Crystalline forms of ethoximod and their preparation and use

Abstract

This application provides crystalline forms of ethoximod, and methods for preparing and using the same. The crystalline forms include crystalline form A and crystalline form B. Crystalline form A and crystalline form B can exist stably and have low hygroscopicity, high solubility, good mechanical stability, low flowability, low adhesion, and good tableting suitability, making them promising for use in the pharmaceutical industry.

Description

[Technical Field]

[0001] The present application belongs to the technical field of medicine, and specifically relates to a crystalline form of ethoximod and its preparation method and use. [Background technology]

[0002] Ethoximod is an immunosuppressant for the S1P1 receptor and a novel drug for treating psoriasis. Its chemical name is 2-amino-2-{2-(4'-(2-ethyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl}-1,3-propanediol hydrochloride, and its structural formula is as follows: [ka]

[0003] Currently, the prior art discloses a method for preparing ethoximod, but does not examine its crystalline form. If the active ingredient used in the preparation process of a pharmaceutical formulation is a mixed crystal, this may have a significant impact on the dissolution performance and efficacy of the formulated product. Therefore, the examination of the crystalline form of ethoximod is of great significance for the research and development of subsequent formulations and the therapeutic effects of pharmaceuticals. Summary of the Invention [Problem to be solved by the invention]

[0004] The present application provides crystalline forms of ethoximod and methods for their preparation and use. [Means for solving the problem]

[0005] In a first aspect, the present application provides crystalline form A of ethoximod, which has diffraction peaks in an X-ray diffraction spectrum at 2θ diffraction angles of 9.295°±0.2°, 14.026°±0.2°, 17.107°±0.2°, 17.774°±0.2°, 21.458°±0.2°, 21.937°±0.2°, 22.396°±0.2°, 26.883°±0.2°, 28.236°±0.2°, and 28.534°±0.2°.

[0006] In a second aspect, the present application provides a method for preparing crystalline form A of ethoximod according to the first aspect, comprising the steps of adding an ethoximod sample to methanol, dissolving at elevated temperature, and evaporating the solvent to dryness to obtain crystalline form A.

[0007] Preferably, the temperature is raised to 50 to 60°C, for example, 50°C, 53°C, 55°C, 58°C or 60°C.

[0008] In a third aspect, the present application provides crystalline form B of ethoximod, having an X-ray diffraction spectrum with diffraction peaks at 2θ diffraction angles of 9.025°±0.2°, 15.108°±0.2°, 16.213°±0.2°, 17.352°±0.2°, 18.151°±0.2°, 19.143°±0.2°, 21.230°±0.2°, 22.113°±0.2°, 23.537°±0.2°, 24.755°±0.2°, and 27.928°±0.2°.

[0009] In a fourth aspect, the present application provides a method for preparing crystalline form B of ethoximod according to the third aspect, comprising: The present invention provides a method for preparing crystalline form B of ethoximod, the method comprising the steps of adding crystalline form A of ethoximod to a mixed solvent, dissolving the crystalline form A until it becomes clear, and spray-drying the solution to obtain crystalline form B of ethoximod.

[0010] Preferably, the mixed solvent is a mixed solvent of acetone and water, or a mixed solvent of ethanol and water.

[0011] Preferably, the volume ratio of acetone to water is 1:0.5 to 2, for example, 1:0.5, 1:0.6, 1:0.8, 1:1.0, 1:1.3, 1:1.5, 1:1.8 or 1:2.

[0012] Preferably, the volume ratio of ethanol to water is 1:0.1 to 1, for example, 1:0.1, 1:0.3, 1:0.5, 1:0.8 or 1:1.

[0013] In this application, it has been found that ethoximod has multiple crystalline forms, including, but not limited to, crystalline form A, crystalline form B, crystalline form C, and crystalline form D. crystalline form A and crystalline form B have value for industrial pharmaceutical applications. Based on a comparison of multiple indicators, including stability, solubility, hygroscopicity, morphology, powder properties, and mechanical performance, it has been found that, compared with crystalline form B, crystalline form A has a simpler preparation form, higher efficiency, is more suitable for industrialized manufacturing, is less expensive, has lower hygroscopicity, higher solubility, and better physicochemical and mechanical stability.

[0014] In a fifth aspect, the present application provides a pharmaceutical composition comprising crystalline form A of ethoximod according to the first aspect and / or crystalline form B of ethoximod according to the third aspect, and pharmaceutically acceptable auxiliary materials.

[0015] In a sixth aspect, the present application provides use of crystalline form A of ethoximod according to the first aspect or crystalline form B of ethoximod according to the third aspect in the preparation of an S1P1 receptor immunosuppressant. [Effects of the Invention]

[0016] Compared with the prior art, the present application has the following beneficial effects:

[0017] The crystalline forms A and B of ethoximod according to the present invention can exist stably, and the crystalline form A has lower hygroscopicity, higher solubility, better mechanical stability, low flowability, low adhesiveness and good tabletability, and is therefore expected to be widely used in the pharmaceutical industry. [Brief explanation of the drawings]

[0018] [Figure 1] 1 is an X-ray powder diffraction (XRPD) spectrum of crystalline form A of ethoximod. [Figure 2] FIG. 1 is a differential scanning calorimetry (DSC) diagram of crystalline form A of ethoximod. [Figure 3] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form A of ethoximod. [Figure 4] 1 is an FT-infrared (FT-IR) spectrum of crystalline form A of ethoximod. [Figure 5] FIG. 1 is a dynamic water sorption (DVS) diagram of crystalline form A of ethoximod. [Figure 6] 1 is an X-ray powder diffraction (XRPD) spectrum of crystalline form B of ethoximod. [Figure 7] FIG. 1 is a differential scanning calorimetry (DSC) diagram of crystalline form B of ethoximod. [Figure 8] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form B of ethoximod. [Figure 9] 1 is an FT-infrared (FT-IR) spectrum of crystalline form B of ethoximod. [Figure 10] FIG. 1 is a dynamic moisture sorption (DVS) diagram of crystalline form B of ethoximod. [Figure 11] 1 is an X-ray powder diffraction (XRPD) spectrum of crystalline form C of ethoximod. [Figure 12] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form C of ethoximod before and after drying. [Figure 13] FIG. 1 is a thermogravimetric (TGA) diagram of a sample of ethoximod crystalline form B left at 92.5% RH for 30 days. [Figure 14] X-ray powder diffraction (XRPD) spectrum of crystalline form D of ethoximod. [Figure 15] FIG. 1 is a differential scanning calorimetry (DSC) diagram of crystalline form D of ethoximod. [Figure 16] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form D of ethoximod. [Figure 17] 1 is a stability-dependent X-ray powder diffraction (XRPD) overlay plot of crystalline form A of ethoximod. [Figure 18] 1 is a stability-dependent X-ray powder diffraction (XRPD) overlay plot of crystalline form B of ethoximod. [Figure 19] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form A of ethoximod before and after polishing. [Figure 20] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form B of ethoximod before and after polishing. [Figure 21] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form A of ethoximod before and after tableting. [Figure 22] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form B of ethoximod before and after tableting. [Figure 23] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form A of ethoximod before and after DVS measurement. [Figure 24] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form B of ethoximod before and after DVS measurement. [Figure 25] Microscopic observation of ethoximod crystalline form A, scale 20 μm. [Figure 26] Microscopic observation of ethoximod crystalline form B, scale 10 μm. DETAILED DESCRIPTION OF THE INVENTION

[0019] The technical solution of the present application will be further described below through specific embodiments. Those skilled in the art should understand that the above examples are only for understanding the present application and should not be considered as specific limitations on the present application.

[0020] In the examples of this application, the X-ray powder diffraction test was performed using a Bruker D2 Phaser. A TA Instruments DSC250 differential scanning calorimeter was used for differential scanning calorimetry. A TA Instruments TGA55 thermogravimetric analyzer was used for thermogravimetric analysis. A Thermo Fourier infrared spectrophotometer, model ID1-summit, was used for FT-infrared testing. A Surface Measurement System (SMS)-DVS Intrinsic was used for dynamic moisture sorption testing. A Suzhou Nanpo Electronics Technology Co., Ltd. microscope, model NJF-120A, was used for microscopy testing.

[0021] Example 1 Preparation of crystalline form A of ethoximod A 3.5 g sample of ethoximod was weighed and placed in a 500 mL single-neck glass flask, and 400 mL of methanol was added. The flask was heated to 55°C to dissolve the sample. After the sample became clear, it was transferred to a rotary evaporator to evaporate the solvent to dryness, yielding 2.9 g of a solid (yield 82.8%). The solid was then analyzed by XRPD. The resulting solid was identified as ethoximod Form A.

[0022] Analysis results: Purity determined by HPLC is 98.84%. 1H-NMR (400MHz, DMSO-d6): δ=8.54(s,1H),7.97(s,3H),7.84(d,J=8.3Hz,2H),7.71(d,J=8.3Hz,2H),7.65(d,J=8.1Hz,2H),7.33(d,J=8. 0Hz,2H),5.44(t,J=5.3Hz,2H),3.57(d,J=4.7Hz,4H),2.82(q,J=7.6Hz,2H),2.72-2.64(m,2H),1.91-1.82(m,2H),1.30(t,J=7.6Hz,3H).

[0023] FIG. 1 shows the XRPD spectrum of isolated crystalline form A of 2-amino-2-{2-(4′-(2-ethyloxazol-4-yl)-[1,1′-biphenyl]-4-yl)ethyl}-1,3-propanediol hydrochloride, and the XRPD parameters in the figure are summarized in Table 1 below. [Table 1]

[0024] The crystalline form A has a differential scanning calorimetry (DSC) diagram shown in Figure 2. As can be seen from the diagram, when crystalline form A was heated to 225°C (the onset temperature), an endothermic peak appeared, which was the melting endothermic peak of crystalline form A.

[0025] The crystalline form A has a thermogravimetric (TGA) diagram shown in Figure 3. As can be seen from the diagram, when crystalline form A was heated to 150°C, there was a mass loss of about -0.2% (instrumental error is ±0.2%).

[0026] The crystalline form A has a Fourier-infrared (FT-IR) diagram shown in Figure 4. As can be seen, the crystalline form A was characterized by Fourier transform attenuated total reflectance infrared spectroscopy (FT-IR), which provided qualitative data of the infrared spectrum and proved that the product conformed to the structure of ethoximod.

[0027] The crystalline form A has a dynamic moisture sorption (DVS) diagram shown in Figure 5. As can be seen from the figure, the DVS spectrum of crystalline form A revealed that the sample absorbed moisture and gained 0.14% in weight, indicating that the sample had little or no moisture absorption (moisture sorption at 25°C / 90% RH).

[0028] Example 2 Preparation of crystalline form B of ethoximod A 5 g sample of ethoximod Form A was weighed into a 500 mL single-neck glass flask, and 225 mL of acetone and 225 mL of water were added to dissolve the sample. After the sample became clear, it was spray-dried to obtain 2.67 g of a solid (yield: 53.4%). The resulting solid was determined to be ethoximod Form B by XRPD.

[0029] Analysis results: Purity determined by HPLC is 98.85%. 1 H-NMR(400MHz,DMSO-d6):δ=8.53(s,1H),8.08-7.79(m,5H),7.71(d,J=8.3Hz,2H),7.65(d,J=7.9Hz,2H),7.32(d,J=7.9Hz,2H), 5.42(t,J=5.0Hz,2H),3.56(d,J=4.8Hz,4H),2.83(q,J=7.6Hz,2H),2.71-2.63(m,2H),1.91-1.79(m,2H),1.30(t,J=7.6Hz,3H).

[0030] FIG. 6 shows the XRPD spectrum of isolated crystalline form B of 2-amino-2-{2-(4′-(2-ethyloxazol-4-yl)-[1,1′-biphenyl]-4-yl)ethyl}-1,3-propanediol hydrochloride, the XRPD parameters of which are summarized in Table 2. [Table 2]

[0031] The crystalline form B has a differential scanning calorimetry (DSC) diagram shown in Figure 7. As can be seen from the diagram, when crystalline form B was heated to 142°C (onset temperature), a first endothermic peak appeared, and when it was heated to 233°C (onset temperature), a second endothermic peak appeared.

[0032] The crystalline form B has a thermogravimetric (TGA) diagram shown in Figure 8. When crystalline form B was heated to 150°C, there was a mass loss of about -0.1% (instrument error ±0.2%). The TGA results indicated that crystalline form B was anhydrous.

[0033] Crystalline Form B can be characterized by Fourier transform attenuated total reflectance infrared spectroscopy (FT-IR) to obtain qualitative data of the infrared spectrum. The FT-IR spectrum of Crystalline Form B is shown in Figure 9.

[0034] The crystalline form B has a dynamic moisture sorption (DVS) diagram shown in Figure 10. As can be seen from the diagram, the sample absorbed moisture and gained 4.6% in weight, indicating that it was hygroscopic (moisture sorption at 25°C / 90% RH).

[0035] Example 3 Preparation of crystalline form B of ethoximod A 5 g sample of ethoximod crystalline form A was weighed and placed in a 500 mL single-neck glass flask, and 270 mL of ethanol and 30 mL of water were added to dissolve the sample. After the sample became clear, the temperature was lowered to precipitate crystals, yielding 3.1 g of a solid (yield: 62%). The resulting solid was determined to be ethoximod crystalline form B by XRPD.

[0036] Example 4 Preparation of crystalline form C of ethoximod A 250 mg sample of ethoximod Form B was weighed and placed in a 10 mL glass vial, and 5 mL of a pH 1.0 hydrochloric acid solution was added to form a suspension, which was then stirred at room temperature for 20 hours. The XRPD analysis results are shown in Figure 11. The resulting solid is ethoximod Form C.

[0037] The sample was dried under vacuum at 50°C overnight and then subjected to XRPD analysis. As shown in Figure 12, a portion of the solid material transformed into ethoximod form A. The sample was then purged with nitrogen gas at room temperature for 3 hours and subjected to XRPD analysis. As shown in Figure 12, a portion of the solid material transformed into ethoximod form A. After DVS analysis of ethoximod form B, the sample transformed into ethoximod form C, and the XRPD comparison is shown in Figure 24. After 30 days of storage at 92.5% RH, ethoximod form B transformed into ethoximod form C, and the XRPD comparison is shown in Figure 18. The sample was subjected to TGA analysis, and the TGA results are shown in Figure 13. From these results, it was estimated that form C is an unstable pipe-shaped hydrate, prone to transformation during both drying and storage, making it difficult to prepare a pure form.

[0038] Analysis of dried samples: Purity: 98.81%. 1 H-NMR(400MHz,DMSO-d6):δ=8.53(s,1H),7.94(s,3H),7.86-7.82(m,2H),7.74-7.70(m,2H),7.67-7.63(m,2H),7.35-7.31(m,2H) ,5.43(t,J=5.2Hz,2H),3.56(d,J=5.1Hz,4H),2.83(q,J=7.6Hz,2H),2.71-2.64(m,2H),1.89-1.82(m,2H),1.30(t,J=7.6Hz,3H).

[0039] Example 5 Preparation of crystalline form D of ethoximod A 13 mg sample of ethoximod Form B was weighed out and placed in an aluminum pan. The pan was heated to 180°C at a rate of 10°C / min using a TA Instruments TGA25, purged with nitrogen gas, and then incubated for 40 minutes. The pan was then cooled to room temperature to obtain an off-white solid. The XRPD analysis results are shown in Figure 14. The resulting solid is ethoximod Form D.

[0040] Ethoximod crystalline form D was obtained by heating and is difficult to expand. Its TGA diagram is shown in Figure 16. The sample lost 1.4% weight before reaching 150°C. Ion chromatography analysis of the heated sample revealed a chloride ion content of 8.32% (theoretical chloride ion content: 8.83%), and the HPLC purity was 98.70%. These results indicate that the heating procedure does not significantly decompose ethoximod. Therefore, crystalline form D is presumed to be an anhydrous form.

[0041] Analysis results: Purity: 98.70%. 1 H-NMR(400MHz,DMSO-d6):δ=8.54(s,1H),8.05-7.80(m,5H),7.75-7.69(m,2H),7.68-7.63(m,2H),7.32(d,J=8.2Hz,2H),5.4 2(t,J=5.0Hz,2H),3.56(d,J=4.3Hz,4H),2.83(q,J=7.6Hz,2H),2.71-2.63(m,2H),1.90-1.80(m,2H),1.30(t,J=7.6Hz,3H).

[0042] Example 6: Solid-state stability of ethoximod forms A and B Through polymorph screening of ethoximod, a total of four crystalline forms were discovered, named Form A, Form B, Form C, and Form D. Form C is a hydrated crystalline form that is unstable and prone to losing water during drying and standing, resulting in a partial transformation to Form A, making it difficult to obtain a pure form. Form D is an anhydrous crystalline form obtained through a heating test and is difficult to expand. In summary, Form A and Form B of ethoximod were further evaluated.

[0043] Samples of ethoximod Form A and Form B were stored under conditions of 60°C, 92.5% RH, light irradiation, and 45°C / 75% RH, respectively. Samples were taken before and after storage to measure the crystal form by XRPD. The results are shown in Table 3. Figures 17 and 18 show comparative XRPD patterns of ethoximod Form A and Form B after storage. As can be seen from the results, Form A is stable for at least 30 days under conditions of 60°C, 92.5% RH, light irradiation, and 45°C / 75% RH. Form B is stable for at least 30 days under conditions of 60°C and light irradiation. However, Form B transformed into Form C after 5 days of storage under conditions of 92.5% RH and 45°C / 75% RH.

[0044] Crystalline Form A showed no significant change in the main purity after 30 days at 40°C / 75% RH, 60°C, and 92.5% RH, but showed a slight decrease in the main purity after 30 days under light irradiation. Crystalline Form B showed no significant change in the main purity after 30 days at 40°C / 75% RH, 60°C, and 92.5% RH, but showed a slight decrease in the main purity after 30 days under light irradiation. [Table 3]

[0045] Example 7: Consideration of the dynamic solubility of ethoximod forms A and B Samples of ethoximod Form A and Form B were prepared as saturated solutions at 37°C in FaSSIF (Fasted State Simulated Intestinal Fluid, artificial fasting fluid, pH 8.0), FeSSIF (Fed State Simulated Intestinal Fluid, artificial postprandial fluid, pH 5.0), SGF (Simulated Gastric Fluid, artificial gastric fluid, pH 1.0), aqueous hydrochloric acid at pH 1.0, acetic acid-sodium acetate buffer at pH 4.0, phosphate buffer at pH 6.8, and water. After 1, 2, 4, and 24 hours, the solutions were filtered to determine the actual concentrations of the samples in the solutions (diluting the filtrate as necessary). XRPD was used to characterize the crystalline forms of the solids before and after the test to determine whether a phase transition occurred. The test results are shown in Table 4. [Table 4]

[0046] The results show that Form A has slightly higher solubility in FaSSIF, FeSSIF, pH 1.0 hydrochloric acid solution, pH 6.8 phosphate buffer solution, and water than Form B, and Form B also underwent a crystal transformation in the solvent. These results indicate that Form A is the predominant crystalline form suitable for drug development.

[0047] Example 8: Consideration of the equilibrium solubility of ethoximod forms A and B Ethoximod Forms A and B were prepared as solutions at room temperature using ethanol, acetone, and ethyl acetate, respectively. After equilibration for 24 hours, the solutions were filtered to obtain saturated solutions. The content of each sample in the saturated solution was measured using high-performance liquid chromatography (HPLC) (the filtrate was diluted as necessary). The crystalline forms of the solids were characterized before and after the test using XRPD to check for phase transition. The test results are shown in Table 5. The results showed that at room temperature, Form A had a slightly higher solubility in acetone and ethyl acetate than Form B, and Form B underwent a crystal transition in the medium. [Table 5]

[0048] Example 9: Morphology of ethoximod forms A and B Microscopic morphology studies were performed on samples of ethoximod forms A and B. Using an optical microscope with a 40x objective, the morphology and particle size of forms A and B were observed. The results of the microscopic observations are shown in Figures 26 and 27. Form A is irregularly sheet-like, with a raw particle size of 35 μm or less and a major axis / minor axis ratio of 1 to 2. Form B is spherical and aggregated, with a raw particle size of 20 μm or less.

[0049] Example 10 Mechanical Stability of Ethoximod Forms A and B 50 mg of ethoximod forms A and B were weighed and polished clockwise in an agate mortar for 5 minutes. XRPD measurements were performed on the samples before and after polishing. The results are shown in Figures 19 and 20. The XRPD results showed that form A did not change its crystal form after polishing, while form B partially transformed into form C after polishing, and form A had better mechanical stability than form B.

[0050] Example 11 Hygroscopicity of Ethoximod Forms A and B Dynamic moisture sorption tests were performed on samples of ethoximod forms A and B. The results are shown in Figures 5 and 10. The test results indicated that form A was not or only slightly hygroscopic (absorbed water at 24.3°C and 90% RH, resulting in a 0.14% weight gain), while form B was slightly hygroscopic (absorbed water at 25.0°C and 90% RH, resulting in a 4.6% weight gain). The dynamic moisture sorption tests revealed that form A did not undergo a crystal transformation, while form B transformed into form C, and the XRPD comparison results are shown in Figures 23 and 24.

[0051] Example 12: Flowability of ethoximod forms A and B The powder properties of a drug substance affect its flowability, and angle of repose and Hausner ratio tests were performed on ethoximod Form A and Form B to compare their flowability. The results of the flowability evaluation are shown in Table 7. Form A and Form B had comparable flowability.

[0052] How to measure the angle of repose: In this study, the angle of repose of two crystalline forms of API was measured using the injection method in conjunction with the residual cone method to analyze their flowability. Specifically, powder was injected into the center of a disk of a finite diameter until the material on the hypotenuse of the powder deposit flowed automatically along the edge of the disk. The injection was then stopped and the height of the cone (H) was measured. The angle of repose was calculated using the disk diameter (D = 2r), and is given by tanQ = H / r. The measurement results for the angle of repose are shown in Table 6.

[0053] Test method for loose bulk density and tapped density: In this test, a tapped density meter was used to measure the powder according to the fixed volume method. Specifically, the weighed powder was placed in a 50 mL measuring cylinder, and the measuring cylinder was fixed to a support stand. The vibration was performed at 55 ± 5 vibrations per minute for 6 to 8 minutes. The change in the volume of the powder in the measuring cup was measured, and the ratio of the mass of the powder to the volume of the material before tapping (50 mL) was the bulk density of the powder, and the ratio of the mass of the powder to the volume of the material after tapping was the tapped density of the powder.

[0054] The conversion methods for the Hausner ratio and compressibility are as follows, and the explanations for the Hausner ratio and fluidity are shown in Table 8.

[0055] Hausner ratio of material = tap density / loose bulk density Material compressibility = (tap density - loose bulk density) / tap density [Table 6] [Table 7] [Table 8]

[0056] Example 13: Adhesion of ethoximod forms A and B Ethoximod crystalline form A and crystalline form B were placed in a self-sealing bag of a certain size, the opening was sealed, and the bag was inverted at a rotation speed of 5 rpm for 10 minutes. After changing the direction and continuing to invert at a constant rotation speed for 10 minutes, the raw material was poured out of the bag, and the mass of the remaining raw material was precisely weighed to calculate the adsorption rate.

[0057] The adsorption rate is calculated as follows. Adsorption rate = (initial material mass - remaining material mass) / contact surface area

[0058] The results of the adhesion of ethoximod forms A and B are shown in Table 9. As can be seen from the results, forms A and B had comparable adsorption properties. [Table 9]

[0059] Example 14 Tableting Suitability of Ethoximod Forms A and B Tableting evaluation was performed on ethoximod crystalline forms A and B. In this test, a 6 mm diameter die was used to compress the samples at the same pressure. After the tablet's elasticity was restored, the crushing force F, diameter D, and thickness L in the radial direction of the tablet were measured, and the tensile strength of the tablet was calculated using the following formula: where tensile strength Ts = 2F / ΠDL.

[0060] The evaluation results of the tableting suitability of ethoximod crystalline forms A and B are shown in Table 10. The XRPD results before and after tableting are shown in Figures 21 and 22. As can be seen from the results, crystalline form A had a smaller degree of sticking than crystalline form B, indicating that it is more suitable for the preparation of solid formulations. [Table 10]

[0061] Although the present application has described the crystalline forms, preparation methods and uses of ethoximod in the present application through the above examples, the applicant declares that the present application is not limited to the above process steps, i.e., the present application does not have to be carried out by the above process steps. It is clear to those skilled in the art that any modifications to the present application, equivalent substitutions for the raw materials selected in the present application, addition of auxiliary ingredients, selection of specific embodiments, etc., are all within the scope of protection and disclosure of the present application.

Claims

1. In the X-ray diffraction spectrum, there are diffraction peaks at 2θ diffraction angles of 9.295°±0.2°, 14.026°±0.2°, 17.107°±0.2°, 17.774°±0.2°, 21.458°±0.2°, 21.937°±0.2°, 22.396°±0.2°, 26.883°±0.2°, 28.236°±0.2°, and 28.534°±0.2°. Ethoximod crystalline form A.

2. 2. A process for preparing crystalline form A of ethoximod according to claim 1, comprising: adding an ethoximod sample to methanol, dissolving at elevated temperature, and evaporating the solvent to dryness to obtain crystalline form A. Preparation method.

3. The temperature is increased to 50 to 60°C. The preparation method according to claim 2.

4. In the X-ray diffraction spectrum, there are diffraction peaks at 2θ diffraction angles of 9.025°±0.2°, 15.108°±0.2°, 16.213°±0.2°, 17.352°±0.2°, 18.151°±0.2°, 19.143°±0.2°, 21.230°±0.2°, 22.113°±0.2°, 23.537°±0.2°, 24.755°±0.2°, and 27.928°±0.2°. Ethoximod crystalline form B.

5. 5. A process for preparing crystalline form B of ethoximod according to claim 4, comprising the steps of: adding crystalline form A of ethoximod to a mixed solvent, dissolving until clear, and spray-drying the solution to obtain crystalline form B of said ethoximod; Preparation method.

6. The mixed solvent is a mixed solvent of acetone and water or a mixed solvent of ethanol and water. The preparation method according to claim 5.

7. The volume ratio of acetone to water is 1:0.5-2; The preparation method according to claim 6.

8. The volume ratio of ethanol to water is 1:0.1 to 1; The preparation method according to claim 6.

9. 1. A pharmaceutical composition comprising crystalline form A of ethoximod according to claim 1 and / or crystalline form B of ethoximod according to claim 4, and pharmaceutically acceptable auxiliary materials. Pharmaceutical compositions.

10. Use of crystalline form A of ethoximod according to claim 1 or crystalline form B of ethoximod according to claim 4 in the preparation of an S1P1 receptor immunosuppressant.

Images