S-indobufen sodium polymorphic substance and preparation method thereof

Abstract

The invention relates to a crystal form I, a crystal form II, a crystal form III, a crystal form IV and a crystal form V of (S)-indobufen sodium salt as well as a preparation method and application of the crystal form I. The five crystal forms of the (S)-indobufen sodium salt are comprehensively characterized by X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The (S)-indobufen sodium salt crystal form provided by the invention is stable in quality and easy to store, and can be used for preparation production. The preparation method is simple to operate, safe, environment-friendly, low in cost and suitable for industrial production.

Description

[0001] This application claims the priority of two prior applications, patent application number 2023109542264, filed with the State Intellectual Property Office of China on August 1, 2023, entitled "A (S)-Indobufen Sodium Polymorph and Preparation Method thereof", and patent application number 2023109609071, filed with the State Intellectual Property Office of China on August 1, 2023, entitled "A (S)-Indobufen Sodium Crystalline Form II and Preparation Method thereof". The full texts of these two applications are incorporated into this application by reference. Technical Field

[0002] The present invention relates to the technical field of drug crystals, and in particular to S-indobufen sodium polymorphs and a preparation method thereof. Background Art

[0003] Indobufen tablets were first marketed in Italy by Farmfalia Carlo Erba in August 1984. They were widely used in South Korea in 2009 and introduced to China in 2005. They are selective and reversible cyclooxygenase inhibitors and were included in the national medical insurance catalog in 2017. They are antiplatelet aggregation drugs and belong to the same category as aspirin.

[0004] The existing public technologies are mainly based on free indobufen, and there are very few studies on indobufen salts. The research on salt compounds may improve the crystallization properties of the compound to facilitate synthesis or purification, and may also improve bioavailability, stability, hygroscopicity, solubility and other physical and chemical properties to improve the developability of the compound. Therefore, the research on indobufen salts plays a key role in the further development of indobufen. Summary of the invention

[0005] The present invention provides (S)-indobufen sodium salt crystal form I (hereinafter referred to as "crystal form I"), which is irradiated with Cu-Kβ to form (S)-indobufen sodium salt in the form of 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic diffraction peaks are selected from any three of 11.46, 14.82, 15.44, and 18.98 or at 11.46, 14.82, 15.44, and 18.98.

[0006] In some embodiments, Form I is irradiated with Cu-Kβ at 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more peaks at the following positions: 23.37, 23.96, 26.73, and 27.36.

[0007] In some embodiments, Form I is irradiated with Cu-Kβ at 2 θThe X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more peaks at the following positions: 14.44, 14.61, 20.31, 22.44, 24.93, 25.53, 26.37, 27.19, 28.78, and 32.38.

[0008] In some embodiments, Form I is irradiated with Cu-Kβ at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 16.71, 22.06, 24.76, 30.11, 30.60, 31.69, and 33.91.

[0009] The X-ray powder diffraction data of the specific crystal form I are as follows:

[0010]

[0011]

[0012] The differential scanning calorimetry spectrum of Form I shows a melting endothermic peak at 82°C and a melting endothermic peak at 334°C.

[0013] Thermogravimetric analysis of Form I showed a weight loss of 14.1% at 120°C and began to decompose at 320°C.

[0014] The present invention provides (S)-indobufen sodium salt form III (hereinafter referred to as "form III"), which is irradiated with Cu-Kβ to form θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic diffraction peaks are selected from any three of 7.63, 11.44, 14.81, and 18.97 or at 7.63, 11.44, 14.81, and 18.97.

[0015] In some embodiments, Form III is 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more of the following characteristic peaks: 6.08, 15.40, 23.35, 23.93, and 27.29.

[0016] In some embodiments, Form III is 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more of the following characteristic peaks: 9.98, 14.43, 14.59, 16.68, 20.26, 21.20, 22.03, 22.40, 25.52, 26.73, and 32.37.

[0017] In some embodiments, Form III is irradiated with Cu-Kβ at 2 θIn the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 3.81, 15.80, 24.76, 24.92, 26.36, and 30.62.

[0018] The X-ray powder diffraction data of the specific crystal form III are as follows:

[0019] Peak <![CDATA[Diffraction angle 2 θ (°)]]> d value Relative strength (%) 1 3.81 23.16 5.67 2 6.08 14.52 24.50 3 7.63 11.58 100.00 4 9.98 8.86 7.82 5 11.44 7.73 40.75 6 14.43 6.14 10.89 7 14.59 6.06 8.51 8 14.81 5.98 35.59 9 15.40 5.75 23.87 10 15.80 5.61 4.90 11 16.68 5.31 7.86 12 18.97 4.67 35.74 13 20.26 4.38 7.54 14 21.20 4.19 9.06 15 22.03 4.03 7.42 16 22.40 3.97 7.49 17 23.35 3.81 26.05 18 23.93 3.72 29.20 19 24.76 3.59 5.80 20 24.92 3.57 5.81 21 25.52 3.49 9.03 22 26.36 3.38 5.06 23 26.73 3.33 13.48 24 27.29 3.27 29.84 25 30.62 2.92 5.53 26 32.37 2.76 8.77

[0020] The differential scanning calorimetry spectrum of Form III shows a melting endothermic peak at 82°C and a melting endothermic peak at 334°C;

[0021] Thermogravimetric analysis of Form III shows a weight loss of 9.4% at 130°C, a weight loss of 1.3% between 130°C and 200°C, and decomposition begins at 320°C.

[0022] The present invention provides (S)-indobufen sodium salt crystal form IV (hereinafter referred to as "crystal form IV"), which is irradiated with Cu-Kβ to form (S)-indobufen sodium salt in the form of 2 θ The characteristic diffraction peaks in the X-ray powder diffraction pattern represented by a value of ±0.2° are selected from any two of 7.21, 7.65, and 11.47 or at 7.21, 7.65, and 11.47.

[0023] In some embodiments, Form IV is 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more of the following characteristic peaks: one or more peaks of 14.86, 19.00, 23.35, 23.93, and 27.30.

[0024] In some embodiments, Form IV is 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more of the following characteristic peaks: 6.04, 10.01, 14.60, 15.45, 16.73, 21.26, 22.09, 24.83, 25.52, 26.76, and 32.38.

[0025] In some specific embodiments, the crystalline form IV is irradiated with Cu-Kβ at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 3.84, 10.01, 12.05, 20.31, 22.43, 26.39, 30.61, and 31.51.

[0026] The X-ray powder diffraction data of the specific crystal form IV are as follows:

[0027]

[0028]

[0029] The differential scanning calorimetry spectrum of Form IV shows a melting endothermic peak at 78°C, followed by a melting endothermic peak at 342°C.

[0030] Thermogravimetric analysis of Form IV shows a weight loss of 3.8% at 130°C, a weight loss of 1.4% between 130°C and 200°C, and decomposition begins at 330°C.

[0031] The present invention provides (S)-indobufen sodium salt form V (hereinafter referred to as "form V"), which is irradiated with Cu-Kβ to form (S)-indobufen sodium salt in the form of 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, any three selected from 7.73, 14.87, 16.63, and 31.65 or at 7.73, 14.87, 16.63, and 31.65.

[0032] In some embodiments, Form V is 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more of the following characteristic peaks: 8.02, 15.53, 19.06, 19.55, 21.66, and 24.03.

[0033] In some embodiments, Form V is 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more of the following characteristic peaks: 11.55, 12.21, 12.83, 15.99, 23.35, 24.89, 27.27, 28.17, and 30.71.

[0034] In some embodiments, Form V is irradiated with Cu-Kβ at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 5.16, 5.95, 8.55, 10.07, 20.88, 22.44, and 25.54.

[0035] The X-ray powder diffraction data of the specific crystal form V are as follows:

[0036]

[0037]

[0038] The differential scanning calorimetry spectrum of Form V shows a melting endothermic peak at 68°C, a melting endothermic peak at 171°C, a melting endothermic peak at 209°C, and then a melting endothermic peak of the recrystallized solid at 225°C.

[0039] Thermogravimetric analysis of Form V shows a weight loss of 1.5% from room temperature to 200°C, and begins to decompose at 300°C.

[0040] The present invention also provides a method for preparing (S)-indobufen sodium crystal form I, comprising the following steps: placing (S)-indobufen sodium in a single solvent or a binary solvent to crystallize and precipitate a solid to obtain crystal form I;

[0041] In some embodiments, the single solvent is selected from methanol or ethanol.

[0042] In some embodiments, the binary solvent includes solvent A or solvent B, and solvent A or solvent B is selected from C1-C4 alkyl alcohol, water, alkane, C1-C6 alkane halogenated alkane, C1-C6 alkyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide. One of the solvents in the binary solvent system is selected from C1-C4 alkyl alcohol or water.

[0043] In some preferred embodiments, solvent A or solvent B is selected from methanol, ethanol, water, n-hexane, dichloromethane, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide or dimethyl sulfoxide. In some preferred embodiments, one of the binary solvents is selected from methanol, ethanol or water.

[0044] The solvent A and the solvent B are in the form of direct addition, reverse addition or mixed solvent.

[0045] After (S)-indobufen sodium is added to solvent A and dissolved, solvent B is added thereto;

[0046] The back addition is to add (S)-indobufen sodium into solvent A to dissolve it, and then add it into solvent B.

[0047] The mixed solvent is in the form of mixing solvent A and solvent B evenly, and then adding (S)-indobufen sodium.

[0048] The present invention also provides a method for preparing (S)-indobufen sodium crystal form III, specifically, the crystal form I is placed at 50±5° C. and dried for 20-30 hours to obtain the crystal form III.

[0049] The present invention also provides a method for preparing (S)-indobufen sodium crystal form IV, which is specifically prepared by drying the crystal form I at 70±5° C. for 20-30 hours.

[0050] The present invention also provides a method for preparing (S)-indobufen sodium crystal form V, which is specifically prepared by drying the crystal form I at 90±5° C. for 40-60 hours.

[0051] The present invention provides (S)-indobufen sodium crystal form II (hereinafter referred to as "crystal form II"), which uses Cu-Kβ radiation to 2 θIn the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic peaks are selected from any three of 14.54, 14.79, 15.40, and 18.92 or at 15.54, 14.79, 15.40, and 18.92.

[0052] In some embodiments, Form II is irradiated with Cu-Kβ at 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more peaks at the following positions: 11.37, 23.32, 23.87, 26.65, 27.29, and 32.36.

[0053] In some embodiments, Form II is irradiated with Cu-Kβ at 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more peaks at the following positions: 16.68, 20.25, 22.37, 24.88, 25.46, 26.26, and 27.08.

[0054] In some specific embodiments, Form II is irradiated with Cu-Kβ at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 3.78, 15.78, 22.03, 24.68, 33.82, and 36.26.

[0055] In some specific embodiments, the X-ray powder diffraction data of Form II are as follows:

[0056]

[0057]

[0058] In some specific embodiments, the differential scanning calorimetry of Form II shows a melting endothermic peak at 74°C, followed by a melting endothermic peak at 333°C;

[0059] And / or, the thermogravimetric analysis spectrum of Form II shows a weight loss of 6.5% from room temperature to 120°C, and starts to decompose at 330°C.

[0060] The present invention also provides a method for preparing the crystal form II, which specifically comprises the following steps: placing (S)-indobufen sodium in a binary solvent system for crystallization, precipitating a solid, and obtaining the crystal form II.

[0061] The crystal form II is a monohydrate.

[0062] The binary solvent system comprises solvent C and solvent D, wherein solvent C is C1-C6 alkyl alcohol, and solvent D is selected from methyl tert-butyl ether or ethyl acetate.

[0063] In some embodiments, solvent C is methanol, propanol or isopropanol.

[0064] In some preferred embodiments, solvent C is ethanol and solvent D is methyl tert-butyl ether; or solvent C is isopropanol and solvent D is ethyl acetate; or C is methyl tert-butyl ether and solvent D is methanol.

[0065] The present invention also provides the use of (S)-indobufen sodium crystal form I, crystal form III, crystal form IV, crystal form V or crystal form II, specifically the use of (S)-indobufen sodium crystal form I, crystal form II, crystal form III, crystal form IV or crystal form V in the preparation of a medicament for preventing and / or treating antiplatelet diseases, wherein the disease is ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis caused by arteriosclerosis, or for preventing thrombosis during hemodialysis.

[0066] The present invention also provides a pharmaceutical composition comprising (S)-indobufen sodium crystal form I, crystal form III, crystal form IV, crystal form V or crystal form II and pharmaceutically acceptable excipients thereof.

[0067] The solubility of the crystal forms I, II and III in the present invention in water medium is significantly better than that of the crystal forms IV and V. Under high humidity and high temperature conditions, the contents of the crystal forms I to V are stable and have no significant changes. In particular, under various conditions of the crystal form II, the isomer content is stable, the crystal state is stable, and it is not easy to transform into a crystal.

[0068] Definition and Description

[0069] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered ambiguous or unclear without special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding product or its activity.

[0070] It should be noted that in the powder X-ray diffraction spectrum, the peak position or relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the peak position may have errors. θ The measurement error of the value can be ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0071] The phenomenon that the lattice planes or crystal edges of some grains in the crystal predominantly diffract certain directions and plane arrays is called preferred orientation. In the powder method, the calculation of the relative intensity of the lines requires that the crystals in the powder sample are completely irregularly oriented. If the number of oriented crystals in the sample increases, the intensity will inevitably increase. This makes the diffraction line intensity and orientation degree have a certain corresponding relationship. ("X-ray Structure Analysis", edited by Qi Jingyu, Tongji University Press, 1st edition, April 2003).

[0072] Preferred orientation will affect the test results of powder diffraction method for determining crystal structure. There are differences in XPRD test results of different batches of crystal forms, but this does not prevent technicians in this field from making judgments on whether they are the same crystal form.

[0073] It should be noted that for the same crystal form, the position of the endothermic peak of DSC may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the endothermic peak, which may be ±5°C or ±3°C. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0074] As used herein, "polymorph" or "polymorph" refers to a crystal form having the same chemical composition but different spatial arrangements of the molecules, atoms and / or particles constituting the crystal. Although polymorphs have the same chemical composition, their packing and geometric arrangements are different and may exhibit different physical properties, such as melting points, shapes, colors, densities, hardness, deformability, stability, solubility, dissolution rates and the like. Depending on their temperature-stability relationship, two polymorphs may be monomorphic or intermorphic. For monomorphic systems, the relative stability between the two solid phases remains unchanged when the temperature changes. In contrast, in intermorphic systems, there is a transition temperature at which the stability of the two phases is swapped ((Theory and Origin of polymorphism in "Polymorphsim in Pharmaceutical Solids" (1999) ISBN:)-8247-0237). This phenomenon of compounds existing in different crystal structures is called pharmaceutical polymorphism.

[0075] The word “comprise” or “comprises” and its English variations such as comprises or comprising should be construed as having an open and non-exclusive meaning, ie, “including but not limited to”.

[0076] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable excipients" refer to inert substances that are administered together with the active ingredient and are conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Non-limiting examples of the excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0077] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0078] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0079] Typical routes of administration of the crystalline forms described herein or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0080] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0081] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0082] The term "treatment" means administering the (S)-indobufen sodium crystalline form I, II, III, IV, V compound or preparation of the present application to improve or eliminate the disease and one or more symptoms associated with the disease, and includes:

[0083] (1) To inhibit a disease or disease state, that is, to curb its development;

[0084] (2) Relief of a disease or disease state, i.e., regression of the disease or disease state.

[0085] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0086] 3. Beneficial effects

[0087] The invention provides a (S)-indobufen sodium salt crystal form, which is not easy to absorb moisture, has stable quality, is easy to store, and can be used for preparation production. The preparation method is simple to operate, safe and environmentally friendly, has low cost, and is suitable for industrial production.

[0088] Crystalline forms I, II and III are easily soluble in aqueous media and have good solubility. In the solid-state stability test, the crystal form I was placed under light conditions for 10 days and 92.5% humidity for 30 days without changing its crystal form, and the crystalline state was stable. Crystalline forms III and V were placed under light conditions for 10 days and 60°C for 30 days without changing their crystal forms, and the crystalline state was stable. Among them, the crystal form II was placed under light conditions for 10 days, 60°C for 30 days, and 92.5% humidity for 30 days without changing its crystal form, and it has excellent stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 This is the crystal form I of the present invention 1 H NMR spectrum.

[0090] Figure 2 This is the XRPD spectrum of Form I of the present invention.

[0091] Figure 3 This is the TGA spectrum of Form I of the present invention.

[0092] Figure 4 This is the DSC spectrum of Form I of the present invention.

[0093] Figure 5 This is the XRPD spectrum of Form III of the present invention.

[0094] Figure 6 This is the TGA spectrum of Form III of the present invention.

[0095] Figure 7 This is the DSC spectrum of Form III of the present invention.

[0096] Figure 8 This is the XRPD spectrum of Form IV of the present invention.

[0097] Fig. 9 This is the TGA spectrum of Form IV of the present invention.

[0098] Fig.10 This is the DSC spectrum of Form IV of the present invention.

[0099] Fig.11 This is the XRPD spectrum of Form V of the present invention.

[0100] Fig.12 This is the TGA spectrum of Form V of the present invention.

[0101] Fig.13 This is the DSC spectrum of Form V of the present invention.

[0102] Fig.14 The crystal form II of the present invention 1 H NMR spectrum.

[0103] Fig.15 This is the XRPD pattern of Form II of the present invention.

[0104] Fig.16 This is the TGA spectrum of Form II of the present invention.

[0105] Fig.17 This is the DSC spectrum of Form II of the present invention. DETAILED DESCRIPTION

[0106] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments of the specification. These embodiments do not mean any limitation to the present application.

[0107] All solvents used in this application were commercially available and used without further purification.

[0108] Explanation of English abbreviations:

[0109] DMF: N,N-dimethylformamide

[0110] DMSO: dimethyl sulfoxide

[0111] MTBE: Methyl tert-butyl ether

[0112] Example 1

[0113] Method 1 for Form I

[0114] In a 50 mL single-mouth bottle, weigh (S)-indobufen sodium salt (500 mg), add a mixed solvent of acetonitrile (10 mL) and water (1 mL), heat to 70 ° C to completely dissolve and clarify, quickly filter the reaction solution through a 46 μm filter membrane while hot, let the filtrate stand, cool naturally to crystallize, and gradually precipitate a white solid. Filter with suction, and dry the filter cake by vacuum rotary evaporation at 46 ° C to obtain Form I.

[0115] Preparation method 2 of crystal form I

[0116] (S)-Indobufen sodium salt (200 mg) was added to solvent 1 to obtain a clear solution, and solvent 2 was slowly added under stirring (positive addition), or the clear solution of solvent 1 was added to solvent 2 (reverse addition). After solids were precipitated, stirring was continued for 10 minutes. If no solids were precipitated, the mixture was placed at -20°C and stirred until solids were precipitated, and then filtered and dried. The results are shown in Table 1 below:

[0117] Table 1: Preparation method II of Form I Crystallization conditions screening

[0118] Solvent 1 Solvent 2 Solvent 1 / Solvent 2 How to join Crystal form results Methanol acetone 1:3 Plus Crystal form I Methanol n-Hexane 1:10 Back Raise Crystal form I Methanol Dichloromethane 1:8 Plus Crystal form I DMF water 20:1 Plus Crystal form I DMSO water 40:1 Back Raise Crystal form I Ethanol acetone 5:6 Plus Crystal form I Ethanol Acetonitrile 5:7 Plus Crystal form I Isopropyl alcohol water 20:1 Back Raise Crystal form I DMF acetone 30:1 Plus No solid precipitated DMSO Acetonitrile 40:1 Plus No solid precipitated

[0119] Preparation method of crystal form I

[0120] (S)-Indobufen sodium salt (100 mg) was placed in a centrifuge tube, and solvent 1 was added to dissolve it, and then it was placed in solvent 2 and allowed to stand to precipitate solids, which were filtered and dried. The characterization results are shown in Table 2 below:

[0121] Table 2: Screening of crystallization conditions for preparation method III of Form I

[0122] temperature Solvent 1 Solvent 1 volume (mL) Solvent 2 Crystal form results Room temperature Methanol 2 acetone Ⅰ Room temperature Methanol 2 Acetonitrile Ⅰ Room temperature Methanol 2 DMSO Ⅰ Room temperature water 1 DMSO Ⅰ Room temperature water 1 acetone Ⅰ 40℃ water 1 acetone Ⅰ Room temperature Methanol 2 Ethyl acetate Ⅰ Room temperature Ethanol 4 Ethyl acetate Ⅰ

[0123] Preparation method 4 of Form I

[0124] Take 200 mg of (S)-indobufen sodium salt, add the following mixed solvent at the corresponding temperature to obtain a clear solution, stir and cool naturally to crystallize, evaporate at room temperature if there is no precipitation, and filter immediately after obtaining the solid to obtain the product. The characterization results are shown in Table 3 below:

[0125] Table 3: Screening of crystallization conditions for preparation method IV of Form I

[0126] temperature Solvent 1 Solvent 2 Solvent 1 / Solvent 2 Crystal form results 70℃ Methanol / 4mL Ⅰ 88℃ Ethanol / 10mL Ⅰ 60℃ Methanol Ethyl acetate 5:12 Ⅰ 66℃ Methanol acetone 1:3 Ⅰ 80℃ Ethanol Acetonitrile 5:2 Ⅰ 70℃ Acetonitrile water 20:3 Ⅰ 85℃ DMSO water 50:1 Ⅰ 82℃ Ethyl acetate Ethanol 6:7 Ⅰ 85℃ DMF water 25 Ⅰ

[0127] For Form I 1 H NMR, XPRD, TGA, DSC characterization, such as Figure 1 As shown, 1 There is no residual solvent peak in the H NMR spectrum, only water peak and deuterated dimethyl sulfoxide peak.

[0128] 1. XRPD spectrum measurement conditions and diffraction peak data

[0129] XRPD spectrum Figure 2 Its X-ray powder diffraction data are shown in Table 4 below:

[0130] XRPD spectrum measurement conditions:

[0131] X-ray generator: 40 kV, 50 mA; Scanning mode: 1D (scanning); Scanning speed / counting time: 10.00° / min;

[0132] Step width: 0.02°; Scan axis: θ / 2θ; Filter: Kβ filter 1D for Cu; Scan range: 3~40°;

[0133] Detector: D / teX Ultra 250; Entrance slit box: 1 / 4deg; Length limiting slit: 10mm.

[0134] Table 4: X-ray powder diffraction data of Form I

[0135]

[0136]

[0137] Among the above characteristic peaks, the main characteristic diffraction peaks are selected from any three of 11.46, 14.82, 15.44, and 18.98 or at 11.46, 14.82, 15.44, and 18.98. It further includes any one or more of 23.37, 23.96, 26.73, and 27.36, or it may also include any one or more of 14.44, 14.61, 20.31, 22.44, 24.93, 25.53, 26.37, 27.19, 28.78, and 32.38, or it may also be at 16.71, 22.06, 24.76, 30.11, 30.60, 31.69, and 33.91. Specifically, the XRPD spectrum of Form I is as follows: Figure 2 shown.

[0138] 2. Thermogravimetric analysis

[0139] like Figure 3 As shown in the TGA spectrum, Form I has a weight loss of 14.1% from room temperature to 120°C and begins to decompose at around 320°C.

[0140] 3. Differential Scanning Calorimetry

[0141] like Figure 4 As shown in the DSC (differential scanning calorimetry) spectrum, Form I exhibits a melting endothermic peak at 82°C, followed by a melting endothermic peak at 334°C.

[0142] Example 2

[0143] Preparation of Form III

[0144] Weigh Form I (200 mg) and place at 50±5°C for 20-30 h to obtain Form III.

[0145] The crystal form III was characterized by XRPD, TGA and DSC.

[0146] 1. XRPD spectrum measurement conditions and diffraction peak data

[0147] XRPD spectrum Figure 5 Its X-ray powder diffraction data are shown in Table 5 below:

[0148] XRPD spectrum measurement conditions:

[0149] X-ray generator: 40 kV, 50 mA; scanning mode: 1D (scanning); scanning speed / counting time: 10.00° / min; step width: 0.02°; scanning axis: θ / 2θ; filter: Kβ filter 1D for Cu; scanning range: 3-40°;

[0150] Detector: D / teX Ultra 250; Entrance slit box: 1 / 4deg; Length limiting slit: 10mm.

[0151] XRPD Figure 5 Its X-ray powder diffraction data are shown in Table 5 below:

[0152] Table 5: X-ray powder diffraction data of Form III

[0153] Peak <![CDATA[Diffraction angle 2 θ (°)]]> d value Relative strength (%) 1 3.81 23.16 5.67 2 6.08 14.52 24.50 3 7.63 11.58 100.00 4 9.98 8.86 7.82 5 11.44 7.73 40.75 6 14.43 6.14 10.89 7 14.59 6.06 8.51 8 14.81 5.98 35.59 9 15.40 5.75 23.87 10 15.80 5.61 4.90 11 16.68 5.31 7.86 12 18.97 4.67 35.74 13 20.26 4.38 7.54 14 21.20 4.19 9.06 15 22.03 4.03 7.42 16 22.40 3.97 7.49 17 23.35 3.81 26.05 18 23.93 3.72 29.20 19 24.76 3.59 5.80 20 24.92 3.57 5.81 21 25.52 3.49 9.03 22 26.36 3.38 5.06 23 26.73 3.33 13.48 24 27.29 3.27 29.84 25 30.62 2.92 5.53 26 32.37 2.76 8.77

[0154] Among the above diffraction peaks, the main characteristic peaks are selected from any three of 7.63, 11.44, 14.81, and 18.97 or at 7.63, 11.44, 14.81, and 18.97, and also include one or more peaks of 6.08, 15.40, 23.35, 23.93, and 27.29, and further include one or more peaks of 9.98, 14.43, 14.59, 16.68, 20.26, 21.20, 22.03, 22.40, 25.52, 26.73, and 32.37, using Cu-Kβ radiation, and the diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ value ± 0.2° are also at 5.67, 4.90, 5.80, 5.81, and 5.53. Specifically, the XRPD spectrum of Form III is as follows: Figure 5 shown.

[0155] 2. Thermogravimetric analysis

[0156] like Figure 6 As shown in the TGA spectrum of Form III, Form III has a weight loss of 9.4% from room temperature to 130°C, a weight loss of 1.3% from 130°C to 200°C, and begins to decompose at around 320°C.

[0157] 3. Differential Scanning Calorimetry Analysis

[0158] like Figure 7 As shown in the DSC spectrum of Form III, Form III exhibits a melting endothermic peak at 79°C, followed by a melting endothermic peak at 341°C.

[0159] Example 3

[0160] Preparation of Form IV

[0161] Weigh Form I (200 mg) and place under vacuum drying at 70±5°C for 20-30 h to obtain Form IV.

[0162] The crystal form IV was characterized by XRPD, TGA and DSC.

[0163] 1. XRPD spectrum measurement conditions and diffraction peak data

[0164] The XRPD pattern of Form IV is as follows: Figure 8 Its X-ray powder diffraction data are shown in Table 6 below:

[0165] XRPD spectrum measurement conditions:

[0166] X-ray generator: 40 kV, 50 mA; Scanning mode: 1D (scanning); Scanning speed / counting time: 10.00° / min;

[0167] Step width: 0.02°; Scan axis: θ / 2θ; Filter: Kβ filter 1D for Cu; Scan range: 3~40°;

[0168] Detector: D / teX Ultra 250; Entrance slit box: 1 / 4deg; Length limiting slit: 10mm.

[0169] Table 6: X-ray powder diffraction data of Form IV

[0170]

[0171]

[0172] Among the above diffraction peaks, the main characteristic peaks are selected from any two of 7.21, 7.65, and 11.47 or at 7.21, 7.65, and 11.47, and further include one or more peaks of 14.86, 19.00, 23.35, 23.93, and 27.30, and also include one or more peaks of 6.04, 10.01, 14.60, 15.45, 16.73, 21.26, 22.09, 24.83, 25.52, 26.76, and 32.38, or at 3.84, 10.01, 12.05, 20.31, 22.43, 26.39, 30.61, and 31.51. Specifically, the XRPD spectrum of Form IV is as follows: Fig. 9 shown.

[0173] 2. Thermogravimetric analysis

[0174] like Fig. 9 The TGA spectrum of Form IV shown in the figure shows that Form IV has a weight loss of 3.8% from room temperature to 130°C, a weight loss of 1.4% from 130°C to 200°C, and begins to decompose at around 330°C.

[0175] 3. Differential Scanning Calorimetry Analysis

[0176] like Fig.10 The DSC spectrum of Form IV shown in FIG. 4 shows a melting endothermic peak at 78°C, followed by a melting endothermic peak at 342°C.

[0177] Example 4

[0178] Preparation of Form V

[0179] Weigh Form I (200 mg) and dry under vacuum at 90±5°C for 40-60 h to obtain Form V.

[0180] The crystal form V was characterized by XRPD, TGA and DSC.

[0181] 1. XRPD spectrum measurement conditions and diffraction peak data

[0182] XRPD Fig.11 Its X-ray powder diffraction data are shown in Table 7 below:

[0183] XRPD spectrum measurement conditions:

[0184] X-ray generator: 40 kV, 50 mA; scanning mode: 1D (scanning); scanning speed / counting time: 10.00° / min; step width: 0.02°; scanning axis: θ / 2θ; filter: Kβ filter 1D for Cu; scanning range: 3-40°;

[0185] Detector: D / teX Ultra 250; Entrance slit box: 1 / 4deg; Length limiting slit: 10mm.

[0186] Table 7: X-ray powder diffraction data of Form V

[0187] Peak <![CDATA[Diffraction Angle 2 θ (°)]]> d value Relative strength (%) 1 5.16 17.11 6.35 2 5.95 14.83 4.76 3 7.73 11.42 100.00 4 8.02 11.02 40.22 5 8.55 10.33 5.33 6 10.07 8.77 4.74 7 11.55 7.66 23.33 8 12.21 7.24 14.54 9 12.83 6.90 21.43 10 14.87 5.95 74.71 11 15.53 5.70 34.21 12 15.99 5.54 23.74 13 16.63 5.33 46.83 14 19.06 4.65 43.82 15 19.55 4.54 33.35 16 20.88 4.25 9.39 17 21.66 4.10 33.53 18 22.44 3.96 5.10 19 23.35 3.81 19.84 20 24.03 3.70 43.32 21 24.89 3.57 12.09 22 25.54 3.49 7.80 23 27.27 3.27 21.59 24 28.17 3.17 18.41 25 30.71 2.91 11.98 26 31.65 2.83 97.94

[0188] Among the above diffraction peaks, the main characteristic peaks are selected from any three of 7.73, 14.87, 16.63, 31.65 or at 7.73, 14.87, 16.63 and 31.65, further including one or more peaks of 8.02, 15.53, 19.06, 19.55, 21.66, 24.03, and 11.55, 12.21, 12.83, 15.99, 23.35, 24.89, 27.27, 28.17, 30.71, or at 5.16, 5.95, 8.55, 10.07, 20.88, 22.44, 25.54. Specifically, the XPRD spectrum of Form V is as follows: Fig.11 shown.

[0189] 2. Thermogravimetric analysis

[0190] like Fig.12 The TGA spectrum of Form V shown in the figure shows that Form V has a weight loss of 1.5% from room temperature to 200°C and begins to decompose at around 300°C.

[0191] 3. Differential Scanning Calorimetry Analysis

[0192] like Fig.13 The DSC spectrum of Form V shown in the figure shows that Form V exhibits a melting endothermic peak at 68°C, a melting endothermic peak at 171°C, a melting endothermic peak at 209°C, and then a melting endothermic peak of the recrystallized solid at 225°C.

[0193] Example 5

[0194] Preparation of Form II

[0195] Preparation method of Form II (1): In a 50 mL single-mouth bottle, weigh (S)-indobufen sodium salt (500 mg), add methyl tert-butyl ether (20 mL) and methanol (4 mL), and heat to 58°C. The reaction solution is completely dissolved and clarified. Turn off the heating, and quickly filter the reaction solution through a 46 μm filter membrane while hot. The filtrate is cooled naturally. After it cools to room temperature, there is no precipitation. The reaction solution is dried by vacuum rotary evaporation at 46°C to obtain Form II.

[0196] Preparation method of crystal form II (2): (S)-indobufen sodium salt (100 mg) was placed in a centrifuge tube, and solvent 1 was added to dissolve it, and then it was placed in the solvent atmosphere of solvent 2 to stand to precipitate solids, which were filtered and dried. The characterization results of the precipitated solids are shown in Table 8 below

[0197] Table 8: Crystallization results in different solvents

[0198] temperature Solvent 1 Solvent 1 volume (mL) Solvent 2 Crystal form results Room temperature Ethanol 4 MTBE Ⅱ Room temperature Isopropyl alcohol 10 Ethyl acetate Ⅱ

[0199] Characterization of (S)-Indobufen Sodium Form Ⅱ

[0200] 1. 1 H NMR spectrum

[0201] like Fig.14 The 1H NMR spectrum shown: no residual solvent peak, only water peak and deuterated dimethyl sulfoxide peak;

[0202] 2. XRPD spectrum measurement conditions and diffraction peak data

[0203] XRPD spectrum Fig.15 Its X-ray powder diffraction data are shown in Table 9 below:

[0204] XRPD spectrum measurement conditions:

[0205] X-ray generator: 40 kV, 50 mA; Scanning mode: 1D (scanning); Scanning speed / counting time: 10.00° / min;

[0206] Step width: 0.02°; Scan axis: θ / 2θ; Filter: Kβ filter 1D for Cu; Scan range: 3~40°;

[0207] Detector: D / teX Ultra 250; Entrance slit box: 1 / 4deg; Length limiting slit: 10mm.

[0208] Table 9: X-ray powder diffraction data of (S)-Indobufen sodium Form II

[0209] Peak <![CDATA[Diffraction angle 2 θ (°)]]> d value Relative strength (%) 1 3.78 23.34 11.89 2 11.37 7.78 55.73 3 14.54 6.09 100.00 4 14.79 5.98 90.07 5 15.40 5.75 57.43 6 15.78 5.61 13.48 7 16.68 5.31 16.88 8 18.92 4.69 88.86 9 20.25 4.38 20.78 10 22.03 4.03 13.88 11 22.37 3.97 22.73 12 23.32 3.81 44.93 13 23.87 3.72 54.38 14 24.68 3.60 12.70 15 24.88 3.58 18.49 16 25.46 3.50 27.35 17 26.26 3.39 15.14 18 26.65 3.34 37.75 19 27.08 3.29 22.60 20 27.29 3.27 50.24 21 32.36 2.76 32.41 22 33.82 2.65 10.33 23 36.26 2.48 5.97

[0210] Among the above characteristic peaks, the main characteristic diffraction peaks are selected from any three of 14.54, 14.79, 15.40, 18.92 or at 11.46, 14.82, 15.44 and 18.98. Further include one or more peaks of 11.37, 23.32, 23.87, 26.65, 27.29, 32.36, further include one or more peaks of 16.68, 20.25, 22.37, 24.88, 25.46, 26.26, 27.08, or at 3.78, 15.78, 22.03, 24.68, 33.82, 36.26.

[0211] 3. Thermogravimetric analysis spectrum determination

[0212] TGA spectrum see Fig.16 : Form II has a weight loss of 6.483% from room temperature to 120°C and begins to decompose at around 330°C.

[0213] 4. Differential Scanning Calorimetry Analysis

[0214] DSC spectrum see Fig.17: Form II has a melting endothermic peak at 74°C, and then a melting endothermic peak at 333°C.

[0215] Example 6

[0216] Solubility determination

[0217] The solubility of (S)-indobufen sodium crystal form I, (S)-indobufen sodium crystal form II, (S)-indobufen sodium crystal form III, (S)-indobufen sodium crystal form IV and (S)-indobufen sodium crystal form V in different media was measured at room temperature. The experimental results are shown in Table 10:

[0218] Table 10: Solubility of Indobufen Sodium Forms I to V in different media

[0219]

[0220] Classification based on conventional solubility:

[0221] Soluble means that the solubility in the specified solvent is greater than or equal to 10g / 100mL;

[0222] Soluble means that the solubility in the specified solvent is greater than or equal to 1.0g / 100mL and less than 10g / 100mL;

[0223] Slightly soluble means that the solubility in the specified solvent is greater than or equal to 0.01 g / 100 mL and less than 1.0 g / 100 mL;

[0224] Insoluble means that the solubility in a specified solvent is less than 0.01 g / 100 mL.

[0225] Example 7

[0226] Solid-state stability test of Form I to Form V samples

[0227] The solid-state stability of the samples of dextrorotatory indobufen sodium crystal form I to dextrorotatory indobufen sodium crystal form V was further evaluated. The stability of the crystal form was tested by XRPD after being placed under light conditions for 10 days (light-10d), at 60°C for 30 days (60°C-30d), and at 92.5% humidity for 30 days (RH92.5%-30d), and the content change was determined by HPLC. The experimental results are shown in Table 11:

[0228] Table 11: Solid-state stability test results of Form I to Form V samples

[0229]

[0230]

[0231] From Table 10 and Table 11, it can be seen that the solubility of crystal form I, crystal form II, and crystal form III in aqueous medium is significantly better than that of crystal form IV and crystal form V. From the results of content determination of crystal form I to crystal form V under the conditions of influencing factors, it can be seen that crystal form I to crystal form V are derived from relevant impurities under light conditions, the content is reduced, and light protection treatment is required. Under high humidity and high temperature conditions, the content of crystal form I to crystal form V is stable and there is no obvious change. In the solid-state stability test, the crystal form I was placed under light conditions for 10 days and 92.5% humidity for 30 days without changing the crystal form, and the crystalline state is stable. The crystal form III and crystal form V were placed under light conditions for 10 days and 60°C for 30 days without changing the crystal form, and the crystalline state is stable. Among them, the crystal form II was placed under light conditions for 10 days, 60°C for 30 days, and 92.5% humidity for 30 days without changing the crystal form, and it has excellent stability.

Claims

1. A (S)-indobufen sodium crystal form I, characterized in that: It uses Cu-Kβ radiation to 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic diffraction peaks are selected from any three of 11.46, 14.82, 15.44, and 18.98 or at 11.46, 14.82, 15.44, and 18.

98.

2. The (S)-Indobufen sodium crystal form I according to claim 1, characterized in that: It uses Cu-Kβ radiation to 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes peaks at one or more of the following positions: 23.37, 23.96, 26.73, 27.36; Preferably, it uses Cu-Kβ radiation at 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes peaks at one or more of the following positions: 14.44, 14.61, 20.31, 22.44, 24.93, 25.53, 26.37, 27.19, 28.78, 32.38; More preferably, it is irradiated using Cu-Kβ radiation at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 16.71, 22.06, 24.76, 30.11, 30.60, 31.69, and 33.

91.

3. The (S)-indobufen sodium crystal form I according to claim 1, characterized in that: Its differential scanning calorimetry spectrum shows a melting endothermic peak at 82°C and a melting endothermic peak at 334°C; And / or, its thermogravimetric analysis spectrum shows a weight loss of 14.1% at 120°C, and starts to decompose at 320°C.

4. A (S)-indobufen sodium crystal form III, characterized in that: It uses Cu-Kβ radiation to 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic diffraction peaks are selected from any three of 7.63, 11.44, 14.81, and 18.97 or at 7.63, 11.44, 14.81, and 18.

97.

5. The (S)-indobufen sodium crystal form III according to claim 4, characterized in that: With 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more of the following characteristic peaks: 6.08, 15.40, 23.35, 23.93, 27.29; Preferably, it is characterized in that 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more of the following characteristic peaks: 9.98, 14.43, 14.59, 16.68, 20.26, 21.20, 22.03, 22.40, 25.52, 26.73, 32.37; More preferably, it is irradiated using Cu-Kβ radiation at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 3.81, 15.80, 24.76, 24.92, 26.36, and 30.

62.

6. The (S) indobufen sodium crystal form III according to any one of claim 4, characterized in that: Its differential scanning calorimetry spectrum shows a melting endothermic peak at 82°C and a melting endothermic peak at 334°C; And / or, its thermogravimetric analysis spectrum shows a weight loss of 9.4% at 130°C, a weight loss of 1.3% between 130°C and 200°C, and decomposition starts to occur at 320°C.

7. A (S)-indobufen sodium crystal form IV, characterized in that: With 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic diffraction peaks are selected from any two of 7.21, 7.65, and 11.47 or at 7.21, 7.65, and 11.

47.

8. The (S)-Indobufen sodium crystal form IV according to claim 7, characterized in that: With 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more of the following characteristic peaks: one or more peaks at 14.86, 19.00, 23.35, 23.93, and 27.30; Preferably, it is characterized in that 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more of the following characteristic peaks: 6.04, 10.01, 14.60, 15.45, 16.73, 21.26, 22.09, 24.83, 25.52, 26.76, 32.38; More preferably, it is irradiated using Cu-Kβ radiation at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 3.84, 10.01, 12.05, 20.31, 22.43, 26.39, 30.61, and 31.

51.

9. The (S)-Indobufen sodium crystal form IV according to any one of claim 7, characterized in that: Its differential scanning calorimetry spectrum shows a melting endothermic peak at 78°C, followed by a melting endothermic peak at 342°C; And / or, its thermogravimetric analysis spectrum shows a weight loss of 3.8% at 130°C, a weight loss of 1.4% between 130°C and 200°C, and decomposition starts to occur at 330°C.

10. A (S)-indobufen sodium crystalline form V, characterized in that: It uses Cu-Kβ radiation to 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, any three selected from 7.73, 14.87, 16.63, and 31.65 or at 7.73, 14.87, 16.63, and 31.

65.

11. The (S)-Indobufen sodium crystalline form V according to claim 10, characterized in that: With 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes one or more of the following characteristic peaks: 8.02, 15.53, 19.06, 19.55, 21.66, 24.03; Preferably, 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes one or more of the following characteristic peaks: 11.55, 12.21, 12.83, 15.99, 23.35, 24.89, 27.27, 28.17, 30.71; More preferably, it is irradiated using Cu-Kβ radiation at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 5.16, 5.95, 8.55, 10.07, 20.88, 22.44, and 25.

54.

12. The (S)-Indobufen sodium crystal form V according to claim 10, characterized in that: Its differential scanning calorimetry spectrum shows a melting endothermic peak at 68°C, a melting endothermic peak at 171°C, a melting endothermic peak at 209°C, and then a melting endothermic peak of a recrystallized solid at 225°C. And / or, its thermogravimetric analysis spectrum shows a weight loss of 1.5% from room temperature to 200°C, and starts to decompose at 300°C.

13. A method for preparing (S)-Indobufen sodium crystal form I, characterized in that: The following steps are involved: (S)-indobufen sodium is placed in a single solvent or a binary solvent to crystallize a solid to obtain Form I; The single solvent is selected from methanol or ethanol; The binary solvent system comprises solvent A and solvent B; Solvent A or solvent B is selected from C1-C4 alkyl alcohol, water, C1-C6 alkane, C1-C6 alkane halogenated alkane, C1-C6 alkyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide; One of the binary solvents is selected from C1-C4 alkyl alcohol or water. Preferably, the solvent A or solvent B is preferably methanol, ethanol, water, n-hexane, dichloromethane, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide or dimethyl sulfoxide; The solvent A and solvent B are in the form of direct addition, reverse addition or mixed solvents; More preferably, one of the binary solvents is selected from methanol, ethanol or water.

14. A method for preparing (S)-Indobufen sodium crystal form III, characterized in that: It is prepared by drying Form I at 50±5°C for 20-30h.

15. A method for preparing (S)-Indobufen sodium crystal form IV, characterized in that: It is prepared by drying Form I at 70±5°C for 20-30h.

16. A method for preparing (S)-Indobufen sodium crystal form V, characterized in that: It is prepared by drying Form I at 90±5°C for 40-60h.

17. A (S)-indobufen sodium crystal form II, characterized in that: It uses Cu-Kβ radiation to 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, its characteristic peaks are selected from any three of 14.54, 14.79, 15.40, and 18.92 or at 15.54, 14.79, 15.40, and 18.

92.

18. The (S)-Indobufen sodium crystal form II according to claim 17, characterized in that: It uses Cu-Kβ radiation to 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° also includes peaks at one or more of the following positions: 11.37, 23.32, 23.87, 26.65, 27.29, 32.36; Preferably, it uses Cu-Kβ radiation at 2 θ The X-ray powder diffraction pattern represented by a value of ±0.2° further includes peaks at one or more of the following positions: 16.68, 20.25, 22.37, 24.88, 25.46, 26.26, 27.08; More preferably, it uses Cu-Kβ radiation at 2 θ In the X-ray powder diffraction pattern represented by a value of ±0.2°, or at one or more diffraction peaks among 3.78, 15.78, 22.03, 24.68, 33.82, and 36.

26.

19. The (S)-Indobufen sodium crystal form II according to any one of claim 17, characterized in that: Its differential scanning calorimetry graph shows a melting endothermic peak at 74°C, followed by a melting endothermic peak at 333°C; And / or, its thermogravimetric analysis spectrum shows a weight loss of 6.4-6.5% from room temperature to 120°C, and starts to decompose at 330°C.

20. A method for preparing (S)-Indobufen sodium crystal form II, characterized in that: The following steps are involved: (S)-indobufen sodium is placed in a binary solvent system to crystallize a solid to obtain Form II; The binary solvent system comprises solvent C and solvent D; The solvent C is a C1-C6 alkyl alcohol, and the solvent D is selected from methyl tert-butyl ether or ethyl acetate. Preferably, the solvent C is methanol, ethanol or isopropanol; More preferably, solvent C is ethanol and solvent D is methyl tert-butyl ether, or solvent C is isopropanol and solvent D is ethyl acetate, or C is methanol and solvent D is methyl tert-butyl ether.

21. Use of (S)-indobufen sodium crystal form I according to any one of claims 1 to 3, (S)-indobufen sodium crystal form III according to any one of claims 4 to 6, (S)-indobufen sodium crystal form IV according to any one of claims 7 to 9, (S)-indobufen sodium crystal form V according to any one of claims 10 to 12, or (S)-indobufen sodium crystal form II according to any one of claims 17 to 19 in the preparation of a medicament for preventing and / or treating antiplatelet diseases, wherein the diseases are ischemic cardiovascular diseases, ischemic cerebrovascular diseases, venous thrombosis caused by arteriosclerosis, or for preventing thrombosis during hemodialysis.

22. A pharmaceutical composition comprising (S)-indobufen sodium crystal form I as described in any one of claims 1 to 3, (S)-indobufen sodium crystal form III as described in any one of claims 4 to 6, (S)-indobufen sodium crystal form IV as described in any one of claims 7 to 9, (S)-indobufen sodium crystal form V as described in any one of claims 10 to 12, or (S)-indobufen sodium crystal form II as described in any one of claims 17 to 19, and pharmaceutically acceptable excipients thereof.

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