Upatinib eutectic crystal form as well as preparation method and application thereof

Abstract

The invention discloses an upatinib eutectic crystal form as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The invention provides an eutectic crystal form I formed by upatinib and vanillic acid and an eutectic crystal form G formed by upatinib and syringic acid, which have definite and reproducible characteristic X-ray powder diffraction pattern and melting point, have excellent solubility in an aqueous medium, do not generate crystal form transformation after being stored for 1 month under the condition of relative humidity of 40 DEG C / 75%, and can be used for preparing a crystal form of upatinib. And the stability is good. The preparation process route is short, the operation condition is mild, the used solvent is conventional, the target eutectic can be efficiently and repeatedly obtained, the defects that some existing eutectic preparation processes are complex, long in period or harsh in condition are overcome, and the method has good process amplification and industrialization prospects.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to the cocrystal form of utpatinib, its preparation method, and its applications. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Upadacitinib, an important JAK1 inhibitor, has broad application prospects in the treatment of immune inflammatory diseases. Its structural formula is shown below: .

[0004] The solid form of a drug, especially its crystal form, directly affects its physicochemical properties, stability, solubility, and manufacturability, thus impacting formulation development and clinical efficacy. Currently, utpatinib exists in several known crystal forms; however, these crystal forms often fail to achieve optimal overall performance, limiting its further development and application.

[0005] In existing technologies, some crystalline forms of utpatinib suffer from insufficient crystallinity or poor physical stability, making them prone to crystal transformation or amorphous transformation during storage or formulation, affecting the uniformity and reliability of product quality. Other crystalline forms, while possessing good stability, have low solubility, which may adversely affect the drug's bioavailability. Furthermore, the preparation processes for certain crystalline forms require stringent reaction conditions, such as controlled humidity or the use of specific solvents, resulting in narrow process windows and poor reproducibility, hindering large-scale industrial production.

[0006] Cocrystallization is an effective strategy for improving key properties of utpatinib, such as solubility. However, its implementation faces several challenges. First, the selection of cocrystallization forms is inherently uncertain; in practice, many potential cocrystallization forms fail to form single crystals with a defined structure with utpatinib, often resulting in amorphous mixtures or excessively high solubility that prevents solid precipitation, thus failing to obtain a stable crystalline form suitable for drug development. Second, even for reported utpatinib cocrystallizations, their preparation methods often suffer from complex processes, long production cycles, or reliance on multiple mixed solvents. These factors not only increase production costs but also challenge the robustness, repeatability, and stability of the final product quality. Therefore, there is an urgent need in the field to develop a simpler, more efficient utpatinib cocrystallization process that simultaneously ensures good solubility and physical stability. Summary of the Invention

[0007] In view of this, the present invention provides the urpatinib cocrystal crystal form, preparation method and application. The urpatinib-vanillic acid cocrystal and urpatinib-syringic acid cocrystal developed by the present invention have simple preparation methods, short preparation time and excellent physicochemical properties, especially outstanding performance in solubility and stability, providing a better option for the development of urpatinib drug formulations.

[0008] In a first aspect, the present invention provides a eutectic form I of utpatinib, wherein the eutectic form I is a eutectic formed by utpatinib and vanillic acid; the X-ray powder diffraction pattern of the eutectic form I under Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.68°±0.2°, 8.36°±0.2°, 11.10°±0.2°, 12.98°±0.2°, 21.01°±0.2°, and 26.33°±0.2°.

[0009] Preferably, the X-ray powder diffraction pattern of the eutectic form I under Cu-Kα radiation also includes the following values: 9.46°±0.2°, 10.64°±0.2°, 11.84°±0.2°, 12.25°±0.2°, 13.88°±0.2°, 14.23°±0.2°, 14.96°±0.2°, 15.38°±0.2°, 15.70°±0.2°, 16.82°±0.2°, 17.76°±0.2°, 19.09°±0.2°, and 19.61°±0.2°. Characteristic peaks are observed at 20.30°±0.2°, 21.75°±0.2°, 22.50°±0.2°, 22.83°±0.2°, 23.57°±0.2°, 23.99°±0.2°, 24.55°±0.2°, 25.32°±0.2°, 25.88°±0.2°, 27.51°±0.2°, 28.68°±0.2°, 29.90°±0.2°, 30.46°±0.2°, and 31.56°±0.2°.

[0010] Preferably, the differential scanning calorimetry curve of the eutectic formed by utpatinib and vanillic acid shows an endothermic peak at 132 ± 0.5 °C.

[0011] Secondly, the present invention provides a method for preparing the above-mentioned eutectic form I of utpatinib, comprising the following steps: Upatinib and vanillic acid were dissolved in a first solvent and stirred to react, resulting in the precipitation of a solid. After separation and drying, the eutectic crystal type I was obtained. Alternatively, utpatinib and vanillic acid can be dissolved in a second solvent by heating, stirring and reacting, then cooling to precipitate a solid, which can be separated and dried to obtain the eutectic crystal form I. Alternatively, utpatinib and vanillic acid can be ball-milled at a frequency of 15-30 Hz for 30-60 min, and the solid can be collected and dried to obtain the eutectic crystal form I.

[0012] Preferably, the molar ratio of utpatinib to vanillic acid is (1~3):1; in the step of dissolving in the first solvent and stirring reaction, the stirring reaction temperature is 15~35℃; in the step of heating and dissolving in the second solvent, the heating and dissolving temperature is 40~80℃.

[0013] Preferably, the first solvent is a nitrile solvent, or the first solvent is a mixture of a nitrile solvent and an alcohol solvent and / or an ester solvent; the second solvent is a mixture of a nitrile solvent and an alkane solvent.

[0014] Thirdly, the present invention provides a eutectic form G of utpatinib, wherein the eutectic form G is a eutectic formed by utpatinib and syringic acid; the X-ray powder diffraction pattern of the eutectic form G under Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.38°±0.2°, 7.71°±0.2°, 10.59°±0.2°, 19.38°±0.2°, 21.09°±0.2°, and 29.21°±0.2°.

[0015] Preferably, the X-ray powder diffraction pattern of the eutectic G under Cu-Kα radiation is also at 8.81°±0.2°, 9.89°±0.2°, 11.54°±0.2°, 12.79°±0.2°, 13.81°±0.2°, 14.63°±0.2°, 15.11°±0.2°, 16.19°±0.2°, 16.67°±0.2°, 17.68°±0.2°, 18.54°±0.2°, and 18.94°. Characteristic peaks are observed at ±0.2°, 19.81°±0.2°, 21.74°±0.2°, 22.73°±0.2°, 23.29°±0.2°, 24.25°±0.2°, 24.67°±0.2°, 25.80°±0.2°, 26.67°±0.2°, 27.33°±0.2°, 27.95°±0.2°, 31.22°±0.2°, 31.84°±0.2°, and 33.06°±0.2°.

[0016] Preferably, the differential scanning calorimetry curve of the eutectic formed by utpatinib and syringic acid shows an endothermic peak at 130 ± 0.5℃.

[0017] Fourthly, the present invention provides a method for preparing the eutectic form G of utpatinib, comprising the following steps: Upatinib and syringic acid were dissolved in a first solvent and stirred to react, resulting in the precipitation of a solid. After separation and drying, the eutectic crystal form G was obtained. Alternatively, utpatinib and syringic acid can be dissolved in a second solvent by heating, stirring and reacting, then cooling to precipitate a solid, which can be separated and dried to obtain the eutectic crystal form G. Alternatively, utpatinib and syringic acid are ball-milled at a frequency of 15-30 Hz for 30-60 min, the solid is collected and dried to obtain the eutectic crystal form G.

[0018] Preferably, the molar ratio of utpatinib to syringic acid is (1~3):1; in the step of dissolving in the first solvent and stirring reaction, the stirring reaction temperature is 15~35℃; in the step of heating and dissolving in the second solvent, the heating and dissolving temperature is 40~80℃.

[0019] Preferably, the first solvent is a nitrile solvent, or the first solvent is a mixture of a nitrile solvent and an alcohol solvent and / or an ester solvent; the second solvent is a mixture of a nitrile solvent and an alkane solvent.

[0020] Fifthly, the present invention provides the use of the co-crystal form I or the co-crystal form G of utpatinib in the preparation of a medicament for treating diseases related to JAK1 activity.

[0021] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) This invention has for the first time obtained a stable eutectic (crystal form I) formed by utpatinib and vanillic acid, which has a well-defined and reproducible characteristic X-ray powder diffraction pattern and melting point. Accelerated stability experiments show that crystal form I did not undergo crystal transformation after being stored at 40℃ / 75% relative humidity for one month, demonstrating excellent physical stability. This solves the problem of insufficient stability of some existing crystal forms and provides a reliable solid form option for formulation development. At the same time, it has excellent solubility in aqueous media.

[0022] (2) The present invention also provides a co-crystal (crystal form G) formed by utpatinib and syringic acid, which also has a unique and structurally defined PXRD pattern. Dynamic solubility test results show that this crystal form exhibits higher solubility in simulated biological media compared to some known stable crystal forms, which may help to potentially improve the dissolution behavior and bioavailability of the drug.

[0023] (3) For the two types of eutectics mentioned above, this invention has developed a variety of preparation methods including slurrying, solution crystallization and mechanical grinding. These methods have short process routes, mild operating conditions, and conventional solvents. They can all obtain the target eutectic efficiently and repeatedly, overcoming the defects of some existing eutectic preparation processes that are complex, have long cycles or harsh conditions. They have good process scalability and industrialization prospects. Attached Figure Description

[0024] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0025] Figure 1 This is an X-ray powder diffraction pattern of the eutectic crystal form I of utpatinib and vanillic acid prepared in Example 1 of this invention; Figure 2 This is a DSC curve of the eutectic crystal form I of utpatinib and vanillic acid prepared in Example 1 of this invention; Figure 3 This is an X-ray powder diffraction pattern of the eutectic crystal form G of utpatinib and syringic acid prepared in Example 3 of this invention; Figure 4 This is a DSC curve of the eutectic crystal form G of utpatinib and syringic acid prepared in Example 3 of this invention; Figure 5 This is the experimental result of replacing vanillic acid with an equimolar amount of mandelic acid in Comparative Example 1 of this invention; Figure 6 This is the X-ray powder diffraction pattern of the solid powder obtained by replacing vanillic acid with an equimolar amount of sebacic acid in Comparative Example 2 of the present invention. Figure 7 This is an X-ray powder diffraction pattern of the accelerated stability test of the eutectic crystal form I of utpatinib and vanillic acid prepared in Example 1 of this invention. Detailed Implementation

[0026] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0027] In this invention, "powder X-ray diffraction" (PXRD) and "X-ray powder diffraction" (XRPD) have the same meaning.

[0028] This invention provides a eutectic form I of utpatinib, wherein eutectic form I is a eutectic formed by utpatinib and vanillic acid; the X-ray powder diffraction pattern of eutectic form I under Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.68°±0.2°, 8.36°±0.2°, 11.10°±0.2°, 12.98°±0.2°, 21.01°±0.2°, and 26.33°±0.2°.

[0029] In this invention, the structural formula of vanillic acid is as follows: ; Vanillic acid has the CAS number 121-34-6. It is a multi-target, multi-functional natural compound with potential therapeutic value in various fields, including the nervous, cardiovascular, digestive, oncological, and metabolic diseases. Because it is a weak acid, it effectively avoids significant consumption of the active pharmaceutical ingredient when reacting with utpatinib. Its molecular structure contains hydrogen-bonded acceptors and donors.

[0030] In an optional embodiment of the present invention, the X-ray powder diffraction pattern of the eutectic form I under Cu-Kα radiation is also at 9.46°±0.2°, 10.64°±0.2°, 11.84°±0.2°, 12.25°±0.2°, 13.88°±0.2°, 14.23°±0.2°, 14.96°±0.2°, 15.38°±0.2°, 15.70°±0.2°, 16.82°±0.2°, 17.76°±0.2°, 19.09°±0.2°, 1 Characteristic peaks are present at 9.61°±0.2°, 20.30°±0.2°, 21.75°±0.2°, 22.50°±0.2°, 22.83°±0.2°, 23.57°±0.2°, 23.99°±0.2°, 24.55°±0.2°, 25.32°±0.2°, 25.88°±0.2°, 27.51°±0.2°, 28.68°±0.2°, 29.90°±0.2°, 30.46°±0.2°, and 31.56°±0.2°.

[0031] In an optional embodiment of the present invention, the differential scanning calorimetry curve of the eutectic formed by utpatinib and vanillic acid shows an endothermic peak at 132 ± 0.5℃, which is the melting point of the eutectic formed by utpatinib and vanillic acid.

[0032] The present invention also provides a method for preparing the above-mentioned eutectic form I of utpatinib, comprising the following steps: Method 1: Upatinib and vanillic acid are dissolved in a first solvent and stirred to react, precipitating a solid. After separation and drying, the eutectic crystal form I is obtained. Alternatively, Method 2: Dissolve utpatinib and vanillic acid in a second solvent by heating, stirring and reacting, cooling to precipitate a solid, and then separating and drying to obtain the eutectic crystal form I. Alternatively, method three: ball mill utpatinib and vanillic acid at a frequency of 15-30 Hz for 30-60 min, collect the solid and dry it to obtain the eutectic crystal form I.

[0033] This invention allows for the preparation of utpatinib eutectic form I using various methods: method one is slurry crystallization, method two is solution cooling crystallization, and method three is mechanical grinding. All three methods can prepare utpatinib and vanillic acid eutectic form I, are simple, suitable for large-scale production, and the obtained eutectic form I exhibits good solubility and stability.

[0034] In an optional embodiment of the present invention, the molar ratio of utpatinib to vanillic acid is (1~3):1; more preferably (1.5~2.5):1, and even more preferably (1.8~2.2):1. In the step of dissolving in the first solvent and then stirring, the stirring temperature is 15~35℃, preferably at room temperature; the specific stirring time depends on the actual crystallization situation. In the step of dissolving in the second solvent by heating, the dissolving temperature is 40~80℃, more preferably 45~65℃, and even more preferably 50~60℃.

[0035] In optional embodiments of the present invention, the first solvent is a nitrile solvent, or the first solvent is a mixture of a nitrile solvent and an alcohol solvent and / or an ester solvent; the second solvent is a mixture of a nitrile solvent and an alkane solvent. In the present invention, the nitrile solvent is preferably acetonitrile, the alcohol solvent is preferably methanol, the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-hexane or n-heptane.

[0036] In an optional embodiment of the present invention, the ball milling frequency is more preferably 22~28Hz; the ball milling process adopts wet ball milling, and the solvent for wet ball milling can be a good solvent such as acetonitrile.

[0037] The drying described in Method 1, Method 2, and Method 3 of this invention is preferably vacuum drying, the drying temperature is preferably 25~45℃, and the drying time is preferably 2~6h.

[0038] This invention provides a eutectic form G of utpatinib, wherein the eutectic form G is a eutectic formed by utpatinib and syringic acid; the X-ray powder diffraction pattern of the eutectic form G under Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.38°±0.2°, 7.71°±0.2°, 10.59°±0.2°, 19.38°±0.2°, 21.09°±0.2°, and 29.21°±0.2°.

[0039] In this invention, the structural formula of eugenol is as follows: ; The CAS number for eugenol is 530-57-4.

[0040] In an optional embodiment of the present invention, the X-ray powder diffraction pattern of the eutectic G under Cu-Kα radiation is also at 8.81°±0.2°, 9.89°±0.2°, 11.54°±0.2°, 12.79°±0.2°, 13.81°±0.2°, 14.63°±0.2°, 15.11°±0.2°, 16.19°±0.2°, 16.67°±0.2°, 17.68°±0.2°, 18.54°±0.2°, 18 Characteristic peaks are observed at 0.94°±0.2°, 19.81°±0.2°, 21.74°±0.2°, 22.73°±0.2°, 23.29°±0.2°, 24.25°±0.2°, 24.67°±0.2°, 25.80°±0.2°, 26.67°±0.2°, 27.33°±0.2°, 27.95°±0.2°, 31.22°±0.2°, 31.84°±0.2°, and 33.06°±0.2°.

[0041] In an optional embodiment of the present invention, the differential scanning calorimetry curve of the eutectic formed by utpatinib and syringic acid shows an endothermic peak at 130 ± 0.5℃, which is the melting point of the eutectic formed by utpatinib and syringic acid.

[0042] The present invention also provides a method for preparing the above-mentioned eutectic form G of utpatinib, comprising the following steps: Method 1: Upatinib and syringic acid are dissolved in a first solvent and stirred to react, precipitating a solid. After separation and drying, the eutectic crystal form G is obtained. Alternatively, Method 2: Dissolve utpatinib and syringic acid in a second solvent by heating, stirring and reacting, cooling to precipitate a solid, and obtaining the eutectic crystal form G after separation and drying; Alternatively, method three: ball mill utpatinib and syringic acid at a frequency of 15-30 Hz for 30-60 min, collect the solid and dry it to obtain the eutectic crystal form G.

[0043] In an optional embodiment of the present invention, the molar ratio of utpatinib to syringic acid is (1~3):1; more preferably (1.5~2.5):1, and even more preferably (1.8~2.2):1. In the step of dissolving in the first solvent and then stirring, the stirring temperature is 15~35℃, preferably at room temperature; the specific stirring time depends on the actual crystallization situation. In the step of dissolving in the second solvent by heating, the dissolving temperature is 40~80℃, more preferably 45~65℃, and even more preferably 50~60℃.

[0044] In optional embodiments of the present invention, the first solvent is a nitrile solvent, or the first solvent is a mixture of a nitrile solvent and an alcohol solvent and / or an ester solvent; the second solvent is a mixture of a nitrile solvent and an alkane solvent. In the present invention, the nitrile solvent is preferably acetonitrile, the alcohol solvent is preferably methanol, the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-hexane or n-heptane.

[0045] In an optional embodiment of the present invention, the ball milling frequency is more preferably 22~28Hz; the ball milling process adopts dry ball milling.

[0046] The drying described in Method 1, Method 2, and Method 3 of this invention is preferably vacuum drying, the drying temperature is preferably 25~45℃, and the drying time is preferably 2~6h.

[0047] The present invention also provides the use of the co-crystal form I or the co-crystal form G of utpatinib in the preparation of a medicament for treating diseases related to JAK1 activity.

[0048] The technical solution of the present invention will be further described below with reference to specific embodiments. The present invention does not impose any special restrictions on the source of reagents used in the following embodiments; commercially available products well known to those skilled in the art can be used.

[0049] In the following examples, the powder X-ray diffraction (PXRD) patterns were obtained using a Rigaku MiniFlex X-ray powder diffractometer manufactured by Rigaku Corporation, Japan. The experimental parameters are as follows: X-ray source: Cu-Kα; Step length: 10° / min; Scan range: 5-35°.

[0050] The differential scanning calorimetry (DSC) curves were obtained using a Netzsch DSC-214 Polyma thermal analyzer (Germany). The experimental parameters are as follows: Protective gas: Nitrogen; Heating rate: 10℃ / min; Test range: 20-180℃ (180℃ for 1 min).

[0051] The dynamic solubility experiment parameters are as follows: Experimental conditions: room temperature, no protective gas; Buffer solutions: FaSSIF (pH 6.5), FeSSIF (pH 5.0); Dissolving conditions: Stir at 75 rpm; Sampling time: Extract the supernatant at 24 hours and 48 hours.

[0052] Concentration measurements were performed using a UV0910M037 UV-Vis spectrophotometer, and the experimental parameters are as follows: Detection range: 200-400 nm; Scan rate: 600 nm / min.

[0053] Example 1 This embodiment provides a method for preparing eutectic form I of utpatinib and vanillic acid.

[0054] Weigh 38 mg of amorphous utpatinib free base (approximately 0.1 mmol) and 16.8 mg of vanillic acid (approximately 0.1 mmol) into a glass bottle, and add 1 ml of acetonitrile. After forming a suspension, slurry the mixture at room temperature (approximately 25°C) for 6 hours. Centrifuge and filter to separate the solid, then vacuum dry at 40°C for 4 hours. The obtained solid was identified as eutectic form I.

[0055] The X-ray powder diffraction pattern of eutectic type I obtained in this embodiment is as follows: Figure 1 As shown, it has characteristic peaks at 7.68°, 8.36°, 9.46°, 10.64°, 11.10°, 11.84°, 12.25°, 12.98°, 13.88°, 14.23°, 14.96°, 15.38°, 15.70°, 16.82°, 17.76°, 19.09°, 19.61°, 20.30°, 21.01°, 21.75°, 22.50°, 22.83°, 23.57°, 23.99°, 24.55°, 25.32°, 25.88°, 26.33°, 27.51°, 28.68°, 29.90°, 30.46°, and 31.56°.

[0056] The DSC curve of eutectic type I obtained in this embodiment is as follows: Figure 2 As shown, an endothermic peak appears when heated to 132℃, which is identified as a melting endothermic peak.

[0057] Example 2 This embodiment provides a method for preparing eutectic form I of utpatinib and vanillic acid.

[0058] Weigh 190 mg of amorphous utpatinib free base (approximately 0.5 mmol) and 42 mg of vanillic acid (approximately 0.25 mmol) into a glass bottle, add 1 ml of acetonitrile and 1 ml of n-hexane, heat to 50 °C to dissolve, filter, and let the filtrate stand at room temperature (approximately 25 °C) for 6 hours. The solid precipitates out, and the obtained solid is crystal form I as determined by PXRD.

[0059] Example 3 This embodiment provides a method for preparing eutectic form I of utpatinib and vanillic acid.

[0060] Weigh 380 mg of amorphous utpatinib free base (approximately 1 mmol) and 84 mg of vanillic acid (approximately 0.5 mmol) into a grinding jar, add 20 μL of acetonitrile, and grind at a frequency of 25 Hz for 30 min. Dry to obtain a solid powder. PXRD analysis showed the solid to be crystal form I.

[0061] Example 4 This embodiment provides a method for preparing the eutectic crystal form G of utpatinib and syringic acid.

[0062] Weigh 38 mg of amorphous utpatinib free base (approximately 0.1 mmol) and 19.8 mg of syringic acid (approximately 0.1 mmol) into a glass bottle, and add 1 ml of acetonitrile. After forming a suspension, slurry the mixture at room temperature (approximately 25°C) for 6 hours. Centrifuge and filter to separate the solid, and dry under vacuum at 40°C for 4 hours. The obtained solid was identified as eutectic G.

[0063] The X-ray powder diffraction pattern of the eutectic form G obtained in this embodiment is as follows: Figure 3 As shown, it is in Characteristic peaks are present at 7.38°, 7.71°, 8.81°, 9.89°, 10.59°, 11.54°, 12.79°, 13.81°, 14.63°, 15.11°, 16.19°, 16.67°, 17.68°, 18.54°, 18.94°, 19.38°, 19.81°, 21.09°, 21.74°, 22.73°, 23.29°, 24.25°, 24.67°, 25.80°, 26.67°, 27.33°, 27.95°, 29.21°, 31.22°, 31.84°, and 33.06°.

[0064] The DSC curve of the eutectic form G obtained in this embodiment is shown in the figure below. Figure 4 As shown, an endothermic peak appears when heated to 130℃, which is identified as a melting endothermic peak.

[0065] Example 5 This embodiment provides a method for preparing the eutectic crystal form G of utpatinib and syringic acid.

[0066] Weigh 190 mg of amorphous utpatinib free base (approximately 0.5 mmol) and 49.5 mg of syringic acid (approximately 0.25 mmol) into a glass bottle, add 1 ml of acetonitrile and 1 ml of n-hexane, heat to 50 °C to dissolve, filter, and let the filtrate stand at room temperature (approximately 25 °C) for 6 hours. The solid precipitates out, and the solid obtained is crystalline form G as determined by PXRD.

[0067] Example 6 This embodiment provides a method for preparing the eutectic crystal form G of utpatinib and syringic acid.

[0068] Weigh 380 mg of amorphous utpatinib free base (approximately 1 mmol) and 99 mg of syringic acid (approximately 0.5 mmol) into a grinding jar, set the grinding frequency to 25 Hz, and grind for 30 min. A solid powder was obtained. PXRD analysis showed that the solid was of crystalline form G.

[0069] Comparative Example 1 This comparative example differs from Example 1 in that vanillic acid is replaced with an equimolar amount of mandelic acid. Experimental results: No slurry phenomenon was observed; the solution remained clear, and no solid powder was obtained even with prolonged processing. Figure 5 As shown, this indicates that other carboxylic acids may not be able to form a co-crystal, or they may form a co-crystal but require a large amount of raw material. Similarly, equimolar amounts of small molecule carboxylic acids such as ferulic acid, benzoic acid, and 2,6-dihydroxybenzoic acid yielded the same experimental results. This indirectly demonstrates that the co-crystal of vanillic acid or syringic acid with utpatinib prepared in the embodiments of this invention not only effectively reduces production costs but also significantly saves raw material resources, making it more sustainable.

[0070] Comparative Example 2 This comparative example differs from Example 1 in that vanillic acid is replaced with an equimolar amount of sebacic acid. Experimental results: The mixture was in a slurry state; after filtration and drying, a solid powder was obtained, as shown below. Figure 6 PXRD analysis revealed it to be a two-phase mixture. This indicates that although there are patent reports on the preparation of sebacic acid eutectic, simple experiments cannot reproduce it, indirectly demonstrating that our developed method for preparing vanillic acid / syringic acid eutectic is simple to operate, has good reproducibility, and is easier to prepare and apply in practice.

[0071] Test case 1. Dynamic solubility test Excess amounts of the eutectic crystal form I prepared in Example 1 of this invention, the eutectic crystal form G prepared in Example 3, and the commercially available crystal form C were weighed, ground, dried, and sieved (200 mesh). Samples were taken at 24 and 48 hours in FaSSIF (pH 6.5) and FeSSIF (pH 5.0) buffer solutions at 37°C. After filtration through a 0.45 μm filter membrane, the concentration of utpatinib in the filtrate was determined using a UV-Vis spectrophotometer. The results are shown in Table 1.

[0072] Table 1 Results of dynamic solubility test

[0073] As can be seen from Table 1, both eutectic form I and eutectic form G exhibit excellent solubility in aqueous media and can maintain high concentration stability over a long period of time.

[0074] 2. Accelerated stability test The eutectic crystal form I sample of Example 1 of this invention was placed in a constant temperature and humidity chamber at 40°C and 75% relative humidity for one month. PXRD analysis was performed on days 0, 7, 15, and 30, as shown below. Figure 7 As shown, the positions and relative intensities of all characteristic diffraction peaks did not change significantly before and after the experiment, and no new diffraction peaks appeared. The results indicate that the eutectic form I of this invention can exist stably under the above-mentioned accelerated conditions, exhibiting good physical stability and suitable for long-term drug storage and formulation development.

[0075] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A eutectic form I of utpatinib, characterized in that, The eutectic form I is a eutectic formed by utpatinib and vanillic acid; the X-ray powder diffraction pattern of the eutectic form I under Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.68°±0.2°, 8.36°±0.2°, 11.10°±0.2°, 12.98°±0.2°, 21.01°±0.2°, and 26.33°±0.2°.

2. The eutectic form I of utpatinib as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the eutectic form I under Cu-Kα radiation is also found at 9.46°±0.2°, 10.64°±0.2°, 11.84°±0.2°, 12.25°±0.2°, 13.88°±0.2°, 14.23°±0.2°, 14.96°±0.2°, 15.38°±0.2°, 15.70°±0.2°, 16.82°±0.2°, 17.76°±0.2°, 19.09°±0.2°, and 19.61°± Characteristic peaks are present at 0.2°, 20.30°±0.2°, 21.75°±0.2°, 22.50°±0.2°, 22.83°±0.2°, 23.57°±0.2°, 23.99°±0.2°, 24.55°±0.2°, 25.32°±0.2°, 25.88°±0.2°, 27.51°±0.2°, 28.68°±0.2°, 29.90°±0.2°, 30.46°±0.2°, and 31.56°±0.2°.

3. The method for preparing eutectic form I of utpatinib as described in any one of claims 1 to 2, characterized in that, Includes the following steps: Upatinib and vanillic acid were dissolved in a first solvent and stirred to react, resulting in the precipitation of a solid. After separation and drying, the eutectic crystal type I was obtained. Alternatively, utpatinib and vanillic acid can be dissolved in a second solvent by heating, stirring and reacting, then cooling to precipitate a solid, which can be separated and dried to obtain the eutectic crystal form I. Alternatively, utpatinib and vanillic acid can be ball-milled at a frequency of 15-30 Hz for 30-60 min, and the solid can be collected and dried to obtain the eutectic crystal form I.

4. The preparation method according to claim 3, characterized in that, The molar ratio of utpatinib to vanillic acid is (1~3):1; in the step of dissolving in the first solvent and stirring reaction, the stirring reaction temperature is 15~35℃; in the step of heating and dissolving in the second solvent, the heating and dissolving temperature is 40~80℃.

5. The preparation method according to claim 3, characterized in that, The first solvent is a nitrile solvent, or the first solvent is a mixture of a nitrile solvent and an alcohol solvent and / or an ester solvent; the second solvent is a mixture of a nitrile solvent and an alkane solvent.

6. A eutectic form G of utpatinib, characterized in that, The eutectic crystal form G is a eutectic formed by utpatinib and syringic acid; the X-ray powder diffraction pattern of the eutectic crystal form G under Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.38°±0.2°, 7.71°±0.2°, 10.59°±0.2°, 19.38°±0.2°, 21.09°±0.2°, and 29.21°±0.2°.

7. The eutectic form G of utpatinib as described in claim 6, characterized in that, The X-ray powder diffraction pattern of the eutectic G under Cu-Kα radiation also shows values ​​at 8.81°±0.2°, 9.89°±0.2°, 11.54°±0.2°, 12.79°±0.2°, 13.81°±0.2°, 14.63°±0.2°, 15.11°±0.2°, 16.19°±0.2°, 16.67°±0.2°, 17.68°±0.2°, 18.54°±0.2°, and 18.94°±0.2°. Characteristic peaks are present at 0.2°, 19.81°±0.2°, 21.74°±0.2°, 22.73°±0.2°, 23.29°±0.2°, 24.25°±0.2°, 24.67°±0.2°, 25.80°±0.2°, 26.67°±0.2°, 27.33°±0.2°, 27.95°±0.2°, 31.22°±0.2°, 31.84°±0.2°, and 33.06°±0.2°.

8. The method for preparing the eutectic form G of utpatinib as described in any one of claims 6 to 7, characterized in that, Includes the following steps: Upatinib and syringic acid were dissolved in a first solvent and stirred to react, resulting in the precipitation of a solid. After separation and drying, the eutectic crystal form G was obtained. Alternatively, utpatinib and syringic acid can be dissolved in a second solvent by heating, stirring and reacting, then cooling to precipitate a solid, which can be separated and dried to obtain the eutectic crystal form G. Alternatively, utpatinib and syringic acid are ball-milled at a frequency of 15-30 Hz for 30-60 min, the solid is collected and dried to obtain the eutectic crystal form G.

9. The preparation method according to claim 8, characterized in that, The molar ratio of utpatinib to syringic acid is (1~3):1; in the step of dissolving in the first solvent and stirring reaction, the stirring reaction temperature is 15~35℃; in the step of heating and dissolving in the second solvent, the heating and dissolving temperature is 40~80℃; the first solvent is a nitrile solvent, or the first solvent is a mixed solvent of nitrile solvent, alcohol solvent and / or ester solvent; the second solvent is a mixed solvent of nitrile solvent and alkane solvent.

10. The use of utpatinib co-crystal form I as described in any one of claims 1 to 2, or utpatinib co-crystal form I prepared by the preparation method as described in any one of claims 3 to 5, or utpatinib co-crystal form G as described in any one of claims 6 to 7, or utpatinib co-crystal form G as described in any one of claims 8 to 9, in the preparation of a medicament for treating diseases related to JAK1 activity.

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