New crystal form of Selanisole

Abstract

The invention provides a polymorphic form of a compound (Z)-3-{3-[3, 5-bis (trifluoromethyl) phenyl]-1H-1, 2, 4-triazole-1-yl}-N '-(pyrazine-2-yl) acryloyl hydrazide shown as a formula (I), and the polymorphic form provided by the invention has better chemical stability, physical stability and lower hygroscopicity, is less influenced by heat, humidity and illumination, and is convenient to store and prepare. The invention further provides a preparation method of the polymorphic form of the compound (Z)-3-{3-[3, 5-bis (trifluoromethyl) phenyl]-1H-1, 2, 4-triazole-1-yl}-N'-(pyrazine-2-yl) acryloyl hydrazide.

Description

Technical Field

[0001] This disclosure provides new crystal forms of celinisox and their preparation methods, as well as their applications in the treatment of tumor diseases. Background Technology

[0002] Celiniso is an orally administered selective nuclear export inhibitor / SINE compound. Celiniso works by binding to and inhibiting the nuclear export protein XP01 (also known as CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This restarts and enhances their tumor suppressor function and is thought to induce selective apoptosis in cancer cells while largely unaffected by normal cells. US 8999996 B2 discloses celiniso, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and use for the treatment of conditions associated with CRM1 activity. Furthermore, it discloses a method for preparing the disclosed compounds (including celiniso) by causing a (Z)-3-(3-(3,5-) reaction. WO 2016025904 A1 discloses various crystal forms of celiniso for treating conditions related to CRM1 activity, namely crystal form A, crystal form B, crystal form C, and crystal form D. WO2017118940 A1 discloses crystal forms α, β, and γ of celiniso. WO2018129227A1 discloses crystal forms T1 to T17 of celiniso.

[0003] Generally speaking, polymorphism refers to the ability of a substance to exist in two or more crystalline phases, which have different spatial arrangements and / or molecular conformations in their crystal lattices. Therefore, "polymorphs" refer to different crystalline forms of the same pure substance, where the molecules have different spatial arrangements of molecules, atoms, and / or ions that form crystals. Different polymorphs may have different physical properties, such as melting point, solubility, etc. Changes in solid form can significantly affect drug properties, such as bioavailability, handling properties, dissolution rate, and stability, which in turn can significantly influence the processing, shelf life, and commercial acceptance of the drug. Research on the crystal forms disclosed in the existing technology revealed the following obvious defects: they have strong hygroscopicity, and impurities increase significantly during long-term storage, resulting in poor stability; in addition, they have low solubility, which is not conducive to the absorption of drug molecules in vivo. Summary of the Invention

[0004] This disclosure provides new crystal forms of celinisosole and their applications in the treatment of cancerous diseases.

[0005] Specifically, this disclosure provides compounds of formula (I).

[0006] Glutaric acid eutectic crystal form I is characterized by the fact that, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 11.38, 14.96, 18.75, and 19.98, with a 2θ error range of ±0.2°.

[0007] In some embodiments of this disclosure, the glutaric acid eutectic crystal form I of the above-mentioned compound (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 7.42, 8.11, 13.38, 16.52, 17.50, and 24.61, with a 2θ error range of ±0.2°.

[0008] In some embodiments of this disclosure, the glutaric acid eutectic crystal form I of the above-mentioned compound (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 9.17, 19.20, 20.49, 21.02, 21.49, with a 2θ error range of ±0.2°.

[0009] In some embodiments disclosed herein, the glutaric acid eutectic crystal form I of the above-mentioned compound of formula (I) has the following X-ray powder diffraction pattern: Figure 1 As shown.

[0010] In some embodiments of this disclosure, the glutaric acid eutectic crystal form I of the above-mentioned formula (I) compound is characterized by the TGA-DSC spectrum of the crystal form as shown in the figure. Figure 2 As shown.

[0011] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the glutaric acid eutectic form I of the above-mentioned formula (Ⅰ) compound are shown in Table 1.

[0012] Table 1. XRPD diffraction peak analysis data of glutaric acid eutectic form I of compound (I)

[0013] This disclosure provides a eutectic form of gallic acid of formula (I), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic form I has characteristic peaks at 2θ values ​​of 5.31, 8.97, 12.68, 18.17, and 20.17, with a 2θ error range of ±0.2°.

[0014] In some embodiments of this disclosure, the gallic acid eutectic crystal form I of the above-mentioned compound (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 6.26, 7.32, 12.00, 14.34, 14.88, and 16.40, with a 2θ error range of ±0.2°.

[0015] In some embodiments of this disclosure, the gallic acid eutectic form I of the above-mentioned compound (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern also has characteristic peaks at one or more of the 2θ values ​​of 11.12, 13.87, 21.35, and 21.96, with a 2θ error range of ±0.2°.

[0016] In some embodiments disclosed herein, the gallic acid eutectic form I of the compound of formula (I) described above has the following X-ray powder diffraction pattern: Figure 3 As shown.

[0017] In some embodiments of this disclosure, the gallic acid eutectic crystal form I of the compound of formula (I) is characterized in that the TGA-DSC spectrum of the crystal form is as follows: Figure 4 As shown.

[0018] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the gallic acid eutectic form I of the above-mentioned formula (Ⅰ) compound are shown in Table 2.

[0019] Table 2. XRPD diffraction peak analysis data of gallic acid eutectic form I of compound (I)

[0020] In some embodiments of this disclosure, the gallic acid eutectic crystal form I of the above-mentioned formula (I) compound is characterized in that the single-crystal diffraction pattern of the crystal form is as follows: Figure 5 As shown.

[0021] In some embodiments of this disclosure, the gallic acid eutectic crystal form I of the compound of formula (I) is characterized in that the single crystal structure information of the crystal form is shown in Table 3. Table 3. Single crystal structure information of gallic acid eutectic form I of compound (I)

[0022] This disclosure provides a eutectic crystal form I of gentianic acid compound (I), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 10.25, 15.44, 17.42, 18.46, and 21.38, with a 2θ error range of ±0.2°.

[0023] In some embodiments of this disclosure, the gentianic acid eutectic crystal form I of the above-mentioned compound (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 9.06, 13.27, 14.17, 20.85, and 22.65, with a 2θ error range of ±0.2°.

[0024] In some embodiments of this disclosure, the gentianic acid eutectic crystal form I of the above-mentioned compound (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern also has characteristic peaks at one or more of the 2θ values ​​of 10.72, 24.07, 25.59, and 25.88, with a 2θ error range of ±0.2°.

[0025] In some embodiments of this disclosure, the gentianic acid eutectic form I of the above-mentioned compound (I) has the following X-ray powder diffraction pattern: Figure 6 As shown.

[0026] In some embodiments of this disclosure, the gentianic acid eutectic crystal form I of the compound of formula (I) is characterized in that the TGA-DSC spectrum of the crystal form is as follows: Figure 7 As shown.

[0027] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the gentian acid eutectic form I of the above-mentioned formula (Ⅰ) compound are shown in Table 4.

[0028] Table 4. XRPD diffraction peak analysis data of gentianic acid eutectic form I of compound (I)

[0029] This disclosure provides a compound of formula (I) with crystal form Q2, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 5.51, 7.70, 10.44, 10.99, and 20.50, with a 2θ error range of ±0.2°.

[0030] In some embodiments of this disclosure, the crystal form Q2 of the compound of formula (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern has characteristic peaks at one or more of the 2θ values ​​of 18.38, 18.97, 20.91, and 22.19, with a 2θ error range of ±0.2°.

[0031] In some embodiments of this disclosure, the crystal form Q2 of the compound of formula (I) described above has the following X-ray powder diffraction pattern: Figure 8 As shown.

[0032] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the crystal form Q2 of the above formula (Ⅰ) compound are shown in Table 5.

[0033] Table 5. XRPD diffraction peak analysis data for crystal form Q2 of compound (I)

[0034] This disclosure provides a compound of formula (I) with crystal form Q7, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 7.26, 10.95, 17.99, and 21.19, with a 2θ error range of ±0.2°.

[0035] In some embodiments of this disclosure, the crystal form Q7 of the compound of formula (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern has characteristic peaks at one or more of the 2θ values ​​of 12.68, 19.56, and 22.80, with a 2θ error range of ±0.2°.

[0036] In some embodiments of this disclosure, the crystal form Q7 of the compound of formula (I) described above has the following X-ray powder diffraction pattern: Figure 9 As shown.

[0037] In some embodiments of this disclosure, the crystal form Q7 of the compound of formula (I) is characterized in that the TGA-DSC spectrum of the crystal form is as follows: Figure 10 As shown.

[0038] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the crystal form Q7 of the above formula (Ⅰ) compound are shown in Table 6.

[0039] Table 6 shows the XRPD diffraction peak analysis data for crystal form Q7 of compound (I).

[0040] This disclosure provides a compound of formula (I) with crystal form Q8, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 6.27, 12.01, 12.67, and 17.41, with a 2θ error range of ±0.2°.

[0041] In some embodiments of this disclosure, the crystal form Q8 of the compound of formula (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern has characteristic peaks at one or more of the 2θ values ​​of 13.00, 22.36, and 25.62, with a 2θ error range of ±0.2°.

[0042] In some embodiments of this disclosure, the crystal form Q8 of the compound of formula (I) described above has the following X-ray powder diffraction pattern: Figure 11 As shown.

[0043] In some embodiments of this disclosure, the crystal form Q8 of the compound of formula (I) is characterized in that the TGA-DSC spectrum of the crystal form is as follows: Figure 12 As shown.

[0044] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the crystal form Q8 of the above formula (Ⅰ) compound are shown in Table 7.

[0045] Table 7. XRPD diffraction peak analysis data of crystal form Q8 of compound (I)

[0046] This disclosure provides a compound of formula (I) with crystal form Q10, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 16.08, 19.27, 21.87, and 23.54, with a 2θ error range of ±0.2°.

[0047] In some embodiments of this disclosure, the crystal form Q10 of the compound of formula (I) is characterized by using Cu-Kα radiation, wherein the X-ray powder diffraction pattern has characteristic peaks at one or more of the 2θ values ​​of 17.89, 18.66, and 22.33, with a 2θ error range of ±0.2°.

[0048] In some embodiments of this disclosure, the crystal form Q10 of the compound of formula (I) described above has the following X-ray powder diffraction pattern: Figure 13 As shown.

[0049] In some embodiments of this disclosure, the crystal form Q10 of the compound of formula (I) is characterized in that the TGA-DSC spectrum of the crystal form is as follows: Figure 14 As shown.

[0050] In some of the schemes disclosed herein, the XRPD diffraction peak analysis data of the crystal form Q10 of the compound of formula (Ⅰ) above are shown in Table 8.

[0051] Table 8. XRPD diffraction peak analysis data for crystal form Q10 of compound (I)

[0052] This disclosure also provides a pharmaceutical composition comprising any of the above-described crystal forms and a pharmaceutically acceptable carrier.

[0053] This disclosure also provides the use of any of the above-described crystal forms or the above-described pharmaceutical compositions in the preparation of drugs for treating tumors.

[0054] In some of the schemes disclosed herein, the aforementioned tumors include multiple myeloma and diffuse large B-cell lymphoma.

[0055] Technical effect The crystal form disclosed herein exhibits good chemical and physical stability as well as low hygroscopicity, and is less affected by temperature, humidity, and light, making it easy to store and develop formulations; it also has high solubility, which helps the drug to be better absorbed and distributed in the body.

[0056] Definitions and Explanations Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0057] The term "pharmaceutical-grade carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the active pharmaceutical agent being formulated, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0058] As is known in the art, X-ray powder diffraction patterns have one or more measurement errors due to minute variations in measurement conditions. The structures of the crystals, crystalline forms, or polymorphs disclosed or claimed in this disclosure may exhibit similar but not identical analytical characteristics within a reasonable error range, depending on the experimental conditions, purity, equipment, and other constant variables known to those skilled in the art. For example, the diffraction angle (2θ) in powder X-ray powder diffraction typically produces an error within ±0.20°. Therefore, this disclosure includes not only crystals with perfectly uniform diffraction angles in powder X-ray powder diffraction, but also crystals with uniform diffraction angles within an error range of ±0.20°. The crystalline form of the compound of formula (polymorph I) of this disclosure is not limited to crystals having the same X-ray powder diffraction pattern as shown in the accompanying drawings; any crystal having a substantially identical X-ray powder diffraction pattern as shown in the accompanying drawings is within the scope of this disclosure.

[0059] The X-ray powder diffraction pattern appearing in this text is substantially the same as the X-ray powder diffraction pattern shown in the accompanying figures. It should be understood that the term "substantially the same" used in this context also indicates that the 2θ angle values ​​of the X-ray powder diffraction pattern may vary slightly due to inherent experimental variations accompanying these measurements, and both are of the same crystalline form.

[0060] It should be understood that different types of equipment or different testing conditions may yield slightly different DSC spectra and endothermic transition temperature readings. DSC data can reflect changes in the state of matter; strong endothermic peaks can indicate that the substance has undergone dehydration or desolvation, or crystal transformation, or melting, etc.; when reflecting the molten state, the corresponding temperature is generally understood as the melting point of the substance. This value will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the testing equipment. Those skilled in the art will understand that the temperature at which a substance changes from a solid to a liquid state is usually a temperature range, not a fixed point value; therefore, the temperature corresponding to the endothermic peak or the melting point of the substance can be characterized by either the onset value, the peak value, or other reasonable values. The maximum endothermic transition temperature of the crystal form can be within ±5.0°C of the specific values ​​disclosed above, preferably within ±2.0°C. For example, an endothermic peak around 253.5°C in the DSC spectrum means an endothermic peak at 253.5°C ±5.0°C, preferably 253.5°C ±2.0°C.

[0061] This disclosure also uses thermogravimetric analysis (TGA) to analyze the relationship between the degree of decomposition, sublimation, or evaporation of the crystal form (weight loss) and temperature. It should be understood that the values ​​obtained for the same crystal form may have some error due to factors such as sample purity, particle size, different types of equipment, and different testing methods. The temperature at which the crystal form decomposes, sublimates, or evaporates can be within ±3.0℃ of the specific values ​​disclosed above, for example, within ±2.0℃.

[0062] The "stability" of a crystal form includes "chemical stability" and / or "physical stability." "Chemical stability" refers to the degree to which the crystal form undergoes degradation reactions under certain temperature, humidity, and light conditions; it reflects the stability of the crystal form under storage conditions. "Physical stability" refers to the degree to which the crystal form undergoes a solid-state transformation under certain specific conditions, such as under conditions of high temperature, high humidity, grinding, tableting, solvent removal, or solvent adsorption, transforming into another crystal form. Therefore, "physical stability" can, to some extent, reflect the stability of the crystal form during its use in formulations and other processes.

[0063] The crystalline structures disclosed herein can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing crystalline structures from solvent mixtures include solvent evaporation, lowering the temperature of the solvent mixture, crystallization of a supersaturated solvent mixture of the molecule and / or salt, lyophilizing the solvent mixture, and adding an antisolvent to the solvent mixture.

[0064] The term "drying" refers to the process of removing solvent from the resulting solid, including but not limited to air drying at room temperature, high-temperature drying, and vacuum drying.

[0065] The intermediate compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0066] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0067] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0068] Instruments and analytical methods: 1. X-ray powder diffraction (XRPD) Solid samples were analyzed using an X-ray powder diffractometer (Aeris). An appropriate amount of fine powder was taken and placed in the groove of the sample holder. A glass slide was used to press the powder into a flat and dense plane. The XRPD measurement parameters are shown in Table 9.

[0069] Table 9 XRPD Test Parameters

[0070] 2. Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) of solids was performed using a Mettler Toledo thermogravimetric analyzer. Samples were placed in peeled crucibles and heated according to the parameters listed in Table 10. Data were analyzed using STARE.

[0071] Table 10 TGA Analysis Method Parameters

[0072] 3. Differential Scanning Calorimetry (DSC) The solid samples were analyzed by differential scanning calorimetry (DSC) using a Mettler Toledo instrument. The samples were precisely weighed and placed in a perforated aluminum sample pan. They were heated according to the parameters listed in Table 11, and the data were analyzed using STARE.

[0073] Table 11 Parameters of DSC Analysis Method

[0074] 4. Simultaneous thermal analysis (TGA-DSC) Thermogravimetric-differential scanning calorimetry (TGC) analysis of solids was performed using a Mettler Toledo simultaneous thermal analyzer. A suitable amount of the sample was placed in a crucible using a small spoon, ensuring even distribution, and weighed. The sample was heated according to the parameters listed in Table 12, and the data were analyzed using STARE.

[0075] Table 12 Parameters of TGA-DSC Analysis Method

[0076] 5. Dynamic moisture adsorption-desorption analysis (DVS) The hygroscopicity of the samples was determined using a DVS Intrinsic dynamic moisture adsorption analyzer. The samples were placed in a pre-peeled sample basket, and the instrument automatically weighed them. The samples were then analyzed according to the parameters in Table 13.

[0077] Table 13 Parameters of DVS Analysis Method

[0078] 6. MicroED Testing Method A small amount of powder sample was placed on a clean glass slide, and the crystallization was confirmed using a polarizing microscope. The powder sample was then taken and evenly dispersed onto a cryo-electron microscope grid. The prepared grid was placed at the front end of the liquid nitrogen cryo-electron microscope rod, and the rod was inserted into the cryo-electron microscope. Microcrystals with high diffraction resolution were selected for MicroED data collection.

[0079] Table 14 Test Parameters Attached Figure Description Figure 1 The image shows the XRPD spectrum of glutaric acid eutectic form I of compound (Ⅰ).

[0080] Figure 2 The TGA-DSC spectrum of glutaric acid eutectic form I of compound (Ⅰ) is shown.

[0081] Figure 3 The image shows the XRPD spectrum of the gallic acid eutectic crystal form I of compound (Ⅰ).

[0082] Figure 4 The TGA-DSC spectrum of gallic acid eutectic form I of compound (Ⅰ) is shown.

[0083] Figure 5 The diagram shows the single-crystal ball-and-stick model of the eutectic form I of the compound (Ⅰ).

[0084] Figure 6 The image shows the XRPD spectrum of gentian acid eutectic crystal form I of compound (Ⅰ).

[0085] Figure 7 The TGA-DSC spectrum of gentian acid eutectic form I of compound (Ⅰ) is shown.

[0086] Figure 8 The image shows the XRPD spectrum of the crystal form Q2 of compound (Ⅰ).

[0087] Figure 9 The image shows the XRPD spectrum of the crystal form Q7 of compound (Ⅰ).

[0088] Figure 10 The TGA-DSC spectrum of the crystal form Q7 of compound (Ⅰ) is shown.

[0089] Figure 11 The image shows the XRPD spectrum of the crystal form Q8 of compound (Ⅰ).

[0090] Figure 12 The TGA-DSC spectrum of the crystal form Q8 of compound (Ⅰ) is shown.

[0091] Figure 13 The image shows the XRPD spectrum of the crystal form Q10 of compound (Ⅰ).

[0092] Figure 14 The TGA-DSC spectrum of the crystal form Q10 of compound (Ⅰ) is shown.

[0093] Figure 15 The dynamic water adsorption (DVS) curve of the gallic acid eutectic crystal form I of compound (Ⅰ) is shown.

[0094] Figure 16 XRPD diagram of gallic acid eutectic form (Ⅰ) after adsorption by DVS. Detailed Implementation

[0095] The present disclosure is described in detail below with reference to examples, but this does not imply any adverse limitation thereof. The compounds of the present disclosure can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof. Specific implementation examples: Example 1 (Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)acrylhydrazine The preparation of (Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)acrylhydrazide (API) was based on patent CN103874690B. Example 2 Preparation of glutaric acid eutectic crystal form I: Approximately 0.2 g of API and 62.6 mg of glutaric acid were weighed and added to a reaction flask. 2 mL of ethanol was added, and the mixture was dissolved at 50 °C. The solution was filtered through a membrane, cooled to 40 °C, and 6 mL of the antisolvent n-heptane was added dropwise. Crystallization was precipitated upon cooling, and the solution was filtered and dried to obtain a solid. The solid was characterized by XRPD and TGA-DSC tests. The solid was identified as a glutaric acid eutectic of type I, and its XRPD spectrum is shown in the figure below. Figure 1 As shown.

[0097] Example 3 Preparation of gallic acid eutectic crystal form I: Approximately 20 mg of API and 8.11 mg of gallic acid were weighed and added to a sample vial. 0.1 mL of ethanol and 0.9 mL of n-heptane were added, and the mixture was stirred to obtain a suspension. After stirring and slurrying at 50°C for 2 days, a solid was obtained. This solid was gallic acid eutectic crystal form I, and its XRPD spectrum was basically as shown in the image. Figure 3 As shown.

[0098] Example 4 Preparation of gallic acid eutectic crystal form I: Approximately 1.0 g of API and 0.2 g of gallic acid were weighed and added to a sample vial. 8.0 mL of ethanol was added, and the temperature was raised to 70 °C to dissolve the compounds. The temperature was then lowered to 60 °C, and 1% of the seed crystals obtained using the above method were added. Crystallization was allowed to occur for 1 hour, followed by the addition of 16.0 mL of n-heptane and cooling to allow crystallization, yielding a solid. The solid was characterized by XRPD, TGA-DSC, and single-crystal analysis. The solid was identified as gallic acid eutectic type I, and its XRPD spectrum is shown in the image. Figure 3 As shown.

[0099] Single crystal structure such as Figure 5 As shown, its asymmetric unit contains four molecules of celiniso and two molecules of gallic acid.

[0100] Example 5 Preparation of gentianic acid eutectic crystal form I: Approximately 0.2 g of API and 7.3 mg of gentianic acid were weighed and added to a sample vial. 2.0 mL of acetone was added, and the mixture was heated to 50 °C to dissolve. The temperature was then lowered to 40 °C, and 1% seed crystals were added. Crystallization was allowed to occur for 1 hour, followed by the addition of 6.0 mL of n-heptane and cooling to allow crystallization, yielding a solid. The solid was characterized by XRPD and TGA-DSC tests. The solid was identified as a eutectic form of gentianic acid, and its XRPD spectrum was approximately as shown in the image. Figure 6 As shown.

[0101] TGA-DSC spectrum as shown Figure 7 As shown, the melting point is 189.47℃, and there is no significant weight loss before the melting point, indicating that this crystal form is anhydrous.

[0102] Example 6 Preparation of crystal form Q2: Approximately 20 mg of amorphous API was weighed and added to a sample vial, dissolved in 0.4 mL of anhydrous ethanol, and stirred to obtain a suspension. The suspension was then stirred and slurried for 10 min to obtain a solid for XRPD characterization. The solid was identified as crystalline Q2, and its XRPD spectrum is shown below. Figure 8 As shown.

[0103] Example 7: Preparation of crystal form Q7: Approximately 20 mg of amorphous API was weighed and added to a sample vial. A suspension was obtained by stirring with 0.2 mL of glycerol and stirring for 30 min. The mixture was then washed with purified water and dried under vacuum at 70 °C to obtain a solid. The solid was characterized by XRPD and TGA-DSC tests. The solid was found to be of crystal form Q7, and its XRPD spectrum is shown below. Figure 9 As shown.

[0104] Example 8 Preparation of crystal form Q8: Approximately 20 mg of API was weighed and added to a sample vial. It was dissolved in 0.1 mL of 1,4-dioxane at room temperature and stirred for 2 min, resulting in the precipitation of a solid. The obtained solid was characterized by XRPD and TGA-DSC tests. The solid was identified as crystalline Q8, and its XRPD spectrum is shown below. Figure 11 As shown.

[0105] Example 9 Preparation of crystal form Q10: Approximately 20 mg of API was weighed and added to a sample vial. It was dissolved in 40 μL of dimethyl sulfoxide at 45 °C, cooled to room temperature, and crystallized, resulting in a solid. The solid was characterized by XRPD and TGA-DSC tests. The solid was identified as crystal form Q10, and its XRPD spectrum is shown below. Figure 13 As shown.

[0106] Example 10 Hygroscopicity Test Referring to the "Guidelines for Hygroscopic Testing of Drugs" in the 2020 edition of the Chinese Pharmacopoeia, the water adsorption / desorption data of gallic acid cocrystalline form I of compound (I) were tested. The DVS curve of gallic acid cocrystalline form I is shown below. Figure 15 As shown, its hygroscopic data are shown in Table 15. The XRPD of the remaining solid after the DVS experiment was tested. The eutectic form of the gallic acid eutectic of compound (I) remained unchanged, as shown... Figure 16 As shown.

[0107] Table 15 Hygroscopicity of Gallic Acid Eutectic Form I

[0108] Example 11: Experiment on Influencing Factors Referring to the "Guidelines for Stability Testing of Raw Materials and Preparations" in the 2020 edition of the Chinese Pharmacopoeia, the stability of compound (I) in glutaric acid cocrystal form I, gallic acid cocrystal form I, and gentianic acid cocrystal form I was investigated under different temperatures and humidity conditions. Purity was tested by HPLC on days 0, 5, and 10, and crystal form was tested by XRPD. The experimental results are shown in Tables 16-18.

[0109] Table 16. Factors influencing the eutectic crystal form of compound (I) glutaric acid (I) - Experimental results

[0110] Conclusion: Under high temperature, high humidity and light conditions, the glutaric acid eutectic crystal form I of compound (I) did not change in crystal form and its purity remained basically unchanged. The physical and chemical properties of the glutaric acid eutectic crystal form I of compound (I) are stable.

[0111] Table 17. Experimental Factors Influencing the Cyclic Form I of Gallic Acid Cocrystal of Formula (I)

[0112] Conclusion: Under high temperature, high humidity and light conditions, the eutectic form of gallic acid of formula (I) did not change and its purity remained basically unchanged; the physical and chemical properties of eutectic form of gallic acid of formula (I) were stable.

[0113] Table 18. Factors influencing the eutectic crystal form of compound (I) gentianic acid (I) - Experimental results.

[0114] Conclusion: Under high temperature, high humidity and light conditions, the eutectic form of gentianic acid of formula (I) did not change and its purity remained basically unchanged. The physical and chemical properties of eutectic form I of gentianic acid of formula (I) are stable.

[0115] Example 12 Solubility Experiment At 37℃, appropriate amounts of the original crystal form A of compound (I) and the eutectic crystal form I of compound (I) were dispersed in water, simulated gastric fluid (SGF), fed-state simulated intestinal fluid (FeSSIF), and fasted-state simulated intestinal fluid (FaSSIF) to prepare suspensions. After equilibration at 200 rpm for 2 h and 24 h, the content (mg / mL) of the sample in the solution was tested by high performance liquid chromatography. The results are shown in Table 19.

[0116] Table 19 Equilibrium solubility of crystalline form A and gallic acid eutectic form I of formula (I) in four media.

[0117] Conclusion: Compared with the original crystal form A, the gallic acid eutectic crystal form I of formula (I) has higher solubility.

[0118] Example 13: Investigation of the stability of gallic acid eutectic crystal form I 1. Experimental Methods Acceleration conditions: Gallic acid eutectic crystal form I samples were placed at 40°C and 75% humidity. Samples were taken at fixed time points after 1 month, 3 months, and 6 months. The XRPD spectra of gallic acid eutectic crystal form I and its purity were measured. Long-term conditions: Gallic acid eutectic crystal form I samples were placed at 30°C and 60% humidity for 3, 6, 9, and 12 months, with samples taken at fixed time points. The XRPD spectra of gallic acid eutectic crystal form I and its purity were measured. For specific stability testing methods, please refer to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" in the 2020 edition of the Chinese Pharmacopoeia; purity is determined by HPLC; for packaging, the materials are packaged in double-layer polyethylene bags, then placed in a single-layer aluminum foil bag and heat-sealed.

[0119] Table 20 Results of Long-Term and Accelerated Experiments

[0120] Conclusion: Experimental results show that gallic acid eutectic crystal form I has good stability.

Claims

1. Compound of formula (Ⅰ) Gallic acid eutectic crystal form I, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I exhibits characteristic peaks at 2θ values ​​of 5.31, 8.97, 12.68, 18.17, and 20.17, with a 2θ error range of ±0.2°. More preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern also exhibits characteristic peaks at one or more of the following 2θ values: 6.26, 7.32, 12.00, 14.34, 14.88, and 16.40, with a 2θ error range of ±0.2°. The range is ±0.2°; more preferably, it is characterized by using Cu-Kα radiation, and the X-ray powder diffraction pattern also has characteristic peaks at one or more of the 2θ values ​​of 11.12, 13.87, 21.35, and 21.96, with a 2θ error range of ±0.2°; more preferably, it is characterized by its X-ray powder diffraction pattern as shown in Figure 3; more preferably, it is characterized by the TGA-DSC pattern of the crystal form as shown in Figure 4.

2. The gallic acid eutectic crystal form I of the compound of formula (I) as described in claim 1, characterized in that, The single-crystal structure information of the crystal form is shown in Table 3, and the ball-and-stick model diagram of the single-crystal structure is shown in Figure 5.

3. The glutaric acid eutectic crystal form I of the compound of formula (Ⅰ), characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I exhibits characteristic peaks at 2θ values ​​of 11.38, 14.96, 18.75, and 19.98, with a 2θ error range of ±0.2°. More preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern also exhibits characteristic peaks at one or more of the following 2θ values: 7.42, 8.11, 13.38, 16.52, 17.50, and 24.61, with a 2θ error range of ±0.2°. The range is ±0.2°; more preferably, it is characterized by using Cu-Kα radiation, and the X-ray powder diffraction pattern also has characteristic peaks at one or more of the 2θ values ​​of 9.17, 19.20, 20.49, 21.02, and 21.49, with a 2θ error range of ±0.2°; more preferably, its X-ray powder diffraction pattern is shown in Figure 1; more preferably, the TGA-DSC spectrum of the crystal form is shown in Figure 2.

4. The gentianic acid eutectic crystal form I of the compound of formula (Ⅰ), characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I exhibits characteristic peaks at 2θ values ​​of 10.25, 15.44, 17.42, 18.46, and 21.38, with a 2θ error range of ±0.2°; more preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern also exhibits characteristic peaks at one or more of the following 2θ values: 9.06, 13.27, 14.17, 20.85, and 22.

65. The 2θ error range is ±0.2°; more preferably, it is characterized by using Cu-Kα radiation, and the X-ray powder diffraction pattern also has characteristic peaks at one or more of the 2θ values ​​of 10.72, 24.07, 25.59, and 25.88, with a 2θ error range of ±0.2°; more preferably, its X-ray powder diffraction pattern is shown in Figure 6; more preferably, it is characterized by the TGA-DSC pattern of the crystal form being shown in Figure 7.

5. A pharmaceutical composition comprising the crystal form and pharmaceutically acceptable carrier as described in any one of claims 1-4.

6. Use of the crystal form according to any one of claims 1-4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating tumors.

7. The use as described in claim 5 or 6, wherein the tumor includes multiple myeloma and diffuse large B-cell lymphoma.

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