Co-crystals of remdesivir and methods of making the same

Abstract

The present application provides a co-crystal of remdesivir and a preparation method thereof, and belongs to the field of medicinal chemistry. The XRPD pattern of the crystal form I contains the following characteristic peaks: diffraction peaks at positions of 5.0, 7.6, 13.1, 14.3, 15.7, 17.2, 17.9, 19.0, 20.5, 22.6, 23.3, 27.5 and 28.6 degrees; the X-ray powder diffraction pattern of the crystal form A contains diffraction peaks at positions of 4.8, 8.9, 10.5, 14.3, 15.9, 16.9, 19.7, 21.4, 23.5, 24.5 and 26.3 degrees. The crystal forms have good stability, good solubility and low hygroscopicity, are beneficial to storage, transfer and operation in the production process, and are suitable for preparation into preparations.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to the cocrystal of remdesivir and its preparation method. Background Technology

[0002] Remdesivir (CAS: 1809249-37-3) is a nucleoside analog developed by Gilead Sciences with antiviral activity. On October 22, 2020, the U.S. Food and Drug Administration (FDA) approved Remdesivir for the treatment of hospitalized COVID-19 patients.

[0003] The structure of Remdesivir is shown in equation (1) below:

[0004]

[0005] Gilead Sciences disclosed four crystal forms (crystal forms I, II, III, and IV) and three mixtures (all mixtures of crystal forms II and IV) of the free base of remdesivir in patent CN110636884A, as well as a maleate crystal form I. Apart from these, no other crystal forms of remdesivir have been disclosed.

[0006] Of the free bases of remdesivir, crystal form II is relatively more stable. However, the preparation of crystal form II often results in a mixture of crystal forms II and IV, affecting the determination of drug dosage in the formulation. Furthermore, the solubility of all crystal forms of the free base is low, leading to poor drug absorption efficiency and low bioavailability. To obtain an effective crystal form that is beneficial for production or drug formulation, a comprehensive investigation of the drug's crystallization behavior is necessary to obtain a crystal form that meets production requirements.

[0007] The remdesivir cocrystal developed in this invention effectively solves the solubility problem of free alkali crystals, which is of great significance for improving efficacy and reducing drug loading. Summary of the Invention

[0008] This invention aims to at least partially solve one of the technical problems in the related art. Therefore, one object of this invention is to provide a eutectic form of remdesivir and a method for preparing the same, the crystalline form exhibiting good stability, solubility, and low hygroscopicity.

[0009] According to one aspect of the present invention, the present invention provides cocrystals of remdesivir and nitrobenzoic acid compounds, including cocrystals of remdesivir and m-nitrobenzoic acid: crystal form I, crystal form II; and cocrystals of remdesivir and 3,5-dinitrobenzoic acid: crystal form A, crystal form B.

[0010] The eutectic of remdesivir and m-nitrobenzoic acid is in crystal form I or crystal form II, comprising remdesivir and m-nitrobenzoic acid; the eutectic is a eutectic comprising remdesivir and m-nitrobenzoic acid in a stoichiometric ratio of 1:1.

[0011] The cocrystal of remdesivir and 3,5-dinitrobenzic acid, in crystal form A or crystal form B, comprises remdesivir and 3,5-dinitrobenzic acid, wherein the cocrystal comprises remdesivir and 3,5-dinitrobenzic acid in a stoichiometric ratio of 1:1.

[0012] Studies of the eutectic provided by this invention have revealed that crystal forms I, II, A, and B exhibit good properties in terms of stability, solubility, and hygroscopicity, and can be used in the production of pharmaceutical formulations.

[0013] The eutectic form I of remdesivir and m-nitrobenzoic acid, when analyzed by Cu-Kα radiation X-ray powder diffraction, exhibits diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles in its X-ray powder diffraction pattern: 5.0, 7.6, 13.1, 14.3, 15.7, 17.2, 17.9, 19.0, 20.5, 22.6, 23.3, 27.5, and 28.6.

[0014] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.7, 10.3, 13.6, 14.9, 16.2, 17.4, 18.6, 19.8, 21.1, 23.0, 24.4 and 28.2.

[0015] In some embodiments, the crystal form I, when used with a Cu-Kα irradiated X-ray powder diffractometer, has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles in its X-ray powder diffraction pattern: 5.0, 5.7, 7.6, 10.3, 13.1, 13.6, 14.3, and 14.9.

[0016] In some embodiments, using a Cu-Kα irradiated X-ray powder diffractometer, the X-ray powder diffraction pattern of crystal form I has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.0, 5.7, 7.6, 10.3, 13.1, 13.6, 14.3, 14.9, 15.7, 16.2, 17.2, 17.4, 17.9, 18.6, 19.0, and 19.8.

[0017] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form I has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.0, 5.7, 7.6, 10.3, 13.1, 13.6, 14.3, 14.9, 15.7, 16.2, 17.2, 17.4, 17.9, 18.6, 19.0, 19.8, 20.5, 21.1, 22.6, 23.0, 23.3, 24.4, 27.5, 28.2, and 28.6.

[0018] In some embodiments, the relative intensity of the peak at 2θ = 17.2 degrees in the X-ray powder diffraction pattern of the eutectic form I of remdesivir and m-nitrobenzoic acid is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

[0019] In some embodiments, the eutectic form I of remdesivir and m-nitrobenzoic acid has substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern (XRPD pattern) shown is shown.

[0020] In some embodiments, the differential scanning calorimetry (DSC) curves of remdesivir and m-nitrobenzoic acid eutectic form I have endothermic peaks at 91°C-101°C and 102°C-112°C, with peak temperatures of the endothermic peaks at 94°C-98°C and 105°C-109°C.

[0021] In some embodiments, crystal form I has substantially as follows Figure 2 The differential scanning calorimetry (DSC) curve is shown.

[0022] In some embodiments, the thermogravimetric analysis (TGA) curve of crystal form I shows weight loss between 30°C and 150°C, with a weight loss of approximately 0.5%.

[0023] In some embodiments, crystal form I has substantially as follows Figure 3 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0024] In some embodiments, relative to the eutectic of remdesivir and m-nitrobenzoic acid, the content of crystal form I is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, the content of crystal form I is at least 85%, or at least 90%, or at least 95%, or at least 99%, relative to the eutectic of remdesivir and m-nitrobenzoic acid.

[0025] The eutectic form II of remdesivir and m-nitrobenzoic acid, when analyzed by Cu-Kα radiation X-ray powder diffraction, exhibits diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 4.8, 9.3, 12.3, 14.4, 15.7, 16.4, 18.2, 20.5, 21.5, 23.9, 25.5, 27.2, and 28.0.

[0026] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form II has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.2, 10.1, 13.6, 15.0, 15.9, 16.9, 20.2, 20.7, 23.4, 24.6, 26.7, 27.3, and 28.3.

[0027] In some embodiments, the crystal form II, when used with a Cu-Kα irradiated X-ray powder diffractometer, has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles in its X-ray powder diffraction pattern: 4.8, 5.2, 9.3, 10.1, 12.3, 13.6, 14.4, and 15.0.

[0028] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form II has diffraction peaks at the following 2θ angles (unit: degrees, error ±0.2 degrees): 4.8, 5.2, 9.3, 10.1, 12.3, 13.6, 14.4, 15.0, 15.7, 15.9, 16.4, 16.9, and 18.2.

[0029] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form II has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 4.8, 5.2, 9.3, 10.1, 12.3, 13.6, 14.4, 15.0, 15.7, 15.9, 16.4, 16.9, 18.2, 20.2, 20.5, 20.7, 21.5, 23.4, 23.9, 24.6, 25.5, 26.7, 27.2, 27.3, 28.0, and 28.3.

[0030] In some embodiments, the relative intensity of the peak at 2θ of 5.2 degrees in the X-ray powder diffraction pattern of the eutectic form II of remdesivir and m-nitrobenzoic acid is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

[0031] In some embodiments, the eutectic form II of remdesivir and m-nitrobenzoic acid has substantially the following characteristics: Figure 4 The X-ray powder diffraction pattern (XRPD pattern) shown is shown.

[0032] In some embodiments, relative to the eutectic of remdesivir and m-nitrobenzoic acid, the content of crystal form II is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, the content of crystal form II is at least 85%, or at least 90%, or at least 95%, or at least 99%, relative to the eutectic of remdesivir and m-nitrobenzoic acid.

[0033] The eutectic form A of remdesivir and 3,5-dinitrobenzic acid, as observed by X-ray powder diffraction using Cu-Kα radiation, exhibits diffraction peaks at the following 2θ (degrees, error ±0.2 degrees) angles: 4.8, 8.9, 10.5, 14.3, 15.9, 16.9, 19.7, 21.4, 23.5, 24.5, and 26.3.

[0034] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form A has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 6.5, 10.1, 13.0, 15.0, 16.4, 19.2, 21.2, 23.0, 24.1, 25.7 and 27.6.

[0035] In some embodiments, crystal form A, when used with a Cu-Kα irradiated X-ray powder diffractometer, has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles in its X-ray powder diffraction pattern: 4.8, 6.5, 8.9, 10.1, 10.5, 13.0, 14.3, and 15.0.

[0036] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form A has diffraction peaks at the following 2θ angles (unit: degrees, error ±0.2 degrees): 4.8, 6.5, 8.9, 10.1, 10.5, 13.0, 14.3, 15.0, 15.9, 16.4, 16.9, 19.2, and 19.7.

[0037] In some embodiments, using a Cu-Kα irradiated X-ray powder diffractometer, the X-ray powder diffraction pattern of crystal form A has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 4.8, 6.5, 8.9, 10.1, 10.5, 13.0, 14.3, 15.0, 15.9, 16.4, 16.9, 19.2, 19.7, 21.2, 21.4, 23.0, 23.5, 24.1, 24.5, 25.7, 26.3, and 27.6.

[0038] In some embodiments, the relative intensity of the peak at 2θ of 4.8 degrees in the X-ray powder diffraction pattern of the eutectic form A of remdesivir and 3,5-dinitrobenzoic acid is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

[0039] In some embodiments, the eutectic form A of remdesivir and 3,5-dinitrobenzoic acid has substantially the same crystal structure as... Figure 5 The X-ray powder diffraction pattern (XRPD pattern) shown is shown.

[0040] In some embodiments, the differential scanning calorimetry (DSC) curve of the eutectic form A of remdesivir and 3,5-dinitrobenzoic acid has an endothermic peak at 102°C-112°C, and the peak temperature of the endothermic peak is at 105°C-109°C.

[0041] In some embodiments, crystal form A has substantially as follows Figure 6 The differential scanning calorimetry (DSC) curve is shown.

[0042] In some embodiments, the thermogravimetric analysis (TGA) curve of crystal form A shows weight loss between 30°C and 170°C, with a weight loss of approximately 2.7%.

[0043] In some embodiments, crystal form A has substantially as follows Figure 7 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0044] In some embodiments, relative to the eutectic of remdesivir and 3,5-dinitrobenzic acid, the content of crystal form A is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, relative to the eutectic of remdesivir and 3,5-dinitrobenzic acid, the content of crystal form A is at least 85%, or at least 90%, or at least 95%, or at least 99%.

[0045] The eutectic form B of remdesivir and 3,5-dinitrobenzic acid, as observed by X-ray powder diffraction using Cu-Kα radiation, exhibits diffraction peaks at the following 2θ (degrees, error ±0.2 degrees) angles: 7.3, 10.8, 13.6, 14.8, 16.1, 17.5, 19.3, 22.3, 24.1, 25.0, and 26.4.

[0046] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form B has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.4, 8.2, 12.1, 14.4, 15.6, 16.5, 18.4, 21.9, 23.7, 24.5, 25.6 and 30.9.

[0047] In some embodiments, crystal form B, when used with a Cu-Kα irradiated X-ray powder diffractometer, has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles in its X-ray powder diffraction pattern: 5.4, 7.3, 8.2, 10.8, 12.1, 13.6, 14.4, and 14.8.

[0048] In some embodiments, using an X-ray powder diffractometer with Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form B has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.4, 7.3, 8.2, 10.8, 12.1, 13.6, 14.4, 14.8, 15.6, 16.1, 16.5, 17.5, 18.4, and 19.3.

[0049] In some embodiments, using a Cu-Kα irradiated X-ray powder diffractometer, the X-ray powder diffraction pattern of crystal form B has diffraction peaks at the following 2θ (unit: degrees, error ±0.2 degrees) angles: 5.4, 7.3, 8.2, 10.8, 12.1, 13.6, 14.4, 14.8, 15.6, 16.1, 16.5, 17.5, 18.4, 19.3, 21.9, 22.3, 23.7, 24.1, 24.5, 25.0, 25.6, 26.4, and 30.9.

[0050] In some embodiments, the relative intensity of the peak at 2θ of 5.4 degrees in the X-ray powder diffraction pattern of the eutectic form B of remdesivir and 3,5-dinitrobenzoic acid is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

[0051] In some embodiments, the eutectic form B of remdesivir and 3,5-dinitrobenzoic acid has substantially the same crystal structure as... Figure 8The X-ray powder diffraction pattern (XRPD pattern) shown is shown.

[0052] In some embodiments, the differential scanning calorimetry (DSC) curve of the eutectic form B of remdesivir and 3,5-dinitrobenzoic acid has endothermic peaks at 65°C-75°C and 112°C-122°C, with peak temperatures of the endothermic peaks at 68°C-72°C and 115°C-119°C.

[0053] In some embodiments, crystal form B has substantially the following characteristics: Figure 9 The differential scanning calorimetry (DSC) curve is shown.

[0054] In some embodiments, the thermogravimetric analysis (TGA) curve of crystal form B shows weight loss between 30°C and 170°C, with a weight loss of approximately 0.9%.

[0055] In some embodiments, crystal form B has substantially the following characteristics: Figure 10 The thermogravimetric analysis curve (TGA spectrum) is shown.

[0056] In some embodiments, relative to the eutectic of remdesivir and 3,5-dinitrobenzic acid, the content of crystal form B is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, relative to the eutectic of remdesivir and 3,5-dinitrobenzic acid, the content of crystal form B is at least 85%, or at least 90%, or at least 95%, or at least 99%.

[0057] The crystal form I, crystal form II, crystal form A and crystal form B described in this invention can be used to treat viral infection-related diseases such as COVID-19.

[0058] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a cocrystal of remdesivir and a pharmaceutically acceptable excipient or formulation. Generally, a pharmaceutical composition or formulation is prepared by mixing or contacting any one or more of the aforementioned crystal forms I, II, A, and B with one or more pharmaceutical excipients, in a manner well known in the pharmaceutical industry. The pharmaceutical composition or formulation can be used to treat viral infection-related diseases such as COVID-19.

[0059] This invention provides a pharmaceutical composition that may contain at least 0.1%-10% by weight of any one or more of the following crystal forms: crystal form I, crystal form II, crystal form A, and crystal form B. This invention also provides a pharmaceutical composition that may contain at least 0.1%-5% by weight of any one or more of the following crystal forms: crystal form I, crystal form II, crystal form A, and crystal form B. Furthermore, this invention provides a pharmaceutical composition that may contain at least 0.1%-1% by weight of any one or more of the following crystal forms: crystal form I, crystal form II, crystal form A, and crystal form B. In some embodiments, this invention provides a pharmaceutical composition that contains at least 0.1%-0.5% by weight of any one or more of the following crystal forms: crystal form I, crystal form II, crystal form A, and crystal form B.

[0060] This invention provides a pharmaceutical composition containing a cocrystal of remdesivir, wherein at least 80% of the remdesivir cocrystal is any one or more of crystal form I, crystal form II, crystal form A, and crystal form B, by mass ratio. In some embodiments, a pharmaceutical composition containing a cocrystal of remdesivir, wherein at least 90% of the remdesivir cocrystal is any one or more of crystal form I, crystal form II, crystal form A, and crystal form B, by mass ratio. In some embodiments, a pharmaceutical composition containing a cocrystal of remdesivir, wherein at least 95% of the remdesivir cocrystal is any one or more of crystal form I, crystal form II, crystal form A, and crystal form B, by mass ratio. In some embodiments, a pharmaceutical composition containing a cocrystal of remdesivir, wherein at least 99% of the remdesivir cocrystal is any one or more of crystal form I, crystal form II, crystal form A, and crystal form B, by mass ratio.

[0061] In some embodiments, relative to the cocrystal of remdesivir, the pharmaceutical composition contains at least 80% crystal form I. In some embodiments, relative to the cocrystal of remdesivir, the pharmaceutical composition contains at least 85%, or at least 90%, or at least 95%, or at least 99% crystal form I.

[0062] In some embodiments, relative to the cocrystal of remdesivir, the pharmaceutical composition contains at least 80% crystalline form II. In some embodiments, relative to the cocrystal of remdesivir, the pharmaceutical composition contains at least 85%, or at least 90%, or at least 95%, or at least 99% crystalline form II.

[0063] In some embodiments, relative to the cocrystal of remdesivir, the content of crystal form A in the pharmaceutical composition is at least 80%. In some embodiments, relative to the cocrystal of remdesivir, the content of crystal form A in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.

[0064] In some embodiments, the content of crystal form B in the pharmaceutical composition is at least 80% relative to the cocrystal of remdesivir. In some embodiments, the content of crystal form B in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99% relative to the cocrystal of remdesivir.

[0065] The pharmaceutical composition comprising any one or more of crystal form I, crystal form II, crystal form A, and crystal form B, as described in this invention, can be used to prepare pharmaceutical formulations related to viral infections such as COVID-19. The pharmaceutical composition comprising any one or more of crystal form I, crystal form II, crystal form A, and crystal form B, as described in this invention, can be used in methods for treating viral infection-related diseases such as COVID-19.

[0066] The crystal forms I, II, A, and B provided by this invention have better stability, and more stable crystal forms are of great significance for improving drug quality.

[0067] The crystal forms I, II, A, and B provided by this invention have good stability, solubility, and low hygroscopicity. They are not prone to deliquescence under high humidity conditions, which facilitates long-term storage of drugs. They can effectively prevent crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and efficacy, and have strong economic value.

[0068] According to a second aspect of the present invention, the present invention provides a method for preparing the aforementioned remdesivir eutectic.

[0069] A method for preparing the eutectic form I of remdesivir and m-nitrobenzoic acid includes: mixing remdesivir with a good solvent, adding m-nitrobenzoic acid to react, evaporating the solvent at a certain temperature, adding a poor solvent, pulping at a pulping temperature, filtering, and drying to obtain crystal form I.

[0070] The good solvent is selected from any one of alcohols and ketones.

[0071] In some embodiments, the good solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, and n-butanone. In some embodiments, the good solvent is selected from methanol or acetone.

[0072] In some embodiments, when the mass of remdesivir is measured in grams (g) and the volume of the undesirable solvent is measured in milliliters (mL), the mass-to-volume ratio of remdesivir to the good solvent is 1:5 to 1:40.

[0073] The undesirable solvent is selected from one of the ethers.

[0074] In some embodiments, the undesirable solvent is selected from at least one of diethyl ether, propyl ether, and isopropyl ether. In some embodiments, the undesirable solvent is isopropyl ether.

[0075] The specified temperature is 20℃-80℃.

[0076] In some embodiments, when the mass of remdesivir is measured in milligrams (mg) and the volume of the undesirable solvent is measured in milliliters (mL), the mass-to-volume ratio of remdesivir to the undesirable solvent is 1:10 to 1:200.

[0077] The pulping temperature is 25℃-40℃.

[0078] A method for preparing the eutectic form I of remdesivir and m-nitrobenzoic acid includes: mixing remdesivir and m-nitrobenzoic acid, adding an alkane solvent, suspending, pulping at a certain temperature, filtering, and drying to obtain crystal form I.

[0079] In some embodiments, the alkane solvent is selected from at least one of n-hexane, cyclohexane, and n-heptane. In some embodiments, the alkane solvent is n-heptane.

[0080] In the aforementioned method, the molar ratio of remdesivir to m-nitrobenzoic acid can be 1:1 to 1:3.

[0081] In some embodiments, when the mass of remdesivir is calculated in milligrams (mg) and the volume of the alkane solvent is calculated in milliliters (mL), the mass-to-volume ratio of remdesivir to the alkane solvent is 1:10 to 1:200.

[0082] The specified temperature is 25℃~40℃.

[0083] The pulping time is 24h to 72h.

[0084] A method for preparing a eutectic form II of remdesivir and m-nitrobenzoic acid includes: mixing the eutectic form I with an aqueous solvent, suspending it at a certain temperature, filtering, and drying to obtain eutectic form II.

[0085] The aqueous solvent is selected from water and hydrochloric acid buffer solution with pH 1.2.

[0086] In some embodiments, the aqueous solvent is water.

[0087] The specified temperature is 20℃ to 80℃. In some embodiments, the specified temperature is 25℃ to 40℃.

[0088] The suspension time is 12h to 36h.

[0089] A method for preparing a eutectic form A of remdesivir and 3,5-dinitrobenzoic acid includes: mixing remdesivir with a good solvent, adding 3,5-dinitrobenzoic acid to react, evaporating the solvent at a certain temperature, adding a poor solvent, pulping at a pulping temperature, filtering, and drying to obtain crystalline form A. The good solvent is selected from at least one of alcohols and ketones. In some embodiments, the good solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, and n-butanone. In some embodiments, the good solvent is selected from methanol or acetone. The poor solvent is selected from at least one of ethers. In some embodiments, the poor solvent is selected from at least one of diethyl ether, propyl ether, and isopropyl ether. In some embodiments, the poor solvent is isopropyl ether.

[0090] In the aforementioned method, the molar ratio of remdesivir to 3,5-dinitrobenzoic acid can be 1:1 to 1:3.

[0091] The specified temperature is 20℃-80℃.

[0092] In some embodiments, when the mass of remdesivir is measured in milligrams (mg) and the volume of the undesirable solvent is measured in milliliters (mL), the mass-to-volume ratio of remdesivir to the undesirable solvent is 1:10 to 1:200.

[0093] The pulping temperature is 25℃-40℃.

[0094] A method for preparing a eutectic form B of remdesivir and 3,5-dinitrobenzoic acid includes: mixing the eutectic form A with a solvent, suspending it at a certain temperature, filtering, and drying to obtain eutectic form B. The solvent is selected from water and a hydrochloric acid buffer solution with pH 1.2.

[0095] In some embodiments, the solvent is water.

[0096] The specified temperature is 20℃ to 80℃. In some embodiments, the specified temperature is 25℃ to 40℃.

[0097] The suspension time is 12h to 36h.

[0098] The "crystal form" described in this invention can exist in a sample at concentrations ranging from 0.0001% to 100%. Therefore, any sample containing even trace amounts of the "crystal form" described in this invention, such as greater than 0.0001%, 0.001%, 0.001%, or 0.01%, should be understood as falling within the scope of protection of this invention. To describe the various parameters of the "crystal form" described in this invention more clearly, this invention characterizes and identifies the crystal form by testing various parameters on samples containing a substantially pure "crystal form."

[0099] In the context of this invention, all figures disclosed herein are approximate values, regardless of whether the words "approximately" or "about" are used. Based on the disclosed figures, the value of each figure may vary by 1%, 2%, or 5%, etc.

[0100] Differential scanning calorimetry (DSC) of the crystal form is subject to experimental error and is slightly affected by the degree of sample dryness. The position and peak value of the endothermic peak may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute.

[0101] In this invention, when calculating the mass-to-volume ratio, the mass unit is milligram and the volume unit is milliliter.

[0102] In this invention, "RH" refers to relative humidity.

[0103] In this invention, the room temperature is in the range of 20℃-40℃. Attached Figure Description

[0104] Figure 1 X-ray powder diffraction (XRPD) pattern of the eutectic form I of remdesivir and m-nitrobenzoic acid;

[0105] Figure 2 Differential scanning calorimetry (DSC) curves of the eutectic form I of remdesivir and m-nitrobenzoic acid;

[0106] Figure 3 Thermogravimetric analysis (TGA) curves of the eutectic form I of remdesivir and m-nitrobenzoic acid;

[0107] Figure 4 X-ray powder diffraction (XRPD) pattern of the eutectic form II of remdesivir and m-nitrobenzoic acid;

[0108] Figure 5 X-ray powder diffraction (XRPD) pattern of the eutectic form A of remdesivir and 3,5-dinitrobenzoic acid;

[0109] Figure 6 Differential scanning calorimetry (DSC) curves of the eutectic form A of remdesivir and 3,5-dinitrobenzoic acid;

[0110] Figure 7 Thermogravimetric analysis (TGA) curves of the eutectic form A of remdesivir and 3,5-dinitrobenzoic acid;

[0111] Figure 8X-ray powder diffraction (XRPD) pattern of the eutectic form B of remdesivir and 3,5-dinitrobenzoic acid;

[0112] Figure 9 Differential scanning calorimetry (DSC) curves of the eutectic form B of remdesivir and 3,5-dinitrobenzoic acid;

[0113] Figure 10 Thermogravimetric analysis (TGA) curves of the eutectic form B of remdesivir and 3,5-dinitrobenzoic acid;

[0114] Figure 11 Results of 15-day influencing factors on the co-crystal form I of remdesivir and m-nitrobenzoic acid;

[0115] Figure 12 Results of 15-day influencing factors on the co-crystal form A of remdesivir and 3,5-dinitrobenzoic acid;

[0116] Figure 13 Isothermal adsorption equilibrium (DVS) curve of maleate crystal form I in CN110636884A;

[0117] Figure 14 Isothermal adsorption equilibrium (DVS) curves of remdesivir and m-nitrobenzoic acid eutectic form I;

[0118] Figure 15 Isothermal adsorption equilibrium (DVS) curve of eutectic form A of remdesivir and 3,5-dinitrobenzoic acid. Detailed Implementation

[0119] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0120] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0121] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0122] Example 1: Preparation method of eutectic form I of remdesivir and m-nitrobenzoic acid

[0123] 300 mg of remdesivir and 99 mg of m-nitrobenzoic acid were added to a 25 mL round-bottom flask, followed by 15 mL of n-heptane solvent. The mixture was suspended and stirred at room temperature for 48 hours. After filtration and drying, approximately 355 mg of a white solid product was obtained. The obtained crystals were confirmed by XPRD analysis to be a eutectic of remdesivir and m-nitrobenzoic acid, crystal form I. Its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, TGA spectrum and Figure 3 Basically the same.

[0124] Detection of the obtained crystal form I: 1 H NMR(CD3OD)δ8.63(s,1H),8.47(d,J=9.6Hz,1H),8.36(d,J=7.7Hz,1H),7.92(s,1H),7.82(t,J=8.0Hz,1H), 7.35(t,J=7.8Hz,2H),7.25–7.11(m,3H),6.90(d,J=4.5Hz,1H),6.83(d,J=4.5Hz,1H),6.33(d,J=5.7Hz,1H) ,6.03(dd,J=12.9,10.1Hz,1H),5.38(s,1H),4.65(s,1H),4.31–4.18(m,2H),4.15–4.04(m,1H),3.96(dd,J= 10.8,5.8Hz,2H),3.90–3.77(m,2H),1.42(dt,J=12.3,6.1Hz,1H),1.31–1.17(m,7H),0.80(t,J=7.4Hz,6H).

[0125] Example 2: Preparation method of eutectic form I of remdesivir and m-nitrobenzoic acid

[0126] 30.0 mg of remdesivir was dissolved in 0.5 mL of acetone, and 9.4 mg of m-nitrobenzoic acid was added. The mixture was reacted at 50 °C for 12 hours. The solvent was then slowly evaporated at room temperature, and 2 mL of isopropyl ether was added. The mixture was stirred until a solid precipitated. The solution was filtered and dried to obtain a white solid product, approximately 25 mg, which was identified as a eutectic of remdesivir and m-nitrobenzoic acid, crystal form I. Its X-ray powder diffraction pattern was consistent with... Figure 1 Basically the same, its DSC spectrum is the same as Figure 2 Basically the same, TGA spectrum and Figure 3 Basically the same.

[0127] Example 3: Preparation method of eutectic form II of remdesivir and m-nitrobenzoic acid

[0128] 20.0 mg of remdesivir in m-nitrobenzoic acid cocrystal form I was suspended in 1 mL of pure water and stirred at 37 °C for 24 h. After filtration and drying, approximately 14 mg of a white solid product was obtained. The solid product was tested using XPRD. The obtained crystals were confirmed by XPRD analysis to be a cocrystal of remdesivir and m-nitrobenzoic acid, crystal form II; its X-ray powder diffraction pattern was consistent with... Figure 4 Basically the same.

[0129] Detection of the obtained crystal form II: 1 H NMR(CD3OD)δ8.62(s,1H),8.47(dd,J=8.2,1.4Hz,1H),8.35(d,J=7.7Hz,1H),7.92(s,1H),7.81(t,J=8.0Hz,1 H),7.34(t,J=7.8Hz,2H),7.24–7.13(m,3H),6.89(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),6.33(d,J=5.0Hz,1 H),6.03(dd,J=12.9,10.2Hz,1H),5.38(s,1H),4.64(s,1H),4.31–4.19(m,2H),4.14–4.02(m,1H),3.95(dd,J =10.8,5.8Hz,2H),3.90–3.77(m,2H),1.41(dt,J=12.3,6.2Hz,1H),1.29–1.18(m,7H),0.79(t,J=7.4Hz,6H).

[0130] Example 4: Preparation method of eutectic form A of remdesivir and 3,5-dinitrobenzoic acid

[0131] 100 mg of remdesivir was dissolved in 2 mL of acetone, and 43 mg of 3,5-dinitrobenzoic acid was added. The mixture was reacted at 50 °C for 12 hours. The solvent was then slowly evaporated at room temperature, and 5 mL of isopropyl ether was added. The mixture was stirred until a solid precipitated. The solution was filtered and dried to obtain a white solid product of approximately 130 mg. The obtained solid product was tested using XPRD. The obtained crystals were confirmed by XPRD analysis to be a eutectic of remdesivir and 3,5-dinitrobenzoic acid, crystal form A. Its X-ray powder diffraction pattern was consistent with... Figure 5 Basically the same, its DSC spectrum is the same as Figure 6 Basically the same, TGA spectrum and Figure 7 Basically the same. Detection of the obtained crystal form A: 1H NMR(CD3OD)δ9.02(t,J=2.1Hz,1H),8.90(d,J=2.1Hz,2H),7.92(s,1H),7.34(t,J=7.9Hz,2H),7. 24–7.13(m,3H),6.90(d,J=4.5Hz,1H),6.83(d,J=4.5Hz,1H),6.33(s,1H),6.03(dd,J=12.9,10. 2Hz,1H),5.37(s,1H),4.64(s,1H),4.25(dd,J=10.0,6.1Hz,2H),4.14–4.03(m,1H),3.95(dd,J= 10.9,5.8Hz,2H),3.90–3.77(m,2H),1.47–1.35(m,1H),1.30–1.18(m,7H),0.79(t,J=7.4Hz,6H).

[0132] Example 5: Preparation method of co-crystal form B of remdesivir and 3,5-dinitrobenzoic acid

[0133] 20.0 mg of remdesivir and 3,5-dinitrobenzic acid cocrystal form A were suspended in 1 mL of pure water and stirred at 37 °C for 24 h. The mixture was filtered and dried to obtain a white solid product of approximately 15 mg. X-ray powder diffraction (XPRD) analysis confirmed that the solid product was a cocrystal of remdesivir and 3,5-dinitrobenzic acid, crystal form B. Its X-ray powder diffraction pattern was consistent with... Figure 8 Basically the same, its DSC spectrum is the same as Figure 9 Basically the same, TGA spectrum and Figure 10 Basically the same.

[0134] Detection of the obtained crystal form B: 1 H NMR(CD3OD)δ9.02(t,J=2.0Hz,1H),8.90(d,J=2.1Hz,2H),7.92(s,1H),7.34(t,J=7.8Hz,2H),7.17(t,J= 8.8Hz,3H),6.90(d,J=4.5Hz,1H),6.83(d,J=4.5Hz,1H),6.33(s,1H),6.03(dd,J=12.9,10.2Hz,1H),5.3 8(s,1H),4.64(s,1H),4.25(dd,J=10.0,6.0Hz,2H),4.14–4.03(m,1H),3.95(dd,J=10.9,5.8Hz,2H),3.8 4(ddd,J=13.1,10.5,4.3Hz,2H),1.41(dt,J=12.4,6.1Hz,1H),1.30–1.18(m,7H),0.79(t,J=7.4Hz,6H).

[0135] Example 6: Stability test of remdesivir eutectic

[0136] In accordance with the guidelines for drug formulation stability testing, influencing factor experiments were conducted on the cocrystal of remdesivir, including high temperature testing, high humidity testing, and strong light irradiation testing, to investigate the factors affecting its crystal stability. XPRD comparison charts are shown below. Figure 11 and Figure 12 As shown.

[0137] 1) High temperature test

[0138] An appropriate amount of remdesivir eutectic sample was placed flat in a weighing bottle and stored in a constant temperature and humidity chamber at 60℃±5℃ and RH 75±5%. The sample was then collected at 5, 10, and 15 days, and its crystal form was tested using X-ray powder diffraction (XRPD). The experimental results are shown in Table 1-2 below.

[0139] 2) High humidity test

[0140] An appropriate amount of remdesivir eutectic sample was placed flat in a weighing bottle and stored in a constant temperature and humidity chamber at 25℃ and RH 92.5±5%. The sample was then taken at 5, 10, and 15 days, and its crystal form was tested by X-ray powder diffraction (XRPD). The experimental results are shown in Table 1-2 below.

[0141] 3) Light test

[0142] An appropriate amount of remdesivir eutectic sample was spread evenly in a weighing bottle and placed in a constant temperature and humidity chamber (25℃, RH 60% ± 5%) under visible light conditions of 4500 Lux ± 500 Lux (VIS) and ultraviolet light conditions of 1.7 W*h / m2 (UV). The sample was then collected at 5, 10, and 15 days, and its crystal form was tested using X-ray powder diffraction (XRPD). The experimental results are shown in Tables 1-2 below.

[0143] Table 1. Stability Study of Remdesivir and m-nitrobenzoic Acid Cocrystal I Crystal Form I

[0144]

[0145] Table 2. Stability Study of Remdesivir and 3,5-dinitrobenzoic A Cocrystal Form A

[0146]

[0147] The above results show that the crystal forms of remdesivir co-crystal I with m-nitrobenzoic acid and remdesivir co-crystal A with 3,5-dinitrobenzoic acid did not change after being placed for 15 days under the three influencing factors of high temperature, high humidity and light, and have good stability.

[0148] Example 7: Solubility Experiment of Remdesivir Eutectic

[0149] The eutectic sample of remdesivir and the free base mixed crystals II and IV from patent CN110636884A were respectively prepared into saturated solutions with pure water at 37°C. After equilibration for 4 hours, the solutions were filtered through an aqueous filter membrane, and the filtrates were collected. The solubility was measured by high performance liquid chromatography (HPLC). Each batch of samples was measured twice in parallel, and the average value was taken. The solubility measurement results are shown in Table 4.

[0150] Table 4: Solubility data of remdesivir eutectic and free base

[0151] Eutectic form Solubility (mg / mL) Free alkali mixed crystals II+IV (control) 0.012 m-Nitrobenzoic acid eutectic crystal form I 0.167 3,5-Dinitrobenzic acid eutectic crystal form A 0.130 m-Nitrobenzoic acid eutectic crystal form II <0.05 3,5-Dinitrobenzic acid eutectic crystal form B <0.05

[0152] As shown in the table above, after equilibration in pure water at 37°C for 4 hours, the solubility of the remdesivir co-crystal form I and the remdesivir co-crystal form A with 3,5-dinitrobenzoic acid and the free base mixed crystal form II+IV of the present invention is increased by 10 to 15 times.

[0153] Example 8: Hygroscopicity analysis of remdesivir eutectic

[0154] Approximately 10 mg of the cocrystal of remdesivir of this invention and maleate crystal form I of patent CN110636884A were respectively subjected to dynamic water adsorption (DVS) tests, and the results are shown in Table 5. The DVS diagram of remdesivir maleate crystal form I is shown below. Figure 13 As shown, the DVS diagram of eutectic form I of m-nitrobenzoic acid is as follows. Figure 14 As shown, the DVS diagram of eutectic form A of 3,5-dinitrobenzic acid is as follows. Figure 15 As shown.

[0155] Table 5: DVS data for remdesivir eutectic and maleate

[0156]

[0157] As shown in the table above, under the conditions of 25℃, 80% and 95% relative humidity, the weight gain of the co-crystal form I of remdesivir and m-nitrobenzoic acid and the co-crystal form A of remdesivir and 3,5-dinitrobenzoic acid of the present invention is lower than that of maleate crystal form I disclosed in patent CN110636884A. This indicates that the co-crystal of the present invention has lower hygroscopicity, which is beneficial for long-term storage of the drug.

[0158] Test instruments and methods

[0159] (1) X-ray powder diffraction (XRPD) study

[0160] X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transmission / reflection sample stage. The radiation source used was (Cu, kα, ... The Kα2 / Kα1 intensity ratio was 0.50, with the voltage set at 45 kV and the current at 40 mA. The X-ray beam divergence, i.e., the effective size of the X-ray confinement on the sample, was 10 mm. A continuous θ-θ scanning mode was used to obtain an effective 2θ range of 3° to 40°. A suitable amount of sample was placed in the circular groove of the zero-background sample holder under ambient conditions (approximately 18°C ​​to 32°C), and gently pressed with a clean glass slide to obtain a flat surface. The zero-background sample holder was then fixed in place. A conventional XRPD pattern was generated on the sample within the 3°–40° 2θ range using a scanning step size of 0.0168°. Data collection software was Data Collector, and the data was analyzed and displayed using Data Viewer and HighScore Plus.

[0161] Using the above conditions, the crystal forms prepared in the examples were subjected to XRPD detection.

[0162] (2) Differential Scanning Calorimetry (DSC) Analysis

[0163] DSC measurement at TA Instruments TM The Q2000 model uses a sealed disc apparatus. The sample (approximately 1–3 mg) is weighed in an aluminum disc, capped with a Tzero, and precisely recorded to the nearest hundredth of a milligram. The sample is then transferred to the instrument for measurement. The instrument is purged with nitrogen at 50 mL / min. Data are collected between room temperature and 300°C at a heating rate of 10°C / min. Endothermic peaks are plotted downwards, and the data are analyzed and presented using TA Universal Analysis.

[0164] (3) Thermogravimetric analysis (TGA)

[0165] TGA measurements at TA Instruments TM The procedure is performed using a model Q500. The empty crucible is tare, and approximately 10 mg of solid sample is placed in the tare crucible and spread evenly. After the instrument stabilizes, data is collected and recorded at a heating rate of 10 °C / min between room temperature and 300 °C under nitrogen purging.

[0166] (4) Dynamic Vapor Adsorption Analyzer (DVS)

[0167] The DVS test is a method for testing isothermal adsorption equilibrium curves. The instrument used is a DVS-INTRINSIC. At 25.0℃, the relative humidity changes from 0% to 95% and then back to 0% in 10% increments. Equilibrium is considered reached when the absolute value of the sample weight change (dm / dt) per unit time under a specific relative humidity condition is less than 0.1%, and then the test proceeds to the next relative humidity level. This test measures the change in hygroscopicity of the product under cyclic relative humidity conditions (0%-95.0%-0%).

[0168] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2010 Edition Appendix: Guidelines for Hygroscopicity Testing of Drugs, Experimental Conditions: 25±0.2℃, 80% relative humidity):

[0169] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0170] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0171] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0172] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0173] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0174] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0175] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A eutectic of remdesivir and a nitrobenzene compound, wherein the stoichiometric ratio of remdesivir to the nitrobenzene compound is 1:1, and the nitrobenzene compound is m-nitrobenzene or 3,5-dinitrobenzoic acid; wherein, The eutectic of remdesivir and m-nitrobenzoic acid is crystal form I, characterized by the following X-ray powder diffraction spectra (expressed as 2θ) using Cu-Kα radiation: Crystal form I exhibits diffraction peaks at 2θ values ​​of 5.0, 7.6, 13.1, 14.3, 15.7, 17.2, 17.9, 19.0, 20.5, 22.6, 23.3, 27.5, and 28.6 degrees; or at 2θ values ​​of 5.7, 10.3, 13.6, 14.9, 16.2, 17.4, 18.6, 19.8, 21.1, 23.0, 24.4, and 28.2 degrees; or at 2θ values ​​of 5.0, 20.5, 22.6, 23.3, 27.5, and 28.2 degrees. Diffraction peaks are observed at 2θ values ​​of 5.7, 7.6, 10.3, 13.1, 13.6, 14.3, and 14.9 degrees; or in the X-ray powder diffraction pattern of crystal form I, diffraction peaks are observed at 2θ values ​​of 5.0, 5.7, 7.6, 10.3, 13.1, 13.6, 14.3, 14.9, 15.7, 16.2, 17.2, 17.4, 17.9, 18.6, 19.0, and 19.8 degrees; or in the X-ray powder diffraction pattern of crystal form I, diffraction peaks are observed at 2θ values ​​of 5.0, 5.7, 7.6, 10.3, 13.1, 13.6, 14.3, 14.9, 15.7, 16.2, 17.2, 17.4, and 17.9 degrees. The X-ray powder diffraction pattern of remdesivir and 3,5-dinitrobenzoic acid exhibits diffraction peaks at 2θ values ​​of 18.6, 19.0, 19.8, 20.5, 21.1, 22.6, 23.0, 23.3, 24.4, 27.5, 28.2, and 28.6 degrees. The pattern is characterized by diffraction peaks at 2θ values ​​of 4.8, 8.9, 10.5, 14.3, 15.9, 16.9, 19.7, 21.4, 23.5, 24.5, and 26.3 degrees; or diffraction peaks at 2θ values ​​of 6.5, 10.1, 13.0, and 15.0 degrees. Diffraction peaks are observed at 2θ values ​​of 16.4, 19.2, 21.2, 23.0, 24.1, 25.7, and 27.6 degrees; or in the X-ray powder diffraction pattern of crystal form A, diffraction peaks are observed at 2θ values ​​of 4.8, 6.5, 8.9, 10.1, 10.5, 13.0, 14.3, and 15.0 degrees; or in the X-ray powder diffraction pattern of crystal form A, diffraction peaks are observed at 2θ values ​​of 4.8, 6.5, 8.9, 10.1, 10.5, 13.0, 14.3, 15.0, 15.9, 16.4, 16.9, 19.2, and 19.A diffraction peak is observed at 2θ 7°; or, in the X-ray powder diffraction pattern of crystal form A, diffraction peaks are observed at 2θ positions of 4.8, 6.5, 8.9, 10.1, 10.5, 13.0, 14.3, 15.0, 15.9, 16.4, 16.9, 19.2, 19.7, 21.2, 21.4, 23.0, 23.5, 24.1, 24.5, 25.7, 26.3, and 27.6°.

2. The eutectic as described in claim 1, wherein, The X-ray powder diffraction pattern of crystal form I is shown in Figure 1.

3. The thermogravimetric analysis curve of the eutectic crystal of claim 1 shows a weight loss of 0.5% between 30℃ and 150℃.

4. The eutectic as described in claim 1, wherein, The X-ray powder diffraction pattern of crystal form A is shown in Figure 5.

5. The eutectic as described in claim 1, wherein, The thermogravimetric analysis curve of crystal form A shows weight loss between 30℃ and 170℃, with a weight loss of 2.7%.

6. A method for preparing crystal form I in the eutectic of claim 1, comprising: Remdesivir was mixed with a good solvent, reacted with m-nitrobenzoic acid, and the solvent was evaporated at 20℃-80℃. Then, a poor solvent was added, and the mixture was pulped at 25℃-40℃, filtered, and dried to obtain crystal form I. The good solvent was at least one of methanol, ethanol, isopropanol, acetone, and n-butanone; the poor solvent was at least one of diethyl ether, propyl ether, and isopropyl ether; the mass-volume ratio of remdesivir to the poor solvent was 1g:10ml~1g:200ml, and the mass-volume ratio of remdesivir to the good solvent was 1g:5ml-1g:40ml. Alternatively, it may include: mixing remdesivir with m-nitrobenzoic acid, adding an alkane solvent, suspending, slurrying at 25℃-40℃, filtering, and drying to obtain crystal form I; wherein the alkane solvent is at least one of n-hexane, cyclohexane, and n-heptane; the mass-to-volume ratio of remdesivir to the alkane solvent is 1mg:10ml~1mg:200ml; The molar ratio of remdesivir to m-nitrobenzoic acid is 1:1 to 1:

3.

7. A method for preparing crystal form A in the eutectic of claim 1, comprising: Remdesivir was mixed with a good solvent, and 3,5-dinitrobenzoic acid was added to react. After evaporating the solvent at 20℃-80℃, a poor solvent was added, and the mixture was pulped at 25℃-40℃, filtered, and dried to obtain crystal form A. The good solvent was at least one of methanol, ethanol, isopropanol, acetone, and n-butanone. The mass-to-volume ratio of remdesivir to the good solvent was 1g:5ml-1g:40ml. The poor solvent was at least one of diethyl ether, propyl ether, and isopropyl ether. The mass-to-volume ratio of remdesivir to the poor solvent was 1g:10ml-1g:200ml. The molar ratio of remdesivir to 3,5-dinitrobenzoic acid was 1:1-1:

3.

8. A pharmaceutical composition comprising a therapeutically effective amount of the cocrystal as described in any one of claims 1-5 or the cocrystal obtained by the method described in any one of claims 6-7, and a pharmaceutically acceptable excipient; wherein, By mass ratio, at least 80% of the remdesivir eutectic is of crystal form I or crystal form A, and the eutectic is at least 0.1%-10% of the total weight of the composition.

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