S-indobufen salts in various crystalline forms, processes for their preparation and uses thereof

Abstract

The present application relates to a plurality of crystal forms of S-indobufen salt, preparation method and use, the plurality of crystal forms specifically relates to 2 potassium salt crystal forms, 5 calcium salt crystal forms, 3 magnesium salt crystal forms, 4 ammonium salt crystal forms, 1 choline salt crystal form Type A, 4 meglumine salt crystal forms, 4 lysine salt crystal forms, 3 betaine salt crystal forms, 1 diethylamine salt crystal form, 5 tromethamine salt crystal forms, 2 proline co-crystals, 1 urea co-crystal and 1 cetylamine salt.The S-indobufen salt has excellent solubility, compressibility and stability, low moisture absorption and adhesion, very uniform particle size distribution, and unique advantages in preparation and application.

Description

Technical Field

[0001] This invention relates to the field of chemical medicine, and in particular to the crystal form of compound S-indobufen, namely GP-046, and its preparation method. Background Technology

[0002] Thromboembolic diseases are a class of systemic diseases affecting the heart, brain, and peripheral blood vessels. They are divided into arterial and venous types. High-risk patients for these diseases include those with a history of ischemic cerebrovascular disease, atrial fibrillation, long-term immobilization, intermittent claudication, etc. Prevention is more important than treatment, and antiplatelet drugs are widely used in the prevention of such thrombotic events.

[0003] The 2008 American College of Chest Physicians (ACCP) guidelines stated that indobufen is an effective inhibitor of platelet cyclooxygenase-1 (Cox-1), comparable to standard-dose aspirin in both biochemical efficacy and clinical effectiveness. Compared to similar drugs, indobufen inhibits platelet factors, exhibiting 2-5 times the antiplatelet aggregation effect of salicylic acid, and has a shorter duration of mild bleeding. There is no significant difference in oral clinical efficacy compared to ticlopidine, but indobufen demonstrates good tolerability.

[0004] Currently available commercially available indobufen are all racemic tablets. Although there are few reports on studies of single-configuration indobufen, analysis of existing literature reveals differences in the in vivo bioactivity of R-indobufen and S-indobufen (i.e., GP-046). In 2001, a study investigated the steady-state pharmacokinetics and bleeding time of the enantiomer of indobufen as racemic indobufen tablets in patients. The study demonstrated that dextrorotatory indobufen has a more significant inhibitory effect on platelet aggregation than indobufen, effectively blocking thrombus formation. Existing reports all focus on the crystal form studies of the racemic indobufen; there is currently no publicly available information on the crystal forms of S- or R-indobufen. Based on the above conclusions, research on the crystal forms of single-configuration indobufen has great application potential. Summary of the Invention

[0005] This invention provides a salt of compound S-indobufen, wherein the salt of S-indobufen is selected from meglumine salt, tromethamine salt, proline cocrystal, urea cocrystal, potassium salt, calcium salt, magnesium salt, ammonium salt, choline salt, lysine salt, betaine salt, diethylamine salt, and hexadecylamine salt.

[0006] In one embodiment of the present invention, the salts of S-indobufen include two potassium salt crystal forms (Type A / B), five calcium salt crystal forms (Type A~E), three magnesium salt crystal forms (Type A~C), four ammonium salt crystal forms (Type A~D), one choline salt crystal form (Type A), four meglumine salt crystal forms (Type A / B / D / E), four lysine salt crystal forms (Type A~D), three betaine salt crystal forms (Type A~C), one diethylamine salt crystal form (Type A), five tromethamine salt crystal forms (Type A~E), two proline cocrystals (Type A / B), one urea cocrystal (Type A), and one hexadecylamine salt (Type A).

[0007] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 11.2°±0.2°, and 14.0°±0.2°.

[0008] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.3°±0.2°, 18.2°±0.2°, and 22.9°±0.2°.

[0009] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 18.2°±0.2°, and 22.9°±0.2°.

[0010] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 10.6°±0.2°, 16.7°±0.2°, and 22.2°±0.2°.

[0011] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at diffraction angles 2θ of 10.6°±0.2°, 16.7°±0.2°, and 22.2°±0.2°.

[0012] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 7.4°±0.2°, 10.6°±0.2°, 11.2°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 16.7°±0.2°, 18.2°±0.2°, 22.2°±0.2°, and 22.9°±0.2°.

[0013] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type A has characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 10.6°±0.2°, 11.2°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 16.7°±0.2°, 18.2°±0.2°, 22.2°±0.2°, and 22.9°±0.2°.

[0014] The present invention provides meglumine salt Type A, wherein the molar ratio of S-indobufen to meglumine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0015] The meglumine salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 1 As shown.

[0016] When thermogravimetric analysis was performed, meglumine salt Type A, when heated to 120±2 ºC, exhibited a mass loss gradient of approximately 0.31±0.2%, and its TGA was essentially as follows: Figure 2 As shown.

[0017] When differential scanning calorimetry (DSC) was performed, meglumine salt Type A began to melt when heated to approximately 148 ± 2 ºC, and its DSC was essentially as follows: Figure 3 As shown.

[0018] The method for preparing meglumine salt Type A provided by the present invention is characterized in that,

[0019] (1) Add the free form of compound GP-046 and meglumine to an acetone solvent system, and stir at room temperature until meglumine salt Type A is obtained; or

[0020] (2) Dissolve the solid meglumine salt in a single or mixed solvent, evaporate the solvent at room temperature until the solid precipitates, to obtain meglumine salt Type A; or

[0021] In one embodiment of the present invention, the single solvent is methanol or trifluoroethanol.

[0022] In one embodiment of the present invention, the mixed solvent is methanol / ethanol, methanol / isopropyl acetate, methanol / 2-methyltetrahydrofuran, methanol / acetonitrile, methanol / toluene, trifluoroethanol / methyl isobutyl ketone, trifluoroethanol / anisole, trifluoroethanol / 1,4-dioxane, or trifluoroethanol / isopropanol.

[0023] In one embodiment of the present invention, the volume ratio of methanol to ethanol is 1:1, the volume ratio of methanol to isopropyl acetate is 2:1, the volume ratio of methanol to 2-methyltetrahydrofuran is 2:1, the volume ratio of methanol to acetonitrile is 2:1, the volume ratio of methanol to toluene is 2:1, the volume ratio of trifluoroethanol to methyl isobutyl ketone is 2:1, the volume ratio of trifluoroethanol to anisole is 1:1, the volume ratio of trifluoroethanol to 1,4-dioxane is 1:1, and the volume ratio of trifluoroethanol to isopropanol is 1:1.

[0024] (3) Dissolve the solid meglumine salt in a single or mixed solvent at high temperature, then place it under low temperature conditions to precipitate the solid, thus obtaining meglumine salt Type A; or

[0025] In one embodiment of the present invention, the single solvent is ethanol.

[0026] In one embodiment of the present invention, the mixed solvent is methanol / isopropanol, methanol / tetrahydrofuran, methanol / methyl isobutyl ketone, methanol / toluene, N,N-dimethylformamide / methyl cyclohexyl ether, or N,N-dimethylformamide / acetonitrile.

[0027] In one embodiment of the present invention, the volume ratio of methanol to isopropanol is 1:10, the volume ratio of methanol to tetrahydrofuran is 1:10, the volume ratio of methanol to methyl isobutyl ketone is 11:10, the volume ratio of methanol to toluene is 1:2, the volume ratio of N,N-dimethylformamide to methyl cyclohexyl ether is 7:5, and the volume ratio of N,N-dimethylformamide to acetonitrile is 7:5.

[0028] In one embodiment of the present invention, the high temperature is 80 ºC; the low temperature is -20 ºC.

[0029] (4) Dissolve the solid meglumine salt in an alcohol solvent, and add an ester, ether, ketone, aromatic hydrocarbon, or alkyl nitrile solvent dropwise while stirring until a solid precipitates, to obtain meglumine salt Type A; or

[0030] In one embodiment of the present invention, the alcohol solvent is methanol or trifluoroethanol, the ester solvent is ethyl acetate or isopropyl acetate, the ether solvent is methyl cyclohexyl ether, anisole or 2-methyltetrahydrofuran, the ketone solvent is methyl isobutyl ketone, the aromatic hydrocarbon solvent is toluene, and the alkyl nitrile solvent is acetonitrile.

[0031] (5) Dissolve the solid meglumine salt in sulfoxide or amide solvents, and add it to a ketone, alcohol, ester, ether, aromatic hydrocarbon, alkyl nitrile or halogenated hydrocarbon solvent under stirring until a solid precipitates to obtain meglumine salt Type A.

[0032] In one embodiment of the present invention, the sulfoxide solvent is dimethyl sulfoxide, the amide solvent is N,N-dimethylformamide, the ketone solvent is 2-butanone or methyl isobutyl ketone, the alcohol solvent is isobutanol, the ester solvent is isobutyl acetate, the ether solvent is tetrahydrofuran or methyl cyclohexyl ether, the aromatic hydrocarbon solvent is toluene, the alkyl nitrile solvent is acetonitrile, and the halogenated hydrocarbon solvent is dichloromethane or 1,2-dichloroethane.

[0033] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at diffraction angles 2θ of 10.7°±0.2°, 16.2°±0.2°, and 22.5°±0.2°.

[0034] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 6.3°±0.2°, 12.0°±0.2°, and 13.9°±0.2°.

[0035] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at diffraction angles 2θ of 6.3°±0.2°, 12.0°±0.2°, and 13.9°±0.2°.

[0036] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 3.2°±0.2°, 21.4°±0.2°, and 27.3°±0.2°.

[0037] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at diffraction angles 2θ of 3.2°±0.2°, 21.4°±0.2°, and 27.3°±0.2°.

[0038] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 3.2°±0.2°, 6.3°±0.2°, 10.7°±0.2°, 12.0°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 21.4°±0.2°, 22.5°±0.2°, and 27.3°±0.2°.

[0039] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type B has characteristic peaks at diffraction angles 2θ of 3.2°±0.2°, 6.3°±0.2°, 10.7°±0.2°, 12.0°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 21.4°±0.2°, 22.5°±0.2°, and 27.3°±0.2°.

[0040] The present invention provides meglumine salt Type B, wherein the molar ratio of S-indobufen to meglumine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0041] The meglumine salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 4 As shown.

[0042] When thermogravimetric analysis was performed, meglumine salt Type B, when heated to 120 ± 2ºC, exhibited a mass loss gradient of approximately 5.17 ± 0.2%, and its TGA was essentially as follows: Figure 5 As shown.

[0043] When performing differential scanning calorimetry (DSC), meglumine salt Type B showed an endothermic signal when heated to approximately 109 ± 2 ºC, and began to melt when heated to approximately 150 ± 2 ºC. Its DSC was essentially as follows: Figure 6 As shown.

[0044] The method for preparing meglumine salt Type B provided by the present invention is characterized in that,

[0045] The free state of compound GP-046 and meglumine were added to a tetrahydrofuran solvent system and stirred at room temperature until meglumine salt Type B was obtained.

[0046] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at diffraction angles 2θ of 6.2°±0.2°, 9.3°±0.2°, and 12.5°±0.2°.

[0047] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at one, two, or three of the diffraction angles 2θ of 13.9°±0.2°, 16.2°±0.2°, and 27.1°±0.2°.

[0048] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at diffraction angles 2θ of 13.9°±0.2°, 16.2°±0.2°, and 27.1°±0.2°.

[0049] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at one, two, or three of the diffraction angles 2θ of 10.8°±0.2°, 22.7°±0.2°, and 30.1°±0.2°.

[0050] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at diffraction angles 2θ of 10.8°±0.2°, 22.7°±0.2°, and 30.1°±0.2°.

[0051] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 6.2°±0.2°, 9.3°±0.2°, 10.8°±0.2°, 12.5°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 22.7°±0.2°, 27.1°±0.2°, and 30.1°±0.2°.

[0052] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type D has characteristic peaks at diffraction angles 2θ of 6.2°±0.2°, 9.3°±0.2°, 10.8°±0.2°, 12.5°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 22.7°±0.2°, 27.1°±0.2°, and 30.1°±0.2°.

[0053] The present invention provides meglumine salt Type D, wherein the molar ratio of S-indobufen to meglumine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0054] The meglumine salt Type D provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 7 As shown.

[0055] When thermogravimetric analysis was performed, meglumine salt Type D exhibited a mass loss gradient of approximately 15.39 ± 0.2% when heated to 120 ± 2ºC, and its TGA was essentially as follows: Figure 8 As shown.

[0056] When performing differential scanning calorimetry (DSC), meglumine salt Type D showed an endothermic signal when heated to around 99 ± 2 ºC, and began to melt when heated to around 144 ± 2 ºC. Its DSC was essentially as follows: Figure 9 As shown.

[0057] The method for preparing meglumine salt Type D provided by the present invention is characterized in that,

[0058] The free state of compound GP-046 and meglumine were added to a chloroform solvent system and stirred at room temperature until meglumine salt Type D was obtained.

[0059] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 11.0°±0.2°, and 19.8°±0.2°.

[0060] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 12.7°±0.2°, 15.1°±0.2°, and 18.0°±0.2°.

[0061] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at diffraction angles 2θ of 12.7°±0.2°, 15.1°±0.2°, and 18.0°±0.2°.

[0062] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at one, two, or three of the diffraction angles 2θ of 3.7°±0.2°, 21.2°±0.2°, and 27.9°±0.2°.

[0063] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at diffraction angles 2θ of 3.7°±0.2°, 21.2°±0.2°, and 27.9°±0.2°.

[0064] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 3.7°±0.2°, 7.4°±0.2°, 11.0°±0.2°, 12.7°±0.2°, 15.1°±0.2°, 18.0°±0.2°, 19.8°±0.2°, 21.2°±0.2°, and 27.9°±0.2°.

[0065] In one embodiment of the present invention, the X-ray powder diffraction pattern of the meglumine salt Type E has characteristic peaks at diffraction angles 2θ of 3.7°±0.2°, 7.4°±0.2°, 11.0°±0.2°, 12.7°±0.2°, 15.1°±0.2°, 18.0°±0.2°, 19.8°±0.2°, 21.2°±0.2°, and 27.9°±0.2°.

[0066] The present invention provides meglumine salt Type E, wherein the molar ratio of S-indobufen to meglumine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0067] The meglumine salt Type E provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 10 As shown.

[0068] When thermogravimetric analysis was performed, meglumine salt Type E exhibited a mass loss gradient of approximately 1.74 ± 0.2% when heated to 120 ± 2 ºC, and its TGA was essentially as follows: Figure 11 As shown.

[0069] When differential scanning calorimetry (DSC) was performed, meglumine salt Type E began to melt when heated to approximately 144 ± 2 ºC, and its DSC was essentially as follows: Figure 12 As shown.

[0070] The method for preparing meglumine salt Type E provided by the present invention is characterized in that,

[0071] Heating meglumine salt Type D to 120 ºC yields meglumine salt Type E.

[0072] In one embodiment of the invention, the heating rate is 10 ºC / min.

[0073] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type A has characteristic peaks at diffraction angles 2θ of 4.0°±0.2°, 5.7°±0.2°, and 9.1°±0.2°.

[0074] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.9°±0.2°, 20.2°±0.2°, and 21.5°±0.2°.

[0075] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type A has characteristic peaks at diffraction angles 2θ of 7.9°±0.2°, 20.2°±0.2°, and 21.5°±0.2°.

[0076] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 23.4°±0.2°, 24.3°±0.2°, and 25.3°±0.2°.

[0077] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type A has characteristic peaks at diffraction angles 2θ of 23.4°±0.2°, 24.3°±0.2°, and 25.3°±0.2°.

[0078] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.0°±0.2°, 5.7°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 20.2°±0.2°, 21.5°±0.2°, 23.4°±0.2°, 24.3°±0.2°, and 25.3°±0.2°.

[0079] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type A has characteristic peaks at diffraction angles 2θ of 4.0°±0.2°, 5.7°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 20.2°±0.2°, 21.5°±0.2°, 23.4°±0.2°, 24.3°±0.2°, and 25.3°±0.2°.

[0080] The present invention provides a tromethamine salt Type A, wherein the molar ratio of S-indobufen to tromethamine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0081] The tromethamine salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 13 As shown.

[0082] When thermogravimetric analysis was performed, tromethamine Type A exhibited a mass loss gradient of approximately 3.73 ± 0.2% when heated to 120 ± 2 ºC, and its TGA was essentially as follows: Figure 14 As shown.

[0083] When performing differential scanning calorimetry (DSC), tromethamine Type A exhibits both exothermic and endothermic signals when heated to approximately 110±2 ºC, both endothermic and exothermic signals when heated to approximately 147±2 ºC, and begins to melt when heated to approximately 154±2 ºC. Its DSC is essentially as follows: Figure 15 As shown.

[0084] The method for preparing aminobutadiene triol salt Type A provided by the present invention is characterized in that,

[0085] The tromethamine salt solid is dissolved in a single or mixed solvent, and the solvent is evaporated at room temperature until the solid precipitates to obtain tromethamine salt Type A.

[0086] In one embodiment of the present invention, the single solvent is methanol or trifluoroethanol.

[0087] In one embodiment of the present invention, the mixed solvent is trifluoroethanol / isopropyl acetate, trifluoroethanol / acetonitrile, trifluoroethanol / toluene, methanol / ethyl lactate, or methanol / isopropanol.

[0088] In one embodiment of the present invention, the volume ratio of trifluoroethanol / isopropyl acetate is 19:5, the volume ratio of trifluoroethanol / acetonitrile is 11:5, the volume ratio of trifluoroethanol / toluene is 2:1, the volume ratio of methanol / ethyl lactate is 2:1, and the volume ratio of methanol / isopropanol is 9:5.

[0089] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type B has characteristic peaks at diffraction angles 2θ of 7.6°±0.2°, 15.2°±0.2°, and 22.1°±0.2°.

[0090] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 12.8°±0.2°, 17.7°±0.2°, and 19.7°±0.2°.

[0091] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type B has characteristic peaks at diffraction angles 2θ of 12.8°±0.2°, 17.7°±0.2°, and 19.7°±0.2°.

[0092] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.4°±0.2°, 22.9°±0.2°, and 27.3°±0.2°.

[0093] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type B has characteristic peaks at diffraction angles 2θ of 6.4°±0.2°, 22.9°±0.2°, and 27.3°±0.2°.

[0094] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 6.4°±0.2°, 7.6°±0.2°, 12.8°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.7°±0.2°, 22.1°±0.2°, 22.9°±0.2°, and 27.3°±0.2°.

[0095] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type B has characteristic peaks at diffraction angles 2θ of 6.4°±0.2°, 7.6°±0.2°, 12.8°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.7°±0.2°, 22.1°±0.2°, 22.9°±0.2°, and 27.3°±0.2°.

[0096] The present invention provides a tromethamine salt Type B, wherein the molar ratio of S-indobufen to tromethamine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0097] The tromethamine salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 16 As shown.

[0098] When thermogravimetric analysis was performed, tromethamine Type B exhibited a mass loss gradient of approximately 0.09 ± 0.2% when heated to 120 ± 2ºC, and its TGA was essentially as follows: Figure 17 As shown.

[0099] When differential scanning calorimetry (DSC) is performed, tromethamine Type B begins to melt when heated to approximately 156 ± 2ºC, and its DSC is essentially as follows: Figure 18 As shown.

[0100] The method for preparing tromethamine salt Type B provided by the present invention is characterized in that,

[0101] (1) Add the free compound GP-046 and tromethamine to an acetonitrile solvent system and stir at room temperature until tromethamine salt Type B is obtained; or

[0102] (2) Dissolve the tromethamine salt solid in a single or mixed solvent at high temperature, then place it under low temperature conditions to precipitate the solid, thus obtaining tromethamine salt Type B; or

[0103] In one embodiment of the present invention, the single solvent is isopropanol or acetone.

[0104] In one embodiment of the present invention, the mixed solvent is ethanol / n-heptane, trifluoroethanol / methyl isobutyl ketone, trifluoroethanol / toluene, methanol / methyl cyclohexyl ether, or methanol / acetonitrile.

[0105] In one embodiment of the present invention, the volume ratio of ethanol to n-heptane is 9:5, the volume ratio of trifluoroethanol to methyl isobutyl ketone is 14:5, the volume ratio of trifluoroethanol to toluene is 1:2, the volume ratio of methanol to methyl cyclohexyl ether is 1:1, and the volume ratio of methanol to acetonitrile is 1:2.

[0106] In one embodiment of the present invention, the high temperature is 80 ºC; the low temperature is -20 ºC.

[0107] (3) Dissolve the tromethamine salt solid in an amide solvent, then allow it to stand in an ether, haloalkane, or alkyl nitrile solvent atmosphere for gas-liquid diffusion until the solid precipitates, yielding tromethamine salt Type B; or

[0108] In one embodiment of the present invention, the amide solvent is N,N-dimethylacetamide, the ether solvent is 2-methyltetrahydrofuran, the halocarbon solvent is dichloromethane, and the alkyl nitrile solvent is acetonitrile.

[0109] (4) Dissolve the tromethamine salt solid in a mixed solvent of trifluoroethanol / 2-methyltetrahydrofuran, and evaporate the solvent at room temperature until the solid precipitates to obtain tromethamine salt Type B; or

[0110] In one embodiment of the present invention, the volume ratio of trifluoroethanol / 2-methyltetrahydrofuran is 19:5.

[0111] (5) Dissolve the tromethamine salt solid in an alcoholic solvent, and while stirring, add dropwise an ester, ether, ketone, aromatic hydrocarbon, halogenated hydrocarbon, or alkyl nitrile solvent until a solid precipitates, to obtain tromethamine salt Type B; or

[0112] In one embodiment of the present invention, the alcohol solvent is methanol or trifluoroethanol, the ester solvent is isopropyl acetate or ethyl acetate, the ether solvent is methyl cyclohexyl ether or anisole, the ketone solvent is acetone, the aromatic hydrocarbon solvent is 4-isopropyltoluene or toluene, the halogenated hydrocarbon solvent is dibromomethane, and the alkyl nitrile solvent is acetonitrile.

[0113] (6) Dissolve the tromethamine salt solid in sulfoxide or alcohol solvents, and add it to ketone, ester, ether, aliphatic hydrocarbon or halogenated hydrocarbon solvents under stirring until a solid precipitates to obtain tromethamine salt Type B.

[0114] In one embodiment of the present invention, the sulfoxide solvent is dimethyl sulfoxide, the alcohol solvent is ethanol, the ketone solvent is methyl isobutyl ketone, the ester solvent is isopropyl acetate or isobutyl acetate, the ether solvent is isopropyl ether, the halogenated hydrocarbon solvent is 1,2-dichloroethane, and the aliphatic hydrocarbon solvent is n-heptane or cyclohexane.

[0115] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type C has characteristic peaks at diffraction angles 2θ of 5.4°±0.2°, 7.4°±0.2°, and 16.0°±0.2°.

[0116] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 4.5°±0.2°, 11.5°±0.2°, and 22.4°±0.2°.

[0117] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type C has characteristic peaks at diffraction angles 2θ of 4.5°±0.2°, 11.5°±0.2°, and 22.4°±0.2°.

[0118] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.9°±0.2°, 19.8°±0.2°, and 24.3°±0.2°.

[0119] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type C has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 19.8°±0.2°, and 24.3°±0.2°.

[0120] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type C has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.5°±0.2°, 5.4°±0.2°, 7.4°±0.2°, 8.9°±0.2°, 11.5°±0.2°, 16.0°±0.2°, 19.8°±0.2°, 22.4°±0.2°, and 24.3°±0.2°.

[0121] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type C has characteristic peaks at diffraction angles 2θ of 4.5°±0.2°, 5.4°±0.2°, 7.4°±0.2°, 8.9°±0.2°, 11.5°±0.2°, 16.0°±0.2°, 19.8°±0.2°, 22.4°±0.2°, and 24.3°±0.2°.

[0122] The present invention provides a tromethamine salt Type C, wherein the molar ratio of S-indobufen to tromethamine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0123] The tromethamine salt Type C provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 19 As shown.

[0124] When thermogravimetric analysis was performed, tromethamine Type C exhibited a mass loss gradient of approximately 6.33 ± 0.2% when heated to 120 ± 2 ºC, and its TGA was essentially as follows: Figure 20 As shown.

[0125] When performing differential scanning calorimetry (DSC), tromethamine Type C exhibits both endothermic and exothermic peaks when heated to approximately 90±2 ºC, and begins to melt when heated to approximately 155±2 ºC. Its DSC is essentially as follows: Figure 21 As shown.

[0126] The method for preparing tromethamine salt Type C provided by the present invention is characterized in that,

[0127] The tromethamine salt solid is dissolved in an amide solvent and then subjected to gas-liquid diffusion in an atmosphere of ether, ester, or haloalkane solvent until the solid precipitates, yielding tromethamine salt Type C.

[0128] In one embodiment of the present invention, the amide solvent is N,N-dimethylacetamide or N-methylpyrrolidone, the ether solvent is diethyl ether, the ester solvent is ethyl acetate, and the halogenated hydrocarbon solvent is dichloromethane.

[0129] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type D has characteristic peaks at diffraction angles 2θ of 5.4°±0.2°, 7.5°±0.2°, and 17.1°±0.2°.

[0130] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type D has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 4.5°±0.2°, 9.0°±0.2°, and 24.7°±0.2°.

[0131] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine Type D has characteristic peaks at diffraction angles 2θ of 4.5°±0.2°, 9.0°±0.2°, and 24.7°±0.2°.

[0132] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type D has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.5°±0.2°, 19.9°±0.2°, and 22.8°±0.2°.

[0133] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type D has characteristic peaks at diffraction angles 2θ of 18.5°±0.2°, 19.9°±0.2°, and 22.8°±0.2°.

[0134] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine Type D has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.5°±0.2°, 5.4°±0.2°, 7.5°±0.2°, 9.0°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 19.9°±0.2°, 22.8°±0.2°, and 24.7°±0.2°.

[0135] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine Type D has characteristic peaks at diffraction angles 2θ of 4.5°±0.2°, 5.4°±0.2°, 7.5°±0.2°, 9.0°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 19.9°±0.2°, 22.8°±0.2°, and 24.7°±0.2°.

[0136] The present invention provides a tromethamine salt Type D, wherein the molar ratio of S-indobufen to tromethamine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0137] The tromethamine salt Type D provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 22 As shown.

[0138] When thermogravimetric analysis was performed, tromethamine Type D exhibited a mass loss gradient of approximately 6.74 ± 0.2% when heated to 120 ± 2 ºC, and its TGA was essentially as follows: Figure 23 As shown.

[0139] When performing differential scanning calorimetry (DSC), tromethamine Type D exhibits endothermic and exothermic peaks when heated to approximately 103±2 ºC, an exothermic peak when heated to approximately 133±2 ºC, and begins to melt when heated to approximately 154±2 ºC. Its DSC is essentially as follows: Figure 24 As shown.

[0140] The method for preparing tromethamine salt Type D provided by the present invention is characterized in that,

[0141] The solid tromethamine salt was dissolved in tetrahydrofuran at high temperature, and then placed under low temperature conditions to precipitate the solid, yielding tromethamine salt Type D.

[0142] In one embodiment of the present invention, the high temperature is 80 ºC; the low temperature is -20 ºC.

[0143] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type E has characteristic peaks at diffraction angles 2θ of 4.8°±0.2°, 10.2°±0.2°, and 14.4°±0.2°.

[0144] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type E has characteristic peaks at one, two, or three of the diffraction angles 2θ of 9.5°±0.2°, 15.9°±0.2°, and 19.4°±0.2°.

[0145] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type E has characteristic peaks at diffraction angles 2θ of 9.5°±0.2°, 15.9°±0.2°, and 19.4°±0.2°.

[0146] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type E has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.7°±0.2°, 19.8°±0.2°, and 23.8°±0.2°.

[0147] In one embodiment of the present invention, the X-ray powder diffraction pattern of the aminobutadiene triol salt Type E has characteristic peaks at diffraction angles 2θ of 18.7±0.2°, 19.8°±0.2°, and 23.8°±0.2°.

[0148] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine Type E has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.8°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, and 23.8°±0.2°.

[0149] In one embodiment of the present invention, the X-ray powder diffraction pattern of the tromethamine salt Type E has characteristic peaks at diffraction angles 2θ of 4.8°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, and 23.8°±0.2°.

[0150] The present invention provides a tromethamine salt Type E, wherein the molar ratio of S-indobufen to tromethamine is 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0151] The tromethamine salt Type E provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 25 As shown.

[0152] When thermogravimetric analysis was performed, the tromethamine Type E exhibited a mass loss gradient of approximately 1.18 ± 0.2% when heated to 120 ± 2ºC, and its TGA was essentially as follows: Figure 26 As shown.

[0153] When differential scanning calorimetry (DSC) is performed, tromethamine Type E begins to melt when heated to approximately 153 ± 2ºC, and its DSC is essentially as follows: Figure 27 As shown.

[0154] The method for preparing aminobutadiene triol salt Type E provided by the present invention is characterized in that,

[0155] (1) Dissolve the tromethamine salt solid in a mixed solvent system of trifluoroethanol and chloroform, and evaporate the solvent at room temperature until the solid precipitates to obtain tromethamine salt Type E; or

[0156] (2) Dissolve the tromethamine salt solid in trifluoroethanol, and add isopropyl ether dropwise while stirring until the solid precipitates to obtain tromethamine salt Type E.

[0157] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at diffraction angles 2θ of 5.9°±0.2°, 12.7°±0.2°, and 14.3°±0.2°.

[0158] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 17.5°±0.2°, 18.7°±0.2°, and 23.5°±0.2°.

[0159] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at diffraction angles 2θ of 17.5°±0.2°, 18.7°±0.2°, and 23.5°±0.2°.

[0160] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 20.3°±0.2°, 22.7°±0.2°, and 24.3°±0.2°.

[0161] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at diffraction angles 2θ of 20.3°±0.2°, 22.7°±0.2°, and 24.3°±0.2°.

[0162] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.9°±0.2°, 12.7°±0.2°, 14.3°±0.2°, 17.5°±0.2°, 18.7°±0.2°, 20.3°±0.2°, 22.7°±0.2°, 23.5°±0.2°, and 24.3°±0.2°.

[0163] In one embodiment of the present invention, the X-ray powder diffraction pattern of the urea eutectic Type A has characteristic peaks at diffraction angles 2θ of 5.9°±0.2°, 12.7°±0.2°, 14.3°±0.2°, 17.5°±0.2°, 18.7°±0.2°, 20.3°±0.2°, 22.7°±0.2°, 23.5°±0.2°, and 24.3°±0.2°.

[0164] The urea eutectic Type A provided by the present invention has a molar ratio of S-indobufen to urea of ​​0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0165] The urea eutectic Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 28 As shown.

[0166] When thermogravimetric analysis was performed, urea eutectic Type A, when heated to 120 ± 2ºC, exhibited a mass loss gradient of approximately 0.26 ± 0.2%, and its TGA was essentially as follows: Figure 29 As shown.

[0167] When differential scanning calorimetry (DSC) is performed, urea eutectic Type A begins to melt when heated to approximately 148 ± 2ºC, and its DSC is essentially as follows: Figure 30 As shown.

[0168] The method for preparing urea eutectic Type A provided by the present invention is characterized in that,

[0169] The free state of compound GP-046 and urea were added to an acetone solvent system and stirred at room temperature until urea eutectic Type A was obtained.

[0170] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at diffraction angles 2θ of 12.2°±0.2°, 14.5°±0.2°, and 25.6°±0.2°.

[0171] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.2°±0.2°, 24.1°±0.2°, and 24.6°±0.2°.

[0172] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at diffraction angles 2θ of 15.2°±0.2°, 24.1°±0.2°, and 24.6°±0.2°.

[0173] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at one, two, or three of the following diffraction angles 2θ: 4.1°±0.2°, 20.4°±0.2°, and 20.9°±0.2°.

[0174] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at diffraction angles 2θ of 4.1°±0.2°, 20.4°±0.2°, and 20.9°±0.2°.

[0175] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.1°±0.2°, 12.2°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 24.1°±0.2°, 24.6°±0.2°, and 25.6°±0.2°.

[0176] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type A has characteristic peaks at diffraction angles 2θ of 4.1°±0.2°, 12.2°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 24.1°±0.2°, 24.6°±0.2°, and 25.6°±0.2°.

[0177] The potassium salt Type A provided by the present invention has a molar ratio of S-indobufen to potassium ions of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0178] The potassium salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 31 As shown.

[0179] When thermogravimetric analysis was performed, potassium salt Type A, when heated to 120 ± 2ºC, exhibited a mass loss gradient of approximately 4.76 ± 0.2%, and its TGA was essentially as follows: Figure 32 As shown.

[0180] When performing differential scanning calorimetry (DSC), potassium salt Type A exhibits an endothermic peak when heated to approximately 160±2 ºC, and endothermic and exothermic peaks when heated to approximately 199±2 and 202±2 ºC, respectively. It begins to melt when heated to approximately 213±2 ºC. Its DSC is essentially as follows: Figure 33 As shown.

[0181] The method for preparing potassium salt Type A provided by the present invention is characterized in that,

[0182] The free state of compound GP-046 was added to an acetone solvent system with potassium hydroxide and stirred at room temperature until potassium salt Type A was obtained.

[0183] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at diffraction angles 2θ of 5.2°±0.2°, 12.6°±0.2°, and 24.3°±0.2°.

[0184] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 6.5°±0.2°, 14.4°±0.2°, and 22.6°±0.2°.

[0185] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at diffraction angles 2θ of 6.5°±0.2°, 14.4°±0.2°, and 22.6°±0.2°.

[0186] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 4.2°±0.2°, 15.1°±0.2°, and 25.9°±0.2°.

[0187] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at diffraction angles 2θ of 4.2°±0.2°, 15.1°±0.2°, and 25.9°±0.2°.

[0188] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.2°±0.2°, 5.2°±0.2°, 6.5°±0.2°, 12.6°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 22.6°±0.2°, 24.3°±0.2°, and 25.9°±0.2°.

[0189] In one embodiment of the present invention, the X-ray powder diffraction pattern of the potassium salt Type B has characteristic peaks at diffraction angles 2θ of 4.2°±0.2°, 5.2°±0.2°, 6.5°±0.2°, 12.6°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 22.6°±0.2°, 24.3°±0.2°, and 25.9°±0.2°.

[0190] The potassium salt Type B provided by the present invention has a molar ratio of S-indobufen to potassium ions of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0191] The potassium salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 34 As shown.

[0192] The method for preparing potassium salt Type B provided by this invention is characterized in that,

[0193] Potassium salt Type A solid was purged with nitrogen and then heated to 160 ºC to obtain potassium salt Type B.

[0194] In one embodiment of the invention, the heating rate is 10 ºC / min.

[0195] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at diffraction angles 2θ of 6.3°±0.2°, 9.6°±0.2°, and 24.3°±0.2°.

[0196] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 6.6°±0.2°, 9.2°±0.2°, and 12.7°±0.2°.

[0197] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at diffraction angles 2θ of 6.6°±0.2°, 9.2°±0.2°, and 12.7°±0.2°.

[0198] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 5.3°±0.2°, 12.0°±0.2°, and 25.6°±0.2°.

[0199] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 12.0°±0.2°, and 25.6°±0.2°.

[0200] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.3°±0.2°, 6.3°±0.2°, 6.6°±0.2°, 9.2°±0.2°, 9.6°±0.2°, 12.0°±0.2°, 12.7°±0.2°, 24.3°±0.2°, and 25.6°±0.2°.

[0201] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type A has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 6.3°±0.2°, 6.6°±0.2°, 9.2°±0.2°, 9.6°±0.2°, 12.0°±0.2°, 12.7°±0.2°, 24.3°±0.2°, and 25.6°±0.2°.

[0202] The calcium salt Type A provided by the present invention has a molar ratio of S-indobufen to calcium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0203] The calcium salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 35 As shown.

[0204] When thermogravimetric analysis was performed, calcium salt Type A, when heated to 150 ± 2ºC, exhibited a mass loss gradient of approximately 4.73 ± 0.2%, and its TGA was essentially as follows: Figure 36 As shown.

[0205] When differential scanning calorimetry (DSC) was performed, calcium salt Type A exhibited an endothermic peak when heated to approximately 150 ±2ºC, and endothermic and exothermic peaks when heated to approximately 187±2 and 220±2 ºC, respectively. Its DSC values ​​were essentially as follows: Figure 37 As shown.

[0206] The method for preparing calcium salt Type A provided by the present invention is characterized in that,

[0207] The free state of compound GP-046 and calcium hydroxide were added to an ethanol solvent system and stirred at room temperature until the calcium salt Type A was obtained.

[0208] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type B has characteristic peaks at diffraction angles 2θ of 5.8°±0.2°, 18.1°±0.2°, and 23.3°±0.2°.

[0209] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type B has characteristic peaks at one or two of the diffraction angles 2θ of 10.6°±0.2° and 20.0°±0.2°.

[0210] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type B has characteristic peaks at diffraction angles 2θ of 10.6°±0.2° and 20.0°±0.2°.

[0211] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type B has characteristic peaks at any four or five locations within the diffraction angle 2θ of 5.8°±0.2°, 10.6°±0.2°, 18.1°±0.2°, 20.0°±0.2°, and 23.3°±0.2°.

[0212] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type B has characteristic peaks at diffraction angles 2θ of 5.8°±0.2°, 10.6°±0.2°, 18.1°±0.2°, 20.0°±0.2°, and 23.3°±0.2°.

[0213] The calcium salt Type B provided by the present invention has a molar ratio of S-indobufen to calcium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0214] The calcium salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 38 As shown.

[0215] When thermogravimetric analysis was performed, calcium salt Type B exhibited a mass loss gradient of approximately 2.69 ± 0.2% when heated to 160 ± 2 ºC, and approximately 4.36 ± 0.2% when heated further to 300 ± 2 ºC. Its TGA was essentially as follows: Figure 39 As shown.

[0216] When performing differential scanning calorimetry (DSC), calcium salt Type B exhibits an endothermic peak when heated to approximately 200±2ºC, and its DSC is essentially as follows: Figure 40 As shown.

[0217] The method for preparing calcium salt Type B provided by the present invention is characterized in that,

[0218] The free state of compound GP-046 and calcium hydroxide were added to an acetonitrile solvent system and stirred at room temperature until the calcium salt Type B was obtained.

[0219] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at diffraction angles 2θ of 11.6°±0.2°, 19.0°±0.2°, and 24.9°±0.2°.

[0220] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 14.3°±0.2°, 23.3°±0.2°, and 26.5°±0.2°.

[0221] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at diffraction angles 2θ of 14.3°±0.2°, 23.3°±0.2°, and 26.5°±0.2°.

[0222] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 21.1°±0.2°, 25.8°±0.2°, and 27.4°±0.2°.

[0223] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at diffraction angles 2θ of 21.1°±0.2°, 25.8°±0.2°, and 27.4°±0.2°.

[0224] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 11.6°±0.2°, 14.3°±0.2°, 19.0°±0.2°, 21.1°±0.2°, 23.3°±0.2°, 24.9°±0.2°, 25.8°±0.2°, 26.5°±0.2°, and 27.4°±0.2°.

[0225] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type C has characteristic peaks at diffraction angles 2θ of 11.6°±0.2°, 14.3°±0.2°, 19.0°±0.2°, 21.1°±0.2°, 23.3°±0.2°, 24.9°±0.2°, 25.8°±0.2°, 26.5°±0.2°, and 27.4°±0.2°.

[0226] The calcium salt Type C provided by the present invention has a molar ratio of S-indobufen to calcium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0227] The calcium salt Type C provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 41 As shown.

[0228] The method for preparing calcium salt Type C provided by the present invention is characterized in that,

[0229] The free state of compound GP-046 and calcium hydroxide were added to a tetrahydrofuran / pure water mixed solvent system and stirred at room temperature until the calcium salt Type C was obtained.

[0230] In one embodiment of the present invention, the volume ratio of tetrahydrofuran to pure water is 19:1.

[0231] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type D has characteristic peaks at diffraction angles 2θ of 5.7°±0.2°, 7.0°±0.2°, and 8.3°±0.2°.

[0232] The calcium salt Type D provided by the present invention has a molar ratio of S-indobufen to calcium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0233] The calcium salt Type D provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 42 As shown.

[0234] When thermogravimetric analysis was performed, the calcium salt Type D exhibited a mass loss gradient of approximately 1.54 ± 0.2% when heated to 260 ± 2ºC, and its TGA was essentially as follows: Figure 43 As shown.

[0235] When differential scanning calorimetry (DSC) is performed, calcium salt Type D begins to melt when heated to approximately 302 ± 2ºC, and its DSC is essentially as follows: Figure 44 As shown.

[0236] The method for preparing calcium salt Type D provided by this invention is characterized in that,

[0237] Calcium salt Type A solid was heated to 240 ºC to obtain calcium salt Type D.

[0238] In one embodiment of the invention, the heating rate is 10 ºC / min.

[0239] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at diffraction angles 2θ of 5.9°±0.2°, 8.9°±0.2°, and 10.5°±0.2°.

[0240] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 5.3°±0.2°, 6.8°±0.2°, and 26.5°±0.2°.

[0241] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 6.8°±0.2°, and 26.5°±0.2°.

[0242] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at one, two, or three of the diffraction angles 2θ of 11.8°±0.2°, 17.0°±0.2°, and 17.9°±0.2°.

[0243] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at diffraction angles 2θ of 11.8°±0.2°, 17.0°±0.2°, and 17.9°±0.2°.

[0244] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.3°±0.2°, 5.9°±0.2°, 6.8°±0.2°, 8.9°±0.2°, 10.5°±0.2°, 11.8°±0.2°, 17.0°±0.2°, 17.9°±0.2°, and 26.5°±0.2°.

[0245] In one embodiment of the present invention, the X-ray powder diffraction pattern of the calcium salt Type E has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 5.9°±0.2°, 6.8°±0.2°, 8.9°±0.2°, 10.5°±0.2°, 11.8°±0.2°, 17.0°±0.2°, 17.9°±0.2°, and 26.5°±0.2°.

[0246] The calcium salt Type E provided by the present invention has a molar ratio of S-indobufen to calcium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0247] The calcium salt Type E provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 45 As shown.

[0248] When thermogravimetric analysis was performed, the calcium salt Type E exhibited a mass loss gradient of approximately 3.17 ± 0.2% when heated to 130 ± 2 ºC, and approximately 3.49 ± 0.2% when heated further to 260 ± 2 ºC. Its TGA was essentially as follows: Figure 46 As shown.

[0249] When performing differential scanning calorimetry (DSC), calcium salt Type E exhibits an endothermic peak when heated to approximately 148±2 ºC, another endothermic peak when heated to approximately 223±2 ºC, and both endothermic and exothermic peaks when heated to approximately 254±2 ºC. Its DSC essentially reflects this. Figure 47 As shown.

[0250] The method for preparing calcium salt Type E provided by the present invention is characterized in that,

[0251] The free state of compound GP-046 was added to an ethanol solvent system with calcium hydroxide, and then stirred at room temperature and 50 °C until the calcium salt Type E was obtained.

[0252] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type A has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 6.6°±0.2°, and 13.1°±0.2°.

[0253] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 9.8°±0.2°, 24.4°±0.2°, and 24.8°±0.2°.

[0254] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type A has characteristic peaks at diffraction angles 2θ of 9.8°±0.2°, 24.4°±0.2°, and 24.8°±0.2°.

[0255] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type A has characteristic peaks at any 4, 5, or 6 locations within the diffraction angle 2θ of 5.1°±0.2°, 6.6°±0.2°, 9.8°±0.2°, 13.1°±0.2°, 24.4°±0.2°, and 24.8°±0.2°.

[0256] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type A has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 6.6°±0.2°, 9.8°±0.2°, 13.1°±0.2°, 24.4°±0.2°, and 24.8°±0.2°.

[0257] The magnesium salt Type A provided by the present invention has a molar ratio of S-indobufen to magnesium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0258] The magnesium salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 48 As shown.

[0259] When thermogravimetric analysis was performed, magnesium salt Type A, when heated to 200±2 ºC, exhibited a mass loss gradient of approximately 8.83±0.2%, and its TGA was essentially as follows: Figure 49 As shown.

[0260] When performing differential scanning calorimetry (DSC), magnesium salt Type A exhibits an endothermic peak when heated to approximately 187±2 ºC, followed by both endothermic and exothermic peaks when heated to approximately 200±2 ºC, and begins to melt when heated to approximately 247±2 ºC. Its DSC is essentially as follows: Figure 50 As shown.

[0261] The method for preparing magnesium salt Type A provided by the present invention is characterized in that,

[0262] The free state of compound GP-046 and magnesium hydroxide were added to an ethanol solvent system and stirred at room temperature until magnesium salt Type A was obtained.

[0263] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at diffraction angles 2θ of 5.8°±0.2°, 7.2°±0.2°, and 10.2°±0.2°.

[0264] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 6.8°±0.2°, 12.5°±0.2°, and 25.1°±0.2°.

[0265] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at diffraction angles 2θ of 6.8°±0.2°, 12.5°±0.2°, and 25.1°±0.2°.

[0266] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 4.8°±0.2°, 23.4°±0.2°, and 26.4°±0.2°.

[0267] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at diffraction angles 2θ of 4.8°±0.2°, 23.4°±0.2°, and 26.4°±0.2°.

[0268] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.8°±0.2°, 5.8°±0.2°, 6.8°±0.2°, 7.2°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 23.4°±0.2°, 25.1°±0.2°, and 26.4°±0.2°.

[0269] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type B has characteristic peaks at diffraction angles 2θ of 4.8°±0.2°, 5.8°±0.2°, 6.8°±0.2°, 7.2°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 23.4°±0.2°, 25.1°±0.2°, and 26.4°±0.2°.

[0270] The magnesium salt Type B provided by the present invention has a molar ratio of S-indobufen to magnesium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0271] The magnesium salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 51 As shown.

[0272] The method for preparing magnesium salt Type B provided by the present invention is characterized in that,

[0273] The free state of compound GP-046 and magnesium hydroxide were added to a tetrahydrofuran / pure water mixed solvent system and stirred at room temperature until magnesium salt Type B was obtained.

[0274] In one embodiment of the present invention, the volume ratio of tetrahydrofuran to pure water is 19:1.

[0275] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type C has characteristic peaks at diffraction angles 2θ of 4.9°±0.2°, 7.0°±0.2°, and 9.8°±0.2°.

[0276] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type C has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 14.1°±0.2° and 26.6°±0.2°.

[0277] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type C has characteristic peaks at diffraction angles 2θ of 14.1°±0.2° and 26.6°±0.2°.

[0278] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type C has characteristic peaks at any four or five locations within the diffraction angle 2θ of 4.9°±0.2°, 7.0°±0.2°, 9.8°±0.2°, 14.1°±0.2°, and 26.6°±0.2°.

[0279] In one embodiment of the present invention, the X-ray powder diffraction pattern of the magnesium salt Type C has characteristic peaks at diffraction angles 2θ of 4.9°±0.2°, 7.0°±0.2°, 9.8°±0.2°, 14.1°±0.2°, and 26.6°±0.2°.

[0280] The magnesium salt Type C provided by the present invention has a molar ratio of S-indobufen to magnesium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0281] The magnesium salt Type C provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 52 As shown.

[0282] The method for preparing magnesium salt Type C provided by the present invention is characterized in that,

[0283] Magnesium salt Type A solid was heated to 220 ºC to obtain magnesium salt Type C.

[0284] In one embodiment of the invention, the heating rate is 10 ºC / min.

[0285] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at diffraction angles 2θ of 4.2°±0.2°, 8.4°±0.2°, and 12.6°±0.2°.

[0286] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.3°±0.2°, 19.8°±0.2°, and 24.3°±0.2°.

[0287] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 19.8°±0.2°, and 24.3°±0.2°.

[0288] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 14.6°±0.2°, 16.8°±0.2°, and 25.4°±0.2°.

[0289] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at diffraction angles 2θ of 14.6°±0.2°, 16.8°±0.2°, and 25.4°±0.2°.

[0290] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.2°±0.2°, 8.4°±0.2°, 12.6°±0.2°, 14.6°±0.2°, 15.3°±0.2°, 16.8°±0.2°, 19.8°±0.2°, 24.3°±0.2°, and 25.4°±0.2°.

[0291] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type A has characteristic peaks at diffraction angles 2θ of 4.2°±0.2°, 8.4°±0.2°, 12.6°±0.2°, 14.6°±0.2°, 15.3°±0.2°, 16.8°±0.2°, 19.8°±0.2°, 24.3°±0.2°, and 25.4°±0.2°.

[0292] The ammonium salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 53 As shown.

[0293] The method for preparing ammonium salt Type A provided by the present invention is characterized in that,

[0294] The free state of compound GP-046 was added to a tetrahydrofuran / pure water mixed solvent system with ammonia water, and stirred at room temperature until ammonium salt Type A was obtained.

[0295] In one embodiment of the present invention, the volume ratio of tetrahydrofuran to pure water is 19:1.

[0296] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at diffraction angles 2θ of 11.7°±0.2°, 15.7°±0.2°, and 23.6°±0.2°.

[0297] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.8°±0.2°, 22.1°±0.2°, and 25.1°±0.2°.

[0298] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at diffraction angles 2θ of 7.8°±0.2°, 22.1°±0.2°, and 25.1°±0.2°.

[0299] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.4°±0.2°, 12.6°±0.2°, and 20.8°±0.2°.

[0300] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 12.6°±0.2°, and 20.8°±0.2°.

[0301] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 7.8°±0.2°, 8.4°±0.2°, 11.7°±0.2°, 12.6°±0.2°, 15.7°±0.2°, 20.8°±0.2°, 22.1°±0.2°, 23.6°±0.2°, and 25.1°±0.2°.

[0302] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type B has characteristic peaks at diffraction angles 2θ of 7.8°±0.2°, 8.4°±0.2°, 11.7°±0.2°, 12.6°±0.2°, 15.7°±0.2°, 20.8°±0.2°, 22.1°±0.2°, 23.6°±0.2°, and 25.1°±0.2°.

[0303] The ammonium salt Type B provided by the present invention has a molar ratio of S-indobufen to ammonium ions of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0304] The ammonium salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 54 As shown.

[0305] When thermogravimetric analysis was performed, ammonium salt Type B exhibited a mass loss gradient of approximately 6.68 ± 0.2% when heated to 150 ± 2 ºC, and its TGA was essentially as follows: Figure 55 As shown.

[0306] When performing differential scanning calorimetry (DSC), ammonium salt Type B exhibits an endothermic peak when heated to approximately 139±2 ºC, and begins to melt upon further heating to approximately 197±2 ºC. Its DSC is essentially as follows: Figure 56 As shown.

[0307] The method for preparing ammonium salt Type B provided by the present invention is characterized in that,

[0308] The free state of compound GP-046 was added to an acetone solvent system with ammonia and stirred at room temperature until the ammonium salt Type B was obtained.

[0309] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 14.8°±0.2°, and 19.6°±0.2°.

[0310] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 12.7°±0.2°, 24.1°±0.2°, and 26.6°±0.2°.

[0311] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at diffraction angles 2θ of 12.7°±0.2°, 24.1°±0.2°, and 26.6°±0.2°.

[0312] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.8°±0.2°, 22.7°±0.2°, and 26.0°±0.2°.

[0313] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at diffraction angles 2θ of 18.8°±0.2°, 22.7°±0.2°, and 26.0°±0.2°.

[0314] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 8.4°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 18.8°±0.2°, 19.6°±0.2°, 22.7°±0.2°, 24.1°±0.2°, 26.0°±0.2°, and 26.6°±0.2°.

[0315] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type C has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 18.8°±0.2°, 19.6°±0.2°, 22.7°±0.2°, 24.1°±0.2°, 26.0°±0.2°, and 26.6°±0.2°.

[0316] The ammonium salt Type C provided by the present invention has a molar ratio of S-indobufen to ammonium ions of 1.5 to 1.7, preferably 1.6.

[0317] The ammonium salt Type C provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 57 As shown.

[0318] When thermogravimetric analysis was performed, the ammonium salt Type C exhibited a mass loss gradient of approximately 8.60 ± 0.2% when heated to 150 ± 2ºC, and its TGA was essentially as follows: Figure 58 As shown.

[0319] When performing differential scanning calorimetry (DSC), the ammonium salt Type C exhibits an endothermic peak when heated to approximately 137±2 ºC, and begins to melt upon further heating to approximately 198±2 ºC. Its DSC is essentially as follows: Figure 59 As shown.

[0320] The method for preparing ammonium salt Type C provided by the present invention is characterized in that,

[0321] The free state of compound GP-046 was added to an acetonitrile solvent system with ammonia and stirred at room temperature until the ammonium salt Type C was obtained.

[0322] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 8.8°±0.2°, and 19.6°±0.2°.

[0323] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at one, two, or three locations within the diffraction angle 2θ of 15.1°±0.2°, 18.9°±0.2°, and 24.6°±0.2°.

[0324] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at diffraction angles 2θ of 15.1°±0.2°, 18.9°±0.2°, and 24.6°±0.2°.

[0325] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 4.4°±0.2°, 13.3°±0.2°, and 25.6°±0.2°.

[0326] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at diffraction angles 2θ of 4.4°±0.2°, 13.3°±0.2°, and 25.6°±0.2°.

[0327] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.4°±0.2°, 5.1°±0.2°, 8.8°±0.2°, 13.3°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 24.6°±0.2°, and 25.6°±0.2°.

[0328] In one embodiment of the present invention, the X-ray powder diffraction pattern of the ammonium salt Type D has characteristic peaks at diffraction angles 2θ of 4.4°±0.2°, 5.1°±0.2°, 8.8°±0.2°, 13.3°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 24.6°±0.2°, and 25.6°±0.2°.

[0329] The ammonium salt Type D provided by the present invention has a molar ratio of S-indobufen to ammonium ions of 4 to 6, preferably 5.

[0330] The ammonium salt Type D provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 60 As shown.

[0331] When thermogravimetric analysis was performed, the ammonium salt Type D exhibited a mass loss gradient of approximately 3.27 ± 0.2% when heated to 150 ± 2 ºC, and its TGA was essentially as follows: Figure 61 As shown.

[0332] When performing differential scanning calorimetry (DSC), the ammonium salt Type D exhibits an endothermic peak when heated to approximately 132 ± 2 ºC, and begins to melt upon further heating to approximately 199 ± 2 ºC. Its DSC is essentially as follows: Figure 62 As shown.

[0333] The method for preparing ammonium salt Type D provided by this invention is characterized in that,

[0334] The solid ammonium salt Type A was dried under vacuum at 50 ºC until ammonium salt Type D was obtained.

[0335] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at diffraction angles 2θ of 12.7°±0.2°, 16.4°±0.2°, and 19.3°±0.2°.

[0336] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 11.4°±0.2°, 15.2°±0.2°, and 23.4°±0.2°.

[0337] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at diffraction angles 2θ of 11.4°±0.2°, 15.2°±0.2°, and 23.4°±0.2°.

[0338] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.7°±0.2°, 20.2°±0.2°, and 23.2°±0.2°.

[0339] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at diffraction angles 2θ of 15.7°±0.2°, 20.2°±0.2°, and 23.2°±0.2°.

[0340] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 11.4°±0.2°, 12.7°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.4°±0.2°, 19.3°±0.2°, 20.2°±0.2°, 23.2°±0.2°, and 23.4°±0.2°.

[0341] In one embodiment of the present invention, the X-ray powder diffraction pattern of the choline salt Type A has characteristic peaks at diffraction angles 2θ of 11.4°±0.2°, 12.7°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.4°±0.2°, 19.3°±0.2°, 20.2°±0.2°, 23.2°±0.2°, and 23.4°±0.2°.

[0342] The choline salt Type A provided by the present invention has a molar ratio of S-indobufen to choline of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0343] The choline salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 63 As shown.

[0344] When thermogravimetric analysis was performed, choline salt Type A, when heated to 120±2 ºC, exhibited a mass loss gradient of approximately 4.17±0.2%, and its TGA was essentially as follows: Figure 64 As shown.

[0345] When performing differential scanning calorimetry (DSC), choline salt Type A exhibits an endothermic peak when heated to approximately 135 ± 2 ºC, and begins to melt upon further heating to approximately 214 ± 2 ºC. Its DSC essentially reflects this. Figure 65 As shown.

[0346] The method for preparing choline salt Type A provided by the present invention is characterized in that,

[0347] The free state of compound GP-046 and choline were added to an acetone solvent system and stirred overnight at room temperature. Then, a 50-5ºC cycling test was conducted until choline salt Type A was obtained.

[0348] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at diffraction angles 2θ of 5.5°±0.2°, 9.1°±0.2°, and 10.1°±0.2°.

[0349] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 5.1°±0.2°, 21.3°±0.2°, and 25.9°±0.2°.

[0350] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 21.3°±0.2°, and 25.9°±0.2°.

[0351] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 19.8°±0.2°, 22.2°±0.2°, and 23.8°±0.2°.

[0352] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at diffraction angles 2θ of 19.8°±0.2°, 22.2°±0.2°, and 23.8°±0.2°.

[0353] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.1°±0.2°, 5.5°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 19.8°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 23.8°±0.2°, and 25.9°±0.2°.

[0354] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type A has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 5.5°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 19.8°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 23.8°±0.2°, and 25.9°±0.2°.

[0355] The lysine salt Type A provided by the present invention has a molar ratio of S-indobufen to lysine of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0356] The lysine salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 66 As shown.

[0357] When thermogravimetric analysis was performed, lysine salt Type A, when heated to 150 ± 2ºC, exhibited a mass loss gradient of approximately 2.86 ± 0.2%, and its TGA was essentially as follows: Figure 67 As shown.

[0358] When differential scanning calorimetry (DSC) was performed, lysine salt Type A exhibited both endothermic and exothermic peaks when heated to approximately 150 ± 2 ºC, and began to melt upon further heating to approximately 205 ± 2 ºC. Its DSC results were essentially as follows: Figure 68 As shown.

[0359] The method for preparing lysine salt Type A provided by the present invention is characterized in that,

[0360] The free state of compound GP-046 and lysine were added to an ethanol solvent system and stirred at room temperature until lysine salt Type A was obtained.

[0361] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type B has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 6.1°±0.2°, and 19.4°±0.2°.

[0362] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type B has characteristic peaks at one, two, three, or four locations within the diffraction angle 2θ of 7.0°±0.2°, 12.1°±0.2°, 21.2°±0.2°, and 24.4°±0.2°.

[0363] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type B has characteristic peaks at diffraction angles 2θ of 7.0°±0.2°, 12.1°±0.2°, 21.2°±0.2°, and 24.4°±0.2°.

[0364] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type B has characteristic peaks at any 4, 5, 6, or 7 locations with diffraction angles 2θ of 5.1°±0.2°, 6.1°±0.2°, 7.0°±0.2°, 12.1°±0.2°, 19.4°±0.2°, 21.2°±0.2°, and 24.4°±0.2°.

[0365] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type B has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 6.1°±0.2°, 7.0°±0.2°, 12.1°±0.2°, 19.4°±0.2°, 21.2°±0.2°, and 24.4°±0.2°.

[0366] The lysine salt Type B provided by the present invention has a molar ratio of S-indobufen to lysine of 0.8 to 1.4, preferably 0.9 to 1.3, and even more preferably 1 to 1.25.

[0367] The lysine salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 69 As shown.

[0368] When thermogravimetric analysis was performed, lysine Type B, when heated to 150±2 ºC, exhibited a mass loss gradient of approximately 7.69±0.2%, and its TGA was essentially as follows: Figure 70 As shown.

[0369] When performing differential scanning calorimetry (DSC), lysine Type B exhibits an endothermic peak when heated to approximately 94 ºC, an exothermic peak when heated to approximately 184±2 ºC, and begins to melt when heated to approximately 210±2 ºC. Its DSC essentially reflects this. Figure 71 As shown.

[0370] The method for preparing lysine salt Type B provided by the present invention is characterized in that,

[0371] The free state of compound GP-046 and lysine were added to a tetrahydrofuran / pure water mixed solvent system and stirred at room temperature until lysine salt Type B was obtained.

[0372] In one embodiment of the present invention, the volume ratio of tetrahydrofuran to pure water is 19:1.

[0373] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at diffraction angles 2θ of 10.0°±0.2°, 16.8°±0.2°, and 23.6°±0.2°.

[0374] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 12.1°±0.2°, 20.1°±0.2°, and 24.9°±0.2°.

[0375] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at diffraction angles 2θ of 12.1°±0.2°, 20.1°±0.2°, and 24.9°±0.2°.

[0376] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.2°±0.2°, 16.1°±0.2°, and 18.7°±0.2°.

[0377] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at diffraction angles 2θ of 6.2°±0.2°, 16.1°±0.2°, and 18.7°±0.2°.

[0378] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 6.2°±0.2°, 10.0°±0.2°, 12.1°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 23.6°±0.2°, and 24.9°±0.2°.

[0379] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type C has characteristic peaks at diffraction angles 2θ of 6.2°±0.2°, 10.0°±0.2°, 12.1°±0.2°, 16.1°±0.2°, 16.8°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 23.6°±0.2°, and 24.9°±0.2°.

[0380] The lysine salt Type C provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 72 As shown.

[0381] The method for preparing lysine salt Type C provided by this invention is characterized in that,

[0382] Lysine salt Type B solid was heated to 150 ºC to obtain lysine salt Type C.

[0383] In one embodiment of the invention, the heating rate is 10 ºC / min.

[0384] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at diffraction angles 2θ of 6.9°±0.2°, 10.3°±0.2°, and 21.8°±0.2°.

[0385] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at one, two, or three of the diffraction angles 2θ of 13.7°±0.2°, 19.2°±0.2°, and 24.7°±0.2°.

[0386] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at diffraction angles 2θ of 13.7°±0.2°, 19.2°±0.2°, and 24.7°±0.2°.

[0387] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 5.0°±0.2°, 17.2°±0.2°, and 20.4°±0.2°.

[0388] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at diffraction angles 2θ of 5.0°±0.2°, 17.2°±0.2°, and 20.4°±0.2°.

[0389] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.0°±0.2°, 6.9°±0.2°, 10.3°±0.2°, 13.7°±0.2°, 17.2°±0.2°, 19.2°±0.2°, 20.4°±0.2°, 21.8°±0.2°, and 24.7°±0.2°.

[0390] In one embodiment of the present invention, the X-ray powder diffraction pattern of the lysine salt Type D has characteristic peaks at diffraction angles 2θ of 5.0°±0.2°, 6.9°±0.2°, 10.3°±0.2°, 13.7°±0.2°, 17.2°±0.2°, 19.2°±0.2°, 20.4°±0.2°, 21.8°±0.2°, and 24.7°±0.2°.

[0391] The lysine salt Type D provided by the present invention has a molar ratio of S-indobufen to lysine of 0.8 to 1.4, preferably 0.9 to 1.3, and even more preferably 1 to 1.25.

[0392] The lysine salt Type D provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 73 As shown.

[0393] When thermogravimetric analysis was performed, lysine salt Type D exhibited a mass loss gradient of approximately 4.11 ± 0.2% when heated to 150 ± 2 ºC, and its TGA was essentially as follows: Figure 74 As shown.

[0394] When performing differential scanning calorimetry (DSC), lysine Type D begins to melt when heated to approximately 205 ± 2 ºC, and its DSC is essentially as follows: Figure 75 As shown.

[0395] The method for preparing lysine salt Type D provided by this invention is characterized in that,

[0396] The free state of compound GP-046 and lysine were added to a tetrahydrofuran / pure water mixed solvent system and stirred at room temperature until a solid precipitated. The solid was dried under vacuum at 50 °C. The resulting solid was then heated to 175 °C to obtain lysine salt Type D.

[0397] In one embodiment of the present invention, the volume ratio of tetrahydrofuran to pure water is 19:1.

[0398] In one embodiment of the present invention, the vacuum drying time at 50 ºC is approximately 3.5 hours.

[0399] In one embodiment of the invention, the heating rate is 10 ºC / min.

[0400] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at diffraction angles 2θ of 10.1°±0.2°, 12.2°±0.2°, and 19.4°±0.2°.

[0401] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 14.8°±0.2°, 17.8°±0.2°, and 25.9°±0.2°.

[0402] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at diffraction angles 2θ of 14.8°±0.2°, 17.8°±0.2°, and 25.9°±0.2°.

[0403] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 19.9°±0.2°, 20.4°±0.2°, and 28.8°±0.2°.

[0404] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at diffraction angles 2θ of 19.9°±0.2°, 20.4°±0.2°, and 28.8°±0.2°.

[0405] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 10.1°±0.2°, 12.2°±0.2°, 14.8°±0.2°, 17.8°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 25.9°±0.2°, and 28.8°±0.2°.

[0406] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type A has characteristic peaks at diffraction angles 2θ of 10.1°±0.2°, 12.2°±0.2°, 14.8°±0.2°, 17.8°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 25.9°±0.2°, and 28.8°±0.2°.

[0407] The betaine salt Type A provided by the present invention has a molar ratio of S-indobufen to betaine of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0408] The betaine salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 76 As shown.

[0409] The method for preparing betaine salt Type A provided by the present invention is characterized in that,

[0410] The free state of compound GP-046 and betaine were added to an acetone solvent system and stirred at room temperature until betaine salt Type A was obtained.

[0411] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at diffraction angles 2θ of 6.6°±0.2°, 16.4°±0.2°, and 22.7°±0.2°.

[0412] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 7.1°±0.2°, 9.0°±0.2°, and 11.5°±0.2°.

[0413] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at diffraction angles 2θ of 7.1°±0.2°, 9.0°±0.2°, and 11.5°±0.2°.

[0414] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 10.0°±0.2°, 15.4°±0.2°, and 23.6°±0.2°.

[0415] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at diffraction angles 2θ of 10.0°±0.2°, 15.4°±0.2°, and 23.6°±0.2°.

[0416] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 6.6°±0.2°, 7.1°±0.2°, 9.0°±0.2°, 10.0°±0.2°, 11.5°±0.2°, 15.4°±0.2°, 16.4°±0.2°, 22.7°±0.2°, and 23.6°±0.2°.

[0417] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type B has characteristic peaks at diffraction angles 2θ of 6.6°±0.2°, 7.1°±0.2°, 9.0°±0.2°, 10.0°±0.2°, 11.5°±0.2°, 15.4°±0.2°, 16.4°±0.2°, 22.7°±0.2°, and 23.6°±0.2°.

[0418] The betaine salt Type B provided by the present invention has a molar ratio of S-indobufen to betaine of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0419] The betaine salt Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 77 As shown.

[0420] The method for preparing betaine salt Type B provided by this invention is characterized in that,

[0421] The free state of compound GP-046 and betaine were added to an acetonitrile solvent system and stirred at room temperature until betaine salt Type B was obtained.

[0422] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at diffraction angles 2θ of 6.8°±0.2°, 11.1°±0.2°, and 19.4°±0.2°.

[0423] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 4.7°±0.2°, 14.9°±0.2°, and 25.0°±0.2°.

[0424] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at diffraction angles 2θ of 4.7°±0.2°, 14.9°±0.2°, and 25.0°±0.2°.

[0425] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at one, two, or three of the diffraction angles 2θ of 17.0°±0.2°, 22.1°±0.2°, and 26.1°±0.2°.

[0426] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at diffraction angles 2θ of 17.0°±0.2°, 22.1°±0.2°, and 26.1°±0.2°.

[0427] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.7°±0.2°, 6.8°±0.2°, 11.1°±0.2°, 14.9°±0.2°, 17.0°±0.2°, 19.4°±0.2°, 22.1°±0.2°, 25.0°±0.2°, and 26.1°±0.2°.

[0428] In one embodiment of the present invention, the X-ray powder diffraction pattern of the betaine salt Type C has characteristic peaks at diffraction angles 2θ of 4.7°±0.2°, 6.8°±0.2°, 11.1°±0.2°, 14.9°±0.2°, 17.0°±0.2°, 19.4°±0.2°, 22.1°±0.2°, 25.0°±0.2°, and 26.1°±0.2°.

[0429] The betaine salt Type C provided by the present invention has a molar ratio of S-indobufen to betaine of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0430] The betaine salt Type C provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 78 As shown.

[0431] When thermogravimetric analysis was performed, betaine Type C exhibited a mass loss gradient of approximately 1.93 ± 0.2% when heated to 120 ± 2 ºC, and its TGA was essentially as follows: Figure 79 As shown.

[0432] When differential scanning calorimetry (DSC) was performed, betaine salt Type C began to melt when heated to approximately 147 ± 2ºC, and its DSC was essentially as follows: Figure 80 As shown.

[0433] The method for preparing betaine salt Type C provided by the present invention is characterized in that,

[0434] The solid betaine salt Type B was vacuum dried at 50 ºC until betaine salt Type C was obtained.

[0435] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at diffraction angles 2θ of 6.3°±0.2°, 11.6°±0.2°, and 12.7°±0.2°.

[0436] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 14.9°±0.2°, 18.5°±0.2°, and 22.4°±0.2°.

[0437] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at diffraction angles 2θ of 14.9°±0.2°, 18.5°±0.2°, and 22.4°±0.2°.

[0438] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.4°±0.2°, 17.1°±0.2°, and 24.0°±0.2°.

[0439] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 17.1°±0.2°, and 24.0°±0.2°.

[0440] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 6.3°±0.2°, 7.4°±0.2°, 11.6°±0.2°, 12.7°±0.2°, 14.9°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 22.4°±0.2°, and 24.0°±0.2°.

[0441] In one embodiment of the present invention, the X-ray powder diffraction pattern of the diethylamine salt Type A has characteristic peaks at diffraction angles 2θ of 6.3°±0.2°, 7.4°±0.2°, 11.6°±0.2°, 12.7°±0.2°, 14.9°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 22.4°±0.2°, and 24.0°±0.2°.

[0442] The diethylamine salt Type A provided by the present invention has a molar ratio of S-indobufen to diethylamine of 0.8 to 1.2, preferably 0.9 to 1.1, and even more preferably 1.

[0443] The diethylamine salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 81 As shown.

[0444] When thermogravimetric analysis (TGA) was performed, diethylamine salt Type A exhibited a mass loss gradient of approximately 13.83 ± 0.2% when heated to 125 ± 2°C, and approximately 6.91 ± 0.2% when heated further to 160 ± 2°C. Its TGA was essentially as follows: Figure 82 As shown.

[0445] When performing differential scanning calorimetry (DSC), diethylamine salt Type A begins to melt when heated to approximately 163 ± 2 ºC, and its DSC is essentially as follows: Figure 83 As shown.

[0446] The method for preparing diethylamine salt Type A provided by this invention is characterized in that,

[0447] The free state of compound GP-046 and diethylamine were added to an acetonitrile solvent system and stirred at room temperature until diethylamine salt Type A was obtained.

[0448] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at diffraction angles 2θ of 5.6°±0.2°, 8.4°±0.2°, and 20.3°±0.2°.

[0449] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at one, two, or three locations within the diffraction angles 2θ of 6.2°±0.2°, 7.4°±0.2°, and 13.4°±0.2°.

[0450] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at diffraction angles 2θ of 6.2°±0.2°, 7.4°±0.2°, and 13.4°±0.2°.

[0451] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 19.7°±0.2°, 22.2°±0.2°, and 23.4°±0.2°.

[0452] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at diffraction angles 2θ of 19.7°±0.2°, 22.2°±0.2°, and 23.4°±0.2°.

[0453] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.6°±0.2°, 6.2°±0.2°, 7.4°±0.2°, 8.4°±0.2°, 13.4°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 22.2°±0.2°, and 23.4°±0.2°.

[0454] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type A has characteristic peaks at diffraction angles 2θ of 5.6°±0.2°, 6.2°±0.2°, 7.4°±0.2°, 8.4°±0.2°, 13.4°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 22.2°±0.2°, and 23.4°±0.2°.

[0455] The proline cocrystal Type B provided by the present invention has a molar ratio of S-indobufen to proline cocrystal of 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0456] The proline eutectic Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 84 As shown.

[0457] When thermogravimetric analysis was performed, the proline eutectic Type A exhibited a mass loss gradient of approximately 0.10 ± 0.2% when heated to 120 ± 2ºC, and its TGA was essentially as follows: Figure 85 As shown.

[0458] When differential scanning calorimetry (DSC) was performed, proline eutectic Type A began to melt when heated to approximately 169 ± 2 ºC, and its DSC was essentially as follows: Figure 86 As shown.

[0459] The method for preparing proline cocrystal Type A provided by the present invention is characterized in that,

[0460] The free state of compound GP-046 and proline were added to an acetonitrile solvent system and stirred at room temperature until a proline eutectic Type A was obtained.

[0461] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 18.1°±0.2°, and 19.6°±0.2°.

[0462] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.2°±0.2°, 19.0°±0.2°, and 25.7°±0.2°.

[0463] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at diffraction angles 2θ of 15.2°±0.2°, 19.0°±0.2°, and 25.7°±0.2°.

[0464] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at one, two, or three of the diffraction angles 2θ of 10.2°±0.2°, 24.2°±0.2°, and 24.9°±0.2°.

[0465] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at diffraction angles 2θ of 10.2°±0.2°, 24.2°±0.2°, and 24.9°±0.2°.

[0466] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 5.1°±0.2°, 10.2°±0.2°, 15.2°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.6°±0.2°, 24.2°±0.2°, 24.9°±0.2°, and 25.7°±0.2°.

[0467] In one embodiment of the present invention, the X-ray powder diffraction pattern of the proline eutectic Type B has characteristic peaks at diffraction angles 2θ of 5.1°±0.2°, 10.2°±0.2°, 15.2°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.6°±0.2°, 24.2°±0.2°, 24.9°±0.2°, and 25.7°±0.2°.

[0468] The proline cocrystal Type B provided by the present invention has a molar ratio of S-indobufen to proline cocrystal of 0.8~1.2, preferably 0.9~1.1, and even more preferably 1.

[0469] The proline eutectic Type B provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 87 As shown.

[0470] The method for preparing proline cocrystal Type B provided by this invention is characterized in that,

[0471] DVS test was performed on proline cocrystal Type A to obtain proline cocrystal Type B.

[0472] In one embodiment of the present invention, the DVS test procedure is: 0%RH-95%RH-0%RH.

[0473] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at diffraction angles 2θ of 4.9°±0.2°, 8.3°±0.2°, and 12.1°±0.2°.

[0474] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 9.8°±0.2°, 14.8°±0.2°, and 20.9°±0.2°.

[0475] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at diffraction angles 2θ of 9.8°±0.2°, 14.8°±0.2°, and 20.9°±0.2°.

[0476] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at one, two, or three of the diffraction angles 2θ of 5.6°±0.2°, 7.4°±0.2°, and 22.3°±0.2°.

[0477] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at diffraction angles 2θ of 5.6°±0.2°, 7.4°±0.2°, and 22.3°±0.2°.

[0478] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at any 4, 5, 6, 7, 8, or 9 locations within the diffraction angle 2θ of 4.9°±0.2°, 5.6°±0.2°, 7.4°±0.2°, 8.3°±0.2°, 9.8°±0.2°, 12.1°±0.2°, 14.8°±0.2°, 20.9°±0.2°, and 22.3°±0.2°.

[0479] In one embodiment of the present invention, the X-ray powder diffraction pattern of the hexadecylamine salt Type A has characteristic peaks at diffraction angles 2θ of 4.9°±0.2°, 5.6°±0.2°, 7.4°±0.2°, 8.3°±0.2°, 9.8°±0.2°, 12.1°±0.2°, 14.8°±0.2°, 20.9°±0.2°, and 22.3°±0.2°.

[0480] The hexadecylamine salt Type A provided by the present invention has a molar ratio of S-indobufen to hexadecylamine of 1.6 to 2.4, preferably 1.8 to 2.2, and even more preferably 2.

[0481] The hexadecylamine salt Type A provided by this invention is characterized in that its X-ray powder diffraction pattern is substantially as follows: Figure 88 As shown.

[0482] When thermogravimetric analysis was performed, hexadecylamine salt Type A exhibited a mass loss gradient of approximately 2.23% when heated to 120 ± 2ºC, and its TGA was essentially as follows: Figure 89 As shown.

[0483] When differential scanning calorimetry (DSC) was performed, hexadecylamine salt Type A exhibited an endothermic peak when heated to approximately 64 ± 2°C and began to melt when heated to approximately 169 ± 2°C. Its DSC essentially showed the following characteristics: Figure 90 As shown.

[0484] The method for preparing hexadecylamine salt Type A provided by the present invention is characterized in that,

[0485] The free state of compound GP-046 and hexadecylamine were added to an acetone solvent system and stirred at room temperature until hexadecylamine salt Type A was obtained.

[0486] The present invention also discloses a pharmaceutical composition, the above-mentioned S-indobufen salt, and one or more pharmaceutically acceptable carriers.

[0487] The present invention also discloses the use of the above-mentioned S-indobufen salt in the preparation of medicaments for the prevention and / or treatment of antiplatelet diseases.

[0488] Furthermore, the disease in question is ischemic cardiovascular disease caused by arteriosclerosis, ischemic cerebrovascular disease, venous thrombosis, or is used for the prevention of thrombosis during hemodialysis.

[0489] In this invention, the X-ray powder diffraction pattern is obtained using Cu-Kα radiation testing.

[0490] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0491] The compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulation, or inhalation administration.

[0492] For these routes of administration, the compositions of the present invention can be administered in suitable dosage forms.

[0493] The dosage form may be a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, and syrups.

[0494] The pharmaceutical composition described in this invention can be prepared by any method known in the art, such as by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, etc.

[0495] As used in this article, the term "therapeutic effective dose" refers to the amount of S-indobufen salt that, when administered, would alleviate one or more symptoms of the treated condition to some extent.

[0496] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0497] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0498] The S-indobufen salt of the present invention has excellent solubility, especially in FaSSIF and water, excellent compressibility and stability, low hygroscopicity, very uniform particle size distribution and low adhesion, giving it unique advantages in formulation and application. Attached Figure Description

[0499] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0500] Figure 1 XRPD plot of meglumine salt Type A;

[0501] Figure 2 TGA graph of meglumine salt Type A;

[0502] Figure 3 DSC plot of meglumine salt Type A;

[0503] Figure 4 XRPD plot of meglumine salt Type B;

[0504] Figure 5 TGA graph of meglumine salt Type B;

[0505] Figure 6 DSC plot of meglumine salt Type B;

[0506] Figure 7 XRPD plot of meglumine salt Type D;

[0507] Figure 8 TGA graph of meglumine salt Type D;

[0508] Figure 9 DSC plot of meglumine salt Type D;

[0509] Figure 10 XRPD plot of meglumine salt Type E;

[0510] Figure 11 TGA graph of meglumine salt Type E;

[0511] Figure 12 DSC plot of meglumine salt Type E;

[0512] Figure 13 XRPD plot of tromethamine salt Type A;

[0513] Figure 14 TGA plot of tromethamine type A;

[0514] Figure 15 DSC plot of tromethamine salt Type A;

[0515] Figure 16 XRPD plot of tromethamine type B;

[0516] Figure 17 TGA graph of tromethamine type B;

[0517] Figure 18 DSC plot of tromethamine type B;

[0518] Figure 19 XRPD plot of tromethamine salt Type C;

[0519] Figure 20 TGA graph of tromethamine Type C;

[0520] Figure 21 DSC plot of tromethamine salt Type C;

[0521] Figure 22 XRPD plot of tromethamine salt Type D;

[0522] Figure 23 TGA plot of tromethamine type D;

[0523] Figure 24 DSC plot of tromethamine type D;

[0524] Figure 25 XRPD plot of tromethamine salt Type E;

[0525] Figure 26 TGA plot of tromethamine Type E;

[0526] Figure 27 DSC plot of Type E tromethamine salt;

[0527] Figure 28 XRPD image of urea eutectic Type A;

[0528] Figure 29 TGA image of urea eutectic Type A;

[0529] Figure 30 DSC diagram of urea eutectic Type A;

[0530] Figure 31 XRPD plot of potassium salt Type A;

[0531] Figure 32 TGA graph of potassium salt Type A;

[0532] Figure 33 DSC plot of potassium salt Type A;

[0533] Figure 34 XRPD plot of potassium salt Type B;

[0534] Figure 35 XRPD plot of calcium salt Type A;

[0535] Figure 36 TGA graph of calcium salt Type A;

[0536] Figure 37 DSC plot of calcium salt Type A;

[0537] Figure 38 XRPD plot of calcium salt Type B;

[0538] Figure 39 TGA graph of calcium salt Type B;

[0539] Figure 40 DSC diagram of calcium salt Type B;

[0540] Figure 41 XRPD plot of calcium salt Type C;

[0541] Figure 42 XRPD plot of calcium salt Type D;

[0542] Figure 43 TGA graph of calcium salt Type D;

[0543] Figure 44 DSC plot of calcium salt Type D;

[0544] Figure 45 XRPD plot of calcium salt Type E;

[0545] Figure 46 TGA graph of calcium salt Type E;

[0546] Figure 47 DSC plot of calcium salt Type E;

[0547] Figure 48 XRPD plot of magnesium salt Type A;

[0548] Figure 49TGA chart of magnesium salt Type A;

[0549] Figure 50 DSC plot of magnesium salt Type A;

[0550] Figure 51 XRPD plot of magnesium salt Type B;

[0551] Figure 52 XRPD plot of magnesium salt Type C;

[0552] Figure 53 XRPD plot of ammonium salt Type A;

[0553] Figure 54 XRPD plot of ammonium salt Type B;

[0554] Figure 55 TGA graph of ammonium salt Type B;

[0555] Figure 56 DSC plot of ammonium salt Type B;

[0556] Figure 57 XRPD plot of ammonium salt Type C;

[0557] Figure 58 TGA graph of ammonium salt Type C;

[0558] Figure 59 DSC plot of ammonium salt Type C;

[0559] Figure 60 XRPD plot of ammonium salt Type D;

[0560] Figure 61 TGA graph of ammonium salt Type D;

[0561] Figure 62 DSC plot of ammonium salt Type D;

[0562] Figure 63 XRPD plot of choline salts Type A;

[0563] Figure 64 TGA graph of choline salts Type A;

[0564] Figure 65 DSC plot of choline salts Type A;

[0565] Figure 66 XRPD plot of lysine salt Type A;

[0566] Figure 67TGA graph of lysine salt Type A;

[0567] Figure 68 DSC plot of lysine salt Type A;

[0568] Figure 69 XRPD plot of lysine salt Type B;

[0569] Figure 70 TGA graph of lysine salt Type B;

[0570] Figure 71 DSC plot of lysine type B salt;

[0571] Figure 72 XRPD plot of lysine salt Type C;

[0572] Figure 73 XRPD plot of lysine salt Type D;

[0573] Figure 74 TGA graph of lysine salt Type D;

[0574] Figure 75 DSC plot of lysine salt Type D;

[0575] Figure 76 XRPD image of betaine salt Type A;

[0576] Figure 77 XRPD diagram of betaine salt Type B;

[0577] Figure 78 XRPD diagram of betaine salt Type C;

[0578] Figure 79 TGA graph of betaine salt Type C;

[0579] Figure 80 DSC diagram of betaine salt Type C;

[0580] Figure 81 XRPD plot of diethylamine salt Type A;

[0581] Figure 82 TGA plot of diethylamine salt Type A;

[0582] Figure 83 DSC plot of diethylamine salt Type A;

[0583] Figure 84 XRPD plot of proline cocrystal Type A;

[0584] Figure 85 TGA image of proline cocrystal Type A;

[0585] Figure 86 DSC plot of proline eutectic Type A;

[0586] Figure 87 XRPD image of proline cocrystal Type B;

[0587] Figure 88 XRPD plot of hexadecylamine salt Type A;

[0588] Figure 89 TGA graph of hexadecylamine salt Type A;

[0589] Figure 90 DSC plot of hexadecylamine salt Type A;

[0590] Figure 91 Solubility curves of different crystal forms in FaSSIF;

[0591] Figure 92 Solubility curves of different crystal forms in pure water;

[0592] Figure 93 XRPD overlay plot of potassium salt Type A stability;

[0593] Figure 94 XRPD overlay plot of the stability of meglumine salt Type A;

[0594] Figure 95 XRPD overlay plot of the stability of Type B tromethamine salt;

[0595] Figure 96 XRPD overlay of the stability of urea eutectic Type A;

[0596] Figure 97 XRPD overlay plot of the stability of Type E tromethamine salt;

[0597] Figure 98 : DVS diagram of free-state Form C;

[0598] Figure 99 DVS diagram of tromethamine type B;

[0599] Figure 100 DVS diagram of Type E of meglumine salt;

[0600] Figure 101 DVS diagram of urea eutectic Type A;

[0601] Figure 102 Particle size distribution diagram of potassium salt Type A;

[0602] Figure 103 Particle size distribution diagram of meglumine salt Type A;

[0603] Figure 104 Particle size distribution of proline eutectic Type A;

[0604] Figure 105 : Particle size distribution diagram of urea eutectic Type A;

[0605] Figure 106 Particle size distribution of tromethamine salt Type E;

[0606] Figure 107 : Particle size distribution of free Form C;

[0607] Figure 108 : Glucamine salt Type A 1 H NMR spectrum;

[0608] Figure 109: Type B of meglumine salt 1 H NMR spectrum;

[0609] Figure 110: Type D of meglumine salt 1 H NMR spectrum;

[0610] Figure 111: Type E of meglumine salt 1 H NMR spectrum;

[0611] Figure 112 Type B tromethamine salt 1 H NMR spectrum;

[0612] Figure 113 : Urea eutectic Type A 1 H NMR spectrum;

[0613] Figure 114 Potassium salt Type A 1 H NMR spectrum;

[0614] Figure 115 Potassium salts, Type B 1 H NMR spectrum;

[0615] Figure 116 Calcium salts, Type B 1 H NMR spectrum;

[0616] Figure 117 Calcium salts of type D 1 H NMR spectrum;

[0617] Figure 118 Calcium salts of Type E 1 H NMR spectrum;

[0618] Figure 119 Magnesium salt Type A 1 H NMR spectrum;

[0619] Figure 120 Ammonium salt Type B 1 H NMR spectrum;

[0620] Figure 121 Ammonium salts of Type C 1 H NMR spectrum;

[0621] Figure 122 Ammonium salt Type D 1 H NMR spectrum;

[0622] Figure 123 Choline salts Type A 1 H NMR spectrum;

[0623] Figure 124 Lysine salt Type A 1 H NMR spectrum;

[0624] Figure 125 Lysine salt Type B 1 H NMR spectrum;

[0625] Figure 126 Lysine salt Type D 1 H NMR spectrum;

[0626] Figure 127 Type C betaine salt 1 H NMR spectrum;

[0627] Figure 128 Type A diethylamine salt 1 H NMR spectrum;

[0628] Figure 129 Proline cocrystal Type A 1 H NMR spectrum;

[0629] Figure 130 Type A hexadecylamine salt 1 H NMR spectrum. Detailed Implementation

[0630] According to the present invention, the compound of formula (I) used as a raw material refers to its solid (crystalline or amorphous), semi-solid, wax, or oil form. Preferably, the compound of formula (I) used as a raw material is in solid powder form. The "stirring" is performed by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50 to 1800 rpm, wherein magnetic stirring is 200 to 1500 rpm, preferably 300 to 1000 rpm, and mechanical stirring is preferably 100 to 300 rpm.

[0631] In this invention, "crystal" or "polymorph" refers to that confirmed by the X-ray diffraction pattern shown. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray diffraction patterns typically change with instrument conditions. It is particularly important to note that the relative intensities of X-ray diffraction patterns can also vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in an X-ray diffraction pattern are related to the preferred orientation of the crystal, and the peak intensities shown herein are illustrative rather than for absolute comparison. Furthermore, experimental errors in peak angles are typically 5% or less, and these angular errors should also be taken into account, generally allowing for ±0.2° errors. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray diffraction pattern of a crystal form in this invention need not be completely identical to the X-ray diffraction pattern in the examples referred to herein. The phrase "same X-ray diffraction pattern" does not mean absolutely identical; the positions of the same peaks may differ by ±0.2°, and the peak intensities are allowed to have some variability. Any crystal form with a pattern having the same or similar characteristic peaks as those in these spectra falls within the scope of this invention. Those skilled in the art can compare the spectra listed in this invention with a spectra of an unknown crystal form to verify whether the two sets of spectra reflect the same or different crystal forms.

[0632] In some embodiments, the crystal form of the present invention is pure and singular, substantially free of any other crystal form. In this invention, "substantially free" when referring to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, particularly less than 10% (by weight), more specifically less than 5% (by weight), and even more specifically less than 1% (by weight). It should be noted that the numerical values ​​and ranges mentioned in this invention should not be narrowly interpreted as numerical values ​​or ranges themselves. Those skilled in the art should understand that they may fluctuate around specific numerical values ​​depending on the specific technical environment, without departing from the spirit and principles of this invention. In this invention, such fluctuation ranges, foreseeable by those skilled in the art, are often expressed using the term "about".

[0633] The upper and lower limits of the numerical range described in this invention specification can be combined arbitrarily.

[0634] In this document, the term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects.

[0635] In this invention, the term "substantially as shown in Figure ×" indicates that the precise position and intensity of the peaks in the figures should not be interpreted as absolute values. For example, the 2θ value of an X-ray powder diffraction pattern may be subject to error due to different measurement conditions (such as the equipment and instruments used) and different samples; the measurement error of the diffraction angle of an X-ray powder diffraction pattern is 5% or less, and generally, a difference of ±0.2° for a given value is considered appropriate. It should also be understood that the relative intensity of peaks may fluctuate with experimental conditions and sample preparation, such as the preferred orientation of particles in the sample. The use of automated or fixed divergence slits can also affect the calculation of relative intensity. The intensities shown in the X-ray powder diffraction patterns included herein are merely exemplary and should not be used for absolute comparisons. Of course, "substantially as shown in Figure ×" itself includes the meaning of "as shown in Figure ×".

[0636] The present invention will be further illustrated by specific embodiments below, but these are not intended to limit the scope of protection of the present invention. Those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

[0637] The abbreviations used in this invention are explained as follows:

[0638] XRPD: X-ray powder diffraction

[0639] DSC: Differential Scanning Calorimetry

[0640] TGA: Thermogravimetric Analysis

[0641] DVS: Dynamic Moisture Adsorption

[0642] PSD: Particle Size Distribution

[0643] UPLC: Ultra-high performance liquid chromatography

[0644] The X-ray powder diffraction pattern described in this invention is in PANalytical Empyrean or X'Pert. 3 Data was collected using an X-ray powder diffractometer. The parameters of the X-ray powder diffraction method described in this invention are as follows:

[0645] X-ray source: Cu, Kα

[0646] Kα1 (Å): 1.54060; Kα2 (Å): 1.54439

[0647] Kα2 / Kα1 intensity ratio: 0.50

[0648] Voltage: 45 kV

[0649] Current: 40 milliamperes (mA)

[0650] Diverging slit: 1 / 8 degree

[0651] Scanning mode: Continuous scan

[0652] Scan range: from 3.0 to 40.0 degrees

[0653] Scan step size: 0.0263 degrees

[0654] Scanning time per step: 46.67 degrees

[0655] Scan time: Approximately 5 minutes

[0656] The differential scanning calorimetry (DSC) images described in this invention were acquired on a TA Discovery 2500. The parameters of the differential scanning calorimetry (DSC) method described in this invention are as follows:

[0657] Method: Linear heating

[0658] Sample tray: Aluminum tray, open

[0659] Temperature range: room temperature to 250 °C

[0660] Scan rate: 10 °C / min

[0661] Protective gas: N2

[0662] The thermogravimetric analysis (TGA) charts described in this invention were acquired using a TA Discovery 5500. The method parameters for the thermogravimetric analysis (TGA) described in this invention are as follows:

[0663] Method: Linear heating

[0664] Sample tray: Aluminum tray, pressure cap

[0665] Temperature range: room temperature to 200 °C

[0666] Scan rate: 10 °C / min

[0667] Protective gas: N2

[0668] The dynamic moisture adsorption map described in this invention is acquired using the DVS Intrinsic module of an SMS system. The parameters of the dynamic moisture adsorption method described in this invention are as follows:

[0669] Temperature: 25 °C

[0670] Sample size: 20 to 40 mg

[0671] Protective gas and flow rate: N2, 200 ml / min

[0672] Maximum mass change at equilibrium, dm / dt: 0.002% / minute

[0673] Minimum dm / dt equilibration time: 10 minutes

[0674] Maximum balancing time: 180 minutes

[0675] Humidity range: 0%RH to 95%RH to 0%RH

[0676] Humidity variation gradient: 10%RH (between 0%RH and 90%RH), 5%RH (between 90%RH and 95%RH)

[0677] The particle size distribution results described in this invention were acquired using a Microtrac S3500 laser particle size analyzer. The Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) sample introduction system. This test employed a wet method, using Isopar G (containing 0.2% lecithin) as the dispersion medium. The method parameters for the laser particle size analyzer are as follows:

[0678]

[0679] 60% of the flow rate is 65 mL / s.

[0680] The ultra-high performance liquid chromatography (UPLC) purity data in this invention were obtained from Waters H-Class, and the detector used was a diode array detector (DAD). The HPLC method parameters for testing purity described in this invention are as follows:

[0681] 1. Column: Xterra MS C18, 4.6 mm × 50 mm, 2.5 μm

[0682] 2. Mobile phase: A: 10 mM KH2PO4 in H2O (pH=4.0)

[0683] B: Acetonitrile

[0684] The elution gradient is as follows:

[0685]

[0686] 3. Flow rate: 1.0 mL / min

[0687] 4. Injection volume: 4 µL

[0688] 5. Detection wavelength: 228 nm

[0689] 6. Column temperature: 30 ºC

[0690] 7. Injector temperature: room temperature

[0691] 8. Diluent: Acetonitrile / water 1:1 (volume ratio)

[0692] Unless otherwise specified, all the following examples are performed at room temperature.

[0693] Example 1: Preparation of meglumine salt Type A

[0694] 1.50 g of free compound GP-046 was weighed into a 65 mL glass vial, and 40 mL of acetone was added to form a suspension. 990.7 mg of meglumine solid was added to the suspension, and the mixture was then magnetically stirred at room temperature for approximately 3 days. The solid was separated by filtration and dried under vacuum at 50 °C overnight. The solid was collected to obtain meglumine salt Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 1-3 As shown, 1 H NMR image as follows Figure 108 As shown, its X-ray powder diffraction data are shown in Table 1.

[0695] Table 1

[0696]

[0697] Examples 2-12: Preparation of meglumine salt Type A (vaporization at room temperature)

[0698] Approximately 20 mg of the meglumine salt solid prepared in Example 1 was weighed into a 3 mL vial and dissolved in different solvents. The supernatant was filtered through a 0.45 μm polytetrafluoroethylene filter into a 4 mL single-crystal vial. The single-crystal vial was left open at room temperature to evaporate until a solid precipitated, yielding meglumine salt Type A. Detailed experimental conditions involved in this example are shown in Table 2. X-ray powder diffraction data for Example 2 are shown in Table 3.

[0699] Table 2

[0700]

[0701] Table 3

[0702]

[0703] Examples 13-19: Preparation of Type A meglumine salt (rapid cooling)

[0704] Approximately 30 mg of the meglumine salt solid prepared in Example 2 was weighed into a 3 mL vial, and different solvents were added. The sample solution was then allowed to stand at 80 ºC for approximately 2 hours to equilibrate. While still hot, the solution was filtered through a 0.45 μm polytetrafluoroethylene filter membrane into another 3 mL vial. After sealing, the vial was allowed to stand at -20 ºC until a solid precipitated, yielding meglumine salt Type A. Detailed experimental conditions involved in this example are shown in Table 4. X-ray powder diffraction data for Example 14 are shown in Table 5.

[0705] Table 4

[0706]

[0707] Table 5

[0708]

[0709] Examples 20-27: Preparation of meglumine salt Type A (antisolvent addition)

[0710] Approximately 30 mg of the meglumine salt solid prepared in Example 2 was weighed into a 20 mL vial and dissolved in different solvents. The supernatant was filtered through a 0.45 μm polytetrafluoroethylene filter membrane into another 20 mL vial. While maintaining magnetic stirring, the antisolvent was added dropwise to the filtrate until the solid precipitated. All samples were stirred at room temperature until meglumine salt Type A was obtained. Detailed conditions of the experiments involved in this example are shown in Table 6. X-ray powder diffraction data of Example 22 are shown in Table 7.

[0711] Table 6

[0712]

[0713] Table 7

[0714]

[0715] Examples 28-37: Preparation of meglumine salt Type A (reverse antisolvent addition)

[0716] Approximately 30 mg of the meglumine salt solid prepared in Example 2 was weighed into a 3 mL vial and dissolved in different solvents. 4 mL of antisolvent was added to a 20 mL vial and pre-cooled at 5 ºC for approximately 30 minutes. Subsequently, the meglumine salt solution was filtered into the antisolvent using a 0.45 μm polytetrafluoroethylene filter membrane and stirred at room temperature until a solid precipitated, yielding meglumine salt Type A. Detailed experimental conditions in this example are shown in Table 8. X-ray powder diffraction data for Example 29 are shown in Table 9.

[0717] Table 8

[0718]

[0719] Table 9

[0720]

[0721] Example 38: Preparation of meglumine salt Type B

[0722] Weigh 60.4 mg of free compound GP-046 into a 3 mL glass vial and dissolve it in 2 mL of a mixed solvent tetrahydrofuran / pure water (19:1, v / v). Add 40.1 mg of meglumine solid to the above solution, and then stir magnetically overnight at room temperature. Centrifuge to separate the solid, and allow it to air dry at room temperature for about 4 hours. Collect the solid to obtain meglumine salt Type B. The XRPD, TGA, and DSC of this example are as follows... Figures 4-6 As shown, 1 H NMR image as follows Figure 109 As shown, its X-ray powder diffraction data are shown in Table 10.

[0723] Table 10

[0724]

[0725]

[0726] Example 39: Preparation of meglumine salt Type D

[0727] Weigh 20.1 mg of free compound GP-046 into a 5 mL glass vial and add 2 mL of chloroform solution. Add 13.2 mg of meglumine solid to the above solution, and then stir magnetically at room temperature for about 3 days. Centrifuge to separate the solid, and allow it to air dry at room temperature overnight. Collect the solid to obtain meglumine salt Type D. The XRPD, TGA, and DSC of this example are as follows... Figures 7-9 As shown, 1 H NMR image as follows Figure 110 As shown, its X-ray powder diffraction data are shown in Table 11.

[0728] Table 11

[0729]

[0730] Example 40: Preparation of meglumine salt Type E

[0731] Weigh an appropriate amount of meglumine salt Type D solid into a DSC crucible, heat to 120°C at a rate of 10 °C / min, hold for 5 minutes, and then cool to 40 °C at a rate of 30 °C / min to obtain meglumine salt Type E. The XRPD, TGA, and DSC in this example are as follows: Figures 10-12 As shown, 1 H NMR image as follows Figure 111 As shown, its X-ray powder diffraction data are shown in Table 12.

[0732] Table 12

[0733]

[0734] Example 41: Preparation of Tromethamine Type B

[0735] Weigh 1.50 g of free compound GP-046 into a 65 mL glass vial, add 40 mL of acetonitrile to form a suspension. Add 620.8 mg of tromethamine solid to the suspension, and then stir magnetically at room temperature for about 3 days. Filter to separate the solid, and dry under vacuum at 50 °C overnight. Collect the solid to obtain tromethamine salt Type B. The XRPD, TGA, and DSC of this example are as follows... Figures 16-18 As shown, 1 H NMR image as follows Figure 112 As shown, its X-ray powder diffraction data are shown in Table 13.

[0736] Table 13

[0737]

[0738] Examples 42-48: Preparation of Tromethamine Type B (rapid cooling)

[0739] Approximately 30 mg of the tromethamine salt solid prepared in Example 41 was weighed into a 3 mL vial, and different solvents were added. The sample solution was then allowed to stand at 80 ºC for approximately 2 hours to equilibrate. While still hot, the solution was filtered through a 0.45 μm polytetrafluoroethylene filter membrane into another 3 mL vial. After sealing, the vial was allowed to stand at -20 ºC until a solid precipitated, yielding tromethamine salt Type B. Detailed experimental conditions involved in this example are shown in Table 14. X-ray powder diffraction data for Example 42 are shown in Table 15.

[0740] Table 14

[0741]

[0742] Table 15

[0743]

[0744] Examples 49-51: Preparation of Tromethamine Type B (Gas-Liquid Diffusion)

[0745] Approximately 30 mg of the tromethamine salt solid prepared in Example 41 was weighed into a 3 mL vial and dissolved in different solvents. The supernatant was filtered through a 0.45 μm polytetrafluoroethylene filter into a 4 mL single-crystal vial. The single-crystal vial was placed open into a 20 mL vial containing 4 mL of antisolvent. After sealing, the vial was left to stand at room temperature until a solid precipitated, yielding tromethamine salt Type B. Detailed experimental conditions involved in this example are shown in Table 16. X-ray powder diffraction data for Example 49 are shown in Table 17.

[0746] Table 16

[0747]

[0748] Table 17

[0749]

[0750] Example 52: Preparation of Tromethamine Type B (Volatile at Room Temperature)

[0751] Weigh 20.1 mg of the tromethamine salt solid prepared in Example 41 into a 3 mL vial, and dissolve it in 1 mL of a trifluoroethanol / 2-methyltetrahydrofuran (19:5, volume ratio) mixed solvent. Filter the supernatant through a 0.45 μm polytetrafluoroethylene filter into a 4 mL single-crystal vial. Leave the single-crystal vial open at room temperature to allow it to evaporate until a solid precipitates, yielding tromethamine salt Type B. The X-ray powder diffraction data for this example are shown in Table 18.

[0752] Table 18

[0753]

[0754] Examples 53-61: Preparation of Tromethamine Type B (antisolvent addition)

[0755] Approximately 20 mg of the tromethamine salt solid prepared in Example 41 was weighed into a 20 mL vial and dissolved in different solvents. The supernatant was filtered through a 0.45 μm polytetrafluoroethylene filter membrane into another 20 mL vial. While maintaining magnetic stirring, the antisolvent was added dropwise to the filtrate until the solid precipitated. All samples were stirred at room temperature until tromethamine salt Type B was obtained. Detailed conditions of the experiments involved in this example are shown in Table 19. X-ray powder diffraction data of Example 60 are shown in Table 20.

[0756] Table 19

[0757]

[0758] Table 20

[0759]

[0760] Examples 62-69: Preparation of Tromethamine Type B (Reverse Antisolvent Addition)

[0761] Approximately 20 mg of the tromethamine salt solid prepared in Example 41 was weighed into a 3 mL vial and dissolved in different solvents. 4 mL of antisolvent was added to a 20 mL vial and pre-cooled at 5 ºC for approximately 30 minutes. Subsequently, the tromethamine salt solution was filtered into the antisolvent using a 0.45 μm polytetrafluoroethylene filter membrane and stirred at room temperature until a solid precipitated, yielding tromethamine salt Type B. Detailed experimental conditions in this example are shown in Table 21. X-ray powder diffraction data for Example 63 are shown in Table 22.

[0762] Table 21

[0763]

[0764] Table 22

[0765]

[0766] Examples 70-76: Preparation of Tromethamine Salt Type A

[0767] Approximately 20 mg of the tromethamine Type B solid prepared in Example 41 was weighed into a 3 mL glass vial and dissolved in different solvents. The supernatant was filtered through a 0.45 μm PTFE membrane into a 4 mL single crystal vial, and then left open at room temperature to evaporate until a solid precipitated, yielding tromethamine Type A. Detailed experimental conditions in this example are shown in Table 23. XRPD, TGA, and DSC of Example 70 are as follows... Figures 13-15 As shown, its X-ray powder diffraction data are shown in Table 24.

[0768] Table 23

[0769]

[0770] Table 24

[0771]

[0772]

[0773] Examples 77-79: Preparation of Tromethamine Salt Type C

[0774] Approximately 30 mg of the tromethamine Type B solid prepared in Example 41 was weighed into a 3 mL glass vial and dissolved in different solvents. The solution was filtered through a 0.45 μm PTFE membrane into a 4 mL single crystal vial, which was then placed openly into a 20 mL vial pre-filled with 4 mL of antisolvent. After sealing, the sample was placed at room temperature for gas-liquid diffusion until a solid precipitated, yielding tromethamine Type C. Detailed experimental conditions in this example are shown in Table 25. XRPD, TGA, and DSC of Example 77 are as follows... Figures 19-21 As shown, its X-ray powder diffraction data are shown in Table 26.

[0775] Table 25

[0776]

[0777] Table 26

[0778]

[0779] Example 80: Preparation of Tromethamine Type D

[0780] Weigh 32.7 mg of the tromethamine Type B solid prepared in Example 41 into a 3 mL glass vial, add 2 mL of tetrahydrofuran, and then let stand at 80 ºC for about 3 hours until dissolved. While still hot, filter the above solution into a 3 mL vial using a 0.45 μm PTFE filter membrane. Then let stand at -20 ºC until a solid precipitates, yielding tromethamine Type D. The XRPD, TGA, and DSC of this example are as follows... Figures 22-24 As shown, its X-ray powder diffraction data are shown in Table 27.

[0781] Table 27

[0782]

[0783] Example 81: Preparation of Tromethamine Salt Type E

[0784] Weigh 27.3 mg of the tromethamine Type B solid prepared in Example 41 into a 3 mL glass vial, add 0.4 mL of trifluoroethanol to dissolve it, and then filter the solution through a 0.45 μm PTFE membrane into a 20 mL vial. Slowly add 10 mL of chloroform to obtain a clear solution. Let the clear solution stand at -20 ºC overnight, then transfer it to room temperature for open evaporation until a solid precipitates, yielding tromethamine Type E. The XRPD, TGA, and DSC of this example are as follows... Figures 25-27 As shown, its X-ray powder diffraction data are shown in Table 28.

[0785] Table 28

[0786]

[0787] Example 82: Preparation of Tromethamine Salt Type E

[0788] Weigh 27.0 mg of the tromethamine Type B solid prepared in Example 41 into a 3 mL glass vial, add 0.4 mL of trifluoroethanol to dissolve it, and then filter the solution through a 0.45 μm PTFE membrane into a 20 mL vial. Slowly add 2 mL of isopropyl ether, and the solid precipitates to obtain tromethamine Type E. The X-ray powder diffraction data of this example are shown in Table 29.

[0789] Table 29

[0790]

[0791] Example 83: Preparation of Urea Eutectic Type A

[0792] 1.50 g of free GP-046 compound was weighed into a 65 mL glass vial, and 40 mL of acetone was added to form a suspension. 310.5 mg of solid urea was added to the suspension, and the mixture was then magnetically stirred at room temperature for approximately 3 days. The solid was separated by filtration and dried under vacuum at 50 ºC overnight. The solid was collected to obtain urea eutectic Type A. The XRPD, TGA, and DSC of this embodiment are as follows... Figures 28-30 As shown, 1 H NMR image as follows Figure 113 As shown, its X-ray powder diffraction data are shown in Table 30.

[0793] Table 30

[0794]

[0795]

[0796] Example 84: Preparation of Potassium Salt Type A

[0797] 1.50 g of compound GP-046 in its free state was weighed into a 65 mL glass vial, and 40 mL of acetone was added to form a suspension. 290.8 mg of potassium hydroxide solid was added to the suspension, and the mixture was then magnetically stirred at room temperature for approximately 3 days. The solid was separated by filtration and dried under vacuum at 50 ºC overnight. The solid was collected to obtain potassium salt Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 31-33 As shown, 1 H NMR image as follows Figure 114 As shown, its X-ray powder diffraction data are shown in Table 31.

[0798] Table 31

[0799]

[0800] Example 85: Preparation of Potassium Salt Type B

[0801] Take an appropriate amount of potassium salt Type A solid prepared in Example 84 and place it on a heating stage. After purging with nitrogen for 20 minutes, heat to 160 ºC to obtain potassium salt Type B. The XRPD in this example is as follows: Figure 34 As shown, its X-ray powder diffraction data are shown in Table 32.

[0802] Table 32

[0803]

[0804] Example 86: Preparation of Calcium Salt Type A

[0805] Approximately 15 mg of free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.8 mL of ethanol was added to form a clear solution. 1.8 mg of solid calcium hydroxide was added to the clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days. The solid was separated by centrifugation and dried under vacuum at 50 °C overnight. The solid was collected to obtain calcium salt Type A. The XRPD, TGA, and DSC parameters in this example are as follows: Figures 35-37 As shown, 1 H NMR image as follows Figure 115 As shown, its X-ray powder diffraction data are shown in Table 33.

[0806] Table 33

[0807]

[0808] Example 87: Preparation of Calcium Salt Type B

[0809] Approximately 15 mg of free compound GP-046 was weighed into a 1.5 mL glass vial, and 1.0 mL of acetonitrile was added to form a clear solution. 2.1 mg of solid calcium hydroxide was added to the clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days. The solid was separated by centrifugation and dried under vacuum at 50 °C overnight. The solid was collected to obtain calcium salt Type B. The XRPD, TGA, and DSC of this example are as follows... Figures 38-40 As shown, 1 H NMR image as follows Figure 116 As shown, its X-ray powder diffraction data are shown in Table 34.

[0810] Table 34

[0811]

[0812] Example 88: Preparation of Calcium Salt Type C

[0813] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.5 mL of a tetrahydrofuran / pure water mixture (19:1, volume ratio) was added to form a clear solution. 2.1 mg of calcium hydroxide solid was added to the clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid, yielding calcium salt Type C. The XRPD in this example is as follows... Figure 41 As shown, its X-ray powder diffraction data are shown in Table 35.

[0814] Table 35

[0815]

[0816] Example 89: Preparation of Calcium Salt Type D

[0817] Weigh an appropriate amount of calcium salt Type A solid into a DSC crucible, heat to 240 °C at a rate of 10 °C / min, hold for 2 minutes, and then cool to 40 °C at a rate of 30 °C / min to obtain calcium salt Type D. The XRPD, TGA, and DSC in this embodiment are as follows: Figures 42-44 As shown, 1 H NMR image as follows Figure 117 As shown, its X-ray powder diffraction data are shown in Table 36.

[0818] Table 36

[0819]

[0820] Example 90: Preparation of Calcium Salt Type E

[0821] Weigh 60.3 mg of free compound GP-046 into a 5 mL glass vial, add 3.2 mL of ethanol to form a clear solution. Add 8.2 mg of calcium hydroxide solid to the above clear solution, then place at room temperature and stir magnetically overnight, followed by stirring at 50 ºC for about 4 days to precipitate a solid. Centrifuge to separate the solid, and vacuum dry at 50 ºC overnight. Collect the solid to obtain calcium salt Type E. The XRPD, TGA, and DSC of this example are as follows... Figures 45-47 As shown, 1 H NMR image as follows Figure 118 As shown, its X-ray powder diffraction data are shown in Table 37.

[0822] Table 37

[0823]

[0824] Example 91: Preparation of Magnesium Salt Type A

[0825] Approximately 15 mg of free GP-046 was weighed into a 1.5 mL glass vial, and 0.8 mL of ethanol was added to form a clear solution. 1.8 mg of solid magnesium hydroxide was added to the clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid. The solid was centrifuged and dried under vacuum at 50 ºC overnight. The solid was collected to obtain magnesium salt Type A. The XRPD, TGA, and DSC parameters in this example are as follows: Figures 48-50 As shown, 1 H NMR image as follows Figure 119 As shown, its X-ray powder diffraction data are shown in Table 38.

[0826] Table 38

[0827]

[0828] Example 92: Preparation of Magnesium Salt Type B

[0829] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.5 mL of a tetrahydrofuran / pure water (19:1, volume ratio) mixed solvent system was added to form a clear solution. 1.5 mg of magnesium hydroxide solid was added to the above clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, precipitating a solid to obtain magnesium salt Type B. The XRPD in this example is as follows... Figure 51 As shown, its X-ray powder diffraction data are shown in Table 39.

[0830] Table 39

[0831]

[0832] Example 93: Preparation of Magnesium Salt Type C

[0833] Weigh an appropriate amount of the magnesium salt Type A solid prepared in Example 91 into a DSC crucible, heat it to 220 °C at a rate of 10 °C / min, hold it at that temperature for 2 minutes, and then cool it to 40 °C at a rate of 30 °C / min to obtain magnesium salt Type C. The XRPD of this example is as follows... Figure 52 As shown, its X-ray powder diffraction data are shown in Table 40.

[0834] Table 40

[0835]

[0836] Example 94: Preparation of Ammonium Salt Type A

[0837] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.5 mL of a tetrahydrofuran / pure water (19:1, volume ratio) mixed solvent system was added to form a clear solution. 3.8 μL of ammonia solution was added to the above clear solution, and the mixture was then placed at room temperature and magnetically stirred for approximately 3 days, resulting in the precipitation of a solid, yielding ammonium salt Type A. The XRPD in this example is as follows... Figure 53 As shown, its X-ray powder diffraction data are shown in Table 41.

[0838] Table 41

[0839]

[0840] Example 95: Preparation of Ammonium Salt Type B

[0841] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.7 mL of acetone was added to form a clear solution. 3.8 μL of ammonia solution was added to the clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid. The solid was centrifuged and dried under vacuum at 50 °C overnight. The solid was collected to obtain ammonium salt Type B. The XRPD, TGA, and DSC parameters in this example are as follows: Figures 54-56 As shown, 1 H NMR image as follows Figure 120 As shown, its X-ray powder diffraction data are shown in Table 42.

[0842] Table 42

[0843]

[0844] Example 96: Preparation of ammonium salt Type C

[0845] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 1.0 mL of acetonitrile was added to form a clear solution. 3.8 μL of ammonia solution was added to the clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid. The solid was centrifuged and dried under vacuum at 50 °C overnight. The solid was collected to obtain ammonium salt Type C. The XRPD, TGA, and DSC parameters in this example are as follows: Figures 57-59 As shown, 1 H NMR image as follows Figure 121 As shown, its X-ray powder diffraction data are shown in Table 43.

[0846] Table 43

[0847]

[0848] Example 97: Preparation of ammonium salt Type D

[0849] Weigh an appropriate amount of the ammonium salt Type A solid prepared in Example 94 and dry it under vacuum at 50 ºC overnight. Collect the solid to obtain ammonium salt Type D. The XRPD, TGA, and DSC of this example are as follows: Figures 60-62 As shown, 1 H NMR image as follows Figure 122 As shown, its X-ray powder diffraction data are shown in Table 44.

[0850] Table 44

[0851]

[0852] Example 98: Preparation of choline salt Type A

[0853] Approximately 15 mg of free GP-046 was weighed into a 1.5 mL glass vial, and 0.7 mL of acetone was added to form a clear solution. 12.3 μL of choline was added to the above solution, and the mixture was then magnetically stirred overnight at room temperature. The solution was then subjected to a 50-5ºC temperature fluctuation test (the procedure was: raising the temperature from room temperature to 50ºC over 20 minutes and holding for 2 hours; then lowering it to 5ºC over 450 minutes and holding for 2 hours; repeating this cycle twice), resulting in the precipitation of a solid. The solid was centrifuged and dried under vacuum at 50ºC overnight. The solid was collected to obtain choline salt Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 63-65 As shown, 1 H NMR image as follows Figure 123 As shown, its X-ray powder diffraction data are shown in Table 45.

[0854] Table 45

[0855]

[0856] Example 99: Preparation of Lysine Salt Type A

[0857] Weigh 60.5 mg of free compound GP-046 into a 5 mL glass vial, add 3.2 mL of ethanol to form a clear solution. Add 29.5 mg of lysine to the above clear solution, then incubate at room temperature with magnetic stirring overnight to precipitate a solid. Centrifuge to separate the solid, and dry it under vacuum at 50 ºC for approximately 3.5 hours. Collect the solid to obtain lysine salt Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 66-68 As shown, 1 H NMR image as follows Figure 124 As shown, its X-ray powder diffraction data are shown in Table 46.

[0858] Table 46

[0859]

[0860] Example 100: Preparation of Lysine Salt Type B

[0861] Approximately 15 mg of free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.5 mL of a tetrahydrofuran / pure water (19:1, volume ratio) mixed solvent was added to form a clear solution. 7.6 mg of lysine was added to the above clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid. The solid was centrifuged to separate the solid, and then vacuum-dried overnight at 50 ºC. The solid was collected to obtain lysine salt Type B. The XRPD, TGA, and DSC of this example are as follows: Figures 69-71 As shown, 1 H NMR image as follows Figure 124 As shown, its X-ray powder diffraction data are shown in Table 47.

[0862] Table 47

[0863]

[0864] Example 101: Preparation of Lysine Salt Type C

[0865] Weigh an appropriate amount of lysine salt Type B solid into a DSC crucible, heat to 150°C at a rate of 10 °C / min, hold for 2 minutes, and then cool to 40 °C at a rate of 30 °C / min to obtain lysine salt Type C. The XRPD in this example is as follows: Figure 72 As shown, its X-ray powder diffraction data are shown in Table 48.

[0866] Table 48

[0867]

[0868] Example 102: Preparation of Lysine Salt Type D

[0869] Weigh 60.5 mg of free compound GP-046 into a 5 mL glass vial, add 2.0 mL of a tetrahydrofuran / pure water (19:1, volume ratio) mixed solvent to form a clear solution. Add 29.7 mg of lysine to the above clear solution, then incubate at room temperature with magnetic stirring overnight to precipitate a solid. Centrifuge to separate the solid, and dry it under vacuum at 50 ºC for about 3.5 hours, collecting the solid.

[0870] Weigh an appropriate amount of the above solid into a DSC crucible, heat to 175 °C at a rate of 10 °C / min, hold for 10 minutes, and then cool to 30 °C at a rate of 30 °C / min to obtain lysine salt Type D. The XRPD, TGA, and DSC in this example are as follows... Figures 73-75 As shown, 1 H NMR image as follows Figure 126 As shown, its X-ray powder diffraction data are shown in Table 49.

[0871] Table 49

[0872]

[0873] Example 103: Preparation of betaine salt Type A

[0874] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 0.7 mL of acetone was added to form a clear solution. 5.7 mg of betaine was added to the above solution, and the mixture was then placed at room temperature and magnetically stirred for approximately 3 days, resulting in the precipitation of a solid, yielding betaine salt Type A. The XRPD in this example is as follows... Figure 76 As shown, its X-ray powder diffraction data are shown in Table 50.

[0875] Table 50

[0876]

[0877] Example 104: Preparation of betaine salt Type B

[0878] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 1.0 mL of acetonitrile was added to form a clear solution. 6.3 mg of betaine was added to the above solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid, yielding betaine salt Type B. The XRPD in this example is as follows... Figure 77 As shown, its X-ray powder diffraction data are shown in Table 51.

[0879] Table 51

[0880]

[0881]

[0882] Example 105: Preparation of betaine salt Type C

[0883] Weigh an appropriate amount of the betaine salt Type B solid prepared in Example 104 and dry it under vacuum at 50 ºC overnight. Collect the solid to obtain betaine salt Type C. The XRPD, TGA, and DSC of this example are as follows: Figures 78-80 As shown, 1 H NMR image as follows Figure 127 As shown, its X-ray powder diffraction data are shown in Table 52.

[0884] Table 52

[0885]

[0886] Example 106: Preparation of diethylamine salt Type A

[0887] Approximately 15 mg of the free compound GP-046 was weighed into a 1.5 mL glass vial, and 1.0 mL of acetonitrile was added to form a clear solution. 5.2 μL of diethylamine was added to the above clear solution, and the mixture was then magnetically stirred at room temperature for approximately 3 days, resulting in the precipitation of a solid. The solid was centrifuged and dried under vacuum at 50 ºC overnight. The solid was collected to obtain diethylamine salt Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 81-83 As shown, 1 H NMR image as follows Figure 128 As shown, its X-ray powder diffraction data are shown in Table 53.

[0888] Table 53

[0889]

[0890] Example 107: Preparation of Proline Cocrystal Type A

[0891] 1.50 g of free compound GP-046 was weighed into a 65 mL glass vial, and 40 mL of acetonitrile was added to form a suspension. 580.8 mg of proline solid was added to the suspension, and the mixture was then magnetically stirred at room temperature for approximately 3 days. The solid was separated by filtration and dried under vacuum at 50 ºC overnight. The solid was collected to obtain proline eutectic Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 84-86 As shown, 1 H NMR image as follows Figure 129 As shown, its X-ray powder diffraction data are shown in Table 54.

[0892] Table 54

[0893]

[0894]

[0895] Example 108: Preparation of Proline Cocrystal Type B

[0896] Approximately 10-20 mg of the proline cocrystal Type A prepared in Example 107 was weighed into a DVS dish and stabilized at 0%RH. A DVS test was then performed (the procedure was: 0%RH-95%RH-0%RH). After the test, the solid was collected to obtain the proline cocrystal Type B. The XRPD in this example is as follows... Figure 87 As shown, its X-ray powder diffraction data are shown in Table 55.

[0897] Table 55

[0898]

[0899] Example 109: Preparation of hexadecylamine salt Type A

[0900] Weigh 300.3 mg of free compound GP-046 into a 20 mL glass vial, add 12 mL of acetone to form a clear solution. Add 245.9 mg of hexadecylamine solid to the above clear solution, and stir magnetically at room temperature overnight, then continue stirring magnetically at 50 ºC for about 3 hours. Filter to separate the solid, and dry under vacuum at room temperature overnight. Collect the solid to obtain hexadecylamine salt Type A. The XRPD, TGA, and DSC of this example are as follows... Figures 88-90 As shown, 1 H NMR image as follows Figure 129 As shown, its X-ray powder diffraction data are shown in Table 56.

[0901] Table 56

[0902]

[0903]

[0904] Example 110: Solubility of the Crystal Form

[0905] S-indobufen free form C, the potassium salt Type A of this invention, meglumine salt Type A / E, tromethamine salt Type A / B / E, and hexadecylamine salt Type A were prepared into suspensions using FaSSIF (artificial intestinal fluid under fasting conditions) and pure water, respectively. After equilibration at 1 hour, 2 hours, 4 hours, and 24 hours, the suspensions were filtered to obtain saturated solutions. The content of the sample in the saturated solution was determined by ultra-high performance liquid chromatography (UPLC). The experimental results are shown in Table 57, and the solubility curves are shown below. Figures 91-92 As shown. Experimental results show that the potassium salts Type A, meglumine salts Type A / E, and tromethamine salts Type A / B / E of the present invention have better solubility in FaSSIF and pure water than in free Form C, and are more easily dissolved by digestive juices in organisms, thus allowing for more effective absorption and utilization by organisms.

[0906] Table 57

[0907]

[0908] Example 111: Compressibility of Crystal Forms

[0909] Tableting was performed using a manual tablet press. A round flat punch suitable for compressing into cylindrical tablets was selected. Appropriate amounts of S-indobufen free Form C, the potassium salt Type A of this invention, and proline eutectic Type A were added, and the tablets were compressed into round tablets under a pressure of 10 kN. The diameter (D) and thickness (L) of the tablets were measured using calipers, and the radial crushing force (hardness, H) was tested using a tablet hardness tester. The tensile strength of the powder at different hardnesses was calculated using the formula T=2H / πDL. The experimental results are shown in Table 58. The experimental results show that the potassium salt Type A and proline eutectic Type A of this invention have a greater tensile strength than the free Form C, indicating that the compressibility of the potassium salt Type A and proline eutectic Type A is better than that of the free Form C, which is more conducive to tablet formation and improves the manufacturability of the drug.

[0910] Table 58

[0911]

[0912] Example 112: Stability Comparison Study

[0913] Approximately 15 mg each of the following components were weighed: potassium salt Type A (initial purity 99.63%), meglumine salt Type A (initial purity 100.00%), tromethamine salt Type B / E (initial purity 100.00%), and urea eutectic Type A (initial purity 100.00%). These were placed in open containers at 25 °C / 60%RH and 40 °C / 75%RH, respectively. Samples were taken after one week to measure XRPD and HPLC. Simultaneously, approximately 10 mg of tromethamine salt Type E (initial purity 100.00%) was weighed and placed in an open container at 80 °C. Samples were taken after one day to test XRPD and HPLC. The experimental results are shown in Table 59. The stability of potassium salt Type A is as follows: Figure 93 As shown, the stability of meglumine salt Type A is as follows: Figure 94 As shown, the stability of tromethamine salt Type B is as follows: Figure 95 As shown, the stability of urea eutectic Type A is as follows: Figure 96 As shown, the stability of tromethamine salt Type E is as follows: Figure 97 As shown. The experimental results show that the potassium salt Type A, meglumine salt Type A, tromethamine salt Type B / E, and urea eutectic Type A of the present invention have good physical / chemical stability, which can meet the stability requirements during drug production and storage.

[0914] Table 59

[0915]

[0916] Relative purity = (Purity after standing / Initial purity) × 100%

[0917] Example 113: Comparative Study of Hygroscopic Properties

[0918] Approximately 10 mg each of S-indobufen free Form C, the tromethamine salt Type B of this invention, meglumine salt Type E, and urea cocrystal Type A were weighed for dynamic water adsorption (DVS) testing, followed by XRPD measurement. The experimental results are shown in Table 60. The DVS of free Form C is as follows: Figure 98 As shown, the DVS of tromethamine Type B is as follows: Figure 99 As shown; the DVS of meglumine salt Type E is as follows Figure 100 As shown; the DVS of urea eutectic Type A is as follows Figure 101 As shown. Experimental results show that the tromethamine salt Type B, meglumine salt Type E, and urea eutectic Type A of the present invention have lower hygroscopicity than the free form Form C, have lower requirements for post-processing such as drying in the production of active pharmaceutical ingredients, and can remain stable under conventional drug storage conditions, showing good application prospects.

[0919] Table 60

[0920]

[0921] Description of hygroscopic characteristics and definition of hygroscopic weight gain (Guidelines for Hygroscopicity Testing of Drugs in the General Chapters of the 2015 Edition of the Chinese Pharmacopoeia):

[0922] Deliquescence: Absorbs sufficient water to form a liquid.

[0923] Extremely hygroscopic: Moisture absorption increases weight by at least 15%.

[0924] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0925] Slightly hygroscopic: Moisture absorption increases weight by less than 2% but not less than 0.2%.

[0926] None or almost none hygroscopicity: moisture absorption weight gain less than 0.2%

[0927] Example 114: Comparative Study of Particle Size Distribution

[0928] Weigh approximately 10-30 mg of the potassium salt Type A, meglumine salt Type A, proline cocrystal Type A, urea cocrystal Type A, tromethamine salt Type E, and S-indobufen free form C of this invention. Then add approximately 5 mL of Isopar G (containing 0.2% lecithin), thoroughly mix the sample, and add it to the SDC injection system. Ensure the shading is within a suitable range, sonicate for 30 seconds, and then test the particle size distribution. The experimental results are shown in Table 61, and the particle size distribution diagram of potassium salt Type A is shown below. Figure 102 As shown, the particle size distribution diagram of meglumine salt Type A is as follows. Figure 103 As shown, the particle size distribution of proline eutectic Type A is as follows. Figure 104 As shown, the particle size distribution diagram of urea eutectic Type A is as follows. Figure 105 As shown, the particle size distribution diagram of tromethamine salt Type E is as follows. Figure 106 As shown, the particle size distribution of free Form C is as follows: Figure 107 As shown in the figure, the experimental results indicate that potassium salt Type A, meglumine salt Type A, proline cocrystal Type A, urea cocrystal Type A, and tromethamine salt Type E all exhibit unimodal particle size distributions, while the free form C shows a multimodal distribution. This suggests that potassium salt Type A, meglumine salt Type A, proline cocrystal Type A, urea cocrystal Type A, and tromethamine salt Type E have more uniform particle size distributions than the free form C. Particle size distribution typically affects various properties of pharmaceutical formulations, such as dissolution rate, flowability, and bulk density. A uniform particle size distribution is more conducive to controlling drug release rate and improving manufacturability, thereby influencing the safety, efficacy, and quality controllability of the final drug product.

[0929] Table 61

[0930]

[0931] Example 115: Comparative Study of Adhesion

[0932] Approximately 100 mg each of the free Form C and tromethamine salt Type B of this invention were weighed and added to a 6 mm circular punch. Tableting was performed using a pressure of 10 kN, with a resting time of approximately half a minute after compression. The final tablet mass was recorded, and the amount of adhesion during the compression process was calculated. The experimental results are shown in Table 62. The results show that the tromethamine salt Type B of this invention is less likely to adhere to the circular punch during tableting than the free Form C, which is more beneficial for saving materials and controlling the stability of the drug loading in the tablets.

[0933] Table 62

[0934]

[0935] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A salt of S-indobufen, which is an S-indobufen tromethamine salt; said S-indobufen tromethamine salt is tromethamine salt Type B; the X-ray powder diffraction pattern of said tromethamine salt Type B has characteristic peaks at diffraction angles 2θ of 6.4°±0.2°, 7.6°±0.2°, 12.8°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 19.7°±0.2°, 22.1°±0.2°, 22.9°±0.2°, and 27.3°±0.2°.

2. The S-indobufen salt of claim 1, wherein the X-ray powder diffraction pattern of the aminobutadiene triol salt Type B is substantially as shown in Figure 16.

3. The S-indobufen salt of claim 1, when heated to 120±2 ºC for thermogravimetric analysis, has a mass loss gradient of 0.09±0.2%. Alternatively, when performing differential scanning calorimetry, tromethamine Type B begins to melt when heated to 156±2 ºC.

4. The salt of S-indobufen according to claim 1, wherein the molar ratio of S-indobufen to tromethamine in the tromethamine salt is 0.8 to 1.

2.

5. A pharmaceutical composition comprising the S-indobufen salt of any one of claims 1-4, and one or more pharmaceutically acceptable carriers.

6. Use of the S-indobufen salt according to any one of claims 1 to 4 in the preparation of a medicament for the prevention and / or treatment of antiplatelet diseases.

7. The use of the S-indobufen salt according to any one of claims 1 to 4 in the preparation of a medicament for the prevention and / or treatment of a disease, wherein the disease is ischemic cardiovascular disease caused by arteriosclerosis, ischemic cerebrovascular disease, venous thrombosis, or for the prevention of thrombosis during hemodialysis.

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