptoms of schizophrenia but fail to treat the negative symptoms and cognitive disorders. Typical antipsychotics generally have severe EPS side effects and are ineffective in one-third of schizophrenic patients.

After the 60's of the 20 th century, a series of new generation antipsychotics, including Ziprasidone (Ziprasidone), Risperidone (Risperidone), etc., called second generation antipsychotics, i.e., new antipsychotics, were developed in succession, although their respective pharmacological actions were not completely consistent, but had a common pharmacological profile, i.e., affinity for the 5-hydroxytryptamine (5-HT) receptor (5-HT1A, 2A, 2c) and Norepinephrine (NA) receptor (α 1, α 2) was much higher than for the D2 receptor, resulting in a lower ratio of D2/5-HT 2A. The clinical effect of the compound has more advantages compared with the first generation antipsychotic, the compound has the same effect on positive symptoms as the traditional antipsychotic, and has the effects on negative symptoms and cognitive deficiency symptoms and wider action spectrum, but the compounds have the adverse effects of QT gap prolongation, hyperprolactinemia, weight gain and the like. Therefore, the search for drugs effective in treating schizophrenia positive and negative symptoms and cognitive impairment with less side effects is the focus of research.

Patent application No. CN 201110086701.8 discloses 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one, the structural formula of which is as follows:

the compound is found to be p-dopamine D₂，D₃，5-HT_1AAnd 5-HT_2AThe receptor has high affinity, and can be used for treating nervous system diseases caused by dopamine dysfunction, especially for treating mental diseases such as schizophrenia, etc., however, the compound and 5-HT_2CThe affinity of (c) is lower.

To overcome the above technical disadvantages, the applicant tried to react 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-chromen-2-one with methanesulfonic acid to make 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-chromen-2-one methanesulfonate. However, during the experiment it was found that: the prepared 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate is not a single crystal but a mixed product of a plurality of crystal forms, and the proportions of the crystal forms in the mixed product are different due to different preparation methods, so that the quality of a drug product is difficult to control. And due to different crystal forms of the drugs, the melting point, the solubility, the stability and the like of the drugs have large differences, so that the absorption and the release of the drugs in vivo can be influenced, and the activity, the curative effect and the safety of the drugs can be further influenced. Meanwhile, different crystal form drugs have large differences in physical and chemical properties, and the difference in physical properties also causes large differences in processing and storage properties of different crystal forms of the same drug.

Therefore, it is necessary to investigate the polymorphism and physical and chemical properties of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-chromen-2-one methanesulfonate, so as to obtain the 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate medicine with stable crystal form and quality, thereby providing a new effective way for treating and preventing mental diseases such as schizophrenia and the like.

Disclosure of Invention

The invention aims to provide a crystal form of an anti-schizophrenia drug mesylate aiming at the problems in the prior art.

In order to achieve the purpose, the invention adopts the technical scheme that:

the first object of the present invention is to provide a crystalline form I of the mesylate salt of the anti-schizophrenia drug.

An anti-schizophrenia drug mesylate in a crystal form I, wherein in an X-ray powder diffraction spectrum of the crystal form I, characteristic diffraction peaks exist at diffraction angles 2 theta of 4.57 +/-0.2 degrees, 9.16 +/-0.2 degrees, 15.01 +/-0.2 degrees, 18.45 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.13 +/-0.2 degrees, 26.45 +/-0.2 degrees and 27.84 +/-0.2 degrees.

As a further limitation of the scheme, in an X-ray powder diffraction spectrum of the crystal form I, characteristic diffraction peaks exist at diffraction angles 2 theta of 4.57 +/-0.2 degrees, 9.16 +/-0.2 degrees, 13.17 +/-0.2 degrees, 13.80 +/-0.2 degrees, 15.01 +/-0.2 degrees, 16.17 +/-0.2 degrees, 18.45 +/-0.2 degrees, 19.22 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.13 +/-0.2 degrees, 26.45 +/-0.2 degrees and 27.84 +/-0.2 degrees.

As a further limitation of the scheme, the differential scanning calorimetry spectrum of the crystal form I has an endothermic peak within the range of 208-210 ℃.

The second purpose of the invention is to provide a preparation method of the crystal form I of the mesylate of the anti-schizophrenia drug, which comprises the following steps:

(1) dissolving 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-ketone in an organic solvent, heating to 30-100 ℃, adding a methanesulfonic acid solution, stirring for 0.5-6 h, filtering and drying for later use;

(2) and (2) recrystallizing the 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydrogen-benzopyran-2-one mesylate prepared in the step (1) in methanol to prepare the crystal form I of the mesylate of the anti-schizophrenia drug.

As a further limitation of the above scheme, the solid-to-liquid ratio of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one to the organic solvent is 1g (10-100) mL; the organic solvent is alcohols, esters or ketones; the alcohol is preferably C₁-C₈Preferably C, or mixtures thereof, and the ester is preferably C₂-C₈Or mixtures thereof, said ketone preferably being C₂-C₈Or a mixture thereof.

Further, said C₁-C₈The alcohol of (b) is preferably methanol, absolute ethanol; said C₂-C₈The ester of (a) is preferably ethyl acetate and the ketone is preferably acetone or butanone.

The third purpose of the invention is to provide a crystal form II of the mesylate of the anti-schizophrenia drug, wherein in the X-ray powder diffraction spectrum of the crystal form II, characteristic diffraction peaks exist at diffraction angles 2 theta of 6.11 +/-0.2 degrees, 8.66 +/-0.2 degrees, 11.06 +/-0.2 degrees, 12.26 +/-0.2 degrees, 19.46 +/-0.2 degrees and 25.48 +/-0.2 degrees.

As a further limitation of the above scheme, in the X-ray powder diffraction spectrum of the crystal form II, the characteristic diffraction peaks are found at diffraction angles 2 theta of 6.11 +/-0.2 degrees, 8.66 +/-0.2 degrees, 11.06 +/-0.2 degrees, 12.26 +/-0.2 degrees, 16.14 +/-0.2 degrees, 18.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 20.35 +/-0.2 degrees, 21.08 +/-0.2 degrees, 24.77 +/-0.2 degrees and 25.48 +/-0.2 degrees.

As a further limitation of the scheme, the differential scanning calorimetry spectrum of the crystal form II has endothermic peaks at 95.9 ℃, 111.9 ℃ and 138.1 ℃.

The fourth purpose of the invention is to provide a preparation method of the crystal form II of the mesylate of the anti-schizophrenia drug, which comprises the following steps:

s1, dissolving 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydrogen-benzopyran-2-ketone in an organic solvent, heating to 30-100 ℃, adding a methanesulfonic acid solution, stirring for 0.5-6 h, filtering and drying for later use;

s2, recrystallizing the 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate prepared in the step S1 in a mixed solvent to prepare the crystal form II of the schizophrenia drug mesylate.

As a further limitation of the above scheme, in step S2, the solid-to-liquid ratio of the 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate to the mixed solvent is 1g (10-100) mL; the mixed solvent is formed by mixing an alcohol or ketone organic solvent and water according to a volume ratio of 10: 1-1: 10.

As a further limitation of the above scheme, in step S2, the alcohol is C1-C8 alcohol or a mixture thereof, and the ketone is C2-C8 ketone or a mixture thereof.

As a further limitation of the above solution, in step S2, the C1-C8 alcohol is one or more of methanol, ethanol or isopropanol; the C2-C8 ketone is acetone.

The fifth purpose of the invention is to provide a pharmaceutical composition, which takes the crystal form I of the mesylate of the anti-schizophrenia drug and/or the crystal form II of the mesylate of the anti-schizophrenia drug as active ingredients.

As a further limitation of the above scheme, each crystal form exists in the active ingredient with a crystal form purity of 50-100%, preferably with a crystal form purity of not less than 80%, and more preferably with a crystal form purity of 100% of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidinyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one methanesulfonate.

As a further limitation of the above scheme, the pharmaceutical composition of the present invention comprises said form I of the mesylate salt of the anti-schizophrenia drug and/or said form ii of the mesylate salt of the anti-schizophrenia drug (active ingredient) and pharmaceutically acceptable excipients, carriers, adjuvants, vehicles or combinations thereof.

The invention also aims to provide application of the crystal form I of the mesylate of the anti-schizophrenia drug or the crystal form II of the mesylate of the anti-schizophrenia drug or the pharmaceutical composition in preparing drugs for treating or preventing neuropsychiatric diseases.

In a further limitation of the above aspect, the neuropsychiatric disease is schizophrenia.

The physical properties of the invention comprise: thermodynamic stability, crystal morphology (crystal form, shape, structure, particle size distribution, crystallinity, color), ripple behavior, flowability, density, bulk density, powder density, apparent density, tap density, depletability (depletability), emptiability (emptyability), hardness, deformability, grindability, compressibility, compactability, brittleness, elasticity, thermal properties (in particular melting point), solubility (in particular equilibrium solubility, pH dependence of solubility), solubility (in particular dissolution rate, characteristic dissolution rate), rehydration, hygroscopicity, tackiness, adhesion, tendency to become electrostatically charged, etc.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention firstly makes 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-ketone react with methanesulfonic acid, and then further makes the solid product of the methanesulfonic acid salt dissolve in mixed solvent containing alcohol to make recrystallization so as to obtain two novel 7- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one methanesulfonic acid salt crystal forms I and II, and makes them pass through X-ray powder diffraction characteristic absorption peak, absorption peak and reaction time, And determining the crystal form of the crystal by using a differential scanning calorimeter characteristic peak and a Fourier infrared spectrum. The novel crystal form prepared by the invention has high purity, high solubility, excellent physicochemical property, good stability and simple preparation process, and the preparation method can effectively improve the crystal form quality and can be applied to the preparation and large-scale production of medicaments for resisting mental diseases such as schizophrenia and the like.

(2) The 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydrogen-benzopyran-2-ketone methanesulfonate prepared by the invention has crystal forms I and II, and is p-dopamine D₂，D₃，5-HT_1A、5-HT_2AAnd 5-HT_2CThe receptors have high affinity, and can be used for treating nervous system diseases caused by dopamine dysfunction, especially for treating and preventing mental diseases such as schizophrenia.

Drawings

FIG. 1 is a powder X-ray diffraction pattern of a crystalline form I of the mesylate salt of the anti-schizophrenia drug.

FIG. 2 is a DSC of form I of the mesylate salt of the anti-schizophrenia drug.

FIG. 3 is an infrared spectrum of the crystal form I of the mesylate salt of the anti-schizophrenia drug.

FIG. 4 is a powder X-ray diffraction pattern of form II of the mesylate salt of the anti-schizophrenia drug.

FIG. 5 is a DSC chart of form II of the mesylate salt of the anti-schizophrenia drug.

FIG. 6 is an infrared spectrum of form II of the mesylate salt of the anti-schizophrenia drug.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more clearly apparent, the present invention is further described in detail with reference to the following embodiments; it should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention; reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

General definitions and terms appearing in the following detailed description of the invention unless otherwise indicated, the terms and phrases used herein have the meanings listed below. No particular term or phrase is to be construed as critical or unclear unless otherwise specifically defined, but rather construed according to meanings commonly understood by those skilled in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

Unless specifically defined otherwise, the proportions (including percentages) or parts used herein are by weight. The weight ratio can also be expressed as a mass ratio, and both have the same meaning.

The terms "about" and "approximately," when used in conjunction with a numerical variable, generally mean that the value of the variable and all values of the variable are within experimental error (e.g., within 95% confidence interval for the mean) or within ± 10% of the specified value, or more.

The expressions "comprising" or similar expressions "including", "containing" and "having" and the like which are synonymous are open-ended and do not exclude additional, unrecited elements, steps or components. The expression "consisting of …" excludes any element, step or ingredient not specified. The expression "consisting essentially of …" means that the scope is limited to the specified elements, steps or components, plus optional elements, steps or components that do not materially affect the basic and novel characteristics of the claimed subject matter. It is to be understood that the expression "comprising" covers the expressions "consisting essentially of …" and "consisting of …".

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "crystalline form" or "crystalline" refers to any solid substance that exhibits a three-dimensional ordering, as opposed to an amorphous solid substance, which produces a characteristic X-ray powder diffraction pattern having well-defined peaks.

The term "hydrate" describes a solvate comprising a drug and a stoichiometric or non-stoichiometric amount of water.

The term "pharmaceutical composition" refers to an active ingredient, optionally in combination with one or more pharmaceutically acceptable chemical ingredients (such as, but not limited to, carriers and/or excipients).

The term "pharmaceutically acceptable carrier" refers to those carriers which do not significantly irritate the organism and which do not impair the biological activity and performance of the active compound, and includes, but is not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier acceptable for use in humans or animals (e.g., livestock). Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like. For additional information on The vector, reference may be made to Remington, The Science and Practice of Pharmacy,21st Ed., Lippincott, Williams & Wilkins (2005), The contents of which are incorporated herein by reference. The term "excipient" generally refers to vehicles, diluents, and/or vehicles and the like, which are required to formulate an effective pharmaceutical composition.

The terms "administration" or "administering" and the like refer to a method that can enable a compound or composition to be delivered to a desired site of biological action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like.

The term "effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition can be that amount which is required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.

The term "X-ray powder diffraction pattern (XRPD)" as used herein refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are generally characterized by peak position (abscissa) and/or peak intensity (ordinate).

In X-ray powder diffraction (XRPD) spectroscopy, the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystalline form, where the relative intensities of the bands (especially at low angles) may vary due to preferential orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and when judging whether the diffraction peaks are the same as the known crystal form, the relative positions of the peaks rather than their relative intensities should be noted. In addition, there may be slight errors in the position of the peaks for any given crystalline form, which is also well known in the crystallography art. For example, the position of the peak may shift due to temperature changes when analyzing the sample, sample movement, calibration of the instrument, or the like, and the error in the measurement of the 2 θ value is sometimes about ± 0.2 °, typically about ± 0.1 °. Therefore, this error should be taken into account when determining each type of structure. The term "substantially" is also intended to encompass such differences in diffraction peak positions if the crystalline forms of the invention are described as being substantially as shown in the designated figures.

The peak position is usually expressed in the XRPD pattern as 2 θ angle or crystal plane distance d, with a simple conversion between the two: d ═ λ/2sin θ, where d represents the interplanar spacing, λ denotes the wavelength of the incident X-rays, and θ denotes the diffraction angle. For the same crystal form of the same compound, the peak positions of the XRPD spectrum have similarity on the whole, and the relative intensity error can be larger. It should also be noted that in the identification of mixtures, the loss of a portion of the diffraction lines may be due to, for example, a reduction in the amount of the compound, in which case it is not necessary to rely on all the bands observed in the high purity sample, and even one band may be characteristic of a given crystal. As described herein, using

As a radiation source. The XRPD patterns herein may be, for example, inCollected on a Bruker D8 Focus X-ray powder diffractometer.

As used herein, the term "substantially the same" or "substantially as shown at …" with respect to an X-ray diffraction peak is meant to take into account representative peak position and intensity variations. For example, those skilled in the art will appreciate that the peak position (2 θ) will show some variation, typically as much as 0.1-0.2 degrees, and that the instruments used to measure diffraction will also cause some variation. In addition, one skilled in the art will appreciate that relative peak intensities will vary due to inter-instrument variations as well as the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered as qualitative measurements only.

The different configuration and orientation of molecules in the unit cell defining a particular polymorphic form of a substance leads to different physical properties that allow solid state analytical characterization of these phases. Different crystal structures have characteristic reflections with more or less characteristic relative intensities in the X-ray powder diffraction pattern, which generally allows for unambiguous identification of polymorphic forms. This variation may cause different thermal performance than other passes. Thermal properties are measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TG) and Differential Scanning Calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular solid phase may also give rise to different spectral properties, which can be detected by solid state nuclear magnetic resonance (nmr) spectrometry, raman spectrometry and fourier infrared (FT-IR) spectroscopy. A particular solid phase has different packing patterns of molecules, and the appearance form of the solid phase, namely the appearance form of the solid phase, can show different appearances, and the appearance forms can be observed by an optical microscope and a scanning electron microscope. These analytical techniques are therefore suitable for characterizing polymorphic forms.

As used herein, "Differential Scanning Calorimetry (DSC)" measures the transition temperature of a crystal when it absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the thermal transition temperature and melting point errors in successive analyses may be within about 5 ℃, typically within about 3 ℃. When a compound is described as having a given DSC peak or melting point, that DSC peak or melting point is referred to as ± 5 ℃. "substantially" also takes such temperature variations into account. DSC provides an auxiliary method to distinguish different crystal forms. Different crystal morphologies can be identified by their different transition temperature characteristics. It is noted that the DSC peak or melting point for the mixture may vary over a larger range. Furthermore, the melting temperature is related to the rate of temperature rise due to decomposition that accompanies the process of melting the substance. The DSC profile can be measured, for example, on an instrument of the german navy DSC 200F 3. An exemplary test condition is that the temperature range is 40-200 ℃, and the temperature rise rate is 15K/min.

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the scope of protection of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

In the examples below, unless otherwise indicated, the experimental procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the figure can be obtained by a commercially available mode.

The X-ray powder diffractogram according to the invention was collected on a Bruker D8 Focus powder X-ray diffractometer. The parameters of the X-ray powder diffraction method are as follows:

x-ray parameters: Cu/Kalpha

Voltage: 40 KV (kV)

Current: 40 milliampere (mA)

Scanning range: from 3.0 to 40 DEG

Sampling step length: 0.02 degree

Sampling pace speed: 0.5 sec/step

The Differential Scanning Calorimetry (DSC) analysis chart is detected by German relaxation-resistant DSC 200F3, and the temperature rise rate is 15K/min; sealing the pricking hole in an aluminum crucible, wherein the purging gas is nitrogen (60mL/min), and the protective gas is nitrogen (40 mL/min).

The Fourier infrared spectrum (FT-IR) is used for detecting each crystal form by matching a 330FT-IR type infrared spectrophotometer of Saimer Feishale company in America with a Smart iTR accessory, and the scanning wave number range is 600-4000 cm^-1Resolution 2.000cm^-1And the number of scanning times is 64.

In some preferred embodiments of the invention below, the pharmaceutical composition comprises about 0.001 to about 40 weight percent of one or more of the crystalline forms of the invention; in some preferred embodiments, the pharmaceutical composition contains about 0.001-30% by weight of one or more of the crystalline forms of the present invention; in some preferred embodiments, the pharmaceutical composition contains about 0.001-20% by weight of one or more of the crystalline forms of the present invention; in some preferred embodiments, the pharmaceutical composition contains about 0.001-15% by weight of one or more of the crystalline forms of the present invention; in some preferred embodiments, the pharmaceutical composition contains about 0.01 to about 12.5 weight percent of one or more of the crystalline forms of the present invention.

In some preferred embodiments, the pharmaceutical composition comprises as active ingredient the crystalline form i of the mesylate salt of the anti-schizophrenia drug.

In some preferred embodiments, form i as the active ingredient in the pharmaceutical composition is present in substantially pure form (e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or even at least about 99% form i in the active ingredient).

In some preferred embodiments, the pharmaceutical composition is preferably formulated for oral administration.

According to some embodiments of the invention, an effective amount of form I of the mesylate salt of the anti-schizophrenia drug and/or form ii of the mesylate salt of the anti-schizophrenia drug may be administered orally with a carrier, such as an inert diluent. Examples of suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.

According to some embodiments of the invention, the compounds of the invention or pharmaceutically acceptable salts thereof may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the crystalline form i of the present invention can be used together with excipients and formulated for use in the form of tablets, troches, capsules, suspensions, syrups and the like.

The crystalline form ii of the present invention may also be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, pills, powders, syrups, solutions and the like. Tablets, pills, capsules and the like, which may contain from about 0.01 to 99% by weight of the active ingredient (form ii) together with binders such as gelatin, corn starch, gum arabic; excipients such as dibasic calcium phosphate; disintegrating agents such as corn starch, potato starch or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose. When the capsule is used, it may also contain a liquid carrier, such as a fat.

According to an embodiment of the invention, such a formulation may contain at least 0.5% by weight of form II, but depending on the particular dosage form, about 4 to 70% by weight may also be used. Preferred oral unit doses of the invention contain 1.0 to 300 mg of form ii of the invention.

The amount of the mesylate salt of an anti-schizophrenia drug of the present invention to be used depends on the type and severity of the disease or disorder, and also on the characteristics of the subject, such as the health, age, sex, weight and tolerance to drugs of the subject. The skilled person will be able to determine the appropriate dosage based on these and other factors. Effective dosages of the cns drug generally employed are well known to the skilled artisan. The total daily dose is usually about 0.05mg to 2000 mg.

The present invention will be described in further detail below with reference to specific embodiments and with reference to the attached drawings.

Example 1

The present example provides a method for preparing form I of the mesylate salt of an anti-schizophrenia drug, comprising the steps of:

(1) weighing 1g of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one base, placing in a three-necked flask, adding 50mL of absolute ethanol, and stirring in a water bath at 40 ℃ for 0.5 h; weighing 0.135mL of methanesulfonic acid, adding 5mL of absolute ethyl alcohol for dilution, slowly dropwise adding the mixture into a three-necked bottle, stirring for 1h, separating out white insoluble substances, filtering, and drying at 50 ℃ for later use;

(2) weighing 3g of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydrogen-benzopyran-2-one methanesulfonate prepared in the step (1) and placing the methanesulfonate into a three-necked bottle, adding 20mL of anhydrous methanol into the three-necked bottle, heating to reflux and dissolve, slowly separating out crystals at room temperature of 25 ℃, separating out blocky crystals, filtering, and drying at 50 ℃ to obtain the crystal form I of the methanesulfonate serving as the anti-schizophrenia drug.

The X-ray powder diffraction results of the form I of the mesylate salt of the anti-schizophrenia drug prepared in this example are shown in the following table and fig. 1. As can be seen from the results in the following table and FIG. 1, the crystal form I has characteristic diffraction peaks at diffraction angles 2 theta of 4.57 +/-0.2 degrees, 9.16 +/-0.2 degrees, 13.17 +/-0.2 degrees, 13.80 +/-0.2 degrees, 15.01 +/-0.2 degrees, 16.17 +/-0.2 degrees, 18.45 +/-0.2 degrees, 19.22 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.13 +/-0.2 degrees, 26.45 +/-0.2 degrees and 27.84 +/-0.2 degrees.

The Differential Scanning Calorimeter (DSC) thermogram result of the crystal form I of the anti-schizophrenia drug mesylate prepared in the embodiment is shown in figure 2, and the Differential Scanning Calorimeter (DSC) thermogram of the crystal form I has a sharp endothermic peak at 209.6 ℃.

The characterization result of the Fourier infrared spectrogram of the crystal form I of the anti-schizophrenia drug mesylate prepared in the embodiment is shown in figure 3. As can be seen from the figure, the one antibody prepared in this exampleThe crystal form I of the schizophrenia drug mesylate is 700-1800 cm^-1There are multiple characteristic absorption peaks within the range.

The stability influencing factor test, including high temperature, high humidity and light test, is carried out on the crystal form I of the mesylate of the anti-schizophrenia drug prepared in the embodiment according to the four 9001 guiding principles of the stability test of raw material drugs and preparations in the Chinese pharmacopoeia 2015 edition. The results are shown in tables 2 to 4.

TABLE 2 stability results of high temperature test

TABLE 3 stability results of high humidity test

TABLE 4 stability results of light test

The results in tables 2 to 4 show that the crystal form I of the mesylate, an anti-schizophrenia drug, prepared in the embodiment can continuously maintain higher stability under the conditions of high temperature, high humidity and/or illumination.

Example 2

The embodiment provides a preparation method of a crystal form II of an anti-schizophrenia drug mesylate, which comprises the following steps:

s1, weighing 1g of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one base, placing in a three-necked flask, adding 50mL of absolute ethyl alcohol, and stirring in a water bath at 40 ℃ for 0.5 h; weighing 0.135mL of methanesulfonic acid, adding 5mL of absolute ethyl alcohol for dilution, slowly dropwise adding the mixture into a three-necked bottle, stirring for 1h, separating out white insoluble substances, filtering, and drying at 50 ℃ for later use;

s2, weighing 0.5g of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate prepared in the step S1, placing the mixture in a round-bottom flask, adding 40mL of 20% methanol aqueous solution (prepared by mixing methanol and water according to the volume ratio of 1: 4), and stirring at 40 ℃ for 1 h; filtering to obtain filtrate, standing to separate out crystals, filtering to obtain white solid, and drying at 50 ℃ to obtain the crystal form II of the anti-schizophrenia drug mesylate.

The X-ray powder diffraction results of the form ii of the mesylate salt of the anti-schizophrenia drug prepared in this example are shown in the following table and fig. 4. As can be seen from the results in the following table and FIG. 4, the crystal form II has characteristic diffraction peaks at diffraction angles 2 theta of 6.11 +/-0.2 degrees, 8.66 +/-0.2 degrees, 11.06 +/-0.2 degrees, 12.26 +/-0.2 degrees, 16.14 +/-0.2 degrees, 18.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 20.35 +/-0.2 degrees, 21.08 +/-0.2 degrees, 24.77 +/-0.2 degrees and 25.48 +/-0.2 degrees.

The Differential Scanning Calorimeter (DSC) thermogram result of the crystal form II of the anti-schizophrenia drug mesylate prepared in the embodiment is shown in figure 5, and the Differential Scanning Calorimeter (DSC) thermogram of the crystal form II has three sharp endothermic peaks at 95.9 ℃, 111.9 ℃ and 138.1 ℃.

The characterization result of the Fourier infrared spectrogram of the crystal form II of the anti-schizophrenia drug mesylate prepared in the embodiment is shown in FIG. 6. As can be seen from the figure, the crystal form II of the mesylate of the anti-schizophrenia drug prepared in the embodiment is 700-1800 cm^-1There are multiple characteristic absorption peaks within the range.

Examples 3 to 7

Examples 3 to 7 provide a method for preparing a crystalline form ii of a mesylate, which is an anti-schizophrenia drug, compared with example 2, except that the volume ratio of the alcohol or ketone to water in the mixed solvent in step S2 is changed, other operations are the same, and are not repeated herein, and specific experimental condition parameters are shown in the following table.

Examples	Mixed solvent
		3	50% aqueous methanol solution
4	80% aqueous methanol solution
		5	20% ethanol aqueous solution
6	50% ethanol aqueous solution
		7	50% acetone in water

The X-ray powder diffraction results of the crystal form II of the mesylate of the anti-schizophrenia drug prepared in examples 3-7 show that the crystal form II has characteristic diffraction peaks at diffraction angles 2 theta of 6.11 +/-0.2 degrees, 8.66 +/-0.2 degrees, 11.06 +/-0.2 degrees, 12.26 +/-0.2 degrees, 16.14 +/-0.2 degrees, 18.33 +/-0.2 degrees, 19.46 +/-0.2 degrees, 20.35 +/-0.2 degrees, 21.08 +/-0.2 degrees, 24.77 +/-0.2 degrees and 25.48 +/-0.2 degrees, and are basically consistent with the results of example 2, thereby showing that the mixed solvent prepared by mixing an alcohol or ketone organic solvent and water according to the volume ratio of 10: 1-1: 10 is used for 7- (4- (3- (6-fluoro-benzisoxazole) -1-n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one, and the mesylate prepared by the invention has better purity after recrystallization and crystallization degree The crystal form II of the mesylate of the anti-schizophrenia drug.

Example 8

Example 8 provides a pharmaceutical composition of form i of the anti-schizophrenia drug methanesulfonic acid, specification 5mg, batch 1000 tablets, the components and their contents in the pharmaceutical composition are shown in the following table:

components	Content (wt.)
		Methanesulfonic acid crystal form I active ingredient	5g
Lactose	55g
		Pregelatinized starch	25g
Microcrystalline cellulose	10g
		Hydroxypropyl methylcellulose	1.5g
Low-substituted hydroxypropyl cellulose	2g
		Colloidal silica	1g
Magnesium stearate	0.5g

A preparation method of a pharmaceutical composition of a crystal form I of an anti-schizophrenia drug mesylate comprises the following steps:

1) weighing the active ingredients, lactose, microcrystalline cellulose and pregelatinized starch according to the prescription in the table, and respectively sieving the raw materials and the auxiliary materials with a 30-mesh sieve;

2) placing the sieved materials in a wet granulator, setting the rotation speed of a stirring paddle to be 500rpm, and mixing for 10 min;

3) adding 10% hydroxypropyl methylcellulose aqueous solution into the mixed materials to prepare soft materials, setting the rotation number of a stirring paddle to be 500rpm and the rotation number of a shearing paddle to be 1000rpm, and granulating for 12 min;

4) placing the granulated material in a swinging granulator, and granulating with a 24-mesh sieve;

5) drying the granulated material in an oven at 60 ℃, and controlling the moisture of the dried material to be 1-3%;

6) placing the dried material in a swing granulator, and granulating with a 24-mesh sieve;

7) mixing the low-substituted hydroxypropyl cellulose with the colloidal silicon dioxide according to the prescription amount, and sieving the mixture by a 30-mesh sieve;

8) placing the whole materials and the mixture of magnesium stearate and low-substituted hydroxypropyl fiber/colloidal silicon dioxide in the formula amount in a three-dimensional mixer, and mixing for 8 min;

9) tablet preparation was carried out using a rotary tablet press.

The tablet weight of the methanesulfonic acid crystal form I pharmaceutical composition prepared by the method provided by the embodiment is controlled to be 95-105 mg, and the hardness is controlled to be 50-110N. Therefore, the crystal form I and/or the crystal form II of the mesylate of the anti-schizophrenia drug prepared by the method provided by the invention can be suitable for preparing the drugs for treating or preventing the neuropsychiatric diseases.

While the invention has been described with respect to specific embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention; those skilled in the art should appreciate that they can readily use the disclosed conception and specific embodiments as a basis for designing or modifying other structures for carrying out the same purposes of the present invention without departing from the spirit and scope of the invention; meanwhile, any equivalent changes, modifications and alterations of the above embodiments according to the spirit and techniques of the present invention are also within the scope of the present invention.

Claims

1. A crystal form I of an anti-schizophrenia drug mesylate is characterized in that in an X-ray powder diffraction spectrum of the crystal form I, characteristic diffraction peaks exist at diffraction angles 2 theta of 4.57 +/-0.2 degrees, 9.16 +/-0.2 degrees, 15.01 +/-0.2 degrees, 18.45 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.13 +/-0.2 degrees, 26.45 +/-0.2 degrees, and 27.84 +/-0.2 degrees.

2. The crystalline form I of the mesylate salt of an anti-schizophrenia drug according to claim 1, wherein the crystalline form I has a characteristic diffraction peak at diffraction angles 2 Θ of 4.57 ± 0.2 °, 9.16 ± 0.2 °, 13.17 ± 0.2 °, 13.80 ± 0.2 °, 15.01 ± 0.2 °, 16.17 ± 0.2 °, 18.45 ± 0.2 °, 19.22 ± 0.2 °, 22.58 ± 0.2 °, 23.13 ± 0.2 °, 26.45 ± 0.2 °, 27.84 ± 0.2 ° in an X-ray powder diffraction spectrum.

3. The crystalline form I of the mesylate salt of the anti-schizophrenia drug according to claim 1, wherein the differential scanning calorimetry of the crystalline form I has an endothermic peak at 208-210 ℃.

4. The process for preparing form I of the mesylate salt of the anti-schizophrenia drug according to claim 1, comprising the steps of:

5. The preparation method of the crystal form I of the mesylate of the anti-schizophrenia drug according to claim 4, wherein the solid-to-liquid ratio of 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one to the organic solvent is 1g (10-100) mL; the organic solvent is alcohols, esters or ketones.

6. The crystal form II of the anti-schizophrenia drug mesylate is characterized in that in an X-ray powder diffraction spectrum of the crystal form II, characteristic diffraction peaks exist at diffraction angles 2 theta of 6.11 +/-0.2 degrees, 8.66 +/-0.2 degrees, 11.06 +/-0.2 degrees, 12.26 +/-0.2 degrees, 19.46 +/-0.2 degrees and 25.48 +/-0.2 degrees.

7. The process for preparing form ii of the mesylate salt of the anti-schizophrenia drug as set forth in claim 6, which comprises the steps of:

8. The method for preparing the crystal form II of the mesylate of the anti-schizophrenia drug according to claim 7, wherein in the step S2, the solid-to-liquid ratio of the 7- (4- (4- (3- (6-fluoro-benzisoxazole) -1-piperidyl) -n-butoxy)) -4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate to the mixed solvent is 1g (10-100) mL; the mixed solvent is formed by mixing an alcohol or ketone organic solvent and water according to a volume ratio of 10: 1-1: 10.

9. A pharmaceutical composition comprising as active ingredients a crystalline form I of an anti-schizophrenia drug mesylate as claimed in any one of claims 1 to 3 and/or a crystalline form ii of an anti-schizophrenia drug mesylate as claimed in claim 6.

10. Use of the crystalline form I of an anti-schizophrenia drug mesylate as claimed in any one of claims 1 to 3, or the crystalline form ii of an anti-schizophrenia drug mesylate as claimed in claim 6, or the pharmaceutical composition as claimed in claim 9, for the preparation of a medicament for the treatment or prevention of a neuropsychiatric disease.