Cocrystal of remdesivir and salicylic acid and preparation method thereof

Abstract

The present application provides a co-crystal of remdesivir and salicylic acid and a preparation method thereof, and belongs to the field of medicinal chemistry. The XRPD pattern of the crystal form I of the co-crystal contains the following characteristic peaks of 2θ (error ± 0.2 degrees): 5.3, 8.4, 11.0, 14.6, 15.1, 16.9, 18.7, 21.6, 24.2, 26.5, 28.8 and 30.8 degrees. The crystal form I has good stability and low hygroscopicity, is beneficial to storage, transfer and operation in the production process, and is suitable for preparation into a preparation.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a co-crystal of remdesivir and salicylic acid and a preparation method thereof. Background Art

[0002] Remdesivir, CAS: 1809249-37-3, is a nucleoside analog with antiviral activity. On October 22, 2020, the U.S. Food and Drug Administration (FDA) approved Gilead Sciences' antiviral drug remdesivir for the treatment of hospitalized COVID-19 patients, making it the first officially approved COVID-19 treatment drug in the United States.

[0003] The structure of Remdesivir is shown in the following formula (1):

[0004]

[0005] Drug polymorphism is a common phenomenon in drug development and a significant factor affecting drug quality. Different crystalline forms of the same drug can exhibit significant and often profound differences in physical and chemical properties, such as appearance, flowability, solubility, storage stability, and bioavailability, impacting storage, transfer, application, stability, and efficacy. To effectively identify crystalline forms that are beneficial for production or drug formulation, a comprehensive investigation of the drug's crystallization behavior is necessary to determine the crystalline form that meets production requirements.

[0006] There is currently no literature disclosing the co-crystal of remdesivir, nor any related literature reports.

[0007] The present invention conducts a large number of experimental studies on the remdesivir compound and obtains the co-crystal of the compound. The co-crystal has good stability and low hygroscopicity, which facilitates the long-term storage of the drug and has high development value. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems in the related art to a certain extent. To this end, one object of the present invention is to provide a co-crystal of remdesivir and salicylic acid and a method for preparing the same, wherein the co-crystal has good stability and low hygroscopicity.

[0009] According to one aspect of the present invention, the present invention provides a co-crystal of remdesivir and salicylic acid: referred to as Form I.

[0010] Studies on the crystalline form I of the present invention have shown that the crystalline form I has good properties in terms of stability and hygroscopicity, and can be used in the preparation of pharmaceutical preparations.

[0011] The crystalline form I has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles in its X-ray powder diffraction pattern using an X-ray powder diffractometer with Cu-Kα radiation: 5.3, 8.4, 11.0, 14.6, 15.1, 16.9, 18.7, 21.6, 24.2, 26.5, 28.8 and 30.8.

[0012] In some embodiments, the Form I has an X-ray powder diffraction pattern using an X-ray powder diffractometer with Cu-Kα radiation, and has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree): 5.3, 8.4, 11.0, 14.6, 14.9, 15.1, 16.9, 17.3, 18.7, 21.6, 23.3, 24.2, 26.5, 28.8 and 30.8.

[0013] The crystalline form I has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles in its X-ray powder diffraction pattern using an X-ray powder diffractometer with Cu-Kα radiation: 5.3, 5.8, 8.4, 9.9, 11.0, 13.1, 14.6 and 14.9.

[0014] In some embodiments, the Form I has an X-ray powder diffraction pattern using an X-ray powder diffractometer with Cu-Kα radiation, and has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree): 5.3, 5.8, 8.4, 9.9, 11.0, 13.1, 14.6, 14.9, 15.1, 16.7, 16.9, 17.3, 18.7, 19.7, 21.6, 23.3 and 24.2.

[0015] In some embodiments, the Form I has an X-ray powder diffraction pattern using an X-ray powder diffractometer with Cu-Kα radiation, and has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree): 5.3, 5.8, 8.4, 9.9, 11.0, 13.1, 14.6, 14.9, 15.1, 16.7, 16.9, 17.3, 18.7, 19.7, 21.6, 23.3, 24.2, 25.4, 26.5, 26.9, 28.8, 29.6 and 30.8.

[0016] In some embodiments, in the X-ray powder diffraction pattern of the co-crystal Form I of remdesivir and salicylic acid, the relative intensity of the peak at 2θ of 5.3 degrees is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

[0017] In some embodiments, the co-crystal Form I of Remdesivir and salicylic acid has substantially Figure 1 The X-ray powder diffraction pattern (XRPD pattern) is shown.

[0018] In some embodiments, the differential scanning calorimetry curve (DSC) of the co-crystal Form I of remdesivir and salicylic acid has an endothermic peak at 149°C-159°C, and the peak temperature of the endothermic peak is at 152°C-156°C.

[0019] In some embodiments, the crystalline Form I has substantially Figure 2 The differential scanning calorimetry curve (DSC spectrum) is shown.

[0020] In some embodiments, the thermogravimetric analysis (TGA) curve of the crystalline Form I shows a weight loss between 30°C and 140°C, with a weight loss of less than 1.0%. In some embodiments, the thermogravimetric analysis (TGA) curve of the crystalline Form I shows a weight loss between 30°C and 140°C, with a weight loss of approximately 0.4%.

[0021] In some embodiments, the crystalline Form I has substantially Figure 3 Thermogravimetric analysis curve (TGA spectrum) shown.

[0022] Relative to the co-crystal of remdesivir and salicylic acid, in some embodiments, the purity of the crystalline 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, relative to the co-crystal of remdesivir and salicylic acid, the purity of the crystalline Form I is at least 85%, or at least 90%, or at least 95%, or at least 99%.

[0023] The co-crystal Form I of remdesivir and salicylic acid described in the present invention can be used to treat viral infection-related diseases such as novel coronavirus pneumonia.

[0024] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a cocrystal Form I of remdesivir and salicylic acid and a pharmaceutically acceptable excipient or excipient. Generally, a therapeutically effective amount of a cocrystal Form I of remdesivir and salicylic acid is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, which is prepared using methods well known in the pharmaceutical art. The pharmaceutical composition or formulation can be used to treat viral infection-related diseases such as novel coronavirus pneumonia.

[0025] The present invention provides a pharmaceutical composition, which may contain at least 0.1%-10% of the crystalline Form I, based on the total weight of the composition. The present invention provides a pharmaceutical composition, which may contain at least 0.1%-5% of the crystalline Form I, based on the total weight of the composition. The present invention provides a pharmaceutical composition, which may contain at least 0.1%-1% of the crystalline Form I, based on the total weight of the composition. In some embodiments, the present invention provides a pharmaceutical composition, which contains at least 0.1%-0.5% of the crystalline Form I, based on the total weight of the composition.

[0026] The present invention provides a pharmaceutical composition containing a co-crystal of remdesivir and salicylic acid, wherein at least 80% of the co-crystal of remdesivir and salicylic acid is the co-crystal Form I of remdesivir and salicylic acid, calculated by mass ratio. In some embodiments, a pharmaceutical composition contains a co-crystal of remdesivir and salicylic acid, wherein at least 90% of the co-crystal of remdesivir and salicylic acid is the co-crystal Form I of remdesivir and salicylic acid, calculated by mass ratio. In some embodiments, a pharmaceutical composition contains a co-crystal of remdesivir and salicylic acid, wherein at least 95% of the co-crystal of remdesivir and salicylic acid is the co-crystal Form I of remdesivir and salicylic acid, calculated by mass ratio. In some embodiments, a pharmaceutical composition contains a co-crystal of remdesivir and salicylic acid, wherein at least 99% of the co-crystal of remdesivir and salicylic acid is the co-crystal Form I of remdesivir and salicylic acid, calculated by mass ratio.

[0027] Relative to the co-crystal of remdesivir and salicylic acid, in some embodiments, the purity of Form I in the pharmaceutical composition is at least 80%. In some embodiments, relative to the co-crystal of remdesivir and salicylic acid, the purity of Form I in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.

[0028] The pharmaceutical composition containing the cocrystal Form I of remdesivir and salicylic acid described in the present invention can be used to prepare pharmaceutical preparations for viral infections such as novel coronavirus pneumonia. The pharmaceutical composition containing the cocrystal Form I of remdesivir and salicylic acid described in the present invention can be used in methods for treating diseases related to viral infections such as novel coronavirus pneumonia.

[0029] The crystal form I provided by the present invention has good stability and low hygroscopicity, is not easily deliquesced under high humidity conditions, is convenient for long-term storage of drugs, can effectively prevent crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and efficacy, and has strong economic value.

[0030] According to the second aspect of the present invention, the present invention proposes a method for preparing the aforementioned co-crystal Form I of remdesivir and salicylic acid.

[0031] A method for preparing a co-crystal form I of remdesivir and salicylic acid includes: mixing remdesivir with a good solvent, adding salicylic acid to react, evaporating the solvent at a certain temperature, adding a poor solvent, beating at a beating temperature, filtering, and drying to obtain form I.

[0032] The good solvent is selected from any one of alcohol and ketone.

[0033] In some embodiments, the good solvent is selected from any one of methanol, ethanol, isopropanol, acetone and n-butyl ketone. In some embodiments, the good solvent is selected from methanol or acetone.

[0034] The poor solvent is selected from one of ethers.

[0035] In some embodiments, the poor solvent is selected from one of diethyl ether, propyl ether and isopropyl ether. In some embodiments, the poor solvent is isopropyl ether.

[0036] The certain temperature is 20°C-80°C.

[0037] In some embodiments, when the mass of remdesivir is calculated in grams (g) and the volume of the poor solvent is calculated in milliliters (mL), the mass-to-volume ratio of remdesivir to the poor solvent is 1:10 to 1:200.

[0038] In some embodiments, when the mass of remdesivir is calculated in grams (g) and the volume of the good solvent is calculated in milliliters (mL), the mass-to-volume ratio of remdesivir to the good solvent can be 1:5-1:40, or 1:10-1:20.

[0039] The beating temperature is 25°C-40°C.

[0040] A method for preparing a co-crystal form I of remdesivir and salicylic acid includes: mixing remdesivir and salicylic acid, adding an alkane solvent, suspending, slurrying at a certain temperature, filtering, and drying to obtain form I.

[0041] In some embodiments, the alkane solvent is selected from one of n-hexane, cyclohexane and n-heptane. In some embodiments, the alkane solvent is n-heptane.

[0042] In some embodiments, when the mass of remdesivir is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-to-volume ratio of remdesivir to the alkane solvent is 1:10 to 1:200.

[0043] The certain temperature is 25°C to 40°C.

[0044] The beating time is 24 hours to 72 hours.

[0045] A method for preparing a co-crystal Form I of remdesivir and salicylic acid comprises: mixing remdesivir and salicylic acid, adding a cosolvent, and grinding in a mortar to obtain Form I.

[0046] The co-solvent is selected from one or more of methanol, ethanol, acetone and ethyl acetate.

[0047] In some embodiments, the co-solvent is ethyl acetate.

[0048] In some embodiments, when the mass of remdesivir is calculated in milligrams (mg) and the volume of the solvent is calculated in microliters (μL), the mass-to-volume ratio of remdesivir to the co-solvent is 1:10 to 10:1.

[0049] In the aforementioned method, the molar ratio of remdesivir to salicylic acid can be 1:1 to 1:3.

[0050] The "crystalline form" described herein may be present in a sample at 0.0001% to 100%. Therefore, even trace amounts of the "crystalline form" described herein, such as greater than 0.0001%, greater than 0.001%, greater than 0.001%, or greater than 0.01%, in a sample should be considered to fall within the scope of protection of the present invention. To more clearly describe the various parameters of the "crystalline form" described herein, the present invention characterizes and identifies the crystalline form by testing various parameters on samples containing substantially pure "crystalline form."

[0051] In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the words "about" or "approximately" are used. Based on the disclosed numbers, the value of each number may vary by 1%, 2%, or 5%.

[0052] The differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the degree of dryness of the sample. The position and peak value of the endothermic peak may differ slightly between one machine and another, and between one sample and another. The numerical value of 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.

[0053] In the present invention, "RH" is relative humidity.

[0054] In the present invention, the room temperature is in the range of 20°C-40°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 : X-ray powder diffraction (XRPD) pattern of Form I of remdesivir and salicylic acid co-crystal;

[0056] Figure 2 : Differential scanning calorimetry (DSC) curve of Form I of remdesivir and salicylic acid co-crystal;

[0057] Figure 3 : Thermogravimetric analysis (TGA) curve of Form I of Remdesivir and salicylic acid co-crystal;

[0058] Figure 4 : 15-day experimental results of factors affecting Form I of Remdesivir and salicylic acid co-crystal;

[0059] Figure 5 : Isothermal adsorption equilibrium (DVS) curve of maleate crystal form I in CN110636884A;

[0060] Figure 6 : Isothermal adsorption equilibrium (DVS) curve of Form I of Remdesivir and salicylic acid cocrystal. DETAILED DESCRIPTION

[0061] The following describes embodiments of the present invention in detail, examples of which are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to be used to explain the present invention, and are not to be construed as limiting the present invention.

[0062] In order 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 further illustrate the present invention in detail.

[0063] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0064] Example 1 Preparation Method of Cocrystal Form I of Remdesivir and Salicylic Acid

[0065] 300 mg of remdesivir and 69 mg of salicylic acid were added to a 25 mL round-bottom flask, and 15 mL of n-heptane solvent was added. The mixture was suspended and slurried at room temperature for 48 hours. Filtered and dried to obtain about 280 mg of a white solid product. The obtained crystals were detected by XRPD and confirmed to be a co-crystal of remdesivir and salicylic acid, Form I; its X-ray powder diffraction pattern was consistent with Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0066] Example 2 Preparation Method of Cocrystal Form I of Remdesivir and Salicylic Acid

[0067] 30.0 mg of remdesivir was dissolved in 0.5 mL of acetone, 6.9 mg of salicylic acid was added, and the mixture was reacted at 50 ° C for 12 hours. Then the solvent was slowly evaporated at room temperature, 2 mL of isopropyl ether was added, and the mixture was beaten until a solid precipitated. Filtered and dried to obtain about 25 mg of a white solid product. The obtained crystals were detected by XRPD and confirmed to be a co-crystal of remdesivir and salicylic acid, Form I; its X-ray powder diffraction pattern was consistent with Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0068] Example 3 Preparation Method of Cocrystal Form I of Remdesivir and Salicylic Acid

[0069] 30.0 mg of remdesivir and 6.9 mg of salicylic acid were added to a mortar, and then 15 μL of ethyl acetate was added dropwise to assist grinding for half an hour. The obtained solid product was tested by XRPD. The obtained crystals were confirmed to be a cocrystal of remdesivir and salicylic acid, Form I, by XRPD detection; its X-ray powder diffraction pattern was consistent with Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0070] Example 4 Stability Experiment of Cocrystal Form I of Remdesivir and Salicylic Acid

[0071] According to the guidelines for drug preparation stability testing, the salicylic acid cocrystal of Remdesivir was subjected to influencing factor experiments, including high temperature test, high humidity test and strong light irradiation test, to investigate the factors affecting the stability of its crystal form. The XRPD comparison diagram is shown below. Figure 4 shown.

[0072] 1) High temperature test

[0073] An appropriate amount of remdesivir and salicylic acid cocrystal sample was placed flat in a weighing bottle and placed in a constant temperature and humidity chamber at 60°C ± 5°C and RH 75 ± 5%. Samples were then taken after 5, 10, and 15 days, and their crystal forms were analyzed using X-ray powder diffraction (XRPD). The experimental results are shown in Table 1.

[0074] Table 1 Stability study of Form I

[0075]

[0076] The above results show that after the sample was placed under high temperature conditions of 60°C (temperature deviation ±5°C) / 75% relative humidity (humidity deviation ±5%) for 5 days, 10 days, and 15 days respectively, the crystal form remained unchanged and the stability was good.

[0077] 2) High humidity test

[0078] An appropriate amount of remdesivir salicylic acid cocrystal sample was placed flat in a weighing bottle and placed in a constant temperature and humidity chamber at 25°C and 92.5±5%. Samples were then taken after 5, 10, and 15 days, and their crystal forms were analyzed using X-ray powder diffraction (XRPD). The experimental results are shown in Table 2.

[0079] Table 2 Stability study of Form I

[0080]

[0081] The above results show that after the sample was placed under 25°C / 92.5% relative humidity (humidity deviation ±5%) for 5 days, 10 days, and 15 days, the crystal form remained unchanged and the stability was good.

[0082] 3) Lighting test

[0083] An appropriate amount of remdesivir salicylic acid cocrystal sample was spread flatly into a weighing bottle and placed in a constant temperature and humidity chamber (25°C, RH 60% ± 5%) with visible light 4500 Lux ± 500 Lux (VIS) and ultraviolet light 1.7 W*h / m2 (UV). The samples were then taken 5, 10, and 15 days later, and their crystal forms were analyzed by X-ray powder diffraction (XRPD). The experimental results are shown in Table 3.

[0084] Table 3 Stability study of Form I

[0085]

[0086] The above results show that the sample has a visible light of 4500Lux±500Lux and a UV light of 1.7W*h / m 2 After being placed in a constant temperature and humidity chamber (25°C, RH60±5%) for 5 days, 10 days, and 15 days respectively, the crystal form remained unchanged and the stability was good.

[0087] Example 5 Stability test of the co-crystal of remdesivir and salicylic acid in pure water and buffer solution

[0088] Remdesivir salicylic acid cocrystal Form I and maleate salt Form I described in patent application CN110636884A were suspended in pure water and pH 1.2 and 4.5 buffer solutions at 37°C for 24 hours, filtered, and the resulting solid products were tested by XRPD. The test results are shown in Table 4:

[0089] Table 4 Experimental results of stability test of co-crystal Form I of Remdesivir and salicylic acid in pure water and buffer solution

[0090]

[0091] As can be seen from the above table: salicylic acid cocrystal Form I of remdesivir can stably exist in pure water and buffer solutions of pH 1.2 and 4.5, while maleate salt Form I will lose salt and return to free base in both pure water and buffer solutions, indicating that the salicylic acid cocrystal of the present invention has better stability.

[0092] Example 6 Solubility Experiment of Cocrystal of Remdesivir and Salicylic Acid

[0093] Remdesivir salicylic acid cocrystal Form I and free base mixed crystals II+IV from patent CN110636884A were prepared into saturated solutions in pure water at 37°C. After equilibration for 4 hours, the filtrate was filtered through an aqueous filter membrane and the solubility was measured by high-performance liquid chromatography (HPLC). Each batch of samples was measured twice in parallel and the average value was obtained. The solubility measurement results are shown in Table 5.

[0094] Table 5 Solubility data of salicylic acid cocrystal and free base of Remdesivir

[0095] Eutectic form Solubility mg / mL Free base mixed crystals II+IV (control) 0.012 Salicylic acid cocrystal Form Ⅰ 0.019

[0096] It can be seen from the above table that after equilibration in pure water at 37°C for 4 hours, the solubility of salicylic acid cocrystal Form I of Remdesivir of the present invention is 1.5 times that of the free base mixed crystals II+IV.

[0097] Example 7 Hygroscopicity Analysis of the Cocrystal of Remdesivir and Salicylic Acid

[0098] About 10 mg of salicylic acid cocrystal Form I of the present invention and maleate salt Form I described in patent application CN110636884A were respectively taken for dynamic moisture adsorption (DVS) test. The results are shown in Table 6. The DVS diagram of maleate salt Form I of remdesivir is shown in Table 6. Figure 5 As shown, the DVS diagram of salicylic acid cocrystal form Ⅰ is as follows Figure 6 shown.

[0099] Table 6 DVS data of salicylic acid cocrystal and maleate salt of Remdesivir

[0100]

[0101]

[0102] As shown in the table above, the salicylic acid cocrystal Form I of remdesivir of the present invention gained weight by 0.1058% at 80% relative humidity and by 0.2708% at 95% relative humidity, indicating low hygroscopicity. In contrast, the maleate salt Form I gained weight by 0.9710% at 80% relative humidity and by 2.234% at 95% relative humidity, indicating high hygroscopicity. This indicates that the salicylic acid cocrystal of the present invention has lower hygroscopicity, facilitating long-term storage of the drug.

[0103] Test instruments and methods

[0104] (1) X-ray powder diffraction (XRPD) study

[0105] X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transflective sample stage. The radiation sources used were (Cu, kα, Kα1 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage was set at 45KV and the current was set at 40mA. The beam divergence of the X-rays, that is, the effective size of the X-ray confinement on the sample, was 10mm. A θ-θ continuous scanning mode was used to obtain an effective 2θ range of 3° to 40°. Take an appropriate amount of sample and place it in the circular groove of the zero background sample holder under ambient conditions (about 18°C ​​to 32°C). Press it lightly with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample was scanned at a step size of 0.0168° to generate a traditional XRPD pattern in the range of 3 to 40° 2θ. The software used for data collection was Data Collector, and the data were analyzed and displayed using Data Viewer and HighScore Plus.

[0106] Using the above conditions, XRPD detection was performed on the crystal forms prepared in the examples.

[0107] (2) Differential scanning calorimetry (DSC) analysis

[0108] DSC measurements at TA Instruments TM The instrument was operated using a sealed pan setup on a Q2000. Samples (approximately 1-3 mg) were weighed into aluminum pans, sealed with a Tzero seal, and recorded to the nearest hundredth of a milligram. The sample was then transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL / min. Data were collected between room temperature and 300°C at a heating rate of 10°C / min. Plots were plotted with the endothermic peak downward, and data were analyzed and displayed using a TA Universal Analyzer.

[0109] (3) Thermogravimetric analysis (TGA)

[0110] TGA measurements at TA Instruments TM The analysis was performed in a Q500. The procedure involved taring an empty crucible, placing approximately 10 mg of the solid sample into the tared crucible, and spreading it evenly. After the instrument stabilized, data was collected at a heating rate of 10°C / min between room temperature and 300°C under a nitrogen purge, and a spectrum was recorded.

[0111] (4) Dynamic Vapor Sorption Analyzer DVS

[0112] The DVS test uses a DVS-INTRINSIC instrument. At 25°C, the relative humidity is varied from 0% to 95% and then to 0% in 10% steps. Equilibrium is achieved when the absolute value of the sample weight change per unit time (dm / dt) is less than 0.1% at a specific relative humidity. The test then moves on to the next relative humidity. This test measures changes in the product's hygroscopicity under cyclic relative humidity conditions (0% to 95% to 0%).

[0113] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for Hygroscopicity Test of Drugs in the Appendix of the 2010 edition of the Chinese Pharmacopoeia, experimental conditions: 25±0.2℃, 80% relative humidity):

[0114] Deliquescent: Absorbs sufficient water to form a liquid;

[0115] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0116] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0117] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0118] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0119] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0120] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. Form I of the co-crystal of remdesivir and salicylic acid, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction spectrum is expressed in 2θ. The X-ray powder diffraction pattern of Form I has diffraction peaks at 2θ of 5.3, 8.4, 11.0, 14.6, 15.1, 16.9, 18.7, 21.6, 24.2, 26.5, 28.8 and 30.8 degrees.

2. The crystalline form I according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form I has diffraction peaks at 2θ of 5.3, 8.4, 11.0, 14.6, 14.9, 15.1, 16.9, 17.3, 18.7, 21.6, 23.3, 24.2, 26.5, 28.8 and 30.8 degrees; or the X-ray powder diffraction pattern of the crystalline form I has diffraction peaks at 2θ of 5.3, 5.8, 8.4, 9.9, 11.0, 13.1, 14.6, 14.9, 15.1, 16.7, 16.9, 17.3, 18.7, 19.7, 21.6, 23.3, 24.2, 25.4, 26.5, 26.9, There are diffraction peaks at 28.8, 29.6 and 30.8 degrees; or the X-ray powder diffraction pattern of Form I is shown in Figure 1.

3. The crystalline form I according to claim 1, wherein the thermogravimetric analysis curve of the crystalline form I shows weight loss between 30°C and 140°C.

4. The crystalline form I according to claim 1, wherein the thermogravimetric analysis curve of the crystalline form I shows a weight loss of 0.4% between 30°C and 140°C.

5. A method for preparing the crystalline form I according to any one of claims 1 to 4, comprising: Remdesivir is mixed with a good solvent, salicylic acid is added for reaction, the solvent is evaporated at 20°C-80°C, a poor solvent is added, the mixture is slurried at 25°C-40°C, filtered, and dried to obtain Form I, wherein the good solvent is at least one of methanol, ethanol, isopropanol, acetone, and n-butanone, and the poor solvent is at least one of diethyl ether, propyl ether, and isopropyl ether; Alternatively, the method comprises: mixing remdesivir with salicylic acid, adding an alkane solvent, suspending, slurrying at 25° C. to 40° C., filtering, and drying to obtain Form I, wherein the alkane solvent is at least one of n-hexane, cyclohexane, and n-heptane; Alternatively, the method comprises mixing remdesivir with salicylic acid, adding a co-solvent, and grinding in a mortar to obtain Form I, wherein the co-solvent is at least one of methanol, ethanol, acetone, and ethyl acetate.

6. The method according to claim 5, characterized in that The mass volume ratio of the remdesivir to the poor solvent is 1g:10ml~1g:200ml; and / or the mass volume ratio of the remdesivir to the good solvent is 1g:5ml-1g:40ml.

7. The method according to claim 5, characterized in that The molar ratio of remdesivir to salicylic acid is 1:1 to 1:

3.

8. The method according to claim 5, characterized in that The mass volume ratio of the remdesivir to the alkane solvent is 1g:10ml~1g:200ml; or the mass volume ratio of the remdesivir to the co-solvent is 1mg:10μl~10mg:1μl.

9. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form I according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9, wherein Based on the mass ratio, at least 80% of the co-crystal of remdesivir and salicylic acid is Form I.

11. The pharmaceutical composition according to claim 9 or 10, characterized in that The crystalline form I is at least 0.1%-10% of the total weight of the composition.

12. Use of the crystalline form I described in any one of claims 1-5 or the composition described in any one of claims 9-11 in the preparation of a medicament for treating diseases related to novel coronavirus infection.

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