Crystal form of compound, preparation method therefor and use thereof

Abstract

Provided are a crystal form of a compound, a preparation method therefor and a use thereof. The compound has a structure as shown in formula I. The crystal form has high crystalline purity, low hygroscopicity, good solid-state stability and good solubility, is beneficial to the preparation and storage of pharmaceutical formulations, and has good application value and drug development potential. In addition, clinical trial results further demonstrate that the crystal form B of the compound as shown in formula I has good pharmacokinetic properties, low clinical toxicity, good safety, high oral bioavailability, and good therapeutic efficacy against multiple diseases.

Description

Crystalline form of a compound, and preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of polymorphism research of pharmaceutical chemistry, and particularly relates to a crystalline form of a compound (4-[9-(6-aminopurinyl)]-2(S)-hydroxybutyric acid methyl ester, referred to as DZ2002) and a preparation method and application thereof. BACKGROUND

[0002] In the medical field, the crystalline form of a compound has an important influence on its drug performance. Different crystalline forms can result in significant differences in solubility, stability, bioavailability, and efficacy of the compound. Therefore, discovering and developing new crystalline forms of a compound is of great significance to improve the clinical application value of a drug.

[0003] 4-[9-(6-aminopurinyl)]-2(S)-hydroxybutyric acid methyl ester ([4-(6-Amino-purin-9-yl)-2(S)-hydroxy-butyric acid methyl ester, referred to as DZ2002) is a reversible inhibitor of S-Adenosyl-L-homocysteine hydrolase (SAHH). DZ2002 has been studied as a therapeutic agent for various diseases, including autoimmune diseases (such as psoriasis, vitiligo, dry eye, etc.), osteoarthritis, etc. (see CN100345545C, CN107550913A, CN112472703B, CN117442623A). In addition to the therapeutic activity, the solid state form (i.e., crystalline or amorphous form) of DZ2002 is also a key factor in evaluating its therapeutic agent.

[0004] However, there is no report on the crystalline form of DZ2002, and a preparation method and application thereof.

[0005] SUMMARY

[0006] In order to overcome the shortcomings of the prior art, the present application provides a crystalline form of a compound, and a preparation method and application thereof.

[0007] In a first aspect of the present application, a crystalline form B of a compound represented by formula I is provided:

[0008] The XRPD pattern of said crystalline Form B (using Cu-Ka radiation) has characteristic peaks at at least three (e.g. three, four, five, six, seven, eight, in particular all) of the following 2Theta values: about 4.3°±0.2°, 8.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 20.0°±0.2°, 21.5°±0.2°, 26.5°±0.2°, 27.0°±0.2°.

[0009] Further, the XRPD pattern of said crystalline Form B (using Cu-Ka radiation) has characteristic peaks at at least three (e.g. three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, in particular all) of the following 2Theta values: about 11.5°±0.2°, 12.9°±0.2°, 13.7°±0.2°, 15.1°±0.2°, 16.8°±0.2°, 22.0°±0.2°, 22.5°±0.2°, 23.2°±0.2°, 24.2°±0.2°, 25.3°±0.2°, 26.2°±0.2°, 27.5°±0.2°, 28.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 35.0°±0.2°, 37.0°±0.2°, 39.0°±0.2°.

[0010] Further, said crystalline Form B has an XRPD pattern substantially as shown in Figure 1.

[0011] Further, the TGA pattern of said crystalline Form B shows a weight loss of 4.45% ± 1% (e.g. 4.35, 4.40, 4.45, 4.50, 4.55%, in particular 4.45%) from 30°C to 160°C and / or a weight loss of 60.4% ± 1% (e.g. 59.4, 60.0, 60.4, 61.0, 61.4%, in particular 60.4%) from 190°C to 400°C.

[0012] In some embodiments of the application, the TGA pattern of said crystalline Form B shows a weight loss of 4.45% from 30°C to 160°C and / or a weight loss of 60.4% from 190°C to 400°C.

[0013] Further, the DSC pattern of said crystalline Form B has an endothermic peak at 160-170°C (e.g. 160, 165, 170°C, in particular 164.6 ± 3°C).

[0014] In some embodiments of the application, the DSC pattern of said crystalline Form B has an endothermic peak at 164.6 ± 3°C.

[0015] Further, said crystalline Form B is an anhydrous crystalline form.

[0016] Further, under polarizing microscope, the crystal form B is columnar crystal.

[0017] In a second aspect of the present application, a preparation method of the crystal form B of the compound of formula I is provided, which comprises using the compound of formula I in amorphous form as starting material, and preparing the crystal form B by suspension stirring method.

[0018] Further, the suspension stirring method is room temperature suspension stirring method.

[0019] Further, the room temperature suspension stirring method comprises the following steps: suspending the compound of formula I in amorphous form with a solvent, and stirring at room temperature (20-30℃, such as 21, 22, 23, 24, 25, 26, 27, 28, 29, 30℃, particularly 25℃) until solid precipitates.

[0020] Further, the solvent is selected from ethyl acetate, isopropyl acetate.

[0021] In some embodiments of the present application, the solvent is isopropyl acetate.

[0022] In a third aspect of the present application, a pharmaceutical composition comprising the crystal form B of the compound of formula I and one or more pharmaceutically acceptable excipients is provided.

[0023] Further, the pharmaceutically acceptable excipients are selected from thickening agents, stabilizers, preservatives, binders, lubricants, disintegrants, bacteriostatic agents, suspending agents, solubilizers, fillers, antioxidants, buffers.

[0024] Further, the pharmaceutical composition can adopt any suitable administration route, such as gastrointestinal administration (e.g. oral, sublingual, rectal administration) or non-gastrointestinal administration (e.g. intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, drip, respiratory administration, etc.).

[0025] Further, the pharmaceutical composition can be in any suitable dosage form selected from the group consisting of oral dosage forms (e.g., tablets, powders, pills, granules, capsules, troches, syrups, liquids, emulsions, suspensions, etc.), injectable dosage forms (e.g., injections for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intraarticular injection, etc.), transdermal dosage forms (e.g., external solution, lotion, ointment, plaster, paste, patch, etc.), mucosal dosage forms (e.g., eye drops, eye ointment, eye gel, nose drops, gargle, sublingual tablet, etc.), cavity dosage forms (e.g., suppositories, aerosols, effervescent tablets, drops, dripping pills, enema liquids, etc. for rectum, vagina, urethra, nasal cavity, ear canal, etc.), respiratory tract dosage forms (e.g., sprays, aerosols, powder sprays, etc.).

[0026] Preferably, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, powders, capsules, injections, ointments, eye drops, eye ointments, eye gels, enema liquids.

[0027] In some embodiments of the present application, the pharmaceutical composition is in oral dosage form, particularly in capsule form.

[0028] Further, the crystalline form B of the compound of formula I is used alone or in combination with other kinds of active ingredients.

[0029] Further, the subject of the pharmaceutical composition is a mammal, particularly a human.

[0030] Further, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form B of the compound of formula I.

[0031] Further, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a capsule, tablet, or any other dosage form; additionally, the unit dosage form can be the packaged preparation, such as a tablet, capsule, or powder packaged in a vial or ampoule. The quantity of active component in such unit doses can be varied or adjusted from 0.1 mg to 1000 mg according to the particular application and the potency of the active component. If desired, the compositions can also contain other suitable therapeutic agents.

[0032] In a fourth aspect of the present application, there is provided a use of the crystalline form B of the compound of formula I or the pharmaceutical composition of the third aspect of the present application in the manufacture of a medicament for the prevention and / or treatment of a disease selected from the group consisting of autoimmune diseases, autoinflammatory diseases.

[0033] Further, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, Sjogren's syndrome, and the like.

[0034] Further, the autoimmune encephalomyelitis is experimental autoimmune encephalomyelitis.

[0035] Further, the Sjogren's syndrome is dry eye.

[0036] Further, the dry eye is a tear deficiency type dry eye.

[0037] Further, the autoimmune disease can also be an autoimmune disease caused by hyperactivity of Th1-mediated cellular immune response.

[0038] Further, the autoimmune inflammatory disease is selected from the group consisting of inflammatory bowel disease (IBD), hereditary periodic fever syndrome, vasculitis, and the like.

[0039] Further, the inflammatory bowel disease is selected from the group consisting of Crohn's disease (CD), ulcerative colitis, and the like.

[0040] In a fifth aspect, the present application provides a use for preventing and / or treating a disease, which comprises administering to a subject in need thereof the crystalline form B of the compound of Formula I according to the first aspect of the present application or the pharmaceutical composition according to the third aspect of the present application, wherein the disease is defined according to the fourth aspect of the present application.

[0041] Further, the subject is a mammal, in particular a human.

[0042] Further, the administration can be performed by any suitable administration route, such as a gastrointestinal administration (e.g., oral, sublingual, rectal administration) or a non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, drip, respiratory tract administration, and the like).

[0043] Based on the previous research results of the inventors, the present application further obtains the crystalline form B of the compound of Formula I through experimental research, which has high crystalline purity, low hygroscopicity, good solid-state stability and good solubility, is beneficial to the preparation and storage of pharmaceutical preparations, and has very good application value and drug development prospects. In addition, the results of clinical trials show that the crystalline form B of the compound of Formula I of the present application has very good pharmacokinetic properties, low clinical toxicity, good safety, high oral bioavailability, and good therapeutic effect on various diseases. BRIEF DESCRIPTION OF DRAWINGS

[0044] FIG. 1 shows the XRPD pattern of the crystalline form B.

[0045] Figure 2 shows a DVS pattern of Form B.

[0046] Figure 3 shows a Raman pattern of Form B.

[0047] Figure 4 shows an IR pattern of Form B.

[0048] Figure 5 shows the DZ2002 whole blood concentration-time curve following administration of Formulation 1 in beagle dogs.

[0049] Figure 6 shows the DZA whole blood concentration-time curve following administration of Formulation 1 in beagle dogs. DETAILED DESCRIPTION

[0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this application belongs.

[0051] The term "crystalline form" is confirmed by X-ray powder diffraction patterns. Those skilled in the art will appreciate that the physico-chemical properties discussed herein can be characterized with experimental error that depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample, among other things. In particular, it is well known in the art that X-ray diffraction patterns will vary somewhat with the conditions of the instrument. In particular, it is noted that the relative intensities of the X-ray powder diffraction patterns can vary with experimental conditions, and therefore the order of peak intensities should not be relied upon as the sole or controlling factor. In fact, the relative intensities of the diffraction peaks in an XRPD pattern are related to the preferred orientation of the crystals, and the peak intensities shown herein are illustrative and not for absolute comparison. In addition, the experimental error in peak angles is typically 5% or less, and this error in angles should be taken into account, typically allowing for a ± 0.2° error. In addition, there can be a general shift in peak angles due to experimental factors such as sample thickness, and some shift is typically allowed for. Thus, those skilled in the art will appreciate that the X-ray powder diffraction pattern of a crystalline form of the application need not be identical to the X-ray powder diffraction pattern shown in the examples herein, and that "XRPD pattern identical" does not mean absolutely identical, but that the same peaks are within ± 0.2° of each other and that the peak intensities allow for some variability. Any crystalline form having a pattern that is the same or similar to the characteristic peaks of these patterns is within the scope of the application. Those skilled in the art will be able to compare the patterns set forth herein with the patterns of an unknown crystalline form to confirm whether the two sets of patterns reflect the same or different crystalline forms. In some embodiments, the Form B of the application is pure, single, and substantially free of any other crystalline form. In the context of the present application, "substantially free of" when referring to a new crystalline form means that the crystalline form contains less than 20% by weight of another crystalline form, more preferably less than 10% by weight of another crystalline form, even more preferably less than 5% by weight of another crystalline form, and even more preferably less than 1% by weight of another crystalline form.

[0052] It should be noted that the numerical values and numerical ranges recited in the application should not be construed as being limited to the numerical values or the numerical ranges themselves, but rather are intended to cover all sub-ranges encompassed therein as well as the individual values forming the ends of those sub-ranges. In other words, all ranges disclosed herein are meant to include any and all sub-ranges unless the context clearly dictates otherwise. This application specifically encompasses all such sub-ranges. As used herein, the term "about" when used before a numerical designation, e.g., "about 10", preferably means ±10%, more preferably ±5%, of the indicated value, as would be within the knowledge of one of ordinary skill in the art.

[0053] It should also be noted that in powder X-ray diffraction patterns, the specific crystal form of a diffraction pattern obtained from a crystalline compound is often characteristic, where the relative intensities of the bands, especially at low angles, can vary due to preferred orientation effects resulting from differences in crystallization conditions, particle size, relative amounts of the mixture, and other testing conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal in question, and in determining whether it is the same as a known crystal form, more attention should be paid to the positions of the peaks than to their relative intensities.

[0054] The term "room temperature" refers to a temperature of an article that is close to or the same as the temperature of the space in which the article is located, e.g., the location of a fume hood in which the article is located. Typically, room temperature is about 20 °C to about 30 °C, or about 22 °C to 27 °C, or about 25 °C.

[0055] The term "subject" refers to any animal or cell thereof, whether in vitro or in situ, treated according to the methods described herein. In particular, the aforementioned animal includes a mammal, e.g., a rat, a mouse, a guinea pig, a rabbit, a dog, a monkey, or a human, particularly a human.

[0056] The term "treatment" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting, and / or stopping one or more clinical symptoms of a disease after the onset of the disease.

[0057] The term "prevention" refers to avoiding, minimizing, or making it difficult for a disease to occur or develop by treatment before the onset of the disease.

[0058] The term "autoimmune disease" refers to a disease caused by an immune response of the body to self-antigens resulting in damage to self-tissues. The American Autoimmune Related Diseases Association has compiled a relatively comprehensive list of autoimmune diseases.

[0059] The term "autoinflammatory disease" refers to an inflammatory disease directed against self tissues, organs, the pathogenesis of which is defined as an abnormal reaction of the body's innate immune system, leading to inflammatory damage of self tissues (see, Li Chengrong, Autoinflammatory Disease, Chinese Journal of Pediatrics, 2008, 46(11): 842-847).

[0060] The disclosures of various publications, patents and published patent specifications, referred to herein are hereby incorporated by reference in their entirety.

[0061] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0062] The DZ2002 bulk drug used in the embodiments can be prepared by the preparation methods (i) to (vi) in the specific embodiments of the patent document CN101456860A (i.e. DZ2002 crude product), which has the following structure:

[0063] The DZA described in the embodiments has the following structure:

[0064] Embodiment 1: Preparation and characterization of the crystal form of DZ2002

[0065] 1. Instruments and methods

[0066] 1.1 X-ray powder diffraction (XRPD)

[0067] Instrument model: Bruker D8 advance X-Ray diffractometer; target: Cu Kα (40KV, 40mA); sample-to-detector distance: 30cm; scanning range: 3°-40° (2theta value); scanning rate: 0.1 sec / step; scanning step: 0.02.

[0068] 1.2 Thermal gravimetric analysis (TGA)

[0069] Instrument model: Netzsch TG 209F3; temperature range: 30-400℃; scanning rate: 10℃ / min; purge gas: 25mL / min; protective gas: 15mL / min.

[0070] 1.3 Differential scanning calorimetry (DSC)

[0071] Instrument model: Perkin Elmer 8500 DSC; Temperature range: 50-200°C; Scanning rate: 10°C / min; Nitrogen flow rate: 50 ml / min.

[0072] 1.4 Dynamic Vapor Sorption (DVS)

[0073] Instrument model: SMS DVS Intrinsic; 0-95% RH; Temperature: 25°C.

[0074] 1.5 Raman Spectroscopy (Raman)

[0075] Instrument model: Thermo Scientific DXR Raman Microscope; Laser detection wavelength: 532 nm; Exposure intensity: 2 sec 5 times.

[0076] 2. Preparation of the crystalline form of DZ2002

[0077] Preparation of Form B: About 25 mg of DZ2002 raw material was stirred with 1 ml of isopropyl acetate at 25°C for at least 24 h, the solution was filtered, and the solid part was dried in air for 10 min. The solid part was subjected to XRPD detection, and if the observed XRPD spectrum was different from the raw material spectrum, the solid was further subjected to other aspects of characterization (such as DSC, TGA, IR, DVS, etc.). The results showed that a new crystalline form of DZ2002 was obtained, which was designated as Form B.

[0078] Preparation of Form C: About 25 mg of DZ2002 raw material was stirred with 1 ml of methyl isobutyl ketone (MIBK) at 25°C for at least 24 h, the solution was filtered, and the solid part was dried in air for 10 min. The solid part was subjected to XRPD detection, and if the observed XRPD spectrum was different from the raw material spectrum, the solid was further subjected to other aspects of characterization (such as DSC, TGA, IR, DVS, etc.). The results showed that a new crystalline form of DZ2002 was obtained, which was designated as Form C.

[0079] 3. Characterization of the crystalline form of DZ2002

[0080] 3.1 Results of XRPD of Form B

[0081] The XRPD spectrum is shown in Figure 1, and the XRPD diffraction peak data is shown in Table 1.

[0082] Table 1 XRPD diffraction peak data of Form B

[0083] 3.2 Results of TGA and DCS of Form B

[0084] TGA profile shows that Form B has a weight loss of 4.45% at 50-160°C, while the corresponding DSC has no obvious melting peak. And from the DSC profile, it can be seen that the melting temperature of Form B is 162°C, and the decomposition temperature is 200°C.

[0085] 3.3 Results of DVS of Form B

[0086] The hygroscopicity of Form B was evaluated by the adsorption and desorption of moisture between 0-95% relative humidity at 25°C.

[0087] The DVS profile is shown in Figure 2. Form B has only 0.5% moisture absorption within the humidity range of 0-95%, indicating that it has slight hygroscopicity.

[0088] 3.4 Results of Raman of Form B

[0089] The Raman spectrum is shown in Figure 3.

[0090] 3.5 Results of IR of Form B

[0091] The IR spectrum is shown in Figure 4.

[0092] Example 2: Stability evaluation

[0093] 5 mg of Form B was mixed with 5 mg of Form C (prepared in Example 1), 0.4 ml of ethyl acetate (EA) was added, and after stirring at room temperature for three days, the solution was filtered, and the solid part was dried in air for 10 min. The solid part was subjected to XRPD detection. The XRPD profile showed that Form B was obtained. Therefore, the stability of Form B is greater than that of Form C.

[0094] Example 3: Pharmacokinetic study of the crystal form of DZ2002

[0095] 1. Experimental animals

[0096] Beagles were obtained from Shanghai Jiagang Biotechnology Co., Ltd. (Experimental Animal Use License No. SYXK (Shanghai) 2020-0042) and were acclimated in the dog housing room of the Shanghai Institute of Pharmaceutical Research Animal Center (room temperature 23-25°C) for 2 weeks, with a body weight of about 8 kg.

[0097] 2. Preparation of formulations

[0098] Formulation 1: Form B powder was filled into capsules, 80 mg / capsule.

[0099] 3. Experimental grouping and administration method

[0100] 3 dogs / group, numbered 1#, 2#, and 3# respectively. After fasting for 12 hours, a single oral dose was administered, with a dose of 1 capsule / dog. Food was restored 4 hours after administration.

[0101] 4. Sample collection and processing

[0102] Blood sampling time points: 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 11 h, 24 h.

[0103] The concentrations of DZ2002 and DZA in the plasma of beagle dogs were detected by LC-MS / MS method. The LC-MS / MS detection method is as follows:

[0104] Liquid chromatograph: Agilent 1290 infinity LC system

[0105] Mass spectrometer: TSQ Vantage mass spectrometer

[0106] LC-MS / MS analysis conditions:

[0107] Chromatographic column: Synergi 4μ Fusion RP, 5μm, 2.0×50mm ID;

[0108] Mobile phase A: H2O (0.2% ammonium formate; 0.04% formic acid);

[0109] Mobile phase B: CH3OH (0.2% ammonium formate; 0.04% formic acid);

[0110] Flow rate: 0.3 mL / min;

[0111] Injection volume: 3μL;

[0112] The elution program is shown in Table 2.

[0113] Table 2 Elution program

[0114] The parameters of Spray Voltage, Vaporizer Temp, Sheath gas, Aux gas, Capillary Temp and S-lens were optimized;

[0115] The m / z of DZ2002 is 252→136, and the fragmentation energy is 23V;

[0116] The m / z of DZA is 238→136, and the fragmentation energy is 23V;

[0117] 5. Experimental results

[0118] It was found that DZ2002 can be rapidly converted to DZA after absorption in vivo after administration. The concentration-time curves of each group are shown in Figures 5-6, and the main pharmacokinetic parameters are shown in Table 3.

[0119] Table 3 Pharmacokinetic parameters of beagle dogs after administration

[0120] The above merely describes preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

[0121] The foregoing embodiments and methods described in the present application can be different based on the ability, experience and preference of a person skilled in the art.

[0122] The steps of the method in the present application are only listed in a certain order and do not constitute any limitation on the order of the steps of the method.

Claims

1. A crystalline form B of a compound of Formula I, characterized by, The XRPD pattern of said crystalline Form B has characteristic peaks at at least three of the following positions: 4.3°±0.2°, 8.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 20.0°±0.2°, 21.5°±0.2°, 26.5°±0.2°, 27.0°±0.2° in terms of 2Θ:

2. The crystalline Form B of claim 1, characterized by, the XRPD pattern of the crystal form B has at least three peaks at positions of 2Q values about 11.5°±0.2°, 12.9°±0.2°, 13.7°±0.2°, 15.1°±0.2°, 16.8°±0.2°, 22.0°±0.2°, 22.5°±0.2°, 23.2°±0.2°, 24.2°±0.2°, 25.3°±0.2°, 26.2°±0.2°, 27.5°±0.2°, 28.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 35.0°±0.2°, 37.0°±0.2°, 39.0°±0.2°; Preferably, the crystal form B has an XRPD pattern substantially as shown in Figure 1.

3. The crystalline Form B of claim 1, characterized by, the TGA pattern of the crystal form B has a weight loss of 4.45%±1% from 30°C to 160°C and / or a weight loss of 60.4%±1% from 190°C to 400°C; Preferably, the TGA pattern of the crystal form B has a weight loss of 4.45% from 30°C to 160°C and / or a weight loss of 60.4% from 190°C to 400°C.

4. The crystal form B according to claim 1, characterized in that, the DSC pattern of the crystal form B has an endothermic peak at 160-170°C; Preferably, the DSC pattern of the crystal form B has an endothermic peak at 164.6±3°C.

5. The crystalline Form B of claim 1, characterized by, the crystal form B is an anhydrous crystal form; Preferably, the crystal form B is a columnar crystal.

6. A process for preparing a crystalline form B of a compound of formula I according to any one of claims 1 to 5, characterized in that the preparation method comprises using the compound of formula I in amorphous form as a starting material to prepare the crystal form B by suspension stirring method.

7. The production method according to claim 6, wherein the suspension stirring method is a room temperature suspension stirring method; Preferably, the room temperature suspension stirring method comprises the following steps: suspending the compound of formula I in amorphous form with a solvent, and stirring at 20-30°C until solid precipitates; preferably at 25°C. Preferably, the solvent is selected from ethyl acetate, isopropyl acetate, preferably isopropyl acetate.

8. A pharmaceutical composition comprising the crystal form B of the compound of formula I according to any one of claims 1-5 or prepared by the method according to any one of claims 6-7, and one or more pharmaceutically acceptable excipients.

9. Use of the crystal form B of the compound of formula I according to any one of claims 1-5 or prepared by the method according to any one of claims 6-7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating a disease selected from autoimmune diseases, autoinflammatory diseases.

10. Use according to claim 9, characterized in that, the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, Sjogren's syndrome; Preferably, the Sjogren's syndrome is dry eye syndrome; the autoinflammatory disease is selected from inflammatory bowel disease, familial periodic fever syndrome, vasculitis; the inflammatory bowel disease is selected from Crohn's disease, ulcerative colitis. the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, Sjogren's syndrome; Preferably, the Sjogren's syndrome is dry eye syndrome; the autoinflammatory disease is selected from inflammatory bowel disease, familial periodic fever syndrome, vasculitis; the inflammatory bowel disease is selected from Crohn's disease, ulcerative colitis.

Images