Crystal form of (S)-2-(1-acetoxy n-amyl) benzoic acid L-arginine salt and preparation method and application thereof

Abstract

The invention relates to the technical field of medicine, in particular to a crystal form of (S)-2-(1-acetoxy n-amyl) benzoic acid L-arginine salt and a preparation method and application thereof.The crystal form is radiated through Cu-K alpha, an X-ray powder diffraction pattern expressed by the diffraction angle 2 theta is obtained, the diffraction angle 2 theta has characteristic peaks at the positions of 5.10, 10.23, 14.13, 17.58, 19.81, 20.63 and 21.73, and the crystal form is shown in the description. And the error range of each characteristic peak 2 theta is + / -0.2. The technical scheme provided by the invention has the following advantages: research shows that the I crystal form of the compound as shown in the formula I prepared by the invention is good in stability and relatively high in purity, and a single crystal of the I crystal form is obtained; the crystal form I of the compound shown in the formula I can meet the medicinal requirements of production, transportation and storage, the production process is stable, repeatable and controllable, and the crystal form I can be suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a crystal form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt and a preparation method and application thereof. Background Art

[0002] Ischemic cardiovascular and cerebrovascular diseases mainly include transient ischemic attack, cerebral infarction, cerebral steal syndrome, coronary heart disease, etc. Ischemic stroke refers to ischemic necrosis or softening of localized brain tissue caused by impaired blood supply to the brain, ischemia, and hypoxia. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% to 70% of the total number of strokes. Occlusion and stenosis of the internal carotid artery and vertebral artery can cause ischemic stroke, which mostly occurs in people over 40 years old, more often in men than in women, and can cause death in severe cases. If rescue is not timely or the measures are inappropriate, the condition will quickly deteriorate and endanger life.

[0003] WO2020107500A1 discloses a new class of compounds represented by formula (I) for treating ischemic cardiovascular and cerebrovascular diseases. The compounds have excellent activity and less side effects, and therefore have broad clinical application prospects.

[0004]

[0005] As we all know, compounds can exist in a variety of crystal forms. The crystal structure of compounds that are active ingredients often affects the chemical and physical stability of the drug. Different crystal forms, preparation methods and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced. The physical and chemical properties of different crystal forms are slightly different, which will also affect the efficacy and stability of the final drug. Therefore, in-depth research to find new crystal forms with high crystal purity and good physical and chemical stability is very necessary to improve the properties of the compound in all aspects. Summary of the invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a crystalline form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt and its preparation method and application, wherein the crystalline form has good crystalline stability and chemical stability.

[0007] On the one hand, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, wherein the diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 17.58, 19.81, 20.63 and 21.73, wherein the error range of each characteristic peak 2θ is ±0.2,

[0008] In a preferred embodiment, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and the diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 15.42, 17.58, 19.81, 20.63, 21.73 and 25.88, wherein the error range of each characteristic peak 2θ is ±0.2.

[0009] In a preferred embodiment, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and the diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 15.42, 17.58, 19.81, 20.63, 21.73, 24.28, 25.36, 25.88, 31.21 and 31.65, wherein the error range of each characteristic peak 2θ is ±0.2.

[0010] In a preferred embodiment, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and the diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 11.30, 14.13, 15.42, 17.58, 19.81, 20.63, 21.73, 24.28, 25.36, 25.88, 31.21 and 31.65, wherein the error range of each characteristic peak 2θ is ±0.2.

[0011] In a preferred embodiment, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt as shown in Formula I, using Cu-Kα radiation, the obtained X-ray powder diffraction pattern is as follows Figure 1 shown.

[0012] In a preferred embodiment, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and the parameters of the diffraction angle 2θ are shown in Table 2.

[0013] The present invention names the newly prepared crystalline form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt as crystalline form I.

[0014] The present invention further provides a method for preparing the I crystal form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, which is selected from any one of the following methods 1 to 7:

[0015] Method 1: volatilization method at room temperature, dissolving the compound represented by formula I in a good solvent, leaving it in the open at room temperature for volatilization and crystallization, filtering, and drying to obtain the I crystal form of the compound represented by formula I.

[0016] Preferably, in the method one, the good solvent is selected from a mixed solvent of one or more of water, a first alcohol, a sulfoxide, an amide or a carboxylic acid solvent; wherein the first alcohol solvent is selected from methanol, ethanol, etc.; the sulfoxide solvent is selected from dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the carboxylic acid solvent is selected from formic acid, acetic acid or benzoic acid.

[0017] More preferably, the good solvent in the method 1 is methanol, dimethyl sulfoxide or water.

[0018] The crystallization method is preferably room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

[0019] Method 2: Suspension crystallization method, the compound represented by formula I and a poor solvent are mixed to form a suspension, which is placed at room temperature or 40-60° C. and shaken to remove the solvent, and then dried to obtain Form I of the compound represented by formula I.

[0020] Preferably, in the second method, the poor solvent is selected from a mixed solvent of one or more of esters, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons, secondary alcohols, nitriles, and ketones; wherein the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane; the alicyclic hydrocarbon solvent is selected from cyclohexane; the secondary alcohol solvent is selected from isopropanol, etc.; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone or N-methylpyrrolidone.

[0021] More preferably, the poor solvent in the method 2 is isopropanol, acetonitrile, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, N-methylpyrrolidone, n-hexane or cyclohexane.

[0022] Method 3: Dissolution crystallization method, dissolving the compound represented by formula I in a good solvent, then adding a poor solvent, crystallizing, filtering, and drying to obtain the I crystal form of the compound represented by formula I.

[0023] Preferably, in the method three, the good solvent is selected from water, a first alcohol, a carboxylic acid, a sulfoxide, and an amide solvent; the first alcohol solvent is selected from methanol, ethanol, etc.; the carboxylic acid solvent is selected from formic acid or acetic acid; the sulfoxide solvent is selected from dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the poor solvent is selected from a second alcohol, an ether, an ester, a ketone or a nitrile solvent; the second alcohol solvent is selected from isopropanol, etc.; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent is selected from acetone or N-methylpyrrolidone; the nitrile solvent is selected from acetonitrile.

[0024] More preferably, the good solvent is selected from methanol, ethanol, acetic acid, dimethyl sulfoxide, N,N-dimethylformamide or water.

[0025] More preferably, the poor solvent is selected from isopropanol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran or N-methylpyrrolidone.

[0026] In some specific embodiments of the present invention, the good solvent-poor solvent combination is specifically: methanol-isopropanol, methanol-acetonitrile, methanol-acetone, methanol-ethyl acetate, methanol-methyl tert-butyl ether, methanol-tetrahydrofuran, ethanol-isopropanol, ethanol-acetonitrile, ethanol-acetone, ethanol-ethyl acetate, ethanol-methyl tert-butyl ether, ethanol-tetrahydrofuran, acetic acid-isopropanol, acetic acid-acetonitrile, acetic acid-ethyl acetate, acetic acid-isopropyl acetate, acetic acid-tetrahydrofuran, water-isopropanol, water-acetonitrile, water-acetone, water-tetrahydrofuran.

[0027] Preferably, the crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

[0028] Method 4: Binary mixed solvent crystallization method, dissolving the compound represented by formula I in a binary mixed solvent, crystallizing, filtering, and drying to obtain Form I of the compound represented by formula I; the binary mixed solvent is a mixed solvent of a good solvent and a poor solvent.

[0029] Preferably, in the method four, the good solvent is selected from a first alcohol solvent or water; the first alcohol solvent is selected from methanol or ethanol; the poor solvent is selected from a second alcohol, nitrile, ketone, ester or ether solvent; the second alcohol solvent is selected from isopropanol; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone or N-methylpyrrolidone; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether.

[0030] More preferably, the binary mixed solvent is a mixed solvent of methanol and a poor solvent, and the poor solvent is preferably isopropanol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran or N-methylpyrrolidone.

[0031] More preferably, the binary mixed solvent is a mixed solvent of water and a poor solvent, and the poor solvent is preferably isopropanol, acetonitrile, acetone, methyl tert-butyl ether, tetrahydrofuran or N-methylpyrrolidone.

[0032] In some specific embodiments of the present invention, the binary mixed solvent is a mixed solvent of methanol-isopropanol, ethanol-acetonitrile, methanol-acetone, methanol-ethyl acetate, methanol-methyl tert-butyl ether, methanol-tetrahydrofuran, methanol-N-methylpyrrolidone, water-isopropanol, water-acetonitrile, water-acetone, water-methyl tert-butyl ether, water-tetrahydrofuran, and water-N-methylpyrrolidone.

[0033] The volume ratio of the good solvent to the poor solvent is preferably 1:5 to 5:1. In some specific embodiments, the volume ratio of the good solvent to the poor solvent is 1:4, 1:1 or 4:1.

[0034] Method 5: grinding crystallization method, mixing the compound represented by formula I with a poor solvent and then grinding to obtain the I crystal form of the compound represented by formula I.

[0035] Preferably, in the method five, the poor solvent is selected from the second alcohol, nitriles, ketones, esters, ethers, ketones, aliphatic hydrocarbons or alicyclic hydrocarbons; the second alcohol solvent is selected from isopropanol, etc.; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone or N-methylpyrrolidone; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane; the alicyclic hydrocarbon solvent is selected from cyclohexane.

[0036] More preferably, the poor solvent is selected from isopropanol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, N-methylpyrrolidone, n-hexane or cyclohexane.

[0037] In the present invention, the compound shown in formula I is mixed with a poor solvent and then ground, and a crystal form is generated after 30 minutes of XRPD spectrum determination.

[0038] Method 6: Rapid cooling crystallization method, dissolving the compound represented by formula I in a good solvent, and then crystallizing, filtering and drying under low temperature conditions to obtain the crystal form I of the compound represented by formula I;

[0039] Preferably, in method six, the good solvent is selected from a first alcohol, a carboxylic acid, a sulfoxide, an amide solvent or water; the first alcohol solvent is selected from methanol, ethanol, etc.; the sulfoxide solvent is selected from dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the carboxylic acid solvent is selected from formic acid, acetic acid or benzoic acid.

[0040] More preferably, the good solvent is selected from methanol.

[0041] Preferably, the low temperature condition is provided by an ice-water mixture.

[0042] Method 7: Vapor diffusion method, dissolving the compound represented by formula I in a good solvent, placing it open in a poor solvent atmosphere, standing at room temperature, crystallizing, filtering, and drying to obtain Form I of the compound represented by formula I.

[0043] Preferably, in the method seven, the good solvent is selected from water, a first alcohol or a carboxylic acid solvent; the first alcohol solvent is selected from methanol or ethanol; the carboxylic acid solvent is selected from formic acid or acetic acid; the poor solvent is selected from a second alcohol, an ether, an ester, a ketone or a nitrile solvent; the second alcohol solvent is selected from isopropanol; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent is selected from acetone or N-methylpyrrolidone; the nitrile solvent is selected from acetonitrile.

[0044] More preferably, the good solvent is selected from methanol, formic acid, acetic acid or water.

[0045] More preferably, the poor solvent is selected from isopropanol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or tetrahydrofuran.

[0046] In some specific embodiments of the present invention, the combination of good solvent and poor solvent is: methanol-isopropanol, water-isopropanol, methanol-acetonitrile, water-acetonitrile, methanol-acetone, acetic acid-acetone, water-acetone, methanol-ethyl acetate, water-ethyl acetate, methanol-isopropyl acetate, water-isopropyl acetate, methanol-methyl tert-butyl ether, water-methyl tert-butyl ether, methanol-tetrahydrofuran.

[0047] The above-mentioned open-top placement in a poor solvent atmosphere specifically includes: dissolving the compound represented by Formula I in a good solvent, placing the open-top in another larger container, adding a poor solvent into the outer container, and capping the outer container tightly or sealing it with a sealing film.

[0048] The above-mentioned crystallization method can be conventional crystallization methods such as room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

[0049] The invention conducts structure determination and crystal form research on the prepared I crystal form through X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).

[0050] The prepared (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt I crystal form is subjected to DSC and TGA detection, and the DSC spectrum results show that the melting point of the (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt I crystal form is 192°C.

[0051] The TGA results showed that the decomposition temperature of the (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt Form I was 195°C.

[0052] The stability test results show that the (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt I crystal prepared by the present invention can withstand high temperature (60°C), high humidity (RH90%±5%), and light (4500lx±500lx, with a total light source illumination of 1.2×10 6 lux·hr) for 10 days, there was no significant difference in the powder diffraction spectrum, DSC spectrum and TGA spectrum, the stability was good and the crystal form did not change.

[0053] The crystallization method of the crystal form in the present invention is conventional, such as evaporation crystallization, cooling crystallization or crystallization at room temperature.

[0054] The starting material used in the method for preparing Form I of the present invention can be any form of the compound represented by Formula I, and specific forms include but are not limited to: amorphous, any crystalline form, etc.

[0055] The present invention also provides a method for preparing (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt I crystal single crystal, the method comprising:

[0056] The (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt Form I was slowly evaporated in a water-acetone mixed solvent to obtain colorless, transparent, long strip crystals.

[0057] The volume ratio of water to acetone is preferably 1:4-4:1.

[0058] The slow volatilization time is preferably 15 to 25 days, more preferably 20 days.

[0059] The colorless, transparent, long strip crystals obtained by the invention meet the requirements of single crystal X-ray diffraction experiments.

[0060] Another aspect of the present invention provides a pharmaceutical composition comprising the crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in the above formula I and a pharmaceutically acceptable adjuvant.

[0061] The above-mentioned auxiliary agents include but are not limited to carriers, diluents or excipients.

[0062] The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form, including but not limited to tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays, etc.

[0063] The pharmaceutical composition of the present invention can be applied to patients or subjects who need such treatment in any suitable manner of administration, such as oral, parenteral, rectal, pulmonary or local administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When prepared into oral preparations, the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants, etc. When used for parenteral administration, the pharmaceutical preparations may be prepared into injections, including injections, sterile powders for injection and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be produced by conventional methods in the existing pharmaceutical field. When preparing injections, additives may not be added to the pharmaceutical preparations, or suitable additives may be added according to the properties of the drug. When used for rectal administration, the pharmaceutical preparations may be prepared into suppositories, etc. When used for pulmonary administration, the pharmaceutical preparations may be prepared into inhalants or sprays, etc. In certain preferred embodiments, the crystal form I of the compound of formula I of the present invention is present in a pharmaceutical composition or medicine in a therapeutic and / or preventive effective amount. In certain preferred embodiments, the crystal form I of the compound of formula I of the present invention is present in a pharmaceutical composition or medicine in the form of a unit dose.

[0064] Another aspect of the present invention provides the use of the I crystal form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in the above formula I or the above pharmaceutical composition in the preparation of drugs for treating ischemic cardiovascular and cerebrovascular diseases.

[0065] The ischemic cardiovascular and cerebrovascular disease is preferably stroke; more preferably cerebral stroke; further preferably ischemic cerebral stroke.

[0066] On the other hand, the present invention provides a method for inhibiting cardiac and cerebral ischemic diseases, which comprises administering a therapeutically and / or preventively effective amount of the crystal form I of the compound of formula I of the present invention, or the pharmaceutical composition of the present invention to a subject in need thereof.

[0067] In the specification and claims of the application, unless otherwise stated, the scientific and technological terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present invention, the definition and explanation of some related terms are provided below. In addition, when the definition and explanation of the terms provided in the application are inconsistent with the meanings commonly understood by those skilled in the art, the definition and explanation of the terms provided in the application shall prevail.

[0068] The "ether solvent" described in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether or 1,4-dioxane.

[0069] The "alcohol solvent" described in the present invention refers to one or more "hydroxyl" substituted "C 1-6 The group is derived from one or more hydrogen atoms on the "alkyl" group, the "hydroxyl" and "C 1-6 "Alkyl" is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isopentanol or trifluoroethanol.

[0070] The "ester solvent" described in the present invention refers to a combination of a low-level organic acid containing 1 to 4 carbon atoms and a low-level alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.

[0071] The "ketone solvent" described in the present invention refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups. Depending on the different hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples include but are not limited to: acetone, acetophenone, methyl isobutyl ketone or N-methylpyrrolidone.

[0072] The "nitrile solvent" described in the present invention refers to a solvent in which one or more "cyano" groups replace "C 1-6 The group derived from one or more hydrogen atoms on the "alkyl" group, the "cyano" and "C 1-6 "Alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.

[0073] The "aliphatic hydrocarbon solvent" mentioned in the present invention refers to hydrocarbons with the basic properties of aliphatic compounds, in which the carbon atoms in the molecule are connected to form a chain-like carbon frame with both ends open and not forming a ring, and the number of carbon atoms is 1-10, such as saturated aliphatic hydrocarbons, including alkane solvents, and specific examples include but are not limited to: n-butane, n-pentane, n-hexane or n-heptane.

[0074] The "alicyclic hydrocarbon solvent" described in the present invention refers to a hydrocarbon compound having a cyclic carbon skeleton, similar properties to aliphatic hydrocarbons, and 1-8 ring atoms, and specific examples include but are not limited to: cyclopentane or cyclohexane.

[0075] The "amide solvent" described in the present invention refers to a compound containing a carbonylamino group (-C(O)N-) and having 1 to 10 carbon atoms, and specific examples include but are not limited to: N,N-dimethylformamide or N,N-dimethylacetamide.

[0076] The "mixed solvent" described in the present invention refers to a solvent formed by mixing one or more different types of organic solvents in a certain proportion, or a solvent formed by mixing an organic solvent and water in a certain proportion; the mixed solvent is preferably a mixed solvent of one or more alcohols, a mixed solvent of alcohols and ethers, a mixed solvent of alcohols and aliphatic hydrocarbons, or ethers, a mixed solvent of aliphatic hydrocarbons, a mixed solvent of alcohols and water, a mixed solvent of halogenated hydrocarbons and nitrile solvents, a mixed solvent of amide solvents and water, a mixed solvent of ethers and water; the alcohols, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, amides, and nitriles are as defined above.

[0077] The "X-ray powder diffraction pattern or XRPD" of the present invention refers to the Bragg formula 2d sinθ=nλ (where λ is the wavelength of the X-ray, The diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1). When X-rays are incident on an atomic plane with a lattice plane spacing of d in a crystal or a part of a crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0078] The "differential scanning calorimetry or DSC" mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample, so as to characterize all physical and chemical changes related to thermal effects and obtain the phase change information of the sample.

[0079] The "2θ or 2θ angle" mentioned in the present invention refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, and more preferably ±0.2.

[0080] The "interplanar spacing or interplanar spacing (d value)" mentioned in the present invention refers to the selection of three non-parallel unit vectors a, b, c connecting two adjacent lattice points by the space lattice, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection lines to obtain a set of straight line grids, called space grids or lattices. The lattice and lattice use geometric points and lines respectively to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is or angstroms.

[0081] Compared with the prior art, the present invention provides a crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I, characterized in that: using Cu-Kα radiation, an X-ray powder diffraction pattern represented by a diffraction angle 2θ is obtained, and its diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 17.58, 19.81, 20.63 and 21.73, wherein the error range of each characteristic peak 2θ is ±0.2.

[0082] The technical solution of the present invention has the following advantages:

[0083] Studies have shown that the crystal form I of the compound represented by formula I prepared by the present invention has good stability and high purity, and single crystals of the crystal form I are obtained, which can be better applied in clinical practice; the crystal form I of the compound represented by formula I obtained by the technical scheme of the present invention can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be adapted to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1 is the PXRD pattern of Form I;

[0085] Figure 2 is the DSC spectrum of Form I;

[0086] Figure 3 is the TGA spectrum of Form I;

[0087] Figure 4 is a three-dimensional structural ellipsoid diagram of the asymmetric unit of a single crystal of the compound represented by formula (I);

[0088] Figure 5 is a three-dimensional structural ellipsoid diagram of a single molecule of a single crystal of the compound represented by formula (I);

[0089] Figure 6 The unit cell stacking projection diagram of the single crystal of the compound represented by formula (I) along the a-axis direction is

[0090] Figure 7 The simulated powder diffraction pattern of the single crystal structure of the compound represented by formula (I) is compared with the pattern of Form I;

[0091] Figure 8 This is the (high temperature) PXRD overlay of Form I;

[0092] Fig. 9 This is the (high temperature) DSC overlay of Form I;

[0093] Fig.10 This is the (high temperature) TGA overlay of Form I;

[0094] Fig.11 This is the (high humidity) PXRD overlay of Form I;

[0095] Fig.12 This is the (high humidity) DSC overlay of Form I;

[0096] Fig.13 This is the (high humidity) TGA overlay of Form I;

[0097] Fig.14 This is the (illumination) PXRD overlay of Form I;

[0098] Fig.15 This is the (illumination) DSC overlay of Form I;

[0099] Fig.16 This is the (illumination) TGA overlay of Form I;

[0100] Fig.17 The PXRD pattern of the compound shown in Formula I prepared in Comparative Example 1. DETAILED DESCRIPTION

[0101] To further illustrate the present invention, the crystal form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt provided by the present invention, its preparation method and application are described in detail below in conjunction with the examples. The examples of the present invention are only used to illustrate the technical scheme of the present invention, and are not intended to limit the essence and scope of the present invention.

[0102] Test conditions of the instruments used in the test:

[0103] 1. Differential Scanning Calorimeter (DSC)

[0104] Instrument model: Q2000 DSC 3+Q500 TGA

[0105] Purge gas: Nitrogen

[0106] Heating rate: 10.0℃ / min

[0107] Temperature range: 30-300℃

[0108] Thermogravimetric analysis (TGA) temperature range is 30℃-350℃, and the heating rate is 10℃ / min

[0109] 2. X-ray Powder Diffraction (XRPD)

[0110] Instrument model: D8 Advance X-ray powder diffractometer

[0111] Ray: Monochromatic Cu-Kα ray (λ=1.5406)

[0112] Scanning mode: θ / 2θ, scanning range: 3-45°

[0113] Voltage: 40KV, Current: 40mA

[0114] 3. Single crystal X-ray diffractometer

[0115] Instrument model: SMART APEX-II

[0116] The compound represented by the following formula (I) was prepared according to the method disclosed in Example 10 of WO2020107500A1.

[0117] Example 1 Normal temperature evaporation method (single solvent)

[0118] 50 mg of the compound represented by formula (I) was weighed and placed in a reaction bottle, and after adding a solvent to fully dissolve, it was placed in a fume hood and slowly evaporated at room temperature, and filtered to obtain a solid of the compound represented by formula (I). The solid was measured by X-ray diffraction, and the results are shown in Table 1:

[0119] Table 1 Test results of room temperature volatilization method (single solvent)

[0120]

[0121]

[0122] The prepared crystal form I was subjected to XRD detection, and the results are shown in Table 2:

[0123] Table 2 Characteristic peaks of Form I

[0124]

[0125]

[0126] Figure 1 is the PXRD spectrum of Form I, wherein curves a and b are the PXRD spectra of different batches of Form I prepared using methanol solvent.

[0127] Figure 2 This is the DSC spectrum of Form I prepared using methanol solvent.

[0128] Figure 3 This is the TGA spectrum of Form I prepared using methanol solvent.

[0129] Figure 1-Figure 3 The results showed that both batches of samples were crystalline with consistent crystal form and did not contain crystallization solvent or crystal water.

[0130] Example 2 Suspension crystallization method

[0131] 30 mg of the compound represented by formula (I) was weighed and placed in a reaction bottle, and a solvent was added to make a suspension. The suspension was placed at room temperature and 50° C. and shaken for 48 hours, respectively, and then the solvent was removed. After drying, a solid of the compound represented by formula (I) was obtained. The X-ray diffraction pattern was measured. The results are shown in Table 3:

[0132] Table 3 Suspension crystallization test results

[0133]

[0134]

[0135] Example 3 Dissolution Crystallization Method

[0136] 50 mg of the compound represented by formula (I) was weighed and put into a reaction bottle, dissolved in a relatively good solubility solvent to prepare a solution, to which a poorly soluble solvent was gradually added until a solid was precipitated, and PXRD was performed on it; if the total solvent amount reached 20 mL and no solid was precipitated, the dropwise addition of the solvent was stopped, and the solution was allowed to stand at room temperature for natural volatilization, and the solid obtained after volatilization was subjected to PXRD measurement, and the results are shown in Table 4:

[0137] Table 4 Dissolution crystallization test results

[0138]

[0139]

[0140] NS: No solid was obtained during the test.

[0141] Example 4 Binary mixed solvent crystallization method

[0142] 50 mg of the compound represented by formula (I) was weighed and placed in a reaction bottle, and a binary mixed solvent (mixed in a volume ratio of 1:4, 1:1, and 4:1) was added. If a clear solution was obtained, it was slowly evaporated at room temperature, and the obtained solid was subjected to PXRD measurement; if a suspension was obtained, it was allowed to stand at room temperature and then the solvent was removed, and the obtained solid was subjected to PXRD measurement. The results are shown in Table 5:

[0143] Table 5 Binary mixed solvent crystallization test results

[0144]

[0145]

[0146] NS: No solid was obtained during the test.

[0147] Example 5 Grinding Crystallization Method

[0148] 50 mg of the compound represented by formula (I) was weighed and put into a mortar, and a small amount of solvent was added to grind it. The PXRD patterns after adding different solvents and grinding for 30 minutes were tested to investigate whether different crystal forms were produced. The results are shown in Table 6:

[0149] Table 6 Grinding crystallization test results

[0150] Solvents result Isopropyl alcohol Crystalline Form I Acetonitrile Crystalline Form I acetone Crystalline Form I Ethyl acetate Crystalline Form I Isopropyl acetate Crystalline Form I Methyl tert-butyl ether Crystalline Form I Tetrahydrofuran Crystalline Form I N-Methylpyrrolidone Crystalline Form I n-Hexane Crystalline Form I Cyclohexane Crystalline Form I

[0151] Example 6 Rapid Cooling Crystallization Method

[0152] Weigh 50 mg of the compound represented by formula (I) into a beaker, add an appropriate amount of solvent to completely dissolve it, place the mother liquor in a 40°C water bath for 20 minutes, then take it out and immediately place it in an ice-water mixture (4°C). If solids are precipitated, remove the supernatant, and perform PXRD measurement after the solids are dried. The results are shown in Table 7:

[0153] Table 7 Rapid cooling crystallization test results

[0154] Solvents result Methanol Crystalline Form I Ethanol Amorphous Acetic acid Amorphous Dimethyl sulfoxide Amorphous N,N-Dimethylformamide NS water NS Formic acid Amorphous

[0155] NS: No solid was obtained during the test.

[0156] Example 7 Vapor Diffusion Method

[0157] 50 mg of the compound represented by formula (I) was weighed into a sample bottle, and an appropriate amount of solvent was added to make it a clear solution state. The sample bottle was placed in another larger glass container with its mouth open, and a solvent with poor solubility was added to the outer container. The outer container was capped and tightened (or sealed with a sealing film), and was incubated at room temperature to allow the outer solvent to continuously evaporate into the inner container. By reducing the solubility of the sample in the mixed solvent system, crystals were precipitated, and whether different crystal forms were produced were examined. The results are shown in Table 8:

[0158] Table 8 Vapor diffusion test results

[0159]

[0160]

[0161] NS: No solid was obtained during the test.

[0162] Example 8 Single Crystal Cultivation

[0163] In the binary mixed solvent crystallization test, under the solvent conditions of water-acetone (1:4, v / v), after about 20 days of slow evaporation, colorless, transparent, long strips of crystals that meet the requirements of single crystal X-ray diffraction experiments were obtained. According to the first method of 0451 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the test conditions are: CuKα radiation, Scan. The single crystal diffraction experiment collected a total of 18678 diffraction points, 10233 independent diffraction points, and 9936 observable points (|F|2≥2σ|F|2). The crystal structure was analyzed using the direct method (Shelxs97), and the results are shown in Table 9:

[0164] Table 9 Unit cell parameters of crystal form I single crystal

[0165]

[0166] The results show that the molecular arrangement in the crystalline state belongs to the first type of space group, the sample should be optically active, and the Flack coefficient is 0.06 (13), which can determine the absolute configuration of the compound in the crystal; in the crystalline state, the molecules are maintained in a stable arrangement in space by hydrogen bonds and van der Waals forces. The three-dimensional structure ellipsoid of the asymmetric unit is shown in Figure 4 , the three-dimensional structure ellipsoid of a single molecule Figure 5 And the unit cell stacking projection diagram along the a-axis direction is shown in Figure 6 ; Using the above single crystal structure data, the corresponding simulated powder diffraction pattern was calculated and compared with the spectrum of Form I. The results showed that the two crystal forms were consistent (see Figure 7 ). Figure 7 In the figure, curve a is the single crystal simulated powder pattern of the compound, and curve b is the PXRD pattern of Form I.

[0167] Comparative Example 1

[0168] The compound of formula (I) was prepared according to the method disclosed in Example 10 of WO2020107500A1. The physical state was solid. The solvent was 95% ethanol. After recrystallization, the PXRD results showed that the solid was amorphous (see Appendix for details). Fig.17 ).

[0169] Example 9 Crystal Stability Study

[0170] The physical stability test of Form I samples was carried out under different storage conditions. The storage conditions were:

[0171] ①High temperature 60℃

[0172] ②High humidity (RH90%±5%)

[0173] ③ Under lighting conditions (4500lx±500lx, the total illumination of the light source reaches 1.2×10 6 lux·hr)

[0174] PXRD, DSC and TGA tests were performed on the samples on the 0th, 5th and 10th days to examine the stability of the samples under high temperature, high humidity and light conditions. The test results are detailed in the attached figure of the specification. Figure 8-Figure 16 .

[0175] Figure 8 In the figure, curve a is day 0, curve b is day 5, and curve c is day 10.

[0176] Fig.11 In the figure, curve a is day 0, curve b is day 5, and curve c is day 10.

[0177] Fig.14 In the figure, curve a is day 0, curve b is day 5, and curve c is day 10.

[0178] Conclusion: Form I can be used under high temperature (60°C), high humidity (RH90%±5%), light (4500lx±500lx, total light source illumination reaches 1.2×10 6 lux·hr) under the condition, there was no significant difference in its powder diffraction pattern, DSC pattern and TGA pattern, indicating that it had good stability and the crystal form did not change.

[0179] Example 10

[0180] Weigh 25 mg of Form I of the sample and place it in an intrinsic dissolution rate metal module, keep it under 20 pounds of pressure for 30 seconds, add 20 mL of SGF (simulated gastric fluid) / FESSIF (simulated fed intestinal fluid) physiological medium, keep it warm at 37°C, maintain 100 rpm throughout the process, and then take 0.5 mL of the solution at 5, 15, 30, 45, 60, 90, and 120 minutes, filter it with a 0.22 um aqueous microfiltration membrane, and replenish 0.5 mL of the same physiological medium at the same time, and determine the concentration according to the HPLC content determination method.

[0181] The results showed that the dissolution rate of Form I was significantly faster than that of the solid obtained in the comparative example.

[0182] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. Form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in Formula I, characterized in that: Using Cu-Kα radiation, an X-ray powder diffraction pattern expressed as a diffraction angle 2θ is obtained, and the diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 17.58, 19.81, 20.63 and 21.73, wherein the error range of each characteristic peak 2θ is ±0.2, 2. The crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I according to claim 1, characterized in that: The diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 15.42, 17.58, 19.81, 20.63, 21.73 and 25.88, wherein the error range of each characteristic peak 2θ is ±0.

2.

3. The crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I according to claim 1, characterized in that: The diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 14.13, 15.42, 17.58, 19.81, 20.63, 21.73, 24.28, 25.36, 25.88, 31.21 and 31.65, wherein the error range of each characteristic peak 2θ is ±0.

2.

4. The crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I according to claim 1, characterized in that: The diffraction angle 2θ has characteristic peaks at 5.10, 10.23, 11.30, 14.13, 15.42, 17.58, 19.81, 20.63, 21.73, 24.28, 25.36, 25.88, 31.21 and 31.65, wherein the error range of each characteristic peak 2θ is ±0.

2.

5. The crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I according to claim 1, characterized in that: The melting point of the crystal form I of the (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I is 192°C; the decomposition temperature of the crystal form I of the (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I is 195°C.

6. A method for preparing the crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I according to any one of claims 1 to 5, characterized in that: Select any one of the following methods 1 to 7: Method 1: volatilization method at room temperature, dissolving the compound represented by formula I in a good solvent, leaving it in an open state at room temperature for volatilization and crystallization, filtering, and drying to obtain the crystal form I of the compound represented by formula I; Method 2: suspension crystallization method, mixing the compound represented by formula I and a poor solvent to form a suspension, shaking at room temperature and 40-60°C, removing the solvent, and drying to obtain the I crystal form of the compound represented by formula I; Method 3: dissolution crystallization method, dissolving the compound represented by formula I in a good solvent, then adding a poor solvent, crystallizing, filtering, and drying to obtain the crystal form I of the compound represented by formula I; Method 4: a binary mixed solvent crystallization method, wherein the compound of formula I is dissolved in a binary mixed solvent, crystallized, filtered, and dried to obtain the crystal form I of the compound of formula I; the binary mixed solvent is a mixed solvent of a good solvent and a poor solvent; Method 5: grinding crystallization method, mixing the compound represented by formula I with a poor solvent and grinding to obtain the crystal form I of the compound represented by formula I; Method 6: Rapid cooling crystallization method, dissolving the compound represented by formula I in a good solvent, and then crystallizing, filtering and drying under low temperature conditions to obtain the crystal form I of the compound represented by formula I; Method 7: Vapor diffusion method, dissolving the compound represented by formula I in a good solvent, placing it open in a poor solvent atmosphere, standing at room temperature, crystallizing, filtering, and drying to obtain Form I of the compound represented by formula I.

7. The preparation method according to claim 6, characterized in that: In the method 1, the good solvent is selected from a mixed solvent of one or more of water, a first alcohol, a sulfoxide, an amide or a carboxylic acid solvent; wherein the first alcohol solvent is selected from methanol and ethanol; the sulfoxide solvent is selected from dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the carboxylic acid solvent is selected from formic acid, acetic acid or benzoic acid; the crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization; In the second method, the poor solvent is selected from a mixed solvent of one or more of esters, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons, second alcohols, nitriles, and ketones; wherein the ester solvent is selected from ethyl acetate, isopropyl acetate, or butyl acetate; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether, or methyl tert-butyl ether; the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane; the alicyclic hydrocarbon solvent is selected from cyclohexane; the second alcohol solvent is selected from isopropanol; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone or N-methylpyrrolidone; In the method three, the good solvent is selected from water, a first alcohol, a carboxylic acid, a sulfoxide, and an amide solvent; the first alcohol solvent is selected from methanol and ethanol; the carboxylic acid solvent is selected from formic acid or acetic acid; the sulfoxide solvent is selected from dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the poor solvent is selected from a second alcohol, an ether, an ester, a ketone or a nitrile solvent; the second alcohol solvent is selected from isopropanol; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent is selected from acetone or N-methylpyrrolidone; the nitrile solvent is selected from acetonitrile; the crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization; In the fourth method, the good solvent is selected from a first alcohol solvent or water; the first alcohol solvent is selected from methanol or ethanol; the poor solvent is selected from a second alcohol, nitrile, ketone, ester or ether solvent; the second alcohol solvent is selected from isopropanol; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone or N-methylpyrrolidone; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; In the method 5, the poor solvent is selected from a second alcohol, nitrile, ketone, ester, ether, ketone, aliphatic hydrocarbon or alicyclic hydrocarbon solvent; the second alcohol solvent is selected from isopropanol; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone or N-methylpyrrolidone; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane; the alicyclic hydrocarbon solvent is selected from cyclohexane; In the sixth method, the good solvent is selected from a first alcohol, a carboxylic acid, a sulfoxide, an amide solvent or water; the first alcohol solvent is selected from methanol and ethanol; the sulfoxide solvent is selected from dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the carboxylic acid solvent is selected from formic acid, acetic acid or benzoic acid; In the method seven, the good solvent is selected from water, a first alcohol or a carboxylic acid solvent; the first alcohol solvent is selected from methanol or ethanol; the carboxylic acid solvent is selected from formic acid or acetic acid; the poor solvent is selected from a second alcohol, an ether, an ester, a ketone or a nitrile solvent; the second alcohol solvent is selected from isopropanol; the ether solvent is selected from tetrahydrofuran, 1,4-dioxane, propylene glycol methyl ether or methyl tert-butyl ether; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent is selected from acetone or N-methylpyrrolidone; the nitrile solvent is selected from acetonitrile.

8. A pharmaceutical composition comprising the crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I according to any one of claims 1 to 5 and a pharmaceutically acceptable adjuvant.

9. Use of the crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of formula I as described in any one of claims 1 to 5 or the pharmaceutical composition as described in claim 8 in the preparation of a drug for treating ischemic cardiovascular and cerebrovascular diseases.

10. The use according to claim 9, characterized in that: The ischemic cardiovascular and cerebrovascular disease is selected from stroke; preferably cerebral stroke; more preferably ischemic cerebral stroke.

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