Crystal form of compound as well as preparation method and application of crystal form

Abstract

The invention discloses a crystal form of a compound as well as a preparation method and application thereof, the compound has a structure as shown in a formula I. The crystal form has higher crystal purity, lower hygroscopicity, better solid stability and better solubility, is beneficial to preparation and storage of pharmaceutical preparations, and has very good application value and patent medicine prospect. Besides, clinical test results show that the crystal form A of the compound as shown in the formula I has very good pharmacokinetic characteristics, low clinical toxicity, better safety and high oral bioavailability, and has a good treatment effect on various diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry polymorph research, and specifically 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 Art

[0002] In the pharmaceutical field, the crystal form of a compound has an important influence on its drug performance. Different crystal forms can lead to significant differences in solubility, stability, bioavailability, and efficacy of the compound. Therefore, discovering and developing new crystal forms of compounds is of great significance for improving the clinical application value of drugs.

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

[0004] However, there is no report on the crystal form of DZ2002, its preparation method and application. Summary of the invention

[0005] To overcome the deficiencies of the prior art, the present invention provides a crystalline form of a compound and a preparation method and application thereof.

[0006] In a first aspect of the present invention, a crystalline form A of a compound of formula I is provided:

[0007]

[0008] The XRPD spectrum of the crystalline form A (using Cu-Kα radiation) has characteristic peaks at at least three (e.g., three, four, five, six, seven, eight, and in particular all) positions among the positions where 2θ values ​​are approximately 5.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 15.1°±0.2°, 17.7°±0.2°, 18.1°±0.2°, 25.8°±0.2°, and 29.8°±0.2°.

[0009] Further, the XRPD spectrum of the crystalline form A (using Cu-Kα radiation) has characteristic peaks at at least three (for example, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, and especially all) positions at which 2θ values ​​are approximately 8.7°±0.2°, 10.8°±0.2°, 14.2°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 23.7°±0.2°, 24.0°±0.2°, 25.4°±0.2°, 28.3°±0.2°, 30.6°±0.2°, 31.6°±0.2°, 33.0°±0.2°, 34.6°±0.2°, and 36.4°±0.2°.

[0010] Further, the crystalline form A has substantially Figure 1 XRPD pattern shown.

[0011] Furthermore, the TGA spectrum of the crystalline form A shows a weight loss of 6.56%±1% (e.g., 5.56, 6.00, 6.56, 7.00, 7.56%, in particular 6.56%) when heated from 30°C to 100°C and / or a weight loss of 57.3%±1% (e.g., 56.3, 56.8, 57.3, 57.8, 58.3%, in particular 57.3%) when heated from 190°C to 400°C.

[0012] In some embodiments of the present invention, the TGA spectrum of the crystalline form A shows a weight loss of 6.56% when heated from 30°C to 100°C and / or a weight loss of 57.3% when heated from 190°C to 400°C.

[0013] Furthermore, the DSC spectrum of the crystalline form A has an endothermic peak at 70-100°C (e.g., 70, 75, 80, 85, 80, 95, 100°C, in particular 90.4±3°C) and / or 160-170°C (e.g., 160, 165, 170°C, in particular 164.4±3°C).

[0014] In some embodiments of the present invention, the DSC spectrum of the crystalline form A has an endothermic peak at 90.4±3°C and / or 164.4±3°C.

[0015] Furthermore, the crystal form A is a hydrate crystal form, especially a monohydrate crystal form.

[0016] Furthermore, under observation under a polarizing microscope, the crystal form A is a columnar crystal.

[0017] Furthermore, the crystal system of the single crystal of the crystal form A is monoclinic; the space group is P2 1 .

[0018] Furthermore, the unit cell parameters of the crystal form A are: α=γ=90°; β=112.9890(10)°.

[0019] Furthermore, the unit cell volume of the crystalline form A is

[0020] Furthermore, the number of molecules in the unit lattice of the crystal form A is 4.

[0021] Furthermore, the goodness of fit of the crystal form A is 1.034.

[0022] Furthermore, the density of the crystal form A is 1.382 g / cm 3 .

[0023] In a second aspect of the present invention, a method for preparing Form A of the compound of Formula I is provided, the method comprising using the amorphous form of the compound of Formula I as a starting material and preparing Form A by a suspension stirring method.

[0024] Furthermore, the suspension stirring method is a room temperature suspension stirring method.

[0025] Furthermore, the room temperature suspension stirring method comprises the following steps: suspending the amorphous raw material of the compound represented by formula I with a solvent, and stirring at room temperature (20-30°C, for example 21, 22, 23, 24, 25, 26, 27, 28, 29, 30°C, especially 25°C) until solid precipitates.

[0026] Furthermore, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, toluene, n-heptane, n-hexane, ethyl ether, dichloromethane, chloroform, and petroleum ether.

[0027] In some embodiments of the present invention, the solvent is methyl tert-butyl ether.

[0028] The third aspect of the present invention provides a pharmaceutical composition comprising the crystalline form A of the compound represented by formula I, and one or more pharmaceutically acceptable excipients.

[0029] Furthermore, the pharmaceutically acceptable excipients are selected from the group consisting of thickeners, stabilizers, preservatives, adhesives, lubricants, disintegrants, antibacterial agents, suspending agents, solubilizers, fillers, antioxidants, and buffers.

[0030] Furthermore, the pharmaceutical composition can be administered by any suitable route, such as gastrointestinal administration (such as oral, sublingual, rectal administration) or parenteral administration (for example, intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, instillation, respiratory tract administration, etc.).

[0031] Furthermore, the pharmaceutical composition can be in any suitable dosage form, selected from: oral dosage forms (such as tablets, granules, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.), injection dosage forms (such as injections for subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, joint cavity injections, etc.), skin dosage forms (such as external solutions, lotions, ointments, plasters, pastes, patches, etc.), mucosal dosage forms (such as eye drops, eye ointments, eye gels, nasal drops, gargles, sublingual tablets, etc.), cavity dosage forms (such as suppositories, aerosols, effervescent tablets, drops, pills, enema liquids, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc.), respiratory tract dosage forms (such as sprays, aerosols, powder mists, etc.).

[0032] Preferably, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, granules, capsules, injections, ointments, eye drops, eye ointments, eye gels, and enema liquids.

[0033] In some embodiments of the present invention, the pharmaceutical composition is an oral dosage form, particularly a capsule.

[0034] Furthermore, the crystalline form A of the compound represented by formula I is used alone or in combination with other types of active ingredients.

[0035] Furthermore, the subject of the pharmaceutical composition is a mammal, especially a human.

[0036] Furthermore, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form A of the compound represented by formula I.

[0037] Further, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a capsule, tablet or any dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules and powders packaged in vials or ampoules. The amount of active ingredient in the unit dosage preparation can be changed or adjusted from 0.1 mg to 1000 mg, depending on the specific application and efficacy of the active ingredient. If necessary, the composition may also contain other suitable therapeutic agents.

[0038] The fourth aspect of the present invention provides a use of Form A of the compound of Formula I or the pharmaceutical composition of the third aspect of the present invention in the preparation of a drug for preventing and / or treating a disease, wherein the disease is selected from: an autoimmune disease, an autoinflammatory disease.

[0039] Furthermore, the autoimmune disease is selected from: systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, Sjögren's syndrome, etc.

[0040] Furthermore, the autoimmune encephalomyelitis is experimental autoimmune encephalomyelitis.

[0041] Furthermore, the Sjögren's syndrome is dry eye.

[0042] Furthermore, the dry eye syndrome is tear deficiency type dry eye syndrome.

[0043] Furthermore, the autoimmune disease may also be an autoimmune disease caused by hyperactivity of Th1-mediated cellular immune response.

[0044] Furthermore, the autoinflammatory disease is selected from: inflammatory bowel disease (IBD), hereditary periodic fever syndrome, vasculitis, etc.

[0045] Furthermore, the inflammatory bowel disease is selected from: Crohn's disease (CD), ulcerative colitis, etc.

[0046] The fifth aspect of the present invention provides an application in preventing and / or treating a disease, which comprises administering the crystalline form A of the compound represented by formula I described in the first aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention to a subject in need thereof, and the disease has the definition of the disease described in the fourth aspect of the present invention.

[0047] Furthermore, the subject is a mammal, particularly a human.

[0048] Furthermore, the administration can be carried out by any suitable route of administration, such as enteral administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, instillation, respiratory tract administration, etc.).

[0049] The present invention is based on the previous research results of the inventors. After experimental research, the crystal of the crystal form A of the compound shown in formula I is further obtained, which has high crystal purity, low hygroscopicity, good solid stability and good solubility, is conducive to the preparation and storage of pharmaceutical preparations, and has very good application value and drug development prospects. In addition, the clinical trial results show that the crystal form A of the compound shown in formula I of the present invention has very good pharmacokinetic properties, low clinical toxicity, good safety, high oral bioavailability, and has good therapeutic effects on various diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 Shown is the XRPD pattern of Form A.

[0051] Figure 2 Shown is the DVS diagram of Form A.

[0052] Figure 3 Shown is the Raman pattern of Form A.

[0053] Figure 4 Shown is the IR pattern of Form A.

[0054] Figure 5 Shown is the Ortep diagram of the single crystal structure of Form A.

[0055] Figure 6 Shown is the whole blood concentration-time curve of DZ2002 after administration of Formulation 1 to beagle dogs.

[0056] Figure 7 Shown is the whole blood concentration-time curve of DZA after administration of Formulation 1 to beagle dogs.

[0057] Figure 8 Shown is the whole blood concentration-time curve of DZ2002 after administration of Formulation 2 to beagle dogs.

[0058] Fig. 9 Shown is the whole blood concentration-time curve of DZA after administration of Formulation 2 to beagle dogs. DETAILED DESCRIPTION

[0059] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0060] The term "crystalline form" is confirmed by characterization of an X-ray powder diffraction pattern. It will be appreciated by those skilled in the art that the physicochemical properties discussed herein can be characterized, with experimental errors depending on the conditions of the instrument, sample preparation, and sample purity, among others. In particular, it is well known to those skilled in the art that X-ray diffraction patterns generally vary with instrument conditions. It is particularly important to note that the relative intensity of the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of peak intensity cannot be used as the sole or determining factor. In fact, the relative intensity of the diffraction peaks in the XRPD spectrum is related to the preferred orientation of the crystal, and the peak intensities shown herein are illustrative rather than for absolute comparison. In addition, the experimental error of the peak angle is generally 5% or less, and the errors of these angles should also be taken into account, and an error of ±0.2° is generally allowed. In addition, due to the influence of experimental factors such as sample thickness, an overall shift in the peak angle may be caused, and a certain shift is generally allowed. Therefore, it can be understood by those skilled in the art that the X-ray powder diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and the "same XRPD pattern" described herein does not mean absolutely identical, the same peak position can differ by ±0.2° and the peak intensity allows a certain variability. Any crystal form having a pattern that is the same or similar to the characteristic peaks in these spectra belongs to the scope of the present invention. Those skilled in the art can compare the spectra listed in the present invention with the spectra of an unknown crystal form to confirm whether the two sets of spectra reflect the same or different crystal forms. In some embodiments, the crystal form A of the present invention is pure and single, and is substantially free of any other crystal forms. In the present invention, "substantially free" when used to refer to a new crystal form means that this crystal form contains less than 20% (by weight) of other crystal forms, especially less than 10% (by weight) of other crystal forms, more less than 5% (by weight) of other crystal forms, and more less than 1% (by weight) of other crystal forms.

[0061] It should be noted that the numerical values ​​and numerical ranges mentioned in the present invention should not be narrowly understood as numerical values ​​or numerical ranges themselves. Those skilled in the art should understand that they can fluctuate around specific numerical values ​​based on different specific technical environments without deviating from the spirit and principles of the present invention. In the present invention, such a fluctuating range that can be foreseen by those skilled in the art is mostly expressed by the term "about". When the term "about" is used before a numerical value of the present invention and refers to the numerical value, it means any value within the range of ±10% of the value, preferably within the range of ±5%, more preferably within the range of ±2%, and more preferably within the range of ±1%. For example, "about 10" should be interpreted as meaning 9-11, preferably 9.5-10.5, more preferably 9.8-10.2, and more preferably 9.9-10.1.

[0062] It should also be noted that in the X-ray diffraction pattern of powder samples, the specific crystal form of the diffraction spectrum obtained from the crystalline compound is often characteristic, and the relative intensity of the bands (especially at low angles) may vary due to the preferred orientation effect caused by differences in crystallization conditions, particle size, relative content of the mixture and other test conditions. Therefore, the relative intensity of the diffraction peak is not characteristic of the crystal in question, and when judging whether it is the same as a known crystal form, more attention should be paid to the position of the peaks rather than their relative intensity.

[0063] The term "room temperature" refers to the temperature of an item being close to or the same as the temperature of a space (e.g., a fume hood in which the item is located). Typically, room temperature is about 20°C to about 30°C, or about 22°C to 27°C, or about 25°C.

[0064] The term "subject" refers to any animal or cell thereof treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, for example, rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, especially humans.

[0065] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0066] The term "prevent" refers to avoiding, minimizing or making the onset or development of a disease difficult by treating it before it occurs.

[0067] The term "autoimmune disease" refers to a disease caused by the body's immune response to its own antigens, which leads to damage to its own tissues. The American Autoimmune Related Diseases Association has listed a relatively comprehensive list of autoimmune diseases.

[0068] The term "autoinflammatory disease" refers to inflammatory diseases targeting one's own tissues and organs. The pathogenesis is defined as an abnormal response of the body's innate immune system, leading to inflammatory damage to one's own tissues (see Li Chengrong, Autoinflammatory Diseases, Chinese Journal of Pediatrics, 2008, 46(11): 842-847).

[0069]

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0070] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0071] The DZ2002 API used in the examples can be prepared by the preparation methods of (i) to (vi) in the specific embodiments of the patent document CN101456860A (i.e., crude DZ2002), which has the following structure:

[0072]

[0073] The DZA described in the embodiment has the following structure:

[0074]

[0075] Example 1: Preparation and characterization of crystal forms of DZ2002

[0076] 1. Instruments and methods

[0077] 1.1 X-ray powder diffraction (XRPD)

[0078] Instrument model: Bruker D8 advance X-Ray diffractometer; target: Cu Kα (40KV, 40mA); distance from sample to detector: 30cm; scanning range: 3°-40° (2theta value); scanning rate: 0.1sec / step; scanning step: 0.02.

[0079] 1.2 Thermogravimetric analysis (TGA)

[0080] Instrument model: Netzsch TG 209F3; temperature range: 30-400°C; scanning rate: 10°C / min; purge gas: 25 mL / min; protective gas: 15 mL / min.

[0081] 1.3 Differential Scanning Calorimetry (DSC)

[0082] Instrument model: Perkin Elmer 8500DSC; temperature range: 50-200°C; scanning rate: 10°C / min; nitrogen flow rate: 50 ml / min.

[0083] 1.4 Dynamic moisture sorption (DVS)

[0084] Instrument model: SMSDVS Intrinsic; 0~95%RH; Temperature: 25℃.

[0085] 1.5 Raman spectroscopy

[0086] Instrument model: Thermo Scientific DXR Raman Microscope; Laser detection wavelength: 532 nm; Exposure intensity: 2 seconds 5 times.

[0087] 1.6 Single crystal X-ray diffraction (SC-XRD)

[0088] X-ray generator: MO Kα; temperature: 100K.

[0089] 2. Preparation of DZ2002 crystal form

[0090] Preparation of Form A: Weigh about 25 mg of DZ2002 API, stir and balance with 1 ml of methyl tert-butyl ether (MTBE) at 25°C for at least 24 hours, filter the solution, and dry the solid part in air for 10 minutes. Perform XRPD detection on the solid part. If the measured XRPD spectrum is different from the raw material spectrum, continue to characterize the solid in other aspects (such as DSC, TGA, IR, DVS, etc.). The results show that a new crystal form of DZ2002 is obtained, which is recorded as Form A.

[0091] Preparation of Form B: Weigh about 25 mg of DZ2002 API, stir and balance with 1 ml of isopropyl acetate at 25°C for at least 24 hours, filter the solution, and dry the solid part in air for 10 minutes. Perform XRPD on the solid part. If the XRPD spectrum is different from that of the raw material, continue to characterize the solid in other aspects (such as DSC, TGA, IR, DVS, etc.). The results show that a new form of DZ2002 is obtained, which is recorded as Form B.

[0092] 3. Characterization of the crystal form of DZ2002

[0093] 3.1 XRPD results of Form A

[0094] XRPD spectrum Figure 1 The XRPD diffraction peak data are shown in Table 1.

[0095] Table 1 XRPD diffraction peak data of Form A

[0096]

[0097]

[0098] 3.2 TGA and DCS results of Form A

[0099] The TGA spectrum shows that Form A has a weight loss of 6.56% at 80-90°C (equivalent to 1 molecule of water, the theoretical value is 6.69%, and the corresponding single crystal analysis data also shows that Form A contains one molecule of water), and the corresponding DSC also has an obvious water melting peak. And from the DSC spectrum, it can be seen that the melting temperature of Form A is 160°C and the decomposition temperature is 200°C.

[0100] 3.3 DVS results of Form A

[0101] The hygroscopicity of Form A was evaluated by water adsorption and desorption experiments at 25°C between 0-95% relative humidity.

[0102] DVS graph Figure 2 As shown, Form A absorbs only 1% moisture in the range of 0-95% humidity, indicating that it is slightly hygroscopic.

[0103] 3.4 Raman results of Form A

[0104] Raman spectrum Figure 3 shown.

[0105] 3.5 IR results of Form A

[0106] IR spectrum Figure 4 shown.

[0107] 3.6 Single crystal data of Form A

[0108] Computer program to solve the single crystal structure: The structure was solved and refined using the Bruker SHELXTL software package, using the space group P 21, the formula unit Z = 4, and the molecular formula C 10 H 13 N 5 O 3 ·H 2 O.F 2 The final anisotropic full-matrix least-squares refinement of has 364 variables and converges at R1 = 3.47% (observed data) and wR2 = 9.38% (all data). The goodness of fit is 1.034. The maximum peak in the final differential electron density synthesis is The maximum hole is The RMS deviation is According to the final model, the calculated density is 1.382 g / cm 3 ,F(000),534e -. (The structure was solved and refined using the Bruker SHELXTLSoftware Package,using the space group P 21,with Z=4for the formula unit,C 10 H 13 N 5 O 3 .H 2 O.The final anisotropic full-matrix least-squares refinement onF 2 with 364 variables converged at R1=3.47%, for the observed data and wR2=9.38% for all data. The goodness-of-fit was 1.034. The largest peak in the final difference electron density synthesis was and the largest hole was- with an RMS deviation of On the basis of the final model, the calculated density was 1.382g / cm 3 and F(000),534e - .)

[0109] The single crystal data of Form A are shown in Table 2, and the single crystal structure Ortep diagram is shown in Figure 5 shown.

[0110] Table 2 Single crystal data of Form A

[0111]

[0112]

[0113] Example 2: Pharmacokinetic study of the crystalline form of DZ2002

[0114] 1. Experimental Animals

[0115] The beagle dogs were obtained from Shanghai Jiagan Biotechnology Co., Ltd. (Experimental Animal Use License No.: SYXK(Shanghai)2020-0042). After acclimating to the environment in the dog breeding room (room temperature 23-25°C) of the Animal Center of Shanghai Institute of Materia Medica for 2 weeks, they weighed about 8 kg.

[0116] 2. Preparation

[0117] Preparation 1: Form B powder packed into capsules, 80 mg / capsule.

[0118] Preparation 2: Form A powder packed into capsules, 85.7 mg / capsule.

[0119] 3. Experimental groups and drug administration

[0120] There were 3 dogs per group, numbered 1#, 2#, and 3#. After fasting for 12 hours, a single oral administration was performed, the dosage was 1 capsule per dog, and feeding was resumed 4 hours after administration.

[0121] 4. Sample collection and processing

[0122] Blood collection time arrangement: 0min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 11h, 24h.

[0123] The concentrations of DZ2002 and DZA in beagle dog plasma were detected by LC-MS / MS method. The LC-MS / MS detection method is as follows:

[0124] Liquid chromatograph: Agilent 1290infinity LC system

[0125] Mass spectrometer: TSQ Vantage mass spectrometer

[0126] LC-MS / MS analysis conditions:

[0127] Column: Synergi 4μ Fusion RP, 5μm, 2.0×50mm ID;

[0128] Mobile phase A: H 2 O (0.2% ammonium formate; 0.04% formic acid);

[0129] Mobile phase B: CH 3 OH (0.2% ammonium formate; 0.04% formic acid);

[0130] Flow rate: 0.3 mL / min;

[0131] Injection volume: 3 μL;

[0132] The elution program is shown in Table 3.

[0133] Table 3 Elution program

[0134]

[0135] Optimize parameters such as Spray Voltage, Vaporizer Temp, Sheath gas, Aux gas, Capillary Temp and S-lens;

[0136] The m / z of DZ2002 is 252→136, and the fragmentation energy is 23V;

[0137] The m / z of DZA is 238→136, and the fragmentation energy is 23V;

[0138] 5. Experimental results

[0139] The experiment found that after administration, DZ2002 can be quickly converted into DZA after absorption in the body. The drug concentration-time curves of each group are shown in Figure 6-9 The main pharmacokinetic parameters are shown in Table 4.

[0140] Table 4 Pharmacokinetic parameters after administration in beagle dogs

[0141]

[0142]

[0143] Relative oral bioavailability (RF) of Formulation 1 = AUC 制剂1 / AUC 制剂2 *100%. It can be seen that compared with Preparation 1 (Crystal Form B), Preparation 2 (Crystal Form A) has better oral availability.

[0144] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0145] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience and preference of those skilled in the art.

[0146] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A crystalline form A of a compound of formula I, It is characterized in that The XRPD spectrum of the crystalline form A has characteristic peaks at at least three positions among the positions where the 2θ values ​​are approximately 5.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 15.1°±0.2°, 17.7°±0.2°, 18.1°±0.2°, 25.8°±0.2°, and 29.8°±0.2°:

2. The crystalline form A according to claim 1, It is characterized in that The XRPD spectrum of the crystalline form A has characteristic peaks at at least three positions among the positions where the 2θ values ​​are approximately 8.7°±0.2°, 10.8°±0.2°, 14.2°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 23.7°±0.2°, 24.0°±0.2°, 25.4°±0.2°, 28.3°±0.2°, 30.6°±0.2°, 31.6°±0.2°, 33.0°±0.2°, 34.6°±0.2°, and 36.4°±0.2°; Preferably, the crystalline form A has an XRPD pattern substantially as shown in Figure 1.

3. The crystalline form A according to claim 1, It is characterized in that The TGA spectrum of the crystalline form A shows a weight loss of 6.56%±1% when heated from 30°C to 100°C and / or a weight loss of 57.3%±1% when heated from 190°C to 400°C; Preferably, the TGA spectrum of the crystalline form A shows a weight loss of 6.56% when heated from 30°C to 100°C and / or a weight loss of 57.3% when heated from 190°C to 400°C.

4. The crystalline form A according to claim 1, It is characterized in that The DSC spectrum of the crystalline form A has an endothermic peak at 70-100°C and / or 160-170°C; Preferably, the DSC spectrum of the crystalline form A has endothermic peaks at 90.4±3°C and / or 164.4±3°C.

5. The crystalline form A according to claim 1, It is characterized in that The crystal form A is a hydrate crystal form, especially a monohydrate crystal form; Preferably, the crystal form A is a columnar crystal; Preferably, the crystal system of the crystalline form A is monoclinic; the space group is P2 1 ; Unit cell parameters: α=γ=90°;β=112.9890(10)°;the unit cell volume of Form A is The density of the crystal form A is 1.382 g / cm 3 .

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

7. The preparation method according to claim 6, It is characterized in that The suspension stirring method is a room temperature suspension stirring method; Preferably, the room temperature suspension stirring method comprises the following steps: suspending the amorphous raw material of the compound represented by formula I with a solvent, and stirring at 20-30°C until solid precipitates; preferably 25°C; Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, toluene, n-heptane, n-hexane, ethyl ether, dichloromethane, chloroform, petroleum ether, preferably methyl tert-butyl ether.

8. A pharmaceutical composition comprising the crystalline form A of the compound of formula I as claimed in any one of claims 1 to 5 or the crystalline form A of the compound of formula I prepared by the preparation method as claimed in any one of claims 6 to 7, and one or more pharmaceutically acceptable excipients.

9. Use of the crystalline form A of the compound of formula I as claimed in any one of claims 1 to 5, or the crystalline form A of the compound of formula I prepared by the preparation method as claimed in any one of claims 6 to 7, or the pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is selected from: autoimmune diseases and autoinflammatory diseases.

10. The use according to claim 9, It is characterized in that The autoimmune disease is selected from the group consisting of systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, and Sjögren's syndrome; Preferably, the Sjögren's syndrome is dry eye; Preferably, the autoinflammatory disease is selected from: inflammatory bowel disease, hereditary periodic fever syndrome, vasculitis; Preferably, the inflammatory bowel disease is selected from: Crohn's disease, ulcerative colitis.

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