Eutectic crystal form DCV1 of Baloxavir marboxil and vitamin C and preparation method thereof

Abstract

The invention discloses a preparation process of a Baloxavir marboxil and vitamin C eutectic crystal form. The X-ray powder diffraction pattern of the Baloxavir marboxil and vitamin C eutectic crystal form under Cu-Ka radiation has diffraction angle 2theta values of 8.7 + / -0.2 degrees, 10.4 + / -0.2 degrees, 10.7 + / -0.2 degrees, 13.1 + / -0.2 degrees, 13.8 + / -0.2 degrees, 14.2 + / -0.2 degrees, 15.7 + / -0.2 degrees, 16.1 + / -0.2 degrees, 16.3 + / -0.2 degrees, 17.4 + / -0.2 degrees, 18.5 + / -0.2 degrees, 19.8 + / -0.2 degrees, 19.8 + / -0.2 degrees, 20.1 + / -0.2 degrees, 20.8 + / -0.2 degrees, 20.9 + / -0.2 degrees, 21.6 + / and characteristic peaks exist at the positions of 25.6 + / -0.2 degrees, 26.4 + / -0.2 degrees, 26.7 + / -0.2 degrees, 27.1 + / -0.2 degrees, 28.0 + / -0.2 degrees, 28.2 + / -0.2 degrees, 29.7 + / -0.2 degrees, 29.9 + / -0.2 degrees and 31.3 + / -0.2 degrees. The eutectic crystal form of Baloxavir marboxil and vitamin C provided by the invention has stable physicochemical properties, excellent solid stability and mechanical stability, and can be stably stored for a long time, and the preparation method is simple and convenient, has good repeatability, and has important application value for the development of the medicine in the future.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical crystal form technology, specifically to the co-crystal form of Baloxavir marboxil and vitamin C and its preparation method. Background Technology

[0002] Baloxavir marboxil is an innovative CAP-dependent endonuclease inhibitor and one of the few new drugs in the world that can treat influenza virus replication. It targets a key step in influenza virus replication, inhibiting the acquisition of the CAP structure at the 5' end of host mRNA from host cells, thereby inhibiting the transcription of influenza virus mRNA itself.

[0003] Currently, the following reports exist regarding the crystal form patents for Baloxavir marboxil. The original drug manufacturer, Shionogi & Co., Ltd. of Japan, disclosed three crystal forms in WO2018030463: Form I, Form II, and Form III. However, the paper did not collect DSC / TGA data, so the crystal types could not be determined. Furthermore, the paper did not report any stability data.

[0004] CN111377944 discloses two crystal forms, of which Form A is Form I in WO2018030463. The paper also conducted DSC studies on this crystal form and confirmed that it is an anhydrous crystal form; Form B is another anhydrous crystal form.

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

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

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

[0008] WO2021057834 discloses the anhydrous crystal form of Baloxavir marboxil, Form C.

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

[0010] Based on the above patents, it is not difficult to see that the crystal form research of Baloxavir marboxil is quite comprehensive, and most of its anhydrous crystal forms can be used medicinally. existing Baloxavir marboxil crystals have poor stability or solubility; therefore, it is of great significance to study its crystal form. Summary of the Invention

[0011] This invention aims to at least partially solve one of the technical problems in related technologies. To this end, this invention also provides comprehensive characterization data and a process preparation method for the aforementioned Baloxavir marboxil-vitamin C co-crystal form, which exhibits good solubility and stability.

[0012] To address the aforementioned technical problems, a first aspect of the present invention provides a eutectic crystal form of Baloxavir marboxil and vitamin C, wherein the X-ray powder diffraction pattern of the eutectic crystal form under Cu-Ka radiation has diffraction angle 2θ values ​​of 8.7±0.2°, 10.4±0.2°, 10.7±0.2°, 13.1±0.2°, 13.8±0.2°, 14.2±0.2°, 15.7±0.2°, 16.1±0.2°, 16.3±0.2°, 17.4±0.2°, 18.5±0.2°, 18.8±0.2°, 19.3±0.2°, 19.8±0.2°, and 20.1°. The following values ​​exhibit characteristic peaks: ±0.2°, 20.8±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 22.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.1±0.2°, 25.2±0.2°, 25.6±0.2°, 26.4±0.2°, 26.7±0.2°, 27.1±0.2°, 28.0±0.2°, 28.2±0.2°, 29.7±0.2°, 29.9±0.2°, and 31.3±0.2°.

[0013] In a preferred embodiment, the differential scanning calorimetry spectrum of the Baloxavir marboxil co-crystal with vitamin C showed endothermic peaks near 137°C and 232°C.

[0014] In a second aspect, the present invention provides a method for preparing the above-mentioned Baloxavir marboxil and vitamin C cocrystalline form, wherein 1000 mg of Baloxavir marboxil and ~308.1 mg of vitamin C are weighed and added to 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 vitamin C cocrystalline form.

[0015] Compared with the prior art, the present invention has the following beneficial effects: (1) The preparation process of the Baloxavir marboxil and vitamin C co-crystal form of the present invention is simple, easy to operate, and easy to scale up. (2) The solvent required for the Baloxavir marboxil and vitamin C co-crystal form of the present invention is a conventional organic solvent, which requires less production and has low production cost.

[0016] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0017] Figure 1 This is the XRPD spectrum of the co-crystal of Baloxavir marboxil and vitamin C prepared in Example 1 of this invention; Figure 2 This is the DSC spectrum of the co-crystal of Baloxavir marboxil and vitamin C prepared in Example 1 of this invention; Figure 3 This is the co-crystal form of Baloxavir marboxil and vitamin C prepared in Example 1 of this invention. 1 HNMR spectrum; Figure 4 This is the XRPD spectrum of the Baloxavir marboxil and vitamin C co-crystal prepared in Example 3 of this invention before and after grinding for 15 minutes; Figure 5 These are XRPD spectra of the Baloxavir marboxil and vitamin C co-crystal prepared in Example 4 of this invention before and after being placed under different temperature and humidity conditions for 4 to 8 weeks. Figure 6 The XRPD spectra of the Baloxavir marboxil and vitamin C co-crystal prepared in Example 5 of this invention before and after being placed at 25°C / 80%RH for 24 hours are shown. Detailed Implementation

[0019] To make the technical means, inventive features, objectives, and effects of the invention readily understandable, the invention is further illustrated below with reference to specific figures. However, the invention is not limited to the embodiments described below.

[0020] It should be noted that the structures, proportions, sizes, etc., illustrated in the accompanying drawings of this specification are only used to complement the content disclosed in the specification for those skilled in the art to understand and read, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes in the proportions, or adjustments to the size, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0021] Low solubility is a common problem among the various crystal forms of Baloxavir marboxil reported in existing literature, resulting in poor efficacy and low bioavailability.

[0022] This application addresses the issue of altering the preparation method of Baloxavir marboxil to obtain a co-crystal form of Baloxavir marboxil and vitamin C. This co-crystal form of vitamin C possesses both stability and high solubility, which avoids the risk of crystal transformation and facilitates drug absorption, thereby improving bioavailability.

[0023] XRPD, or X-ray powder diffraction, was used to acquire the X-ray powder diffraction pattern in this application using a Bruker D2 PHASER X-ray powder diffractometer. The X-ray powder diffraction method parameters are as follows: X-ray source: Cu Ka; Ka1 (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kV; current: 10 mA; scanning range: 3.0-40.0°.

[0024] DSC, or Differential Scanning Calorimetry, was used to acquire the differential scanning calorimetry (DSC) images in this application on a TA DSC X3. The method parameters for differential scanning calorimetry (DSC) are as follows: scan rate: 10 ℃ / min; protective gas: nitrogen.

[0025] TGA, or thermogravimetric analysis, was used to acquire the TGA images in this application on a TA TGA55 thermogravimetric analyzer. The TGA method parameters were as follows: scan rate: 10 °C / min; protective gas: nitrogen.

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

[0027] The "stirring" described in the following embodiments is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm. Magnetic stirring is preferably performed at 300-900 rpm, and mechanical stirring is preferably performed at 100-300 rpm.

[0028] The "separation" described in the following examples was accomplished using conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation was as follows: the sample to be separated was placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all the solids settled to the bottom of the centrifuge tube.

[0029] The "drying" described in the following examples can be carried out at room temperature or higher. The drying temperature is from room temperature to approximately 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. The drying is carried out in a fume hood, a forced-air oven, or a vacuum oven.

[0030] In the following embodiments, "crystal" refers to a solid confirmed by X-ray powder diffraction (XPD) characterization. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, but experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray powder diffraction patterns typically vary with different instrument conditions. It should be particularly noted that the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions; therefore, the order of diffraction peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystal. The diffraction peak intensities shown in this invention are illustrative and not for absolute comparison. Furthermore, experimental errors in diffraction peak positions are typically 5% or less, and these positional errors should also be taken into account, generally allowing for ±0.2%. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in diffraction peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention need not be completely identical to the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern with the same or similar characteristic peaks as those in these patterns is within the scope of the present invention.

[0031] Those skilled in the art can compare the X-ray powder diffraction pattern listed in this invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0032] The Baloxavir marboxil co-crystal of the present invention is pure and substantially free of any other crystalline forms. In this invention, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more specifically less than 5% (by weight) of other crystalline forms, and even more specifically less than 1% (by weight) of other crystalline forms.

[0033] In this invention, the term "about" when used to refer to a measurable value, such as mass, time, temperature, etc., means that it can fluctuate within a certain range around a specific value, which can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%.

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

[0035] The preparation method of the Baloxavir marboxil and vitamin C co-crystal form in this application is as follows: 1000 mg of Baloxavir marboxil and ~308.1 mg of vitamin C are weighed and added to a 40 ml vial, followed by the addition of 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 vitamin C co-crystal form.

[0036] In this application, the different crystallization times during the preparation of the Baloxavir marboxil and vitamin C co-crystal form also affect 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 ~308.1 mg of Vitamin C were weighed and added to a 40 ml vial. Solvent was then added (see Table 1 for details) to obtain a suspension. The suspension was stirred at room temperature for 48 h. The solids were separated by centrifugation and dried. XRPD analysis showed that the obtained solids were all of the eutectic form DCVI shown in this invention. The XRPD diagram is shown below. Figure 1 As shown in Table 2, the XRPD data is illustrated in the DSC plot. Figure 2 As shown.

[0039] Table 1

[0040] serial number Sample mass (mg) Citric acid mass (mg) solvent Solvent volume (ml) XRPD Sample 1 1000 308.1 acetic acid 5 Eutectic DCVI Sample 2 1000 308.1 tert-Butanol 5 Eutectic DCVI Sample 3 1000 308.1 dichloromethane 5 Eutectic DCVI

[0041] Table 2

[0042] Diffraction angle 2θ d value relative strength Diffraction angle 2θ d value relative strength Diffraction angle 2θ d value relative strength 8.66 10.20 62.30% 19.29 4.60 12.80% 25.62 3.47 10.60% 10.39 8.51 17.10% 19.75 4.49 37.00% 26.39 3.38 30.40% 10.69 8.27 16.10% 20.14 4.40 20.50% 26.73 3.33 13.10% 13.09 6.76 10.00% 20.76 4.28 8.10% 27.13 3.28 6.30% 13.82 6.40 4.00% 20.95 4.24 9.20% 27.96 3.19 100.00% 14.23 6.22 37.70% 21.60 4.11 16.70% 28.20 3.16 12.10% 15.70 5.64 21.50% 21.90 4.05 24.90% 29.66 3.01 24.40% 16.12 5.50 27.40% 22.21 4.00 21.20% 29.94 2.98 53.50% 16.34 5.42 12.40% 23.42 3.80 3.20% 31.34 2.85 5.70% 17.39 5.10 37.80% 23.81 3.73 9.60% 25.22 3.53 27.80% 18.55 4.78 19.70% 24.06 3.70 36.70% 18.85 4.71 15.60% 25.22 3.53 27.80%

[0043] from Figure 2 As can be seen from the above, the eutectic crystal form of Baloxavir marboxil and vitamin C prepared in Example 1 has an endothermic peak around 176°C.

[0044] MRI scan Figure 3 As shown, the specific data is 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), 5.42 (dd, J =14.6, 1.9 Hz, 1H), 4.71 (d, J = 1.4 Hz, 1H), 4.47-4.37 (m, 2H), 4.08-3.98 (m,2H), 3.77-3.67 (m, 4H), 3.47-3.40 (m, 2H), 3.27 (dd, J = 11.5, 2.5 Hz, 1H),2.99-2.91 (m, 1H).

[0045] Example 2: Biological solubility of the present application's crystalline form DCVI

[0046] When conducting drug solubility tests to predict drug performance in vivo, it is important to simulate in vivo conditions as closely as possible. For oral medications, SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under eating conditions) can simulate in vivo conditions and predict the effects of eating. Solubility tested in these media is closer to solubility in the human body environment.

[0047] To compare the solubility of crystal form I in biological media in the original patent WO2018030463 and the crystal form DCVI of this application, experiments were conducted with reference to the USP method for determining the solubility of biological media. Experimental method: Approximately 25 mg of the crystal form DCVI prepared in Example 1 was weighed and added to 1 mL of pre-prepared SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under feeding conditions), respectively. The mixture was stirred at a constant temperature of 37 ℃ ± 1℃, and samples were taken at 1 hour and 2 hours. The supernatant was used to determine its content by HPLC. The same experimental sampling procedure was performed for crystal form I in patent WO2018030463. The experimental conditions and results are shown in Table 3.

[0048] Table 3

[0049]

[0050] Solubility experiments in biological solvents showed that, compared to crystal form I in patent WO2018030463, the crystal form DCVI of this invention exhibits higher solubility in SGF (simulated gastric juice), FeSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under feeding conditions). Within 4 hours, the solubility of crystal form DCVI of this invention is 1.5 to 2 times that of crystal form I reported in prior art WO2018030463. Higher solubility is beneficial for improving drug absorption in the human body, increasing drug bioavailability, and achieving better therapeutic effects with a smaller drug load. Furthermore, reducing the drug load while ensuring drug efficacy can reduce drug toxicity and side effects, improve drug safety, and has significant clinical implications.

[0051] Example 3 Mechanical stability of the DCVI crystal form of this application

[0052] Ten milligrams of the crystalline DCVI prepared in Example 1 were 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 below. Figure 4 As shown.

[0053] according to Figure 3 It is evident that the crystal form of DCVI remains unchanged after grinding, and no significant decrease in crystallinity was observed, indicating that DCVI possesses good mechanical stability. This good mechanical stability ensures that the sample will not easily undergo crystal transformation due to external forces such as mechanical grinding or pulverization during subsequent formulation processes, reducing the risk of crystal transformation during formulation and improving the developability of the formulation process.

[0054] Example 4 Packaging stability of the DCVI crystal form of this application

[0055] Approximately 5 mg of the crystalline DCVI prepared in Example 1 was weighed and placed under ambient temperature (25 °C / 60%RH) and accelerated conditions (40 °C / 75%RH and 60 °C / 75%RH), respectively. The crystal form was determined using XRPD. The experimental conditions and results are shown in Table 4, and the XRPD overlay images are shown below. Figure 5 As shown.

[0056] Table 4

[0057] Placement conditions Placement time Crystal form Purity (peak area %) Start —— Crystal form DCVI 99.65 25 ℃ / 60%RH 8 weeks Crystal form DCVI 99.64 40 ℃ / 75%RH 8 weeks Crystal form DCVI 99.68 60 ℃ / 75%RH 4 weeks Crystal form DCVI 99.57

[0058] The results showed that the crystalline form of DCVI of this invention remained unchanged after being placed under three conditions: 25 ℃ / 60%RH, 40 ℃ / 75%RH, and 60 ℃ / 75%RH, for 4 to 8 weeks, indicating that crystalline DCVI has good physical stability. In particular, under the accelerated condition of 60 ℃ / 75%RH, it remained stable after 4 weeks without crystal transformation, further demonstrating that crystalline DCVI still has good physical stability even under high temperature and high humidity conditions. This ensures that the drug is not prone to crystal transformation during subsequent processes, production, and transportation. Furthermore, the chemical purity of crystalline DCVI did not change before and after being placed under 40 ℃ / 75%RH (relative humidity), remaining above 99%, indicating good chemical stability. Moreover, even under the accelerated condition of 60 ℃ / 75%RH, the chemical purity did not decrease significantly, further demonstrating the good chemical stability of crystalline DCVI. Good physicochemical stability ensures that the quality of the drug remains stable during subsequent formulation development, manufacturing processes, and transportation, thus guaranteeing drug quality and efficacy, which is of great significance.

[0059] Example 5: Hygroscopicity of the DCVI crystal form of this application

[0060] The hygroscopicity of drugs was determined according to the guidelines for hygroscopicity testing of drugs in General Chapter 9103 of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were 25 ± 1 ℃ and 80% relative humidity.

[0061] Definition of hygroscopic weight gain: Extremely hygroscopic: hygroscopic weight gain of not less than 15.0%; Hygroscopic: hygroscopic weight gain of less than 15.0% but not less than 2.0%; Slightly hygroscopic: hygroscopic weight gain of less than 2.0% but not less than 0.2%; No or almost no hygroscopicity: hygroscopic weight gain of less than 0.2%.

[0062] Approximately 20 mg of the crystalline DCVI prepared in Example 1 of this application was weighed and placed at 25 ± 1 °C and 80% relative humidity for 24 hours. The mass of the sample before and after the event was recorded, and the crystalline form was determined using XRPD. The specific results are shown in Table 5 below, and the XRPD overlay images are shown below. Figure 6 As shown.

[0063] Table 5

[0064] Starting mass (mg) Placement conditions Placement time Mass after storage (mg) Weight gain (mg) Percentage of weight gain 22.1 25 ± 1 ℃, 80%RH 24 hours 22.4 0.30 1.8%

[0065] As shown in Table 6, the crystalline DCVI of the present invention is slightly hygroscopic, which indicates that the crystalline DCVI is not prone to deliquescence during the production and storage of pharmaceuticals.

[0066] Crystal form stability is crucial for drug development. Crystal transformation directly impacts drug solubility and, consequently, bioavailability, thus altering efficacy. Good chemical stability ensures minimal formation or increase in impurity levels during storage, guaranteeing drug safety. Good humidity stability prevents crystal transformation during storage, transportation, and formulation, reducing the risk of transformation and enhancing product development potential. Low hygroscopicity ensures minimal weight gain and prevents deliquescence during production, processing, storage, and transportation, ensuring stable drug quality.

[0067] Therefore, the good physical stability and good humidity stability of the crystalline form DCVI, with slight hygroscopicity, provide a guarantee for the subsequent production and development of drugs, and have high industrialization development value.

[0068] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A eutectic form of Baloxavir marboxil and vitamin C, characterized in that, The X-ray powder diffraction patterns of the Baloxavir marboxil and vitamin C eutectic form DCVI under Cu-Ka radiation have diffraction angles of 2θ values ​​of 8.7±0.2°, 10.4±0.2°, 10.7±0.2°, 13.1±0.2°, 13.8±0.2°, 14.2±0.2°, 15.7±0.2°, 16.1±0.2°, 16.3±0.2°, 17.4±0.2°, 18.5±0.2°, 18.8±0.2°, 19.3±0.2°, and 19.8±0.2°. Characteristic peaks are present at 2°, 20.1±0.2°, 20.8±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 22.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.1±0.2°, 25.2±0.2°, 25.6±0.2°, 26.4±0.2°, 26.7±0.2°, 27.1±0.2°, 28.0±0.2°, 28.2±0.2°, 29.7±0.2°, 29.9±0.2°, and 31.3±0.2°.

2. A method for preparing a eutectic form of baloxavir marboxil and vitamin C, characterized in that, Baloxavir marboxil and vitamin C 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 the eutectic form of Baloxavir marboxil and vitamin C, DCVI.

3. The Baloxavir marboxil and vitamin C co-crystal form DCVI as described in claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of the eutectic crystal form DCVI of Baloxavir marboxil and vitamin C showed an endothermic peak at 176±3℃.

4. The method for preparing the eutectic form DCVI of Baloxavir marboxil and vitamin C as described in claim 2, characterized in that, The organic solvent is selected from any one of acetic acid, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, acetone, tetrahydrofuran, and acetonitrile.

5. The method for preparing the eutectic form DCVI of Baloxavir marboxil and vitamin C as described in claim 2, characterized in that, The crystallization temperature is 0-40℃.

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