Polymorphic forms of baricitinib as well as preparation method and application thereof

Abstract

The invention discloses a baricitinib polymorph as well as a preparation method and application thereof, and belongs to the technical field of medicine crystal forms. The baricitinib polymorphic form provided by the invention comprises a eutectic of baricitinib and 5-nitroisophthalic acid, a eutectic of baricitinib and mefenamic acid and amorphous baricitinib, the baricitinib crystal form provided by the invention has higher solubility compared with a commercially available BRT crystal form I, and the solubility can be up to nearly 17 times of that of the BRT crystal form I; compared with the prior art, the preparation method disclosed by the invention has the advantages that the bioavailability is higher, the eutecticum of baricitinib and 5-nitroisophthalic acid and the eutecticum of baricitinib and mefenamic acid have lower hygroscopicity, and the structural stability can be kept in the subsequent processing and storage process of medicines.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical crystal forms, and in particular to polymorphs of baricitinib, and their preparation methods and applications. Background Art

[0002] The information disclosed in the background art of the present invention is only intended to increase the understanding of the overall background of the present invention, and does not necessarily constitute an admission or imply in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Janus kinase signal transduction and activator of transcription (JAK-STAT) is an intracellular signal transduction pathway closely related to cytokines, and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. When the signal level is imbalanced, it often causes the over-differentiation and proliferation of specific immune cells, as well as resistance to apoptotic signals. The release of abnormally high levels of cytokines will cause inflammatory reactions in different parts, which will further lead to a variety of clinically autoimmune-mediated inflammatory diseases, including hematological malignancies, rheumatic immune diseases, skin and gastrointestinal diseases. Therefore, inhibiting or blocking the JAK-STAT signal pathway has become an important direction for targeted treatment of immune-mediated inflammatory diseases.

[0004] Baricitinib (BRT) is a second-generation JAK inhibitor jointly developed by Eli Lilly and Incyte Corporation, and the compound was first disclosed in International Patent Application No. WO2009114512. Currently, BRT is on the market in some countries and regions, mainly used for the treatment of rheumatoid arthritis, and also has potential efficacy in the treatment of diseases such as cancer, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and reactive arthritis. The patent with the authorization announcement number CN105924444B details the original research crystal form I of BRT, the acetic acid solvate of BRT, and various phosphate forms of BRT. It is worth noting that the currently commercially available BRT crystal form I has poor solubility in water (0.073 mg / mL, pH = 6.6 phosphate buffer solution). Low solubility will limit the dissolution rate of the drug, affect drug absorption, and thus affect the bioavailability of the drug in the human body. To achieve the therapeutic effect, it may be necessary to increase the drug dose, which may lead to an increase in side effects, a decrease in patient compliance, and an increase in the cost of the active pharmaceutical ingredient. In particular, different crystal forms of drugs have different morphologies, melting points, solubilities, dissolution characteristics, hygroscopicity, chemical stability, mechanical stability, etc. These characteristics can affect the quality, safety, and effectiveness of drug preparations, resulting in differences in clinical efficacy. Therefore, it is an urgent problem to develop a new crystal form of baricitinib with high solubility, good stability, and low hygroscopicity to improve the bioavailability of the drug. Summary of the Invention

[0005] In view of this, the present invention provides a polymorph of baricitinib, a preparation method thereof and an application thereof, which solves the problems of low solubility and low bioavailability of the existing BRT crystal form.

[0006] In the first aspect, the present invention provides a crystal form of baricitinib, which is a co-crystal of baricitinib and 5-nitroisophthalic acid, wherein the molar ratio of baricitinib to 5-nitroisophthalic acid is 1:(0.8 - 1.2).

[0007] Preferably, the molar ratio of baricitinib to 5-nitroisophthalic acid is 1:1.

[0008] Preferably, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ values of 8.6°±0.2°, 9.4°±0.2°, 10.8°±0.2°, 12.0°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 18.8°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.7°±0.2°, 24.8°±0.2°, 25.4°±0.2°, 25.6°±0.2°, 26.0°±0.2°, 26.4°±0.2°, 28.0°±0.2°, 28.5°±0.2°.

[0009] In the second aspect, the present invention provides a preparation method of the above crystal form of baricitinib, comprising the following steps: Mix baricitinib and 5-nitroisophthalic acid in an alcohol solvent or an ester solvent, heat up to dissolve, and then cool and crystallize to obtain; Or, mix baricitinib and 5-nitroisophthalic acid in an alcohol solvent or an ester solvent, and stir and react for a set time by the slurry method to obtain; Or, mix baricitinib and 5-nitroisophthalic acid and then grind for a set time by the grinding method to obtain.

[0010] Preferably, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol or n-butanol; the ester solvent is selected from one or two of methyl formate or ethyl formate.

[0011] Preferably, in the slurry method, the stirring speed is 50 - 1800 r / min, the stirring time is 1 - 7 days; the grinding time is 30 - 90 min; the grinding includes dry grinding and wet grinding, and the solvent added in the wet grinding is selected from one or more of methanol, ethanol, isopropanol, n-butanol, methyl formate or ethyl formate, and the addition amount of the solvent in the wet grinding is 0.01 - 0.2 μL / mg.

[0012] In a third aspect, the present invention provides a crystal form of baricitinib, which is a co-crystal of baricitinib and mefenamic acid. Among them, the molar ratio of baricitinib to mefenamic acid is 1:1. The X-ray powder diffraction pattern of this crystal form has characteristic peaks at 2θ values of 11.5±0.2°, 11.8±0.2°, 12.4±0.2°, 12.6±0.2°, 13.6±0.2°, 13.9±0.2°, 14.3±0.2°, 14.9±0.2°, 15.3±0.2°, 15.9±0.2°, 16.2±0.2°, 16.6±0.2°, 17.3±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, 19.5±0.2°, 19.9±0.2°, 20.3±0.2°, 20.6±0.2°, 22.0±0.2°, 22.4±0.2°, 24.8±0.2°, 25.1±0.2°, 25.5±0.2°, 26.5±0.2°, 26.9±0.2°, 27.4±0.2°, 29.3±0.2°, 29.8±0.2°, 30.7±0.2°, 31.1±0.2°.

[0013] In a fourth aspect, the present invention provides a preparation method for the crystal form in the third aspect above, including the following steps: (1) Mix baricitinib and mefenamic acid and grind them for a set time by the grinding method to obtain co-crystal powder; among them, the grinding time is 30 - 90 min; the grinding includes dry grinding and wet grinding, and the solvent added in the wet grinding is selected from one or more of methanol, ethanol, isopropanol, n-butanol, methyl formate or ethyl formate; (2) After mixing baricitinib and mefenamic acid, first heat up to make the mixture melt, and then slowly cool it below the melting point. During this process, add a small amount of the co-crystal powder obtained in step (1) as a seed crystal to obtain it.

[0014] When the grinding method is used in the present invention, the addition amount of the solvent added in the wet grinding is 0.01 - 0.2 μL / mg; when the melt method is used in the present invention, the melting temperature is 193 - 220 °C.

[0015] In a fifth aspect, the present invention provides a crystal form of baricitinib, which is amorphous baricitinib, and the diffraction peaks of its X-ray powder diffraction present a hump without obvious diffraction peaks.

[0016] In a sixth aspect, the present invention provides a preparation method for the crystal form in the fifth aspect above, including the following steps: Using baricitinib crystal form I as a raw material, adopting the melt method, heating up to complete melting, and then cooling to room temperature at a cooling rate of more than 50 °C / min to obtain it; Alternatively, using the solvate of baricitinib as the raw material, by the melt method, after heating to complete melting, and then heating to complete melting, cooling to room temperature at a cooling rate of more than 50 °C / min to obtain it; the solvate of baricitinib is selected from the acetic acid solvate of baricitinib or the 1,4-dioxane solvate of baricitinib.

[0017] When preparing amorphous baricitinib in the present invention, after heating to 5-10 °C above the melting point and the system is completely melted, the cooling step should be carried out rapidly to avoid thermal decomposition of baricitinib. The room temperature referred to in the present invention means the temperature range of 10-30 °C.

[0018] In a seventh aspect, the present invention provides a pharmaceutical composition, comprising a therapeutically effective amount of the crystalline form described in any one of the above and a pharmaceutically acceptable carrier.

[0019] In an eighth aspect, the present invention provides the use of the crystalline form described in any one of the above or the above pharmaceutical composition in the preparation of a drug for treating an autoimmune disease, an inflammatory disease or a cancer disease participated by JAK.

[0020] In the present invention, the autoimmune diseases include rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, etc., and the inflammatory diseases include reactive arthritis, etc.

[0021] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) The co-crystal (BRT-5-Na) of baricitinib and 5-nitroisophthalic acid provided by the present invention has higher solubility compared with the commercially available BRT crystalline form I. Especially in the phosphate buffer solution with pH = 6.6, the solubility is nearly 17 times that of the commercially available BRT crystalline form I; the improvement of solubility can increase the dissolution rate of the drug, and thus improve its bioavailability. In addition, this crystalline form has low hygroscopicity, belonging to the category of "slightly hygroscopic" in the Chinese Pharmacopoeia, which will not bring an additional burden to the subsequent processing of the drug and can also reduce the degradation of the drug caused by moisture absorption.

[0022] (2) The co-crystal (BRT-Ma) of baricitinib and mefenamic acid provided by the present invention has higher solubility compared with the commercially available BRT crystalline form I. Especially in the phosphate buffer solution with pH = 6.6, the solubility is 1.5 times that of the commercially available BRT crystalline form I; the dissolution rate is also significantly improved, and the saturation concentration can be reached within 30 minutes; at the same time, its hygroscopicity is low, which can improve the solubility of the drug while reducing the degradation of the drug caused by moisture absorption; in addition, the melting point of BRT-Ma is low. For drugs with poor thermal stability, the low melting point can reduce the energy consumption in the production of drug preparations and can prevent the decomposition of the drug caused by high temperature.

[0023] (3) The amorphous baricitinib provided by the present invention has higher solubility compared with the commercially available BRT Form I. Especially in the phosphate buffer solution with pH = 6.6, the solubility is 1.8 times that of the commercially available BRT Form I. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention and do not constitute an improper limitation to the present invention. Obviously, for those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0025] Figure 1 is the X-ray powder diffraction pattern of BRT-5-Na in Example 1 of the present invention; Figure 2 is the simultaneous thermal analysis (TG-DSC) diagram of BRT-5-Na in Example 1 of the present invention; Figure 3 is the X-ray powder diffraction pattern of BRT-Ma in Example 4 of the present invention; Figure 4 is the simultaneous thermal analysis (TG-DSC) diagram of BRT-Ma in Example 4 of the present invention; Figure 5 is the X-ray powder diffraction pattern of BRT-A in Example 5 of the present invention; Figure 6 is the simultaneous thermal analysis (TG-DSC) diagram of BRT-A in Example 5 of the present invention; Figure 7 is the dynamic vapor sorption (DVS) diagram of BRT-5-Na in Example 1 of the present invention; wherein, the solid squares represent the water adsorption process, and the hollow squares represent the water desorption process; Figure 8 is the dynamic vapor sorption (DVS) diagram of BRT-Ma in Example 4 of the present invention; wherein, the solid squares represent the water adsorption process, and the hollow squares represent the water desorption process; Figure 9 is the dynamic vapor sorption (DVS) diagram of BRT-A in Example 5 of the present invention; wherein, the solid squares represent the water adsorption process, and the hollow squares represent the water desorption process; Figure 10 is the dynamic vapor sorption (DVS) diagram of the commercially available BRT Form I; wherein, the solid squares represent the water adsorption process, and the hollow squares represent the water desorption process; Figure 11 is the accelerated stability experiment of BRT-5-Na in Example 1 of the present invention; Figure 12It is the accelerated stability experiment of BRT-Ma in Example 4 of the present invention; Figure 13 It is the accelerated stability experiment of BRT-A in Example 5 of the present invention; Figure 14 It is the dissolution curve of commercially available BRT polymorph I; Figure 15 It is the dissolution curve of BRT-5-Na in Example 1 of the present invention; Figure 16 It is the dissolution curve of BRT-Ma in Example 4 of the present invention; Figure 17 It is the dissolution curve of BRT-A in Example 5 of the present invention; Figure 18 It is the X-ray powder diffraction pattern of BRT-A in Example 5 of the present invention after the dissolution experiment. Detailed Description of the Invention

[0026] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0027] The technical solution of the present invention will be further described below in conjunction with specific examples. Unless otherwise specified, the present invention has no special restrictions on the sources of the reagents used in the following examples, and commercially available products well-known to those skilled in the art can be used.

[0028] The BRT polymorph I (M r = 371.4 g / mol, T m = 213.4 °C) used in the following examples was provided by Shandong Daohe Pharmaceutical Co., Ltd. In the following examples, room temperature refers to 25 ± 3 °C; X-ray powder diffraction uses Cu-Kα radiation.

[0029] Example 1 This example provides a preparation method for a co-crystal of baricitinib and 5-nitroisophthalic acid (BRT-5-Na).

[0030] Dissolve BRT polymorph I (74.2 mg, 0.2 mmol) in 10 ml of methanol, heat to 60 °C to obtain a clear solution. Subsequently, add 5-nitroisophthalic acid (42.2 mg, 0.2 mmol), and ultrasonically mix for 10 minutes. Then transfer the solution to room temperature and cool for crystallization for 24 hours, and filter to obtain the BRT-5-Na co-crystal.

[0031] Figure 1X-ray powder diffraction pattern of BRT-5-Na prepared in this example, which has characteristic peaks at diffraction angles 2θ values of 8.6°±0.2°, 9.4°±0.2°, 10.8°±0.2°, 12.0°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 18.8°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.7°±0.2°, 24.8°±0.2°, 25.4°±0.2°, 25.6°±0.2°, 26.0°±0.2°, 26.4°±0.2°, 28.0°±0.2°, 28.5°±0.2°.

[0032] Figure 2 Synchronous thermal analysis (TG-DSC) diagram of BRT-5-Na prepared in this example. It can be seen from the figure that the melting point of BRT-5-Na is 251.0 °C.

[0033] Example 2 This example provides a preparation method of a co-crystal (BRT-5-Na) of baricitinib and 5-nitroisophthalic acid.

[0034] Add BRT crystal form I (74.2 mg, 2 mmol) and 5-nitroisophthalic acid (42.2 mg, 2 mmol) to 5 ml of methanol, and then use the slurry method to stir at a speed of 300 r / min for 48 h at room temperature to achieve complete reaction and obtain BRT-5-Na co-crystal powder. It was measured that its X-ray powder diffraction pattern and TG-DSC curve were basically the same as those in Example 1.

[0035] Example 3 This example provides a preparation method of a co-crystal (BRT-5-Na) of baricitinib and 5-nitroisophthalic acid.

[0036] Mix BRT crystal form I (74.2 mg, 2 mmol) and 5-nitroisophthalic acid (42.2 mg, 2 mmol) evenly, and add methanol as an auxiliary agent at a ratio of 0.1 μL / mg. Grind for 60 min under the condition of 25 Hz to obtain BRT-5-Na co-crystal powder. It was measured that its X-ray powder diffraction pattern and TG-DSC curve were basically the same as those in Example 1.

[0037] Example 4 This example provides a preparation method of a co-crystal (BRT-Ma) of baricitinib and mefenamic acid.

[0038] (1) Mix BRT polymorph I (74.2 mg, 0.2 mmol) and mefenamic acid (48.2 mg, 0.2 mmol) evenly, add a methanol auxiliary agent at a ratio of 0.1 μL / mg, and grind for 60 min under the condition of 25 Hz to obtain BRT-Ma cocrystal powder.

[0039] (2) Mix BRT polymorph I (74.2 mg, 0.2 mmol) and mefenamic acid (48.2 mg, 0.2 mmol) evenly, heat up to 200 °C to make it completely melt, then cool to 160 °C, add a small amount of the BRT-Ma cocrystal product obtained in step (1) as a seed crystal, and rapid crystallization can be achieved to obtain the BRT-Ma cocrystal.

[0040] Figure 3 This is the X-ray powder diffraction pattern of BRT-Ma prepared in this example. Characteristic peaks are present at diffraction angles 2θ values of 11.5 ± 0.2°, 11.8 ± 0.2°, 12.4 ± 0.2°, 12.6 ± 0.2°, 13.6 ± 0.2°, 13.9 ± 0.2°, 14.3 ± 0.2°, 14.9 ± 0.2°, 15.3 ± 0.2°, 15.9 ± 0.2°, 16.2 ± 0.2°, 16.6 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 19.0 ± 0.2°, 19.2 ± 0.2°, 19.5 ± 0.2°, 19.9 ± 0.2°, 20.3 ± 0.2°, 20.6 ± 0.2°, 22.0 ± 0.2°, 22.4 ± 0.2°, 24.8 ± 0.2°, 25.1 ± 0.2°, 25.5 ± 0.2°, 26.5 ± 0.2°, 26.9 ± 0.2°, 27.4 ± 0.2°, 29.3 ± 0.2°, 29.8 ± 0.2°, 30.7 ± 0.2°, 31.1 ± 0.2°.

[0041] Figure 4 This is the TG-DSC curve of BRT-Ma prepared in this example. It can be seen from the figure that the melting point of BRT-Ma is 190.3 °C. The lower melting point can reduce the energy consumption during the production of pharmaceutical preparations and can prevent drug decomposition caused by high temperature.

[0042] Example 5 This example provides a preparation method of amorphous baricitinib (BRT-A).

[0043] Take 20 mg of BRT polymorph I and place it on a hot stage, heat up to 220 °C. After the system is completely melted and becomes a transparent liquid, cool it to room temperature at a cooling rate of 50 °C / min, and the obtained sample is BRT-A. As Figure 5As shown, in the X-ray powder diffraction pattern of BRT-A, the diffraction peaks show an obvious bulging shape, and no obvious diffraction peaks are seen, indicating that an amorphous form with uniform structure is obtained.

[0044] Figure 6 The TG-DSC curve of BRT-A prepared in this example is shown. It can be seen that its glass transition temperature is 69.3 °C. When the temperature is further raised to 153.3 °C, an exothermic peak appears, and the final melting point is 213.3 °C.

[0045] Test Example 1. Hygroscopicity determination: Approximately 20 mg of BRT-5-Na of Example 1, BRT-Ma of Example 4, BRT-A of Example 5, and commercially available BRT polymorph I were taken respectively. Under the condition of 25 °C, the humidity was increased from 0% to 90% and then decreased to 0% to measure their hygroscopicity. Figure 7 、 Figure 8 、 Figure 9 and Figure 10 are the dynamic vapor sorption (DVS) diagrams of BRT-5-Na of Example 1, BRT-Ma of Example 4, BRT-A of Example 5, and commercially available BRT respectively. Among them, solid squares represent the water adsorption process, and hollow squares represent the water desorption process.

[0046] Compared with commercially available BRT polymorph I, BRT-A shows higher hygroscopicity. Compared with commercially available BRT polymorph I, BRT-5-Na maintains the low hygroscopicity of the active pharmaceutical ingredient, meeting the standard of "slightly hygroscopic" in the Chinese Pharmacopoeia and not bringing an additional burden to the subsequent processing of the drug. BRT-Ma also maintains the low hygroscopicity of the active pharmaceutical ingredient, meeting the relevant regulations of the Chinese Pharmacopoeia and not causing an additional burden to the subsequent processing of the drug.

[0047] 2. Accelerated stability determination: Figure 11 、 Figure 12 and Figure 13 are the accelerated stability test diagrams of BRT-5-Na of Example 1, BRT-Ma of Example 4, and BRT-A of Example 5 placed at 40 °C / 75% RH for 6 months. It can be seen from the figure that both BRT-5-Na and BRT-Ma cocrystals have good environmental stability and no obvious phase change occurs within 6 months; while the stability of amorphous BRT-A is poor, and recrystallization occurs after 7 days of storage, showing obvious crystallization peaks.

[0048] 3. Solubility and dissolution curve determination: Under room temperature conditions and in an environment without protective gas, a phosphate buffer solution with a pH value of 6.6 was selected, and excessive BRT-5-Na of Example 1, BRT-Ma of Example 4, BRT-A of Example 5, and commercially available BRT were respectively formulated into suspensions. Using the paddle method, stirring was carried out at a speed of 100 r / min, and the supernatant was extracted at 5, 10, 15, 20, 25, 30, 45, 60, 120, 180, 240, 300 min, and detected using an ultraviolet-visible spectrophotometer.

[0049] The dissolution curve of BRT-5-Na of Example 1 is as Figure 15 shown, with an equilibrium solubility of 1.21 mg / ml, which is Figure 14 16.6 times the equilibrium solubility (0.073 mg / ml) of the commercially available BRT shown.

[0050] The dissolution curve of BRT-Ma of Example 4 is as Figure 16 shown, with an equilibrium solubility of 0.11 mg / ml, whose equilibrium solubility is 1.5 times that of the commercially available BRT, and the dissolution rate has also been significantly improved.

[0051] The dissolution curve of BRT-A of Example 5 is as Figure 17 shown, and the dissolution curve shows a trend of rising first and then falling. This is because during the stirring process, partial crystal transformation of BRT-A occurred. As Figure 18 shown, a crystal peak appears in the X-ray diffraction pattern of the sample after solubility testing, proving that its crystal form has changed. In addition, under the given test conditions, the equilibrium solubility of BRT-A is 0.13 mg / ml, which is 1.8 times that of the commercially available BRT.

[0052] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A crystal form of baricitinib, characterized in that, The crystal form is a co-crystal of baricitinib and 5-nitroisophthalic acid, wherein the molar ratio of baricitinib to 5-nitroisophthalic acid is 1:(0.8 - 1.2).

2. The crystalline form of baricitinib according to claim 1, characterized in that, The molar ratio of baricitinib to 5-nitroisophthalic acid is 1:1; the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ values of 8.6°±0.2°, 9.4°±0.2°, 10.8°±0.2°, 12.0°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 18.8°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.7°±0.2°, 24.8°±0.2°, 25.4°±0.2°, 25.6°±0.2°, 26.0°±0.2°, 26.4°±0.2°, 28.0°±0.2°, 28.5°±0.2°.

3. The preparation method of the crystalline form of baricitinib according to any one of claims 1 to 2, characterized in that, It includes the following steps: Mix baricitinib and 5-nitroisophthalic acid in an alcohol solvent or an ester solvent, heat up to dissolve, and then cool to crystallize to obtain the product; Or, mix baricitinib and 5-nitroisophthalic acid in an alcohol solvent or an ester solvent, and carry out a slurry method stirring reaction for a set time to obtain the product; Or, mix baricitinib and 5-nitroisophthalic acid and then grind for a set time by a grinding method to obtain the product.

4. The preparation method according to claim 1, characterized in that, The alcohol solvent is selected from one or more of methanol, ethanol, isopropanol or n-butanol; the ester solvent is selected from one or two of methyl formate or ethyl formate; In the slurry method, the stirring speed is 50 - 1800 r / min, and the stirring time is 1 - 7 days; the grinding time is 30 - 90 min; the grinding includes dry grinding and wet grinding. The solvent added in the wet grinding is selected from one or more of methanol, ethanol, isopropanol, n-butanol, methyl formate or ethyl formate, and the addition amount of the solvent in the wet grinding is 0.01 - 0.2 μL / mg.

5. A crystal form of baricitinib, characterized in that, The crystal form is a co-crystal of baricitinib and mefenamic acid, wherein the molar ratio of baricitinib to mefenamic acid is 1:

1. The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ values of 11.5±0.2°, 11.8±0.2°, 12.4±0.2°, 12.6±0.2°, 13.6±0.2°, 13.9±0.2°, 14.3±0.2°, 14.9±0.2°, 15.3±0.2°, 15.9±0.2°, 16.2±0.2°, 16.6±0.2°, 17.3±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, 19.5±0.2°, 19.9±0.2°, 20.3±0.2°, 20.6±0.2°, 22.0±0.2°, 22.4±0.2°, 24.8±0.2°, 25.1±0.2°, 25.5±0.2°, 26.5±0.2°, 26.9±0.2°, 27.4±0.2°, 29.3±0.2°, 29.8±0.2°, 30.7±0.2°, 31.1±0.2°.

6. The preparation method of the crystal form of baricitinib according to claim 1, characterized in that, Comprising the following steps: (1) Mix baricitinib and mefenamic acid and grind for a set time by the grinding method to obtain co-crystal powder; wherein, the grinding time is 30-90 min; the grinding includes dry grinding and wet grinding, and the solvent added in the wet grinding is selected from one or more of methanol, ethanol, isopropanol, n-butanol, methyl formate or ethyl formate; (2) After mixing baricitinib and mefenamic acid, first heat up to melt the mixture, and then slowly cool it below the melting point. During this process, add a small amount of the co-crystal powder obtained in step (1) as a seed crystal to obtain it.

7. A crystalline form of baricitinib, characterized in that, The crystal form is amorphous baricitinib, and the diffraction peaks of its X-ray powder diffraction present a bulge without obvious diffraction peaks.

8. The preparation method of the crystal form of baricitinib according to claim 1, characterized in that, Comprising the following steps: Using baricitinib crystal form I as a raw material, adopting the melt method, heating up to complete melting and then cooling to room temperature at a cooling rate of more than 50°C / min to obtain it; Or, using a solvate of baricitinib as a raw material, adopting the melt method, heating up to complete melting, and then cooling to room temperature at a cooling rate of more than 50°C / min to obtain it; the solvate of baricitinib is selected from the acetic acid solvate of baricitinib or the 1,4-dioxane solvate of baricitinib.

9. A pharmaceutical composition, characterized in that, Comprising an effective therapeutic amount of the crystal form according to any one of claims 1 or 2, claim 5 or claim 7 and a pharmaceutically acceptable carrier.

10. Use of the crystal form according to any one of claims 1 or 2, claim 5 or claim 7 or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating an autoimmune disease, an inflammatory disease or a cancer disease involving JAK.

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