Crystalline forms of proximod and methods for its preparation and use

Abstract

This application provides crystalline forms of proximod, as well as 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 and low flowability, as well as low adhesion and good tabletability, making them promising for use in the pharmaceutical industry.

Description

[Technical Field]

[0001] The present application is in the field of pharmaceutical technology, and specifically relates to a crystalline form of Proximod and its preparation and use. [Background technology]

[0002] Proximod (2-amino-2-{2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl}-1,3-propanediol hydrochloride, H001) is an agonist of the S1P1 receptor. It belongs to the prodrug form, which can be phosphorylated in the body and converted to H001-P to activate the S1P1 receptor and can be used to prepare medicines for treating autoimmune diseases. [ka] [ka]

[0003] Although the prior art discloses a method for preparing Proximod, it does not disclose the state of 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 formulation product. Therefore, investigation into the crystalline form of Proximod is of great significance for the research and development of subsequent formulations. Summary of the Invention [Problem to be solved by the invention]

[0004] The present application provides crystalline forms of proximod and methods for their preparation and use.

[0005] In a first aspect, the present application provides crystalline form A of Proximod, which has diffraction peaks in an X-ray diffraction spectrum at 2θ diffraction angles of 3.2°±0.2°, 9.7°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 23.8°±0.2°, 26.5°±0.2°, and 26.8°±0.2°. [Means for solving the problem]

[0006] In the present application, the XRPD chart of the crystalline form A is shown in FIG. 1, and the XRPD parameters of the crystalline form A are shown in the table below. [Table 1]

[0007] In a second aspect, the present application provides a method for preparing crystalline form A of Proximod according to the first aspect, comprising the steps of adding a crude sample of Proximod to a mixed solvent of tetrahydrofuran and water, maintaining the pH of the system at 6 to 6.5, heating and dissolving until a clear solution is obtained, adding the clear solution to methyl t-butyl ether, stirring, precipitating a solid, isolating the solid, and drying under reduced pressure to obtain crystalline form A.

[0008] Preferably, the mixed solvent is tetrahydrofuran and water in a volume ratio of 9:1.

[0009] Preferably, the temperature is increased to reflux.

[0010] In this application, the addition of the clear solution to methyl t-butyl ether is carried out dropwise.

[0011] Preferably, the temperature of the reduced pressure drying is 40 to 50°C, for example, 40°C, 42°C, 45°C, 48°C, or 50°C.

[0012] In the present application, the pH of the system is maintained at 6 to 6.5 during the preparation of Crystalline Form A, for example, 6, 6.1, 6.2, 6.3, 6.4, or 6.5. The means for achieving a pH of 6 to 6.5 may be any pH adjusting means commonly used in the art, such as adding an acid or alkali or a buffer solution.

[0013] In the present application, crystalline form A can be obtained by maintaining the pH of the system at 6 to 6.5 during the preparation process of the crystalline form. If the pH of the system changes, for example, if the pH of the system is lower than 6, mixed crystals will form, and if the pH of the system is higher than 6.5, crystals will not form.

[0014] In a third aspect, the present application provides crystalline form B of Proximod, which has diffraction peaks in an X-ray diffraction spectrum at 2θ diffraction angles of 4.5°±0.2°, 9.0°±0.2°, 13.6°±0.2°, 18.1°±0.2°, 19.2°±0.2°, 21.8°±0.2°, 24.5°±0.2°, 27.5°±0.2°, and 27.8°±0.2°.

[0015] In the present application, the XRPD chart of the crystalline form B is shown in FIG. 6, and the XRPD parameters of the crystalline form A are shown in the table below. [Table 2]

[0016] In a fourth aspect, the present application provides a method for preparing crystalline form B of Proximod according to the third aspect, comprising the steps of adding the above-mentioned crystalline form A of Proximod to a mixed solvent, adding an acid to adjust the pH to 1-2, heating the mixture until a clear solution is refluxing, cooling the mixture to 40-50°C, stirring, cooling to room temperature, isolating the solid, and drying under reduced pressure to obtain crystalline form B.

[0017] Preferably, the pH of the system is adjusted with an acid, said acid being concentrated hydrochloric acid.

[0018] Preferably, the mixed solvent contains ethanol and water.

[0019] Preferably, the volume ratio of ethanol to water is 9:1.

[0020] In the present application, the temperature may be lowered naturally.

[0021] Preferably, the temperature of the reduced pressure drying is 45 to 55°C, for example, 45°C, 48°C, 50°C, 53°C, or 55°C.

[0022] Preferably, the temperature is naturally lowered to 40 to 50°C, and then seed crystals of crystalline form B are added to the system. In the present application, when crystalline form B is obtained and then prepared again, it is more advantageous to add seed crystals of crystalline form B during the preparation process to produce crystalline form B.

[0023] In this application, crystalline forms A and B can exist stably and have low hygroscopicity, high solubility, good mechanical stability, low flowability, low adhesion, and good tabletability, making them promising for industrialization in the pharmaceutical industry. Crystalline forms A and B are pH-dependent, and by adjusting the preparation process, crystalline forms A and B of Proximod can be obtained under different pH conditions. Using crude Proximod as the starting material, crystalline form A of Proximod can be obtained when the pH of the system is 6 to 6.5, and crystalline form B of Proximod can be obtained by preparation with crystalline form A when the pH of the system is 1 to 2.

[0024] During the process of preparing crystalline form B from crystalline form A, if the pH of the system exceeds 2, mixed crystals will form, and if the pH is less than 1, the compound will decompose.

[0025] Crystalline Form B according to the present invention is obtained by recrystallization from Crystalline Form A when the pH of the system is 1 to 2. If a crude sample of Proximod is added directly to a mixed solvent, the pH of the system is adjusted to 1 to 2, the temperature is raised until a clear solution is refluxed, the temperature is lowered to 40 to 50°C, the mixture is stirred, and the mixture is cooled to room temperature, Crystalline Form B cannot be obtained.

[0026] In the present application, compared to crystalline form B, crystalline form A of Proximod has lower hygroscopicity, higher solubility, better mechanical stability and flowability.

[0027] According to the study of the present application, it has been found that proximod has multiple crystalline forms, including, but not limited to, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, and crystalline form F. Compared to other crystalline forms, crystalline form A and crystalline form B are more stable crystalline forms and have low hygroscopicity, high solubility, good mechanical stability and low flowability, as well as low adhesion and good tabletability, making them promising for use in the pharmaceutical industry.

[0028] In a fifth aspect, the present application provides a pharmaceutical composition comprising crystalline form A of Proximod according to the first aspect and / or crystalline form B of Proximod according to the third aspect, and pharmaceutically acceptable auxiliary materials.

[0029] Preferably, the pharmaceutically acceptable auxiliary material comprises microcrystalline cellulose.

[0030] In the present application, by using microcrystalline cellulose as an auxiliary material, it is possible to improve the tableting suitability of crystalline forms A and B of Proximod, and to improve the hardness and tensile strength of the tablets.

[0031] Preferably, the pharmaceutical composition comprises the above-mentioned crystalline form A of proximod and pharmaceutically acceptable auxiliary materials including microcrystalline cellulose.

[0032] Compared with crystalline form B, the use of microcrystalline cellulose can significantly improve the tableting suitability of crystalline form A, resulting in better tableting effect and higher tablet quality.

[0033] In a sixth aspect, the present application provides the use of crystalline form A of Proximod according to the first aspect, or crystalline form B of Proximod according to the third aspect, or a pharmaceutical composition according to the fifth aspect, in the preparation of a pharmaceutical product having immunomodulatory activity.

[0034] Preferably, the pharmaceutical agent having an immunomodulatory effect is selected from pharmaceutical agents for treating immune disorders, immunosuppression, immunosuppression, organ transplant rejection, or autoimmune diseases.

[0035] Preferably, the pharmaceutical agent having immunomodulatory activity is selected from pharmaceutical agents for treating rheumatoid arthritis. [Effects of the Invention]

[0036] Compared with the prior art, the present application has the following beneficial effects:

[0037] The crystalline forms A and B of proximod according to the present application can exist stably, and have low hygroscopicity, high solubility, good mechanical stability and low flowability, as well as low adhesion and good tableting suitability, making them promising for use in the pharmaceutical industry.

[0038] Crystalline forms A and B of Proximod according to the present application are pH-dependent, and by adjusting the preparation process, crystalline forms A and B of Proximod can be obtained under different pH conditions. Using a crude Proximod sample as the starting material, when the pH of the system is 6 to 6.5, crystalline form A of Proximod can be obtained, and when the pH of the system is 1 to 2, crystalline form B of Proximod can be obtained.

[0039] Compared to crystalline form B, crystalline form A of proximod has lower hygroscopicity, higher solubility, better mechanical stability, lower flowability and better tabletability. [Brief explanation of the drawings]

[0040] [Figure 1] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form A of Proximod. [Figure 2] 1 is a differential scanning calorimetry (DSC) diagram of crystalline form A of Proximod. [Figure 3] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form A of Proximod. [Figure 4]1 is an FT-infrared (FT-IR) spectrum of crystalline form A of Proximod. [Figure 5] FIG. 1 is a dynamic water sorption (DVS) diagram of crystalline form A of Proximod. [Figure 6] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form B of Proximod. [Figure 7] 1 is a differential scanning calorimetry (DSC) diagram of crystalline form B of Proximod. [Figure 8] Thermogravimetric (TGA) diagram of crystalline form B of Proximod. [Figure 9] 1 is an FT-infrared (FT-IR) spectrum of crystalline form B of Proximod. [Figure 10] FIG. 1 is a dynamic water sorption (DVS) diagram of crystalline form B of Proximod. [Figure 11] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form C of Proximod. [Figure 12] FIG. 1 is a differential scanning calorimetry (DSC) diagram of crystalline form C of Proximod. [Figure 13] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form C of Proximod. [Figure 14] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form D of Proximod. [Figure 15] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form D of Proximod after drying. [Figure 16] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form D of Proximod after drying. [Figure 17] 1 is a thermogravimetric (TGA) diagram of crystalline form D of Proximod after drying and standing at room temperature for 2 days. [Figure 18] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form E of Proximod. [Figure 19] 1 is a differential scanning calorimetry (DSC) diagram of crystalline form E of Proximod. [Figure 20] FIG. 1 is a thermogravimetric (TGA) diagram of crystalline form E of Proximod. [Figure 21] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form F of Proximod. [Figure 22] 1 is an X-ray powder diffraction (XRPD) chart of crystalline form F of Proximod after drying. [Figure 23] 1 is an X-ray powder diffraction (XRPD) overlay plot of stability of crystalline form A of Proximod. [Figure 24] 1 is an X-ray powder diffraction (XRPD) overlay plot of stability of crystalline form B of Proximod. [Figure 25] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form A of Proximod before and after polishing. [Figure 26] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form B of Proximod before and after polishing. [Figure 27] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form A of Proximod before and after tableting. [Figure 28] 1 is an X-ray powder diffraction (XRPD) overlay plot of crystalline form B of Proximod before and after tableting. [Figure 29] 1 shows the microscopic observation of crystalline form A of Proximod, of which the scale is 150 μm. [Figure 30] 1 shows the microscopic observation of crystalline form B of Proximod, of which the scale is 50 μm. DETAILED DESCRIPTION OF THE INVENTION

[0041] 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.

[0042] 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 microscopic testing.

[0043] Example 1 Preparation of Crystalline Form A of Proximod A 0.5 g sample of crude proximod was weighed and placed in a 3 mL glass flask. 2 mL of tetrahydrofuran / water (9:1, v / v) was added, and the temperature was raised to a clear solution while maintaining the pH of the system at 6-6.5. The clear solution was added dropwise to 10 mL of methyl t-butyl ether and stirred magnetically at room temperature for 30 min. The solid was isolated and dried overnight under reduced pressure at 45°C to obtain 0.42 g (yield: 84.0%). The resulting solid was Form A as determined by XRPD.

[0044] FIG. 1 shows the XRPD spectrum of isolated crystalline form A of 2-amino-2-{2-(4′-(2-propyloxazol-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 3]

[0045] 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 188°C (start temperature), a first endothermic peak, which is a melting endothermic peak, appeared, and when it was heated to 214°C (start temperature), a second endothermic peak, which is a decomposition endothermic peak, appeared.

[0046] 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%).

[0047] The crystalline form A has a Fourier-infrared (FT-IR) diagram shown in Figure 4. As can be seen from the diagram, the crystalline form A can be characterized by Fourier transform attenuated total reflectance infrared spectroscopy (FT-IR) to obtain qualitative data of the infrared spectrum. The following important wavelength ranges (reciprocal of wavelength data (cm)) are shown: -1 Qualitative analysis was performed using the data shown in Table 2 below. [Table 4]

[0048] The crystalline form A has a dynamic moisture sorption (DVS) diagram shown in Figure 5. As can be seen from the diagram, the sample absorbed moisture and gained 0.26% in weight, indicating that it was slightly hygroscopic (moisture sorption at 25°C / 90% RH).

[0049] Comparative Example 1 The only difference from Example 1 was that the pH of the system was maintained at 5.0 during the preparation process; all other steps were the same as in Example 1. Analysis revealed that mixed crystals of A and B were formed.

[0050] Comparative Example 2 The only difference from Example 1 is that the pH of the system is maintained at 7.0 during the preparation process, and all other steps are the same as in Example 1, so that crystals cannot be formed.

[0051] Comparative Example 3 The only difference from Example 1 was that the preparation process did not include the step of adding the clear solution dropwise to methyl t-butyl ether. Analysis revealed that mixed crystals of A and B were formed.

[0052] Example 2 Preparation of Crystalline Form B of Proximod A 4.0 g sample of crystalline form A of Proximod was weighed and placed in an 80 mL glass flask. 48.0 mL of a mixed solvent of ethanol / water (9:1, v / v) was added, and concentrated hydrochloric acid was added to adjust the pH of the system to 1-2. The temperature was then raised until a clear solution was refluxing. The temperature was naturally lowered to 45°C under magnetic stirring, and after stirring for 30 minutes, the temperature was naturally lowered to room temperature and stirring was continued. The solid was isolated and dried under vacuum at 50°C overnight to obtain 2.99 g of an off-white solid, crystalline form B (yield: 74.8%). XRPD analysis revealed that the obtained solid was crystalline form B of the present application.

[0053] FIG. 6 shows the X-ray powder diffraction (XRPD) spectrum of isolated crystalline form B of 2-amino-2-{2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl}-1,3-propanediol hydrochloride, of which the XRPD parameters are summarized in Table 3. [Table 5]

[0054] 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 173.9°C (initiation temperature), a first endothermic peak, which is a melting endothermic peak, appeared, and when it was heated to 213.1°C (initiation temperature), a second endothermic peak, which is a decomposition endothermic peak, appeared.

[0055] The crystalline form B has a thermogravimetric (TGA) diagram shown in Figure 8. When crystalline form B was heated to 150°C, it had a mass loss of about -0.2% (instrument error ±0.2%), and the TGA results showed that crystalline form B was anhydrous.

[0056] The crystalline form B has a Fourier-infrared (FT-IR) diagram shown in Figure 9. As can be seen from the diagram, the 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 following important wavelength ranges (reciprocal of wavelength data (cm)) are shown: -1Qualitative analysis was performed using the data shown in Table 4 below. [Table 6]

[0057] 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 0.26% in weight, indicating that it was slightly hygroscopic (moisture sorption at 25°C / 90% RH).

[0058] Comparative Example 4 The only difference from Example 2 was that concentrated hydrochloric acid was added to adjust the pH of the system to 3. All other steps were the same as in Example 2. Analysis showed that mixed crystals of A and B were formed.

[0059] Comparative Example 5 The only difference from Example 2 was that concentrated hydrochloric acid was added to adjust the pH of the system to 0.5; all other steps were the same as in Example 2, and analysis showed that the compound decomposed under these conditions.

[0060] Comparative Example 6 A 4.0 g sample of crude proximod was weighed and placed in an 80 mL glass flask. 48.0 mL of a mixed solvent of ethanol / water (9:1, v / v) was added, and concentrated hydrochloric acid was added to adjust the pH of the system to 1-2. The temperature was then raised until a clear solution was refluxing. The temperature was naturally lowered to 45°C under magnetic stirring, and after stirring for 30 minutes, the temperature was naturally lowered to room temperature and continued stirring. The solid was isolated and dried overnight under reduced pressure at 50°C. Analysis revealed that mixed crystals of A and B had formed.

[0061] Example 3 Preparation of Crystalline Form C of Proximod A 38 mg sample of crystalline form A of Proximod was weighed and placed in an aluminum pan. The pan was heated to 200°C at a rate of 10°C / min using a TA Instruments TGA25. The pan was then kept at 200°C for 40 minutes with a nitrogen gas purge, and then cooled to room temperature to obtain a pale yellow solid.

[0062] Ion chromatography analysis of a sample heated to 200°C revealed a chloride ion content of 8.05% (theoretical chloride ion content is 8.51%). Purity testing of the heated sample revealed an HPLC purity result of 98.42%. These results demonstrate that heating does not cause significant decomposition of Proximod.

[0063] The X-ray powder diffraction (XRPD) spectrum of crystalline form C measured by XRPD is shown in Figure 11. The resulting solid is crystalline form C of the present application. Crystalline form C of Proximod was produced by a heating test and is difficult to commercialize. Its DSC diagram is shown in Figure 12. It can be seen that when crystalline form C was heated to 114.1°C (onset temperature), a first endothermic peak, which is a melting endothermic peak, appeared; when heated to 137.5°C (onset temperature), a heat-release peak, which is a crystalline transition heat-release peak, appeared; when heated to 184.2°C (onset temperature), a second endothermic peak, which is a melting endothermic peak, appeared; and when heated to 211.8°C (onset temperature), a third endothermic peak, which is a decomposition endothermic peak, appeared. The TGA diagram is shown in Figure 13, and the weight loss of the sample up to 150°C was 1.4%. The ion chromatography analysis of the heated sample showed a chloride ion content of 8.05% (theoretical chloride ion content is 8.51%), and the purity measured by HPLC was 98.42%. These results indicate that the heating procedure does not cause significant decomposition of Proximod. Based on the above characterization results, it is assumed that crystalline form C is an anhydrous form.

[0064] Example 4 Preparation of Crystalline Form D of Proximod

[0065] A 500 mg sample of Form A of Proximod was weighed into a 10 mL glass vial, and 5 mL of 1,4-dioxane was added to form a suspension. The suspension was stirred at room temperature for 72 hours and isolated to give a white solid. XRPD analysis showed that the resulting solid was Form D of the present application, as shown in Figure 14.

[0066] The sample was dried under vacuum at 50°C for 6 hours and then subjected to XRPD analysis. As shown in Figure 15, a portion of the solid underwent a crystalline transformation to the present crystalline form A. Figures 16 and 17 show TGA thermal analysis patterns for a dried sample of crystalline form D of Proximod and a sample left at room temperature for two days after drying. As can be seen, a TGA test was performed on a dried sample of crystalline form D, which was heated to 150°C and showed a mass loss of approximately 5.4% (as shown in Figure 16). A TGA test was also performed on a sample of crystalline form D left at room temperature for two days after drying and showed a mass loss of approximately 4.8% (as shown in Figure 17). The theoretical weight loss of Proximod sesquihydrate is 6.1%. As can be seen from the TGA results, crystalline form D continuously lost water of crystallization during the storage process. Based on the above test results, it was estimated that crystalline form D is an unstable sesquihydrate. Since crystalline form D is an unstable sesquihydrate, it is likely to undergo crystal transformation during both drying and standing, making it difficult to prepare a pure form.

[0067] Example 5 Preparation of Crystalline Form E of Proximod A 50 mg sample of crystalline form A of Proximod was weighed into a 20 mL glass vial, and 10 mL of water was added to form a suspension. The suspension was then magnetically stirred at room temperature for 24 hours and isolated to yield a white solid. The resulting solid was identified as crystalline form E of the present application by XRPD, and its X-ray powder diffraction spectrum is shown in Figure 18. Crystalline form E of Proximod is obtained by chance and is difficult to repeatedly prepare. The thermogravimetric diagram of crystalline form E of Proximod is shown in Figure 19, and the TGA diagram of crystalline form E of Proximod is shown in Figure 20. As can be seen from the TGA results, crystalline form E is anhydrous.

[0068] Example 6 Preparation of Crystalline Form F of Proximod A 50 mg sample of crystalline form A of Proximod was weighed and placed in a 20 mL glass vial. 10 mL of water was added to form a suspension, which was then magnetically stirred at 50°C for 24 hours and isolated to give a white solid. The resulting wet sample was analyzed by XRPD. The resulting solid is crystalline form F of the present application, and its X-ray powder diffraction (XRPD) spectrum is shown in Figure 21. The wet sample was dried under reduced pressure at 50°C for 2 hours and then analyzed by XRPD. The results are shown in Figure 22. After drying, a portion of the sample underwent a crystalline transformation to crystalline form A. As can be seen, crystalline form F is a metastable crystalline form, and it is difficult to prepare a pure form.

[0069] Example 7 Solid State Stability of Proximod Forms A and B Through polymorph screening of Proximod, a total of six crystalline forms were discovered, named Form A, Form B, Form C, Form D, Form E, and Form F. Form C is an anhydrous crystalline form obtained through heating tests and is difficult to scale up industrially. Form D is a hydrate crystalline form that is unstable and prone to dehydration during storage, making it difficult to obtain a pure form. Form E is an anhydrous crystalline form obtained by chance and is difficult to repeatedly prepare. Form F is an unknown type of metastable crystalline form that is prone to crystal transformation to Form A and is difficult to prepare a pure form. In summary, Forms A and B of Proximod have industrial applicability.

[0070] Samples of crystalline form A and crystalline 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 5. XRPD comparison diagrams are shown in Figures 23 and 24. As can be seen from the results, crystalline form A and crystalline form B can be stabilized for at least 30 days under conditions of 60°C, 92.5% RH, and 45°C / 75% RH. After 30 days of storage under conditions of 40°C / 75% RH, 60°C, and 92.5% RH, the main purity did not change significantly, but after 30 days of storage under light irradiation, the main purity decreased. [Table 7]

[0071] Example 8 Dynamic Solubility Considerations of Proximod Forms A and B Samples of Form A and Form B of the present invention were prepared as saturated solutions at 37°C in FaSSIF (Fasted State Simulated Intestinal Fluid, artificial simulated fasting intestinal fluid, pH 8.0), FeSSIF (Fed State Simulated Intestinal Fluid, artificial simulated postprandial intestinal fluid, pH 5.0), SGF (Simulated Gastric Fluid, artificial simulated gastric fluid, pH 1.0), a pH 1.0 aqueous hydrochloric acid solution, a pH 4.0 acetic acid-sodium acetate buffer system, a pH 6.8 phosphate buffer system, and water. The saturated solutions were obtained by filtration after 1, 2, 4, and 24 hours, respectively. The actual concentrations of the samples in the saturated solutions (diluted as necessary) were measured by high-performance liquid chromatography (HPLC). The crystalline forms of the solids were characterized by XRPD before and after the test to check for the occurrence of a phase transition. The test results are shown in Table 6. [Table 8]

[0072] As can be seen from the results, crystalline form A has higher solubility in FeSSIF, SGF, hydrochloric acid solution at pH 1.0, acetic acid-sodium acetate buffer solution at pH 4.0, and water than crystalline form B. Furthermore, after stirring in FeSSIF at 37°C for 24 hours, no change in crystalline form occurred between crystalline form A and crystalline form B. These results indicate that crystalline form A is the predominant crystalline form suitable for drug development.

[0073] Example 9: Equilibrium solubility considerations for crystalline forms A and B of Proximod Crystalline Form A and Crystalline Form B of the present invention were prepared as saturated solutions using ethanol, acetone, and ethyl acetate, respectively, at room temperature. After equilibration for 24 hours, the saturated solutions were obtained by filtration. The content of each sample in the saturated solution was measured by high-performance liquid chromatography (HPLC) (the filtrate was diluted as necessary). The crystalline forms of the solids before and after the test were characterized by XRPD to check whether a phase transition occurred. The test results are shown in Table 7. The results showed that the solubility of Crystalline Form A in ethanol, acetone, and ethyl acetate was higher than that of Crystalline Form B at room temperature. [Table 9]

[0074] Example 10 Intrinsic dissolution of crystalline forms A and B of Proximod The dissolution rates of crystalline forms A and B of the present application were measured after tableting. The intrinsic dissolution rates of crystalline forms A and B of Proximod are shown in Table 8. The results show that the dissolution amounts of the two crystalline forms in aqueous media are extremely low, and that both crystalline forms can be rapidly released at a low flow rate of 4 mL / min in a pH 4.0 medium (the medium is an acetic acid-sodium acetate buffer system, prepared by dissolving 1.22 g of sodium acetate and 20.5 mL of 2 mol / L acetic acid solution in water, diluting to 1000 mL, and shaking uniformly). Comparing the dissolution rates over the first 30 minutes, crystalline form A released faster, demonstrating its pharmaceutical advantages. [Table 10]

[0075] Example 11 Morphological study of crystalline forms A and B of Proximod The morphology of samples of crystalline form A and crystalline form B of the present application was examined under a microscope, and the results of the microscopic observation are shown in Figures 29 and 30. Crystal form A is sheet-like and has a large particle size, with most particles having a particle size of 100 to 300 μm and a major axis / minor axis ratio of 1 to 3. Crystal form B is rod-like and has a maximum particle size of less than 100 μm, a particle size range of mainly 20 to 50 μm, and a major axis / minor axis ratio of 1 to 6.

[0076] Example 12 Mechanical Stability of Proximod Forms A and B 50 mg of each of the crystalline forms A and B of the present invention was weighed and polished clockwise in an agate mortar for 5 minutes. XRPD measurements were performed on the samples before and after polishing, and the results are shown in Figures 25 and 26. The XRPD results showed that crystalline form A did not change after polishing, while crystalline form B partially transformed into crystalline form A after polishing, and that crystalline form A had better mechanical stability than crystalline form B.

[0077] Example 13 Hygroscopicity of Proximod Forms A and B Dynamic moisture sorption tests were performed on samples of crystalline form A and crystalline form B of the present application. The results are shown in Figures 5 and 10. The test results showed that crystalline form A has no or little hygroscopicity (weight gain upon water absorption at 24.4°C and 90% RH was 0.06%), while crystalline form B has slight hygroscopicity (weight gain upon water absorption at 25.6°C and 90% RH was 0.30%).

[0078] Example 14 Flowability of Crystalline Forms A and B of Proximod The powder properties of the drug substance affect its flowability, and angle of repose and Hausner ratio tests were performed on Proximod crystalline forms A and B to compare their flowability. The results of the flowability evaluation are shown in Table 9. There is little difference in the adsorption rate between the two crystalline forms, and the flowability of crystalline form A is slightly better than that of crystalline form B.

[0079] Test method for loose bulk density and tapped density: In this test, a tapped density meter was used to measure the density 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 loose 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.

[0080] 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 10.

[0081] Hausner ratio of material = tap density / loose bulk density

[0082] Material compressibility = (tap density - loose bulk density) / tap density

[0083] How to measure the angle of repose: This study used the injection method in conjunction with the residual cone method to measure the angle of repose of two crystalline forms of APIs and 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 pile 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 (2r), where tanQ = h / r. [Table 11] [Table 12]

[0084] Example 15 Adhesion of Proximod Forms A and B Crystalline Form A and Crystalline Form B of the present invention 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, and then the direction was changed and the bag was continuously inverted at a constant rotation speed for another 10 minutes. After that, 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.

[0085] The adsorption rate is calculated as follows. Adsorption rate = (mass of initial material - mass of remaining material) / contact surface area

[0086] The results of the adhesion of Proximod crystalline forms A and B are shown in Table 11. As can be seen from the results, crystalline forms A and B had comparable adsorption rates. [Table 13]

[0087] Example 16 Tableting Suitability of Proximod Crystalline Forms A and B A tableting evaluation was performed on the crystalline forms A and B of the present invention. In this test, a 6 mm diameter die was used to compress the active ingredient and the active ingredient plus auxiliary materials at the same pressure. After the tablet's elasticity was restored, the crushing force F, diameter D, and thickness L of the tablet in the radial direction were measured, and the tensile strength of the tablet was calculated using the following formula: where tensile strength Ts = 2F / ΠDL.

[0088] The tableting suitability evaluation results for Proximod crystalline forms A and B are shown in Table 12, and the XRPD results before and after tableting are shown in Figures 27 and 28. As can be seen from the results, the two crystalline raw materials have poor tableting suitability, both of which suffer from severe sticking and are difficult to form. However, when used in combination with auxiliary materials with good tableting suitability, the tableting suitability of the raw material for crystalline form A can be quickly improved, so the tableting suitability of crystalline form A is superior to that of crystalline form B. [Table 14]

[0089] Although the present application has described the crystalline form, preparation method and use of Proximod 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 improvements to the present application, equivalent substitution of the raw materials selected in the present application and addition of auxiliary components, 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 3.2°±0.2°, 9.7°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 23.8°±0.2°, 26.5°±0.2°, and 26.8°±0.2°. Crystalline form A of proximod.

2. 2. A process for preparing crystalline form A of Proximod according to claim 1, comprising: adding a crude sample of Proximod to a mixed solvent, maintaining the pH of the system at 6 to 6.5, and dissolving at elevated temperature until a clear solution is obtained; adding the clear solution to methyl t-butyl ether, stirring, and precipitating a solid; isolating the solid and drying it under reduced pressure to obtain said crystalline form A. Preparation method.

3. The mixed solvent is a mixed solvent of water and any one of methanol, ethanol, and tetrahydrofuran. The preparation method according to claim 2.

4. In the mixed solvent, the volume ratio of methanol, ethanol or tetrahydrofuran to water is 9:1; Preferably, the temperature is increased to reflux, Preferably, the temperature of the reduced pressure drying is 40 to 50°C.

4. The preparation method according to claim 2 or 3.

5. In the X-ray diffraction spectrum, there are diffraction peaks at 2θ diffraction angles of 4.5°±0.2°, 9.0°±0.2°, 13.6°±0.2°, 18.1°±0.2°, 19.2°±0.2°, 21.8°±0.2°, 24.5°±0.2°, 27.5°±0.2°, and 27.8°±0.2°. Crystalline form B of proximod.

6. 6. A process for preparing crystalline form B of Proximod according to claim 5, comprising: adding crystalline form A of Proximod as claimed in claim 1 to a mixed solvent, adjusting the pH of the system to 1-2, heating until a clear solution is refluxed, cooling to 40-50°C, stirring, cooling to room temperature, isolating the solid, and drying under reduced pressure to obtain said crystalline form. Preparation method.

7. the pH of the system is adjusted with an acid, the acid being concentrated hydrochloric acid; Preferably, the mixed solvent comprises ethanol and water, Preferably, the volume ratio of ethanol to water is 9:1; Preferably, the temperature of the reduced pressure drying is 45 to 55°C, Preferably, the temperature is naturally lowered to 40 to 50°C, and then seed crystals of crystalline form B are added to the system. The preparation method according to claim 6.

8. crystalline form A of Proximod according to claim 1 and / or crystalline form B of Proximod according to claim 5, and pharmaceutically acceptable auxiliary materials. Pharmaceutical compositions.

9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable auxiliary material comprises microcrystalline cellulose.

10. The pharmaceutical composition comprises the above-mentioned crystalline form A of proximod and pharmaceutically acceptable auxiliary materials including microcrystalline cellulose. The pharmaceutical composition according to claim 8 or 9.

11. Use of crystalline form A of Proximod according to claim 1 or crystalline form B of Proximod according to claim 5 or a pharmaceutical composition according to any one of claims 8 to 10 in the preparation of a medicament with immunomodulatory activity, Preferably, the pharmaceutical agent having an immunomodulatory effect is selected from pharmaceutical agents for treating immune disorders, immunosuppression, immunosuppression, organ transplant rejection, or autoimmune diseases; Preferably, the pharmaceutical agent having an immunomodulatory effect is selected from pharmaceutical agents for treating rheumatoid arthritis. use.

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