Crystal form of l-arginine (s)-2-(1-acetoxy-n-pentyl)benzoate, and preparation method therefor and use thereof

Abstract

The present invention relates to the technical field of pharmaceuticals. Specifically provided in the present invention are a crystal form of L-arginine (S)-2-(1-acetoxy-n-pentyl)benzoate, and a preparation method therefor and the use thereof. For the crystal form, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is obtained by means of Cu-Kα radiation. The X-ray powder diffraction pattern has characteristic peaks at diffraction angle 2θ of 5.10, 10.23, 14.13, 17.58, 19.81, 20.63 and 21.73, wherein the error range of 2θ of each characteristic peak is ±0.2. The technical solution of the present invention has the following advantages: studies show that the crystal form I of the compound as shown in formula I prepared in the present invention has good stability and high purity, and a single crystal of the crystal form I is obtained; and the crystal form I of the compound as shown in formula I obtained by the technical solution of the present invention can satisfy the medicinal requirements of production, transportation and storage, has a stable, repeatable and controllable production process, and can be adapted to industrial production.

Description

A crystal form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt and its preparation method and application

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on October 26, 2023, with application number 202311403517.0 and invention name “A crystalline form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt, its preparation method and application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] 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, a preparation method and an application thereof. Background Art

[0003] Ischemic cardiovascular and cerebrovascular diseases primarily include transient ischemic attack, cerebral infarction, cerebral steal syndrome, and coronary heart disease. Ischemic stroke refers to localized ischemic necrosis or softening of brain tissue caused by impaired blood supply to the brain, resulting in ischemia and hypoxia. Ischemic stroke is more common than hemorrhagic stroke, accounting for 60% to 70% of all strokes. Occlusion and stenosis of the internal carotid and vertebral arteries can cause ischemic stroke, most commonly affecting those over 40 years old and more commonly affecting men than women. Severe cases can be fatal. If emergency treatment is delayed or inappropriate, the condition can rapidly worsen and become life-threatening.

[0004] WO2020107500A1 discloses a new class of compounds represented by formula (I) for treating ischemic cardiovascular and cerebrovascular diseases. The compounds have excellent activity and fewer side effects, and therefore have broad clinical application prospects.

[0005] It is well known that compounds can exist in a variety of crystal forms. The crystal structure of a compound as a pharmaceutically active ingredient often affects the chemical and physical stability of the drug. Differences in crystal form, preparation method, and storage conditions can lead to changes in the compound's crystal structure, sometimes accompanied by the formation of other morphologies. Different crystal forms have slightly different physical and chemical properties, which can also affect the efficacy and stability of the final drug. Therefore, in-depth research to find new crystal forms with high purity and good physical and chemical stability is essential for improving various properties of the compound.

[0006] Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a crystal form of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt and its preparation method and application, which has good crystal stability and chemical stability.

[0008] 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,

[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 expressed in diffraction angles 2θ, and the diffraction angles 2θ have 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.

[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 expressed as 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.

[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 shown in Formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern expressed as 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.

[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 of Formula I, using Cu-Kα radiation, the obtained X-ray powder diffraction pattern is shown in Figure 1.

[0013] In a preferred embodiment, the present invention provides a crystalline form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of Formula I, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern expressed in diffraction angle 2θ, and the parameters of the diffraction angle 2θ are shown in Table 2.

[0014] 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.

[0015] The present invention further provides a method for preparing the crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt of Formula I, which is selected from any one of the following methods 1 to 7:

[0016] Method 1: Room temperature evaporation method, dissolving the compound represented by formula I in a good solvent, leaving it in the open at room temperature to evaporate and crystallize, filtering, and drying to obtain Form I of the compound represented by formula I.

[0017] 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; and the carboxylic acid solvent is selected from formic acid, acetic acid or benzoic acid.

[0018] More preferably, the good solvent in the method 1 is methanol, dimethyl sulfoxide or water.

[0019] The crystallization method is preferably room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

[0020] 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.

[0021] 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.

[0022] More preferably, the poor solvent in the second method is isopropyl alcohol, acetonitrile, acetone, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, N-methylpyrrolidone, n-hexane or cyclohexane.

[0023] 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 Form I of the compound represented by formula I.

[0024] 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, ether, ester, ketone or 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.

[0025] More preferably, the good solvent is selected from methanol, ethanol, acetic acid, dimethyl sulfoxide, N,N-dimethylformamide or water.

[0026] More preferably, the poor solvent is selected from isopropyl alcohol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran or N-methylpyrrolidone.

[0027] 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.

[0028] Preferably, the crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

[0029] 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.

[0030] Preferably, 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.

[0031] 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.

[0032] More preferably, the binary mixed solvent is a mixed solvent of water and a poor solvent, and the poor solvent is preferably isopropyl alcohol, acetonitrile, acetone, methyl tert-butyl ether, tetrahydrofuran or N-methylpyrrolidone.

[0033] 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.

[0034] 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.

[0035] Method 5: Grinding crystallization method, mixing the compound represented by formula I with a poor solvent and then grinding to obtain Form I of the compound represented by formula I.

[0036] Preferably, in the method five, the poor solvent is selected from a second alcohol, nitriles, ketones, esters, ethers, ketones, aliphatic hydrocarbons or alicyclic hydrocarbons; the second alcohol solvent is selected from isopropyl alcohol, 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.

[0037] More preferably, the poor solvent is selected from isopropyl alcohol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, N-methylpyrrolidone, n-hexane or cyclohexane.

[0038] In the present invention, the compound represented by formula I is mixed with a poor solvent and then ground. After 30 minutes, the XRPD pattern is used to determine the crystal form.

[0039] Method 6: Rapid cooling crystallization method, dissolving the compound represented by Formula I in a good solvent, then crystallizing under low temperature conditions, filtering, and drying to obtain Form I of the compound represented by Formula I;

[0040] Preferably, 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, 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.

[0041] More preferably, the good solvent is selected from methanol.

[0042] Preferably, the low temperature condition is provided by an ice-water mixture.

[0043] Method 7: Vapor diffusion method, dissolving the compound represented by Formula I in a good solvent, placing the mixture 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.

[0044] 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, ether, ester, ketone or 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.

[0045] More preferably, the good solvent is selected from methanol, formic acid, acetic acid or water.

[0046] More preferably, the poor solvent is selected from isopropyl alcohol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or tetrahydrofuran.

[0047] 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.

[0048] The above-mentioned opening is placed in a poor solvent atmosphere specifically as follows: after dissolving the compound represented by Formula I in a good solvent, the opening is placed in another larger container, a poor solvent is added to the outer container, and the outer container is covered and tightened or sealed with a sealing film.

[0049] 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.

[0050] The present 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).

[0051] The prepared (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt Form I was subjected to DSC and TGA detection. The DSC spectrum results showed that the melting point of the (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt Form I was 192°C.

[0052] 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.

[0053] 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%), light (4500lx±500lx, the total illumination of the light source reaches 1.2×10 6 lux·hr) for 10 days, the powder diffraction pattern, DSC pattern and TGA pattern had no significant difference, indicating good stability and no change in crystal form.

[0054] The crystallization method of the crystal form of the present invention is conventional, such as evaporation crystallization, cooling crystallization or crystallization at room temperature.

[0055] 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, including but not limited to amorphous form and any crystalline form.

[0056] The present invention also provides a method for preparing a single crystal of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt Form I, the method comprising:

[0057] 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.

[0058] The volume ratio of water to acetone is preferably 1:4-4:1.

[0059] The slow volatilization time is preferably 15 to 25 days, more preferably 20 days.

[0060] The colorless, transparent, long strip crystals obtained by the invention meet the requirements of single crystal X-ray diffraction experiments.

[0061] 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 represented by the above formula I and a pharmaceutically acceptable adjuvant.

[0062] The above-mentioned adjuvants include but are not limited to carriers, diluents or excipients.

[0063] 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.

[0064] The pharmaceutical compositions of the present invention can be administered to patients or subjects in need of such treatment by any suitable route of administration, such as oral, parenteral, rectal, pulmonary, or topical administration. For oral administration, the pharmaceutical compositions can be formulated as oral preparations, such as solid oral preparations, such as tablets, capsules, pills, granules, or oral liquid preparations, such as oral solutions, oral suspensions, and syrups. When formulated as oral preparations, the pharmaceutical preparations can further include suitable fillers, binders, disintegrants, lubricants, and the like. For parenteral administration, the pharmaceutical preparations can be formulated as injectables, including injectable solutions, sterile powders for injection, and concentrated solutions for injection. When formulated as injectables, the pharmaceutical compositions can be produced using conventional methods in the pharmaceutical industry. When formulated as injectables, additives may be omitted or added as appropriate, depending on the properties of the drug. For rectal administration, the pharmaceutical preparations can be formulated as suppositories, etc. For pulmonary administration, the pharmaceutical preparations can be formulated as inhalers or sprays. In certain preferred embodiments, the crystalline form I of the compound of formula I of the present invention is present in a pharmaceutical composition or medicine in a therapeutically and / or prophylactically effective amount. In certain preferred embodiments, the crystalline 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.

[0065] Another aspect of the present invention provides the use of the crystal form I of (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt represented by the above formula I or the above pharmaceutical composition in the preparation of a drug for treating ischemic cardiovascular and cerebrovascular diseases.

[0066] The ischemic cardiovascular and cerebrovascular disease is preferably stroke; more preferably cerebral stroke; further preferably ischemic cerebral stroke.

[0067] On the other hand, the present invention provides a method for inhibiting cardiac and cerebral ischemic diseases, which comprises administering a therapeutically and / or prophylactically 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.

[0068] In the specification and claims of the application, unless otherwise indicated, the scientific and technological terms used herein have the implication 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 term provided in the application are inconsistent with the implication commonly understood by those skilled in the art, the definition and explanation of the term provided in the application shall be as the criterion.

[0069] 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, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether or 1,4-dioxane.

[0070] The "alcohol solvent" of 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.

[0071] The "ester solvent" mentioned in the present invention refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to ethyl acetate, isopropyl acetate or butyl acetate.

[0072] 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 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.

[0073] The "nitrile solvent" of the present invention refers to one or more "cyano" substituted "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.

[0074] The "aliphatic hydrocarbon solvent" mentioned in the present invention refers to a hydrocarbon compound with the basic properties of an aliphatic compound, in which the carbon atoms in the molecule are connected to form a chain-like carbon skeleton with the two ends open and not forming a ring, and the number of carbon atoms is 1-10, such as a saturated aliphatic hydrocarbon, including alkane solvents, specific examples of which include but are not limited to: n-butane, n-pentane, n-hexane or n-heptane.

[0075] The "alicyclic hydrocarbon solvent" mentioned in the present invention refers to a hydrocarbon compound having a cyclic carbon skeleton, similar properties to aliphatic hydrocarbons, and 1-8 ring atoms. Specific examples include but are not limited to cyclopentane or cyclohexane.

[0076] The "amide solvent" described in the present invention refers to a compound containing a carbonylamino group (-C(O)N-) and having 1-10 carbon atoms, and specific examples include but are not limited to: N,N-dimethylformamide or N,N-dimethylacetamide.

[0077] 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, or a mixed solvent of ethers and water; the alcohols, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, amides, and nitriles are as defined above.

[0078] The "X-ray powder diffraction pattern or XRPD" in 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 as n=1). When X-rays are incident on an atomic plane with a lattice plane spacing 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.

[0079] 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 the sample at a constant temperature, so as to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0080] 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.

[0081] The term "interplanar spacing" (d-value) used in this invention refers to the three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in a spatial lattice. These vectors divide the lattice into juxtaposed parallelepiped units, known as the interplanar spacing. The spatial lattice is divided along the lines connecting the parallelepiped units to form a set of rectilinear grids, known as spatial lattices or crystal lattices. The lattice and crystal lattice, respectively, use geometric points and lines 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 units are Å or Å.

[0082] Compared with the prior art, the present invention provides a crystalline 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 in 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.

[0083] The technical solution of the present invention has the following advantages:

[0084] 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 crystal form I are obtained, which can be better used in clinical practice; the crystal form I of the compound represented by formula I obtained by the technical solution of the present invention can meet the pharmaceutical 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

[0085] Figure 1 is the PXRD pattern of Form I;

[0086] FIG2 is a DSC spectrum of Form I;

[0087] FIG3 is a TGA spectrum of Form I;

[0088] FIG4 is an ellipsoid diagram of the three-dimensional structure of the asymmetric unit of a single crystal of the compound represented by formula (I);

[0089] FIG5 is an ellipsoidal diagram of the three-dimensional structure of a single molecule of a single crystal of the compound represented by formula (I);

[0090] Figure 6 is a projection diagram of the unit cell stacking along the a-axis of the single crystal of the compound represented by formula (I)

[0091] FIG7 is a comparison of the simulated powder diffraction pattern of the single crystal structure of the compound represented by formula (I) and the pattern of Form I;

[0092] FIG8 is a (high temperature) PXRD overlay of Form I;

[0093] FIG9 is a (high temperature) DSC overlay of Form I;

[0094] FIG10 is a (high temperature) TGA overlay of Form I;

[0095] FIG11 is a (high humidity) PXRD overlay of Form I;

[0096] FIG12 is a (high humidity) DSC overlay of Form I;

[0097] FIG13 is a TGA overlay of Form I (high humidity);

[0098] FIG14 is an overlay of (illumination) PXRD patterns of Form I;

[0099] FIG15 is a (illumination) DSC overlay of Form I;

[0100] FIG16 is a TGA overlay of Form I (illumination);

[0101] FIG17 is a PXRD pattern of the compound of Formula I prepared in Comparative Example 1. DETAILED DESCRIPTION

[0102] To further illustrate the present invention, the crystalline 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 solutions of the present invention and are not intended to limit the essence and scope of the present invention.

[0103] Test conditions of the instruments used in the test:

[0104] 1. Differential Scanning Calorimeter (DSC)

[0105] Instrument model: Q2000 DSC 3+Q500 TGA

[0106] Purge gas: nitrogen

[0107] Heating rate: 10.0℃ / min

[0108] Temperature range: 30-300℃

[0109] Thermogravimetric analysis (TGA) temperature range is 30℃-350℃, and the heating rate is 10℃ / min

[0110] 2. X-ray Powder Diffraction (XRPD)

[0111] Instrument model: D8 Advance X-ray powder diffractometer

[0112] Radiation: Monochromatic Cu-Kα radiation (λ=1.5406)

[0113] Scanning mode: θ / 2θ, scanning range: 3-45°

[0114] Voltage: 40KV, Current: 40mA

[0115] 3. Single crystal X-ray diffractometer

[0116] Instrument model: SMART APEX-II

[0117] The compound represented by the following formula (I) was prepared according to the method disclosed in Example 10 of WO2020107500A1.

[0118] Example 1 Normal temperature evaporation method (single solvent)

[0119] 50 mg of the compound represented by formula (I) was weighed and placed in a reaction flask. After adding solvent to fully dissolve, the mixture was placed in a fume hood and slowly evaporated at room temperature. After filtration, a solid of the compound represented by formula (I) was obtained. The X-ray diffraction pattern of the solid was measured, and the results are shown in Table 1:

[0120] Table 1 Test results of room temperature volatilization method (single solvent)

[0121] The prepared crystal form I was subjected to XRD detection, and the results are shown in Table 2:

[0122] Table 2 Characteristic peaks of Form I

[0123] FIG1 is a PXRD pattern of Form I, wherein curves a and b are PXRD patterns of different batches of Form I prepared using methanol solvent.

[0124] FIG2 is a DSC spectrum of Form I prepared using methanol solvent.

[0125] FIG3 is a TGA spectrum of Form I prepared using methanol solvent.

[0126] The results of Figures 1 to 3 show that the two batches of samples are crystalline and have the same crystal form, and do not contain crystallization solvent or crystal water.

[0127] Example 2 Suspension Crystallization

[0128] 30 mg of the compound represented by formula (I) was weighed and placed in a reaction flask. A solvent was added to form a suspension. The suspension was shaken at room temperature and 50°C for 48 hours, 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 determined, and the results are shown in Table 3:

[0129] Table 3 Suspension crystallization test results

[0130] Example 3 Dissolution Crystallization Method

[0131] 50 mg of the compound represented by formula (I) was weighed and placed in a reaction flask, dissolved in a relatively well-soluble solvent to prepare a solution, to which a poorly soluble solvent was gradually added until a solid was precipitated, which was then subjected to PXRD analysis. If no solid was precipitated after the total solvent amount reached 20 mL, the dropwise addition of solvent was stopped, and the solution was allowed to stand at room temperature for natural evaporation. The solid obtained after evaporation was subjected to PXRD analysis. The results are shown in Table 4:

[0132] Table 4 Dissolution crystallization test results

[0133] NS: No solid was obtained during the test.

[0134] Example 4 Binary mixed solvent crystallization method

[0135] 50 mg of the compound represented by formula (I) was weighed and placed in a reaction flask, and a binary mixed solvent was added (mixed in a volume ratio of 1:4, 1:1, and 4:1). If a clear solution was obtained, it was slowly evaporated at room temperature, and the resulting solid was subjected to PXRD analysis; if a suspension was obtained, it was allowed to stand at room temperature and the solvent was removed, and the resulting solid was subjected to PXRD analysis. The results are shown in Table 5:

[0136] Table 5 Binary mixed solvent crystallization test results

[0137] NS: No solid was obtained during the test.

[0138] Example 5 Grinding Crystallization Method

[0139] 50 mg of the compound represented by formula (I) was weighed and placed in a mortar. A small amount of solvent was added dropwise to grind the mixture. The PXRD patterns of the mixture after grinding for 30 minutes with different solvents were tested to determine whether different crystal forms were produced. The results are shown in Table 6:

[0140] Table 6 Grinding crystallization test results

[0141] Example 6 Rapid Cooling Crystallization Method

[0142] 50 mg of the compound represented by formula (I) was weighed and placed in a beaker. An appropriate amount of solvent was added to completely dissolve the mixture. The mother liquor was placed in a 40°C water bath for 20 minutes, then immediately placed in an ice-water mixture (4°C). If solids precipitated, the supernatant was removed. After the solids were dried, PXRD analysis was performed. The results are shown in Table 7:

[0143] Table 7 Rapid cooling crystallization test results

[0144] NS: No solid was obtained during the test.

[0145] Example 7 Vapor Diffusion Method

[0146] 50 mg of the compound of formula (I) was weighed into a sample vial, and an appropriate amount of solvent was added to form a clear solution. The open sample vial was placed in another larger glass container. A poorly soluble solvent was added to the outer container, and the outer container was tightly capped (or sealed with a sealing film). The solution was incubated at room temperature to allow the outer solvent to evaporate continuously into the inner container. By reducing the solubility of the sample in the mixed solvent system, crystals were precipitated, and whether different crystalline forms were produced. The results are shown in Table 8:

[0147] Table 8 Vapor diffusion test results

[0148] NS: No solid was obtained during the test.

[0149] Example 8 Single Crystal Cultivation

[0150] In the binary mixed solvent crystallization test, under the conditions of water-acetone (1:4, v / v) solvent, 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 18,678 diffraction points, 10,233 independent diffraction points, and 9,936 observable points (|F|² ≥ 2σ|F|²). The crystal structure was solved using the direct method (Shelxs97), and the results are shown in Table 9:

[0151] Table 9 Unit cell parameters of Form I single crystal

[0152] 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 is shown in Figure 5, and the unit cell stacking projection along the a-axis is shown in Figure 6; using the above single crystal structure data, the corresponding simulated powder diffraction pattern was calculated and compared with the crystal form I spectrum. The results show that the two crystal forms are consistent (see Figure 7 for details). In Figure 7, curve a is the single crystal simulated powder pattern of the compound, and curve b is the PXRD pattern of crystal form I.

[0153] Comparative Example 1

[0154] The compound represented by formula (I) was prepared according to the method disclosed in Example 10 of WO2020107500A1. The physical state of the compound was solid, and the solvent was 95% ethanol. After recrystallization, PXRD results showed that the solid was amorphous (see Figure 17 for details).

[0155] Example 9 Crystal Stability Investigation

[0156] The physical stability test of Form I samples was carried out under different storage conditions. The storage conditions were:

[0157] ①High temperature 60℃

[0158] ②High humidity (RH90%±5%)

[0159] ③ Under lighting conditions (4500lx±500lx, the total illumination of the light source reaches 1.2×10 6 lux·hr)

[0160] PXRD, DSC and TGA tests were performed on the samples on day 0, day 5 and day 10, respectively, to investigate the stability of the samples under high temperature, high humidity and light conditions. The test results are detailed in Figures 8 to 16 of the accompanying drawings of the specification.

[0161] In Figure 8, curve a is day 0, curve b is day 5, and curve c is day 10.

[0162] In Figure 11, curve a is day 0, curve b is day 5, and curve c is day 10.

[0163] In Figure 14, curve a is day 0, curve b is day 5, and curve c is day 10.

[0164] Conclusion: Form I can be synthesized under high temperature (60°C), high humidity (RH90%±5%), and light intensity (4500lx±500lx, with a total light intensity of 1.2×10 6 lux·hr) under the conditions of 40 lux·hr, there was no significant difference in the powder diffraction pattern, DSC pattern and TGA pattern, indicating that it had good stability and the crystal form did not change.

[0165] Example 10

[0166] 25 mg of Form I of the sample was weighed separately and placed in an intrinsic dissolution rate metal module, maintained at 20 pounds of pressure for 30 seconds, and then added to 20 mL of SGF (simulated gastric fluid) / FESSIF (simulated fed intestinal fluid) physiological medium, kept warm at 37°C, and maintained at 100 rpm throughout the process. Then, 0.5 mL of the solution was taken at 5, 15, 30, 45, 60, 90, and 120 minutes respectively, and filtered with a 0.22 μm aqueous microfiltration membrane. At the same time, 0.5 mL of the same physiological medium was replenished, and the concentration was determined according to the HPLC content determination method.

[0167] The results showed that the dissolution rate of Form I was significantly faster than that of the solid obtained in the comparative example.

[0168] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such 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 (S)-2-(1-acetoxy-n-pentyl)benzoic acid L-arginine salt shown in formula I is 192°C; the decomposition temperature of the I crystal form of (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 7, 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; and 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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