Baloxavir marboxil and L-tartaric acid eutectic crystal form DCTI and preparation method thereof

Abstract

The invention discloses a preparation process of a Baloxavir marboxil and L-tartaric acid eutectic crystal form. The X-ray powder diffraction pattern of the Baloxavir marboxil and L-tartaric acid eutectic crystal form under Cu-Ka radiation has diffraction angle 2theta values of 8.7 + / -0.2 degrees, 10.8 + / -0.2 degrees, 11.6 + / -0.2 degrees, 13.2 + / -0.2 degrees, 13.8 + / -0.2 degrees, 14.3 + / -0.2 degrees, 15.8 + / -0.2 degrees, 16.2 + / -0.2 degrees, 16.4 + / -0.2 degrees, 17.5 + / -0.2 degrees, 18.6 + / -0.2 degrees, 18.9 + / -0.2 degrees, 19.4 + / -0.2 degrees, 19.8 + / -0.2 degrees, 20.1 + / -0.2 degrees, 20.7 + / and characteristic peaks exist at the positions of 25.7 + / -0.2 degrees, 26.4 + / -0.2 degrees, 26.8 + / -0.2 degrees, 27.6 + / -0.2 degrees, 28.3 + / -0.2 degrees, 28.6 + / -0.2 degrees, 29.1 + / -0.2 degrees, 29.7 + / -0.2 degrees, 31.4 + / -0.2 degrees, 32.0 + / -0.2 degrees, 35.4 + / -0.2 degrees, 35.8 + / -0.2 degrees, 36.1 + / -0.2 degrees, 36.7 + / -0.2 degrees and 37.4 + / -0.2 degrees. The Baloxavir marboxil and L-tartaric acid eutectic crystal form provided by the invention has stable physicochemical properties, excellent solid stability and mechanical stability, and can be stably stored for a long time, the preparation method is simple and convenient, the repeatability is good, and the Baloxavir marboxil and L-tartaric acid eutectic crystal form has important application value for the development of the medicine in the future.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug crystal forms, in particular to a co-crystal of baloxavir marboxil and L-tartaric acid and a preparation method thereof. BACKGROUND

[0002] Baloxavir marboxil is an innovative CAP-dependent endonuclease inhibitor, and is also one of the few new drugs in the world that can treat influenza virus proliferation. It can treat the key link of influenza virus replication, treat it to obtain the CAP structure of the host mRNA 5' end from the host cell, and thus treat the transcription of the influenza virus itself mRNA.

[0003] At present, the crystal form patents of baloxavir marboxil have the following reports. The original research drug company Japan Shanyi disclosed three crystal forms in WO2018030463, namely Form I, Form II, and Form III, but the DSC / TGA data were not collected in the text, so the crystal type cannot be obtained, and the stability data is also not reported in the text.

[0004] CN111377944 discloses two crystal forms, wherein Form A is Form I in WO2018030463, and the DSC research on the crystal form is also carried out in the text, confirming that it is an anhydrous crystal form; Form B is another anhydrous crystal form.

[0005] WO2022100395 discloses two crystal forms, namely methyl benzoate solvate Form C and anhydrous Form D.

[0006] CN111875619 discloses a new crystal form of baloxavir marboxil and a preparation method.

[0007] WO2020181025 discloses six crystal forms of baloxavir marboxil, including three anhydrous crystal forms Form BM1, BM2, and BM3, and three solvate crystal forms Form BM4, BM5, and BM6, and the solvents thereof are 1,4-dioxane, N,N-dimethylacetamide, and 2-methyltetrahydrofuran, respectively.

[0008] WO2021057834 discloses an anhydrous crystal form Form C of baloxavir marboxil.

[0009] Drug crystal form is an important factor affecting the quality of medicine. Different crystal forms of the same drug molecule will have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability and other properties, thereby directly affecting the stability, bioavailability and efficacy of the drug.

[0010] From the above patents, it is not difficult to find that the crystal form of Baloxavir marboxil is more comprehensive, and most of the anhydrous crystal forms can be used as medicine, but Prior art Baloxavir marboxil crystal form has poor stability or solubility; therefore, it is of great significance to carry out crystal form research. SUMMARY

[0011] The present application aims to at least solve one of the technical problems in the related art. To this end, the present application also provides comprehensive characterization data of the above-mentioned Baloxavir marboxil and L-tartaric acid co-crystal form and its process preparation method, which has good solubility and stability.

[0012] In order to solve the above technical problems, the first aspect of the present application provides a Baloxavir marboxil and L-tartaric acid co-crystal form, which has characteristic peaks at diffraction angles 2theta values of 8.7±0.2°, 10.8±0.2°, 11.6±0.2°, 13.2±0.2°, 13.8±0.2°, 14.3±0.2°, 15.8±0.2°, 16.2±0.2°, 16.4±0.2°, 17.5±0.2°, 18.6±0.2°, 18.9±0.2°, 19.4±0.2°, 19.8±0.2°, 20.1±0.2°, 20.7±0.2°, 21.6±0.2°, 21.9±0.2°, 22.2±0.2°, 23.0±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 26.4±0.2°, 26.8±0.2°, 27.6±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.7±0.2°, 31.4±0.2°, 32.0±0.2°, 35.4±0.2°, 35.8±0.2°, 36.1±0.2°, 36.7±0.2°, 37.4±0.2° under Cu-Ka radiation.

[0013] As a preferred embodiment, the differential scanning calorimetry spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form shows endothermic peaks near 137℃ and 232℃.

[0014] In the second aspect of the present application, a preparation method of the above-mentioned Baloxavir marboxil and L-tartaric acid co-crystal form is provided. 1000 mg of Baloxavir marboxil and 262.6 mg of L-tartaric acid are taken and added into a 40 ml vial, followed by adding a solvent to obtain a suspension. The suspension is stirred at room temperature for 48 h, and the solid is separated by centrifugation and dried, thereby obtaining the Baloxavir marboxil and L-tartaric acid co-crystal form.

[0015] Compared with the prior art, the present application has the following beneficial effects: (1) The preparation process of the Baloxavir marboxil and L-tartaric acid co-crystal form is simple and easy to operate, and is easy to scale up; (2) The solvent required by the Baloxavir marboxil and L-tartaric acid co-crystal form is a conventional organic solvent, the production amount is small, and the production cost is low.

[0016] The concept, specific structure and generated technical effects of the present application will be further described below with reference to the accompanying drawings, so as to fully understand the purpose, features and effects of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 is the XRPD spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form prepared in Example 1 of the present application; Figure 2 is the DSC spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form prepared in Example 1 of the present application; Figure 3 is the XRPD spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form prepared in Example 1 of the present application; 1 HNMR spectrum; Figure 4 is the XRPD spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form prepared in Example 3 of the present application before and after grinding for 15 minutes; Figure 5 is the XRPD spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form prepared in Example 4 of the present application before and after being placed under different temperature and humidity conditions for 4-8 weeks; Figure 6 is the XRPD spectrum of the Baloxavir marboxil and L-tartaric acid co-crystal form prepared in Example 5 of the present application before and after being placed under 25℃ / 80%RH conditions for 24 hours. DETAILED DESCRIPTION

[0019] In order to make the technical means, creative features, purposes and effects of the application easy to understand, the application will be further described below in combination with specific drawings. However, the application is not limited to the following embodiments.

[0020] It should be understood that the structures, proportions, sizes, etc. shown in the drawings attached to the present specification are only used to cooperate with the content disclosed in the specification for understanding and reading by those skilled in the art, and do not have technical substantive significance, and any modification of the structure, change of the proportion relationship or adjustment of the size, without affecting the effects and purposes that can be achieved by the application, should still fall within the scope of the technical content disclosed by the application.

[0021] Among the various crystal forms of Baloxavir marboxil reported in the prior art, the solubility is generally low, resulting in poor drug efficacy and low bioavailability.

[0022] From the perspective of changing the preparation method of Baloxavir marboxil, the present application obtains a new L-tartaric acid co-crystal form of Baloxavir marboxil, which has both stability and high solubility. On the one hand, it can avoid the risk of crystal transformation, and on the other hand, it is convenient for drug absorption and improves the bioavailability.

[0023] XRPD, i.e. X-ray powder diffraction, the X-ray powder diffraction pattern of the present application is collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of X-ray powder diffraction are as follows: X-ray source: Cu Ka; Kal (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kilovolts (kV); current: 10 milliampere (mA); scanning range: 3.0-40.0°.

[0024] DSC, i.e. differential scanning calorimetry analysis, the differential scanning calorimetry (DSC) pattern of the present application is collected on a TA company DSC X3, and the method parameters of differential scanning calorimetry (DSC) are as follows: scanning rate: 10 ℃ / min; protective gas: nitrogen.

[0025] TGA, i.e. thermal gravimetric analysis, the thermal gravimetric analysis (TGA) pattern of the present application is collected on a TA company TGA55, and the method parameters of thermal gravimetric analysis (TGA) are as follows: scanning rate: 10 ℃ / min; protective gas: nitrogen.

[0026] Unless otherwise specified, the following examples are all operated at room temperature, and the "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30 ℃.

[0027] The term "stirring" as used in the following examples is accomplished by conventional means known in the art, such as magnetic or mechanical stirring, at a rate of 50 to 1800 rpm, with magnetic stirring preferably at 300 to 900 rpm and mechanical stirring preferably at 100 to 300 rpm.

[0028] The term "separating" as used in the following examples is accomplished by conventional means known in the art, such as centrifugation or filtration, with "centrifugation" being accomplished by placing the sample to be separated in a centrifuge tube and centrifuging at 10,000 rpm until the solids have all settled to the bottom of the centrifuge tube.

[0029] The term "drying" as used in the following examples can be accomplished at room temperature or at an elevated temperature. The drying temperature is from room temperature to about 50 °C, or to 40 °C. The drying time can be from 2 to 48 hours, or overnight. The drying is performed in a fume hood, in a forced air oven, or in a vacuum oven.

[0030] The term "crystal" as used in the following examples refers to a solid characterized by an X-ray powder diffraction pattern. Those skilled in the art will appreciate that the physical and chemical properties discussed herein can be characterized with experimental error that depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known in the art that X-ray powder diffraction patterns can vary with the conditions of the instrument, and in particular, it is noted that the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern can vary with experimental conditions, and therefore the order of the diffraction peaks cannot be used as the sole or determining factor. In fact, the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal, and the intensities shown in the X-ray powder diffraction patterns of the present application are illustrative and not for absolute comparison. In addition, the experimental error in the positions of the diffraction peaks is typically 5% or less, and this error in the positions should be taken into account, typically allowing for a ±0.2 error. In addition, there can be an overall shift in the diffraction peak angles due to experimental factors such as sample thickness, and some shift is typically allowed. Thus, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the present application are not required to be identical to the X-ray powder diffraction patterns shown in the examples herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks of these patterns is within the scope of the present application.

[0031] Those skilled in the art can compare the X-ray powder diffraction patterns shown in the present application to the X-ray powder diffraction pattern of an unknown crystal form to determine whether the two sets of patterns reflect the same or different crystal forms.

[0032] The Baloxavir marboxil and L-tartaric acid co-crystal of the present application is pure, substantially free of any other crystal form. By "substantially free" when referring to a new crystal form, it is meant that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, more especially less than 5% by weight of other crystal forms, and more especially less than 1% by weight of other crystal forms.

[0033] The term "about", when used to refer to a measurable value such as mass, time, temperature, and the like, means that the value can be "off" by a range of plus or minus ten percent, plus or minus five percent, plus or minus one percent, plus or minus 0.5 percent, or plus or minus 0.1 percent.

[0034] Baloxavir marboxil as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oil, liquid form, and solution. Preferably, it is in solid form.

[0035] The method for preparing the Baloxavir marboxil and L-tartaric acid co-crystal of the present application: 1000 mg of Baloxavir marboxil and ~262.6 mg of L-tartaric acid are weighed into a 40 ml vial, followed by the addition of a solvent to obtain a suspension, the suspension is stirred at room temperature for 48 h, the solid is separated by centrifugation and dried, which is the Baloxavir marboxil and L-tartaric acid co-crystal.

[0036] In the process of preparing the Baloxavir marboxil and L-tartaric acid co-crystal of the present application, the crystallization time is different, which also affects the degree of crystallization or the yield of crystals, and can be flexibly selected according to actual needs.

[0037] Example 1

[0038] 1000 mg of Baloxavir marboxil and ~262.6 mg of L-tartaric acid are weighed into a 40 ml vial, followed by the addition of a solvent (see Table 1 for details) to obtain a suspension, the suspension is stirred at room temperature for 48 h, the solid is separated by centrifugation and dried, and the obtained solid is detected by XRPD, which is the co-crystal DCTI shown in the present application. The XRPD pattern is shown in Figure 1 , the XRPD data is shown in Table 2, and the DSC pattern is shown in Figure 2 .

[0039] Table 1

[0040] Number Sample mass (mg) L-tartaric acid mass (mg) Solvent Solvent volume (ml) XRPD Sample 1 1000 262.6 Acetic acid 5 Co-crystal DCTI Sample 2 1000 262.6 Isopropanol 5 Co-crystal DCTI Sample 3 1000 262.6 Dichloromethane 5 Co-crystal DCTI

[0041] Table 2

[0042] Diffractogram angle 2 theta d-value Relative intensity Diffractogram angle 2 theta d-value Relative intensity Diffractogram angle 2 theta d-value Relative intensity 8.74 10.11 100.00% 19.78 4.49 4.60% 27.60 3.23 3.20% 10.76 8.22 30.10% 20.14 4.41 46.20% 28.28 3.15 16.20% 11.60 7.62 6.70% 20.66 4.30 38.70% 28.62 3.12 4.80% 13.15 6.73 14.40% 21.64 4.10 31.70% 29.15 3.06 24.00% 13.85 6.39 7.80% 21.94 4.05 27.80% 29.71 3.01 51.50% 14.28 6.20 45.00% 22.24 3.99 29.10% 31.37 2.85 10.70% 15.79 5.61 19.30% 23.02 3.86 4.30% 31.96 2.80 31.70% 16.17 5.48 36.30% 23.82 3.73 8.10% 35.45 2.53 11.50% 16.40 5.40 18.90% 24.10 3.69 61.10% 35.76 2.51 10.10% 17.53 5.06 29.10% 25.02 3.56 8.30% 36.11 2.49 13.70% 18.59 4.77 21.70% 25.65 3.47 21.20% 36.68 2.45 15.70% 18.87 4.70 22.50% 26.42 3.37 55.70% 37.38 2.40 25.50% 19.36 4.58 17.30% 26.83 3.32 5.80%

[0043] From Figure 2 the above, it can be known that the baloxavir marboxil prepared in Example 1 and the L-tartaric acid co-crystal form have endothermic peaks near 150°C, respectively.

[0044] The nuclear magnetic chart is as shown in Figure 3 , and the specific data are as follows: 1 H-NMR (400 MHz, DMSO-D6) δ 7.45-7.37 (m,2H), 7.24-7.00 (m, 4H), 6.88-6.83 (m, 1H), 5.75-5.66 (m, 4H), 5.44-5.40 (m,1H), 4.47-4.39 (m, 2H), 4.32 (s, 2H), 4.08-3.98 (m, 2H), 3.77-3.67 (m, 4H),3.45 (t, J = 10.3 Hz, 1H), 3.27 (dd, J = 11.7, 2.3 Hz, 1H), 2.99-2.91 (m, 1H)

[0045] Example 2: Biological medium solubility of the crystal form DCTI of the application

[0046] When performing drug solubility tests to predict the performance of the drug in the body, it is very important to simulate the in-vivo conditions as much as possible. For oral drugs, SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid) can simulate in-vivo conditions and predict the effects of eating. The solubility tested in such media is closer to the solubility in the human body environment.

[0047] In order to compare the solubility of the crystal form I in the original research patent WO2018030463 and the crystal form DCTI of the application in the biological medium, the experiment was performed according to the method for determining the biological medium solubility of USP. Experimental method: about 25 milligrams of the crystal form DCTI prepared in Example 1 was weighed and added into 1 milliliter of pre-configured SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid), respectively. The mixture was stirred at 37 ℃±1℃ constant temperature, and samples were taken at 1 hour and 2 hours, respectively. The supernatant was determined for content by HPLC method. The crystal form I in the patent WO2018030463 was also subjected to the above-mentioned operation for sampling. The experimental conditions and results are shown in Table 3.

[0048] Table 3

[0049] The solubility experiment results in biological solvents show that, compared with the crystal form I in the WO2018030463 patent, the crystal form DCTI of the present application has higher solubility in SGF (simulated gastric juice), FeSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid). Within 4 hours, the solubility of the crystal form DCTI of the present application is 2-3 times that of the crystal form I reported in the prior art WO2018030463. Higher solubility is conducive to improving the absorption of the drug in the human body, improving the bioavailability of the drug, and achieving better therapeutic effect with less drug loading. In addition, under the premise of ensuring the efficacy of the drug, reducing the drug loading can reduce the toxic side effects of the drug and improve the safety of the drug use, which has important clinical significance.

[0050] Example 3 Mechanical stability of the crystal form DCTI of the present application

[0051] 10 mg of the crystal form DCTI prepared in Example 1 was placed in a mortar and manually ground for 15 minutes. XRPD tests were performed before and after grinding. The XRPD comparison before and after grinding is shown in Figure 4 .

[0052] According to Figure 3 , the crystal form DCTI of the present application does not change after grinding, and the crystallinity does not show a significant decrease. Therefore, it is shown that the crystal form DCTI has good mechanical stability. Good mechanical stability can ensure that the sample will not easily undergo crystal transformation during the later preparation process due to mechanical grinding, crushing and other external forces, thereby reducing the risk of crystal transformation during the preparation process and improving the developability of the preparation process.

[0053] Example 4 Packaging stability of the crystal form DCTI of the present application

[0054] About 5 mg of the crystal form DCTI prepared in Example 1 was placed in a mortar and manually ground for 15 minutes. XRPD tests were performed before and after grinding. The XRPD comparison before and after grinding is shown in Figure 5 .

[0055] Table 4

[0056] Storage condition Storage time Crystal form Purity (peak area %) Initial —— Crystal form DCTI 99.44 25 °C / 60% RH 8 weeks Crystal form DCTI 99.46 40 °C / 75% RH 8 weeks Crystal form DCTI 99.48 60 °C / 75% RH 4 weeks Crystal form DCTI 99.40

[0057] The results show that: the crystal form DCTI prepared by the application remains unchanged after being placed for 4-8 weeks under three conditions of 25 DEG C / 60%RH, 40 DEG C / 75%RH and 60 DEG C / 75%RH, which indicates that the crystal form DCTI has good physical stability. Especially under the accelerated condition of 60 DEG C / 75%RH, the crystal form remains stable after being placed for 4 weeks without crystal transformation, which further indicates that the crystal form DCTI still has good physical stability even under high temperature and high humidity conditions, which ensures that the drug is not prone to crystal transformation in the subsequent process, production and transportation process; in addition, the chemical purity of the crystal form DCTI does not change before and after being placed under the condition of 40 DEG C / 75%RH (relative humidity), and the purity is maintained above 99%, which indicates that the crystal form DCTI has good chemical stability, and in addition, even under the accelerated condition of 60 DEG C / 75%RH, the chemical purity does not decrease obviously, which further indicates that the crystal form DCTI has good chemical stability. The good physical and chemical stability ensures that the drug can maintain stable quality during the subsequent preparation development and process production process, and the drug production and transportation process, ensures the drug quality and curative effect, and has important significance.

[0058] Example 5: Hygroscopicity of the crystal form DCTI of the application

[0059] The hygroscopicity is determined according to the guidance principle of drug hygroscopicity experiment in Chinese Pharmacopoeia 2020 edition general rule 9103, and the determination condition is 25 ± 1 DEG C, 80% relative humidity.

[0060] The definition of hygroscopic weight gain: extremely hygroscopic: hygroscopic weight gain is not less than 15.0%; hygroscopic: hygroscopic weight gain is less than 15.0% but not less than 2.0%; slightly hygroscopic: hygroscopic weight gain is less than 2.0% but not less than 0.2%; no or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%.

[0061] About 20 milligrams of the crystal form DCTI prepared in Example 1 of the application is placed under the condition of 25 ± 1 DEG C, 80% relative humidity for 24 hours, the mass of the sample before and after is recorded, and the crystal form is determined by XRPD. The specific results are shown in Table 5, and the XRPD overlay is shown in Figure 6 .

[0062] Table 5

[0063] Initial mass (mg) Storage condition Storage time Mass after storage (mg) Mass gained (mg) Percentage mass gained 22.1 25 ± 1 °C, 80% RH 24 hours 22.3 0.20 0.90%

[0064] As shown in Table 6, the crystal form DCTI of the application has slight hygroscopicity, which indicates that the crystal form DCTI is not prone to deliquescence during the production and storage of the drug.

[0065] Crystal form stability is of great significance to drug development. If crystal transformation occurs, it will directly affect the solubility of the drug and in turn affect the bioavailability of the drug, thereby changing the efficacy of the drug. Good chemical stability can ensure that almost no new impurities are produced or the content of impurities almost does not increase during the storage of the drug, thereby ensuring the safety of the drug. Good humidity stability can ensure that the sample will not easily undergo crystal transformation during the later storage, transportation and preparation process of the preparation process due to changes in environmental humidity, thereby reducing the risk of crystal transformation during the sample storage, transportation and preparation process and improving the developability of the product. Lower hygroscopicity can ensure that the sample can maintain a lower moisture weight gain without deliquescence during the later production, processing and storage and transportation processes, thereby ensuring the stability of the quality of the drug.

[0066] Therefore, the good physical stability and good humidity stability of the crystal form DCTI, and almost no hygroscopicity, provide a guarantee for the subsequent production and development of the drug, and have a high industrialization development value.

[0067] The above describes in detail the preferred embodiments of the present application. It should be understood that those skilled in the art can make many modifications and changes to the embodiments of the present application without creative labor based on the concept of the present application. Therefore, any technical solution obtained by logical analysis, reasoning or limited experiment based on the concept of the present application and the prior art should be within the protection scope defined by the claims.

Claims

1. A eutectic crystal form of Baloxavir marboxil and L-tartaric acid, characterized in that, The X-ray powder diffraction patterns of the Baloxavir marboxil and L-tartaric acid eutectic crystal form under Cu-Ka radiation showed diffraction angles of 2θ values ​​of 8.7±0.2°, 10.8±0.2°, 11.6±0.2°, 13.2±0.2°, 13.8±0.2°, 14.3±0.2°, 15.8±0.2°, 16.2±0.2°, 16.4±0.2°, 17.5±0.2°, 18.6±0.2°, 18.9±0.2°, 19.4±0.2°, 19.8±0.2°, 20.1±0.2°, 20.7±0.2°, and 21.6°. Characteristic peaks are present at ±0.2°, 21.9±0.2°, 22.2±0.2°, 23.0±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 26.4±0.2°, 26.8±0.2°, 27.6±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.7±0.2°, 31.4±0.2°, 32.0±0.2°, 35.4±0.2°, 35.8±0.2°, 36.1±0.2°, 36.7±0.2°, and 37.4±0.2°.

2. A method for preparing a eutectic of Baloxavir marboxil and L-tartaric acid, characterized in that, Baloxavir marboxil and L-tartaric acid were placed in an organic solvent at a molar ratio of 1:1 to obtain a suspension. The resulting suspension was stirred, separated, and dried to obtain a eutectic of Baloxavir marboxil and L-tartaric acid.

3. The eutectic crystal form of Baloxavir marboxil and L-tartaric acid as described in claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of the Baloxavir marboxil eutectic with L-tartaric acid showed an endothermic peak at 150±3℃.

4. The method for preparing a eutectic of Baloxavir marboxil and L-tartaric acid as described in claim 2, characterized in that, The organic solvent is selected from any one of acetic acid, dichloromethane, methanol, ethanol, isopropanol, n-propanol, acetone, and tetrahydrofuran.

5. The method for preparing a eutectic of Baloxavir marboxil and L-tartaric acid as described in claim 2, characterized in that, The crystallization temperature is 0-40℃.

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