Sparsentan crystal form DCI and preparation method and application thereof

Abstract

The invention discloses a Sparsentan crystal form DCI, a preparation method and application thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of drugs for treating primary immunoglobulin A nephropathy (lgAN) and focal segmental glomerulosclerosis (FSGS) related diseases. The Sparsentan crystal form DCI provided by the invention has good physical and chemical stability, good humidity stability and mechanical stability and almost no hygroscopicity, provides guarantee for subsequent production and development of medicines, and has relatively high industrial development value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical crystal form technology, specifically to the Sparsentan crystal form DCI, its preparation method, and its uses. Background Technology

[0002] Focal segmental glomerulosclerosis (FSGS) is a manifestation of nephrotic syndrome and a major cause of end-stage renal disease. Its pathogenesis is complex and not yet fully understood. Current drug treatments, primarily glucocorticoids and immunosuppressants, show mixed responses and cannot ideally control the occurrence and progression of FSGS, with significant side effects. There is currently no approved treatment for FSGS, and the complete remission rate is less than 30%. One-third of patients progress to chronic renal failure within five years, requiring long-term dialysis or kidney transplantation to sustain life, placing a severe economic burden on families and society. Therefore, exploring new treatment options has become a priority.

[0003] Endogenous vasoactive peptides angiotensin II (AngII) and endothelin-I (ET-I) are two potent vasoconstrictors believed to play a role in controlling vascular tone and pathological tissue remodeling associated with a variety of diseases, including diabetic nephropathy, heart failure, and chronically or persistently elevated blood pressure. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid balance, and sodium balance. Overactivation of the RAAS can promote systemic and regional glomerular capillary hypertension, causing glomerular hemodynamic lock-up, leading to renal lock-up and renal fibrosis through pro-fibrotic and pro-inflammatory pathways. RAAS system drugs, such as angiotensin receptor blockers (ARBs), have been used to treat diabetic nephropathy, heart failure, and chronically or persistently elevated blood pressure. Furthermore, increasing data demonstrate the potential therapeutic benefits of ETA receptor antagonists (ERAs) in hypertension and diabetic nephropathy.

[0004] Sparsentan is a novel dual endothelin-angiotensin receptor antagonist (DEARA) that has demonstrated significant efficacy in treating primary immunoglobulin A nephropathy (lgAN) and focal segmental glomerulosclerosis (FSGS). This drug not only effectively lowers blood pressure but also reduces proteinuria caused by disease progression, thereby slowing disease progression.

[0005] Sparsentan reduces proteinuria in patients with IgA glomerulonephritis (IgA AB) by simultaneously blocking endothelin A receptors and angiotensin II receptors, thereby lowering the risk of renal function deterioration. Studies have shown that sparsentan also significantly improves proteinuria in patients with focal segmental glomerulosclerosis (FSG), significantly improving their quality of life.

[0006] Sparsentan is a polymorphic compound. Drug polymorphism refers to the phenomenon where a solid drug molecule exists in two or more different crystal forms. Because different crystal forms have different physicochemical properties, different crystal forms of solid drug molecules may exhibit different dissolution and absorption rates in vivo, thus affecting the clinical efficacy and safety of the drug to some extent. This is especially true for poorly soluble solid drugs, where the impact of crystal form on bioavailability is even greater. Therefore, drug crystal form is a crucial aspect of solid-state drug research and development, and also an important component of drug quality control.

[0007] CN1149196C discloses a method for synthesizing the compound Sparsentan, but does not disclose the crystal form of Sparsentan.

[0008] The inventors of this application have discovered a crystalline solid of the compound Sparsentan provided by this invention, which exhibits excellent properties in terms of hygroscopicity and stability, and is of great significance for the development of drugs containing the compound Sparsentan. Summary of the Invention

[0009] The main objective of this invention is to provide a new crystal form of the compound Sparsentan, its preparation method, and its uses.

[0010] According to the purpose of this invention, the present invention provides a crystal form of the compound Sparsentan.

[0011] Furthermore, the present invention provides that the crystal form of the compound Sparsentan can be crystal form DCI (hereinafter referred to as crystal form DCI).

[0012] On the one hand, using Cu-Ka radiation, the X-ray powder diffraction of the crystalline DCI has characteristic peaks at one, two, three, or four locations with diffraction angles of 2θ values ​​of 7.0±0.2, 13.9±0.2, 15.5±0.2, and 21.2±0.2.

[0013] Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the crystalline DCI exhibits characteristic peaks at one, two, three, or four locations with diffraction angles of 2θ values ​​of 12.3±0.2, 16.6±0.2, 23.6±0.2, and 28.5±0.2; preferably, the X-ray powder diffraction of the crystalline DCI exhibits characteristic peaks at four locations with diffraction angles of 2θ values ​​of 12.3±0.2, 16.6±0.2, 23.6±0.2, and 28.5±0.2.

[0014] Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the crystalline DCI exhibits characteristic peaks at one, two, or three locations with diffraction angle 2θ values ​​of 12.7±0.2, 17.5±0.2, 18.4±0.2, and 22.7±0.2; preferably, the X-ray powder diffraction of the crystalline DCI exhibits characteristic peaks at four locations with diffraction angle 2θ values ​​of 12.7±0.2, 17.5±0.2, 18.4±0.2, and 22.7±0.2.

[0015] Non-limiting, the X-ray powder diffraction pattern of crystalline DCI is basically as follows: Figure 1 As shown.

[0016] Non-limiting, the crystalline form DCI begins to show an endothermic peak around 142 degrees, and the differential scanning calorimetry (DSC) chromatogram is basically as follows. Figure 2 As shown.

[0017] In a second aspect, the present invention provides a method for preparing the above-mentioned Sparsentan crystal form DCI, wherein Sparsentan is placed in a mixed solvent of tetrahydrofuran and water, and the resulting suspension is separated and dried to obtain the crystal form DCI.

[0018] In a preferred embodiment, the crystallization temperature is 0-25°C.

[0019] A third aspect of the present invention provides a pharmaceutical composition comprising the above-described Sparsentan crystal form DCI and its pharmaceutically acceptable carrier or excipient.

[0020] A fourth aspect of the present invention provides the use of the above-described Sparsentan crystal form DCI in the preparation of a pharmaceutical.

[0021] Compared with the prior art, the present invention has the following beneficial effects: (1) The Sparsentan DCI of the present invention maintains stable crystal form under conditions of 25°C and 22.5%RH~92.5%RH, without crystal transformation, and has excellent humidity stability, which brings convenience to subsequent production, storage and formulation processes, reduces the risk of crystal transformation and improves product stability. (2) The Sparsentan DCI of the present invention has almost no hygroscopicity, thus ensuring that it can maintain a low hygroscopic weight gain and does not deliquescence during subsequent production, processing and storage and transportation, thereby ensuring the stability of drug quality. (3) The Sparsentan DCI of the present invention maintains stable crystal form under accelerated conditions, without crystal transformation, and the chemical purity does not change significantly, exhibiting excellent physicochemical stability. (4) The Sparsentan DCI of the present invention also maintains stable crystal form during grinding, without crystal transformation or significant deterioration of crystallinity, thereby ensuring stability in the formulation process. (5) The Sparsentan crystal form DCI prepared by the method of the present invention has excellent stability, avoids the risk of crystal transformation, and also has good production scalability, making it suitable for industrial development.

[0022] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0023] Figure 1 This is the XRPD spectrum of the Sparsentan crystal form DCI prepared in Example 1 of this invention; Figure 2 This is the DSC spectrum of the Sparsentan crystal form DCI prepared in Example 1 of this invention; Figure 3 This is the XRPD spectrum of the Sparsentan crystal form DCI prepared in Example 2 of this invention; Figure 4 These are the XRPD spectra of the Sparsentan crystal form DCI prepared in Example 1 of this invention before and after grinding; Figure 5 These are XRPD spectra of the Sparsentan crystal form DCI prepared in Example 1 of this invention before and after being placed under different humidity conditions for 30 days; Figure 6 These are XRPD spectra of the Sparsentan crystal form DCI prepared in Example 1 of this invention before and after being placed under different temperature and humidity conditions for 2 weeks; Figure 7 The XRPD spectra of the Sparsentan crystal form DCI prepared in Example 1 of this invention before and after being placed at 25℃ / 80%RH for 24 hours are shown. Detailed Implementation

[0025] To make the technical means, inventive features, objectives, and effects of the invention readily understandable, the invention is further illustrated below with reference to specific figures. However, the invention is not limited to the embodiments described below.

[0026] It should be noted that the structures, proportions, sizes, etc., illustrated in the accompanying drawings of this specification are only used to complement the content disclosed in the specification for those skilled in the art to understand and read, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes in the proportions, or adjustments to the size, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0027] Sparsentan, with the compound name 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, has the molecular formula C 32 H 40 N4O5S, structural formula as follows:

[0028] Sparsentan is a novel dual endothelin-angiotensin receptor antagonist (DEARA) that has demonstrated significant efficacy in treating primary immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). This drug not only effectively lowers blood pressure but also reduces proteinuria caused by disease progression, thereby slowing disease progression. Studies have shown that Sparsentan also significantly improves proteinuria in patients with FSGS, significantly enhancing their quality of life.

[0029] This application addresses the issue of altering the preparation method of Sparsentan to obtain a new crystalline form of Sparsentan, DCI. The DCI crystalline form combines stability and high solubility, which avoids the risk of crystal transformation and facilitates drug absorption, thereby improving bioavailability.

[0030] XRPD, or X-ray powder diffraction, was used to acquire the X-ray powder diffraction pattern in this application using a Bruker D2 PHASER X-ray powder diffractometer. The X-ray powder diffraction method parameters are as follows: X-ray source: Cu Ka; Ka1 (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kV; current: 10 mA; scanning range: 3.0-40.0.

[0031] DSC, or Differential Scanning Calorimetry, was used to acquire the differential scanning calorimetry (DSC) images in this application on a TA DSC X3. The method parameters for differential scanning calorimetry (DSC) are as follows: scan rate: 10 ℃ / min; protective gas: nitrogen.

[0032] TGA, or thermogravimetric analysis, was used to acquire the TGA images in this application on a TA TGA55 thermogravimetric analyzer. The TGA method parameters were as follows: scan rate: 10 °C / min; protective gas: nitrogen.

[0033] Unless otherwise specified, all the following examples are performed at room temperature. "Room temperature" is not a specific temperature value, but refers to a temperature range of 10-30 ℃.

[0034] The "stirring" described in the following embodiments is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm. Magnetic stirring is preferably performed at 300-900 rpm, and mechanical stirring is preferably performed at 100-300 rpm.

[0035] The "separation" described in the following examples was accomplished using conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation was as follows: the sample to be separated was placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all the solids settled to the bottom of the centrifuge tube.

[0036] The "drying" described in the following examples can be carried out at room temperature or higher. The drying temperature is from room temperature to approximately 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. The drying is carried out in a fume hood, a forced-air oven, or a vacuum oven.

[0037] In the following embodiments, "crystal" refers to a solid confirmed by X-ray powder diffraction (XPD) characterization. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, but 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 powder diffraction patterns typically vary with different instrument conditions. It should be particularly noted that the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions; therefore, the order of diffraction peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystal. The diffraction peak intensities shown in this invention are illustrative and not for absolute comparison. Furthermore, experimental errors in diffraction peak positions are typically 5% or less, and these positional errors should also be taken into account, generally allowing for ±0.2%. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in diffraction 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 powder diffraction pattern of the protected crystal form of the present invention need not be completely identical to the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern with the same or similar characteristic peaks as those in these patterns is within the scope of the present invention.

[0038] Those skilled in the art can compare the X-ray powder diffraction pattern listed in this invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0039] The DCI crystal form of the present invention is pure and substantially free from any other crystal form. In the present 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, more particularly less than 10% (by weight) of other crystal forms, even more particularly less than 5% (by weight) of other crystal forms, and even more particularly less than 1% (by weight) of other crystal forms.

[0040] Sparsentan as a raw material includes, but is not limited to, solid forms (crystalline or amorphous), oily forms, liquid forms, and solutions. Preferably, it is in solid form.

[0041] The preparation method of Sparsentan crystal form DCI in this application is as follows: Sparsentan is placed in a solvent and recrystallized at a temperature of 0-25℃. After centrifugation and drying, crystal form DCI is obtained.

[0042] The solvent is a mixture of alcohol, ester, ether, or ketone with water. Preferably, the solvent is any one of tetrahydrofuran and acetone, or a mixture of both.

[0043] The recrystallization temperature is -20℃ to 30℃. Preferably, the recrystallization temperature is 0℃ to 25℃.

[0044] The drying temperature is 20-40℃. Preferably, the drying temperature is 30℃.

[0045] The crystallization time also affects the degree of crystallization or the yield of crystals, and can be flexibly selected according to actual needs.

[0046] Example 1

[0047] Weigh 50 mg of Sparsentan and add it to a liquid chromatography vial; add 0.5 mL of tetrahydrofuran / water (1 / 9 volume ratio), stir at 20 ± 5 °C, centrifuge, and filter to obtain crystals, i.e., crystalline DCI. Its XRPD diagram is shown below. Figure 1 As shown in Table 1, the XRPD data is illustrated in the DSC plot. Figure 2 As shown.

[0048] Table 1

[0049] Diffraction angle 2θ d value relative strength 6.95 12.41 87.20% 8.09 10.70 7.40% 8.55 10.13 10.70% 9.20 9.43 10.90% 10.50 8.29 10.70% 12.28 7.11 25.30% 12.65 6.90 31.10% 13.06 6.69 6.00% 13.92 6.28 56.60% 14.96 5.85 14.80% 15.52 5.64 60.80% 16.13 5.43 11.00% 16.64 5.27 55.10% 17.51 5.02 18.50% 18.09 4.86 9.60% 18.40 4.78 50.40% 19.79 4.44 22.60% 20.32 4.33 35.70% 20.79 4.24 27.40% 21.22 4.15 100.00% 22.25 3.96 7.30% 22.73 3.88 31.80% 23.57 3.75 48.00% 24.37 3.63 8.10% 24.85 3.56 18.70% 25.48 3.47 12.20% 27.75 3.19 12.00% 28.45 3.12 75.80% 30.34 2.93 7.80% 31.76 2.80 10.20%

[0050] from Figure 2 As can be seen from the above, the Sparsentan crystal form DCI prepared in Example 1 begins to show an endothermic peak around 143℃.

[0051] Example 2

[0052] Weigh 50 mg of Sparsentan and add it to a liquid chromatography vial; add 0.5 mL of ethanol / methyl tert-butyl ether (1 / 1, v / v), stir at 0 ± 5 °C, centrifuge and filter to obtain crystals, i.e., crystalline DCI. Its XRPD diagram is shown below. Figure 3 As shown.

[0053] Table 2

[0054] Diffraction angle 2θ d value relative strength 6.95 12.63 79.10% 8.09 10.86 6.50% 8.57 10.25 9.20% 9.21 9.54 10.70% 10.49 8.39 10.30% 12.30 7.16 24.10% 12.63 6.97 26.80% 13.08 6.74 5.30% 13.93 6.33 51.60% 14.98 5.89 11.70% 15.53 5.68 54.10% 16.16 5.46 9.50% 16.64 5.30 47.60% 17.51 5.04 16.20% 18.07 4.89 7.60% 18.43 4.79 41.70% 19.81 4.46 16.90% 20.34 4.35 32.10% 20.80 4.25 21.70% 21.23 4.17 100.00% 22.29 3.97 6.90% 22.73 3.90 34.50% 23.58 3.76 43.80% 24.39 3.64 7.60% 24.84 3.57 18.40% 25.51 3.48 14.20% 27.77 3.20 10.60% 28.27 3.15 14.90% 30.38 2.93 7.30% 31.77 2.81 8.70%

[0055] Example 3: Biological solubility of the crystal form DCI of this application

[0056] When conducting drug solubility tests to predict drug performance in vivo, it is crucial to simulate in vivo conditions as closely as possible. For oral medications, SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under eating conditions) can simulate in vivo conditions and predict the effects of food intake. Solubility tested in these media more closely resembles solubility in the human body environment. Experimental conditions and results are shown in Table 3.

[0057] Table 3

[0058] Solubility experiments in biological solvents showed that the crystalline DCI of this invention has high solubility in SGF (simulated gastric juice). Solubility affects drug absorption and bioavailability in the human body; higher solubility requires less drug loading to achieve better therapeutic effects. Furthermore, reducing drug loading while ensuring efficacy can reduce drug toxicity and side effects, and improve drug safety, which has significant clinical implications.

[0059] Example 4 Mechanical stability of the crystal form DCI of this application

[0060] Ten milligrams of the crystalline DCI prepared in Example 1 were placed in a mortar and manually ground for 15 minutes. XRPD tests were performed before and after grinding. The XRPD comparison before and after grinding is shown below. Figure 4 As shown.

[0061] according to Figure 4 It is evident that the crystal form of DCI remains unchanged after grinding, and no significant decrease in crystallinity was observed, indicating that the crystal form of DCI possesses good mechanical stability. This good mechanical stability ensures that the sample will not easily undergo crystal transformation due to external forces such as mechanical grinding or pulverization during subsequent formulation processes, reducing the risk of crystal transformation during formulation and improving the developability of the formulation process.

[0062] Example 5: Humidity stability of the crystal form DCI of this application

[0063] Approximately 5 mg of the crystalline DCI prepared in Example 1 was weighed and placed in open containers at 25°C at 22.5% RH, 45% RH, and 60% RH, respectively. The crystal form was determined using XRPD. The experimental conditions and results are shown in Table 4, and the XRPD overlay images are shown below. Figure 5 As shown.

[0064] Table 4 Placement conditions Placement time Crystal form Start —— Crystal form DCI 22.5%RH 30 days Crystal form DCI 45%RH 30 days Crystal form DCI 75%RH 30 days Crystal form DCI 92.5%RH 30 days Crystal form DCI

[0065] The results showed that the crystal form of DCI of the present invention remained unchanged after being placed at 25 °C under conditions of 22.5%RH to 92.5%RH for 30 days, indicating that the crystal form of DCI has good physical stability. This ensures that the drug is not prone to crystal transformation during subsequent processes, production and transportation. Good physical stability ensures that the drug maintains quality stability during subsequent formulation development and process production, as well as during drug production and transportation, which is of great significance for ensuring drug quality and efficacy.

[0066] Example 6: Stability of the crystal form DCI of this application

[0067] Approximately 5 mg of the crystalline DCI prepared in Example 1 was weighed and placed under ambient temperature (25 °C / 60%RH) and accelerated conditions (40 °C / 75%RH and 60 °C / 75%RH), respectively. The crystal form was determined using XRPD. The experimental conditions and results are shown in Table 5, and the XRPD overlay images are shown below. Figure 6 As shown.

[0068] Table 5 Placement conditions Placement time Crystal form Purity (peak area %) Start —— Crystal form DCI 99.74 25 ℃ / 60%RH 4 weeks Crystal form DCI 99.77 40 ℃ / 75%RH 4 weeks Crystal form DCI 99.79 60 ℃ / 75%RH 4 weeks Crystal form DCI 99.73

[0069] The results showed that the crystal form of DCI remained unchanged after 4 weeks under three conditions: 25 ℃ / 60%RH, 40 ℃ / 75%RH, and 60 ℃ / 75%RH, indicating that the crystal form of DCI has good physical stability. In particular, under the accelerated condition of 60 ℃ / 75%RH, the crystal form remained stable after 4 weeks without crystal transformation, further demonstrating that the crystal form of DCI still has good physical stability even under high temperature and high humidity conditions. This ensures that the drug is not prone to crystal transformation during subsequent processes, production, and transportation. Furthermore, the chemical purity of the crystal form of DCI did not change before and after being placed under 40 ℃ / 75%RH (relative humidity), remaining above 99%, indicating good chemical stability. Moreover, even under the accelerated condition of 60 ℃ / 75%RH, the chemical purity did not decrease significantly, further demonstrating the good chemical stability of the crystal form of DCI. Good physicochemical stability ensures that the quality of the drug remains stable during subsequent formulation development, manufacturing processes, and transportation, thus guaranteeing drug quality and efficacy, which is of great significance.

[0070] Example 7: Hygroscopicity of the DCI crystal form of this application

[0071] The hygroscopicity of drugs was determined according to the guidelines for hygroscopicity testing of drugs in General Chapter 9103 of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were 25 ± 1 ℃ and 80% relative humidity.

[0072] Definition of hygroscopic weight gain: Extremely hygroscopic: hygroscopic weight gain of not less than 15.0%; Hygroscopic: hygroscopic weight gain of less than 15.0% but not less than 2.0%; Slightly hygroscopic: hygroscopic weight gain of less than 2.0% but not less than 0.2%; No or almost no hygroscopicity: hygroscopic weight gain of less than 0.2%.

[0073] Approximately 20 mg of the crystalline DCI prepared in Example 1 of this application was weighed and placed at 25 ± 1 °C and 80% relative humidity for 24 hours. The mass of the sample before and after the treatment was recorded, and the crystalline form was determined using XRPD. The specific results are shown in Table 6 below, and the XRPD overlay images are shown below. Figure 7 As shown.

[0074] Table 6 Starting mass (mg) Placement conditions Placement time Mass after storage (mg) Weight gain (mg) Percentage of weight gain 22.2 25 ± 1 ℃, 80%RH 24 hours 22.3 0.10 0.45%

[0075] As can be seen from Table 6, the crystalline DCI of the present invention has no or almost no hygroscopicity, which indicates that the crystalline DCI is not prone to deliquescence during the production and storage of pharmaceuticals.

[0076] Crystal form stability is crucial for drug development. Crystal transformation directly impacts drug solubility and, consequently, bioavailability, thus altering efficacy. Good chemical stability ensures minimal formation or increase in impurity levels during storage, guaranteeing drug safety. Good humidity stability prevents crystal transformation during storage, transportation, and formulation, reducing the risk of transformation and enhancing product development potential. Low hygroscopicity ensures minimal weight gain and prevents deliquescence during production, processing, storage, and transportation, ensuring stable drug quality.

[0077] Therefore, the excellent physical and humidity stability of crystal form DCI, with almost no hygroscopicity, provides a guarantee for the subsequent production and development of drugs, and has high industrialization development value.

[0078] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A crystalline form of sparsentan, DCI, characterized by, The X-ray powder diffraction spectrum of the crystal form DCI has characteristic peaks at diffraction angle 2theta values of 7.0±0.2, 13.9±0.2, 15.5±0.2, 21.2±0.2 under Cu-Ka radiation.

2. A crystalline form of sparsentan, DCI, according to claim 1, characterized in that, The X-ray powder diffraction spectrum of the crystal form DCI has characteristic peaks at diffraction angle 2theta values of 12.3±0.2, 16.6±0.2, 23.6±0.2, 28.5±0.2 under Cu-Ka radiation.

3. A crystalline form of sparsentan, DCI, according to claim 1 or 2, characterized in that, The X-ray powder diffraction spectrum of the crystal form DCI has characteristic peaks at diffraction angle 2theta values of 12.7±0.2, 17.5±0.2, 18.4±0.2, 22.7±0.2 under Cu-Ka radiation.

4. A crystalline form of sparsentan, DCI, according to claim 1 or 2 or 3, characterized in that, The differential scanning calorimetry spectrum of the crystal form DCI shows an endothermic peak at 142±3℃.

5. A method of preparing a crystalline form of Sparsentan DCI, characterized in that, Sparsentan is placed in a solvent, recrystallized at a temperature of -20℃-30℃, centrifuged and dried to obtain the crystal form DCI.

6. A method of preparing a crystalline form of sparsentan, DCI, according to claim 5, wherein, The solvent is an alcohol, a ketone, an ester, an ether or a mixture of any proportion of the above solvents and water.

7. A method of preparing a crystalline form of sparsentan, DCI, according to claim 5, wherein, The crystallization temperature is 0-20℃.

8. A pharmaceutical composition, characterized by, Sparsentan crystal form DCI according to any one of claims 1-4, and a pharmaceutically acceptable carrier or excipient thereof.

9. Use of the Sparsentan crystal form DCI according to any one of claims 1-4, or the preparation method of the Sparsentan crystal form DCI according to any one of claims 5-7, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing or treating focal segmental glomerulosclerosis in a subject.

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