A favipiravir co-crystal and a preparation method thereof

Abstract

The present application relates to a kind of favipiravir co-crystal and its preparation method, belong to the field of pharmaceutical chemistry.The favipiravir co-crystal includes favipiravir-isonicotinic acid co-crystal, favipiravir-urea co-crystal or favipiravir-orthoaminobenzoic acid co-crystal, the favipiravir co-crystal has good solubility and stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals and relates to favipiravir cocrystal and its preparation method. Background Technology

[0002] Favipiravir (T-705, CAS No. 259793-96-9), chemically known as 6-fluoro-3-hydroxy-2-pyrazinamide, is used to treat novel and recurrent influenza.

[0003] Patent application CN201210535512.9 discloses a favipiravir crystal form α, but studies have found that it has low solubility and low bioavailability. Commercially available dosage forms using this crystal form are large in size and require a large daily dose, requiring two doses of 1600mg (8 tablets) each time on the first day, which is very inconvenient for patients and results in low patient compliance.

[0004] CN201711103203.3 discloses a new crystal form, but the preparation process of this crystal form has poor reproducibility. The preparation of this crystal form cannot be reproduced according to its preparation process, and it is not suitable for industrial production. In addition, the water solubility and dissolution results of this crystal form are still poor.

[0005] Therefore, it is still necessary to study a solid form of favipiravir with high solubility and a reproducible preparation method to obtain a more convenient solid form of favipiravir and a method that is simple to operate, easy to implement, has high yield, high purity, low cost, and is environmentally friendly. Summary of the Invention

[0006] To address the above problems, the present invention provides a eutectic, its preparation method, a pharmaceutical composition, and its uses.

[0007] In a first aspect, the present invention provides a favipiravir eutectic.

[0008] A favipiravir eutectic, wherein the favipiravir eutectic includes favipiravir-isonicotinic acid eutectic, favipiravir-urea eutectic, or favipiravir-o-aminobenzoic acid eutectic.

[0009] The molar ratio of favipiravir to isonicotinic acid in the favipiravir-isonicotinic acid eutectic is 1:1.

[0010] The X-ray powder diffraction pattern of the favipiravir-isonicotinic acid eutectic exhibits characteristic peaks at diffraction angles 2θ: 7.10°±0.2°, 13.94°±0.2°, 14.16°±0.2°, 19.44°±0.2°, 21.26°±0.2°, 23.58°±0.2°, 27.09°±0.2°, and 29.16°±0.2°. In some embodiments, the X-ray powder diffraction pattern of the favipiravir-isonicotinic acid eutectic has characteristic peaks at diffraction angles 2θ: 7.10°±0.2°, 13.94°±0.2°, 14.16°±0.2°, 18.47°±0.2°, 19.44°±0.2°, 21.26°±0.2°, 23.02°±0.2°, 23.58°±0.2°, 25.40°±0.2°, 27.09°±0.2°, 28.03°±0.2°, 28.24°±0.2°, 29.16°±0.2°, 30.65°±0.2°, 32.69°±0.2°, 34.85°±0.2°, 35.76°±0.2°, and 36.34°±0.2°. In some embodiments, the favipiravir-isoniacin eutectic has substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0011] The differential scanning calorimetry (DSC) spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 150–175 °C. In some embodiments, the DSC spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 155–165 °C. In some embodiments, the DSC spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 158–162 °C. In some embodiments, the DSC spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 160 °C. In some embodiments, the favipiravir-isonicotinic acid eutectic has substantially the following characteristics: Figure 2 The differential scanning calorimetry (DSC) spectrum is shown.

[0012] The favipiravir-isoniacin eutectic exhibits minimal weight loss in the 30-125°C range. In some embodiments, the favipiravir-isoniacin eutectic experiences a weight loss of less than 0.2% in the 30-125°C range. In some embodiments, the favipiravir-isoniacin eutectic experiences a weight loss of approximately 0.1% in the 30-125°C range. In some embodiments, the favipiravir-isoniacin eutectic exhibits substantially the following characteristics: Figure 3 The thermogravimetric analysis spectrum is shown.

[0013] The molar ratio of favipiravir to urea in the favipiravir-urea eutectic is 2:1.

[0014] The X-ray powder diffraction pattern of the favipiravir-urea eutectic exhibits characteristic peaks at diffraction angles 2θ: 9.91°±0.2°, 15.17°±0.2°, 15.40°±0.2°, 15.70°±0.2°, 16.45°±0.2°, 19.84°±0.2°, 25.20°±0.2°, and 27.88°±0.2°. In some embodiments, the X-ray powder diffraction pattern of the favipiravir-urea eutectic has characteristic peaks at diffraction angles 2θ: 9.02°±0.2°, 9.91°±0.2°, 11.85°±0.2°, 15.17°±0.2°, 15.40°±0.2°, 15.70°±0.2°, 16.45°±0.2°, 17.84°±0.2°, 19.64°±0.2°, 19.84°±0.2°, 21.18°±0.2°, 23.59°±0.2°, 25.20°±0.2°, 27.15°±0.2°, 27.88°±0.2°, and 36.09°±0.2°. In some embodiments, the favipiravir-urea eutectic has substantially the following characteristics. Figure 4 The X-ray powder diffraction pattern shown is shown.

[0015] The differential scanning calorimetry (DSC) spectrum of the favipiravir-urea eutectic exhibits an endothermic peak at 100-150°C. In some embodiments, the DSC spectrum of the favipiravir-urea eutectic exhibits an endothermic peak at 125-130°C. In some embodiments, the DSC spectrum of the favipiravir-urea eutectic exhibits an endothermic peak at 128°C. In some embodiments, the favipiravir-urea eutectic has substantially the following characteristics: Figure 5 The differential scanning calorimetry (DSC) spectrum is shown.

[0016] The favipiravir-urea eutectic exhibits minimal weight loss in the 30-100°C range. In some embodiments, the favipiravir-urea eutectic loses less than 0.3% of its weight in the 30-100°C range. In some embodiments, the favipiravir-urea eutectic loses approximately 0.2% of its weight in the 30-100°C range. In some embodiments, the favipiravir-urea eutectic has substantially the following characteristics: Figure 6 The thermogravimetric analysis spectrum is shown.

[0017] The molar ratio of favipiravir to anthranilic acid in the favipiravir-o-aminobenzoic acid eutectic is 1:1.

[0018] The X-ray powder diffraction pattern of the favipiravir-o-aminobenzoic acid eutectic exhibits characteristic peaks at diffraction angles 2θ: 7.43°±0.2°, 14.83°±0.2°, 15.57°±0.2°, 23.80°±0.2°, 24.15°±0.2°, 25.78°±0.2°, 27.46°±0.2°, 28.21°±0.2°, and 28.75°±0.2°. In some embodiments, the X-ray powder diffraction patterns of the favipiravir-o-aminobenzoic acid eutectic are as follows: at diffraction angles 2θ: 7.43°±0.2°, 13.81°±0.2°, 14.02°±0.2°, 14.83°±0.2°, 15.57°±0.2°, 17.93°±0.2°, 18.16°±0.2°, 23.80°±0.2°, 24.15°±0.2°. Characteristic peaks are present at 0.2°, 25.78°±0.2°, 27.46°±0.2°, 28.21°±0.2°, 28.75°±0.2°, 29.87°±0.2°, 30.86°±0.2°, 34.15°±0.2°, 36.77°±0.2°, 37.58°±0.2°, 40.71°±0.2°, and 41.49°±0.2°. In some embodiments, the favipiravir-o-aminobenzoic acid eutectic has substantially the following characteristics. Figure 7 The X-ray powder diffraction pattern shown is shown.

[0019] The differential scanning calorimetry (DSC) spectrum of the favipiravir-o-aminobenzoic acid eutectic exhibits an endothermic peak at 130-160 °C. In some embodiments, the DSC spectrum of the favipiravir-o-aminobenzoic acid eutectic exhibits an endothermic peak at 140-150 °C. In some embodiments, the DSC spectrum of the favipiravir-o-aminobenzoic acid eutectic exhibits an endothermic peak at 144-146 °C. In some embodiments, the favipiravir-o-aminobenzoic acid eutectic has substantially the following characteristics: Figure 8 The differential scanning calorimetry (DSC) spectrum is shown.

[0020] The favipiravir-o-aminobenzoic acid eutectic has essentially the following properties: Figure 9 The thermogravimetric analysis (TGA) chromatogram is shown. In some embodiments, the favipiravir-o-aminobenzoic acid eutectic exhibits a small weight loss in the range of 30-100°C. In some embodiments, the weight loss of the favipiravir-o-aminobenzoic acid eutectic is less than 0.4% in the range of 30-100°C. In some embodiments, the weight loss of the favipiravir-o-aminobenzoic acid eutectic is approximately 0.3% in the range of 30-100°C.

[0021] Secondly, the present invention provides a method for preparing the aforementioned favipiravir-isonicotinic acid eutectic and favipiravir-urea eutectic.

[0022] A method for preparing a eutectic includes: mixing favipiravir and a eutectic ligand separately with a solvent, wherein the eutectic ligand is selected from isonicotinic acid and urea; stirring to form a favipiravir saturated suspension and a eutectic ligand saturated suspension, respectively; allowing the mixture to stand and separate into layers; taking equal volumes of the upper layer solution of the favipiravir saturated suspension and the upper layer solution of the eutectic ligand saturated suspension, and mixing them thoroughly; allowing the solvent to evaporate to obtain the eutectic.

[0023] The solvent includes at least one selected from methanol, ethanol, n-propanol, and isopropanol.

[0024] The stirring time is 2-12 hours. In some embodiments, the stirring time is 3-10 hours; in some embodiments, the stirring time is 5-8 hours; in some embodiments, the stirring time is 6-7 hours.

[0025] The evaporation temperature is 10-40°C. In some embodiments, the evaporation temperature is 15-40°C; in some embodiments, the evaporation temperature is 20-35°C; in some embodiments, the evaporation temperature is 25-30°C.

[0026] In some embodiments of the present invention, a method for preparing the aforementioned favipiravir-isoniacin cocrystal or favipiravir-urea cocrystal includes: mixing favipiravir and the cocrystal ligand separately with a solvent, stirring for 2-12 hours to form a favipiravir saturated suspension and a cocrystal ligand saturated suspension, respectively; allowing the mixture to stand and separate into layers, taking equal volumes of the upper layer of the favipiravir saturated suspension and the upper layer of the cocrystal ligand saturated suspension, and mixing them thoroughly; then allowing the solvent to evaporate at 10°C-40°C to obtain the cocrystal; wherein the cocrystal ligand is selected from isoniazid and urea, and the solvent is selected from at least one of methanol, ethanol, n-propanol, and isopropanol.

[0027] In some embodiments of the present invention, a method for preparing the aforementioned favipiravir-isonin eutectic includes: mixing favipiravir and the eutectic ligand separately with a solvent, stirring for 2-12 hours to form a favipiravir saturated suspension and a eutectic ligand saturated suspension, respectively; allowing the mixture to stand and separate into layers, taking equal volumes of the upper layer of the favipiravir saturated suspension and the upper layer of the eutectic ligand saturated suspension, and mixing them thoroughly; then allowing the solvent to evaporate at 10°C-40°C to obtain the eutectic; wherein the eutectic ligand is isonicotinic acid, and the solvent is selected from at least one of methanol, ethanol, n-propanol, and isopropanol.

[0028] Thirdly, the present invention provides a method for preparing favipiravir-o-aminobenzoic acid eutectic.

[0029] A method for preparing favipiravir-o-aminobenzoic acid eutectic includes: dissolving favipiravir and o-aminobenzoic acid in water, stirring, allowing to cool naturally, and crystallizing to obtain the eutectic.

[0030] In some embodiments, the dissolution order is to dissolve favipiravir first and then dissolve anthranilic acid. Favipiravir and anthranilic acid are dissolved in this order, which results in a more complete combination of favipiravir and anthranilic acid and a higher yield of the resulting favipiravir-anthranilic acid eutectic.

[0031] The molar ratio of favipiravir to anthranilic acid can be 0.5:1-2.1. In some embodiments, the molar ratio of favipiravir to anthranilic acid is 1:1-1.5:1. In some embodiments, the molar ratio of favipiravir to anthranilic acid is 0.8:1-1.5:1.

[0032] The mass-to-volume ratio of favipiravir to water can be 10.0-50.0 mg / ml. In some embodiments, the mass-to-volume ratio of favipiravir to water is 15.0-45.0 mg / ml; in some embodiments, the mass-to-volume ratio of favipiravir to water is 20.0-40.0 mg / ml; in some embodiments, the mass-to-volume ratio of favipiravir to water is 25.0-35.0 mg / ml; in some embodiments, the mass-to-volume ratio of favipiravir to water is 20.0-30.0 mg / ml. In some embodiments, the mass-to-volume ratio of favipiravir to water is 30.0 mg / ml. In some embodiments, the mass-to-volume ratio of favipiravir to water is 23.3 mg / ml.

[0033] The dissolution temperature is 60.0-100.0℃. In some embodiments, the dissolution temperature is 65.0-95.0℃; in some embodiments, the dissolution temperature is 70.0-90.0℃; in some embodiments, the dissolution temperature is 75.0-85.0℃; in some embodiments, the dissolution temperature is 80.0℃.

[0034] In some embodiments, favipiravir and anthranilic acid are dissolved in water at 60.0-100.0°C.

[0035] The crystallization time can be 4-24 hours. In some embodiments, the crystallization time is 6-20 hours; in some embodiments, the crystallization time is 8-15 hours; in some embodiments, the crystallization time is 10-15 hours.

[0036] The crystallization temperature can be 10-40°C. In some embodiments, the crystallization temperature is 15-40°C; in some embodiments, the crystallization temperature is 20-35°C; in some embodiments, the crystallization temperature is 25-30°C.

[0037] In some embodiments, the aforementioned method for preparing favipiravir-o-aminobenzoic acid eutectic includes: dissolving favipiravir and o-aminobenzoic acid in water at 60.0-100.0°C, stirring, allowing to cool naturally, and crystallizing at 10°C-40°C for 4-24 hours to obtain the eutectic; wherein the molar ratio of favipiravir to o-aminobenzoic acid is 1:1-1.5:1, and the mass-to-volume ratio of favipiravir to water is 10.0-50.0 mg / ml.

[0038] Fourthly, the present invention also provides a pharmaceutical composition comprising at least one of the aforementioned cocrystals, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0039] In some embodiments, a pharmaceutical composition comprises the favipiravir-isoniacin cocrystal described in the first aspect or the favipiravir-isoniacin cocrystal obtained by the method described in the second aspect, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0040] The pharmaceutical composition can be prepared as a pharmaceutically acceptable formulation, such as an injection, tablet, capsule, granule, or dry suspension.

[0041] Fifthly, the eutectic or pharmaceutical composition of the present invention can be used to prepare medicaments for the prevention, treatment, therapy or relief of diseases or infections caused by influenza viruses, coronaviruses (including COVID-19 and SARS), hepatitis C or bovine diarrhea viruses.

[0042] Beneficial effects

[0043] Compared with the prior art, the present invention has the following beneficial technical effects:

[0044] (1) The favipiravir-isonicotinic acid cocrystal of the present invention has good solubility. Its solubility is twice that of the favipiravir crystal form α used in commercial formulations. Using the favipiravir-isonicotinic acid cocrystal of the present invention can reduce the formulation specifications, improve bioavailability, reduce the dosage, and improve patient compliance.

[0045] (2) The favipiravir-isonicotinic acid cocrystal of the present invention has good stability in water and under influencing factors (high temperature, high humidity, light), which can improve the stability of formulations containing the cocrystal and extend the shelf life of the active pharmaceutical ingredient and the formulation.

[0046] (3) The preparation method described in this invention has the advantages of good reproducibility, simple operation, environmental protection, high yield and purity.

[0047] (4) The pharmaceutical composition containing favipiravir cocrystal of the present invention has beneficial technical effects such as high solubility, high bioavailability, small dosage form, and convenient administration.

[0048] Terminology Explanation

[0049] In this invention, mmol represents millimole, h represents hour, g represents gram, ml represents milliliter, μl represents microliter, ℃ represents degree Celsius, mg represents milligram, rpm represents revolutions per minute, RH represents humidity, lux represents lux (the unit of measurement for illuminance), W represents watt, and m 2 It represents square meters.

[0050] In this invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C; and in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0051] The term "pharmaceutically acceptable" as used in this invention refers to a substance that is acceptable from a toxicological point of view for pharmaceutical use and will not adversely interact with the active ingredient.

[0052] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0053] "Amorphous" or "amorphous form" refers to matter formed when its particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. It is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous matter is a special physical form of solid matter; its locally ordered structural features suggest a close connection to crystalline substances. The amorphous form of matter can be obtained through many methods known in the art. These methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, etc.

[0054] A solvent is a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid).

[0055] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0056] A "solvent" is a substance that has a solvent on its surface, in its lattice, or both on its surface and in its lattice. The solvent can be water, ... and mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent on its surface, in its lattice, or both on its surface and in its lattice is water. A hydrate may or may not have other solvents besides water on its surface, in its lattice, or both on its surface and in its lattice.

[0057] Crystalline or amorphous forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0058] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0059] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature by continuously heating or cooling under programmed control. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plot provided in the accompanying drawings. However, DSC spectra can be subject to experimental errors; the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3°C for the melting peak.

[0060] The glass transition refers to the transition of an amorphous substance between a rubbery state and a glassy state, and is an inherent property of the substance. The corresponding transition temperature is called the glass transition temperature (Tg), which is an important physical property of amorphous substances. The glass transition is a phenomenon related to molecular motion; therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance and is relatively insensitive to experimental details. Based on the instrumentation used in this experiment, the melting peak has an error tolerance of ±3℃.

[0061] Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon in the crystal form.

[0062] Solids with the same chemical composition often form isomers, or polymorphs, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase polymorphism. When temperature and pressure conditions change, these polymorphs can transform into each other; this phenomenon is called crystal form transformation. Due to crystal form transformation, the mechanical, electrical, and magnetic properties of the crystal undergo significant changes. When the temperature of the crystal form transformation is within a measurable range, this transformation process can be observed on a differential scanning calorimeter (DSC) chart. The DSC chart is characterized by an exothermic peak reflecting this transformation process, along with two or more endothermic peaks, which are characteristic endothermic peaks of the different crystal forms before and after the transformation.

[0063] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.

[0064] Raman spectroscopy is a spectroscopic technique used to study the vibrational modes, rotational modes, and other low-frequency modes of molecules within a system. Different spatial structures (different crystalline or amorphous forms) of the same molecule exhibit different Raman activities; therefore, Raman spectroscopy can be used to determine and identify crystalline or amorphous forms. The peak positions in Raman spectra are primarily related to the structure of the substance and are relatively insensitive to experimental details, while peak intensities depend on factors such as sample preparation and instrumentation. Therefore, the characteristic of the crystalline or amorphous form in this invention lies in the Raman spectrum with characteristic peak positions, which are essentially as shown in the Raman spectra provided in the accompanying drawings. However, Raman spectroscopy can be subject to experimental errors; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the numerical values ​​of the peak positions or peak intensities in the Raman spectra should not be considered absolute. Based on the instrumentation used in this experiment, the absorption peaks are within ±2 cm⁻¹. -1 Error tolerance.

[0065] In different spatial structures of the same molecule, the bond lengths and bond angles of certain chemical bonds may differ, resulting in different vibrational-rotational transition energy levels. Consequently, certain key characteristics of the corresponding infrared spectra, such as absorption band frequencies, peak shapes, peak positions, and peak intensities, will also vary. Therefore, infrared spectroscopy can be used for the study of drug polymorphism. The crystalline or amorphous characteristics of this invention are manifested in Fourier transform infrared (FT-IR) spectra with characteristic peak positions, which are essentially as shown in the FT-IR spectra provided in the accompanying drawings. However, FT-IR spectra can be subject to experimental errors; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak intensities described in the FT-IR spectra should not be considered absolute. Based on the instrument used in this experiment, the absorption peaks have a range of ±2 cm⁻¹. -1 Error tolerance.

[0066] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0067] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0068] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0069] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0070] "Substantially free of" means that one or more other crystal forms account for less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal form.

[0071] "Relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in an X-ray powder diffraction pattern (XRPD) is 100%.

[0072] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%, for example, "about 0.3%" means 0.27%-0.33%. Alternatively, to those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0073] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0074] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Additionally, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more distinct atoms. Isotope-enriched compounds have the structures given in this invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, etc., such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl、 125 I……

[0075] On the other hand, the compounds described in this invention include isotopically enriched compounds as defined in this invention, for example, compounds containing radioactive isotopes, such as...3 H, 14 C and 18 Compounds of F, or compounds containing non-radioactive isotopes, such as 2 H and 13 Compounds containing C. Compounds enriched in this type of isotope can be used for metabolic studies (using...). 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compounds of formula (I) or (Ia) can be prepared using conventional techniques familiar to those skilled in the art, or by replacing the previously used unlabeled reagent with a suitable isotopic labeling reagent, as described in the examples and preparation procedures of this invention.

[0076] In addition, heavier isotopes, especially deuterium (i.e., 2 Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this invention is considered as a substituent in the compounds represented by formula (I) or (Ia). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. As used in this invention, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of the specified isotope and its native abundance. If the substituent of the compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0077] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name the symbols for the plane polarization rotation of compounds. (-) or l indicates that the compound is levorotatory, while the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0078] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0079] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0080] The pharmaceutical compositions of the compounds of the present invention can be administered in any of the following manner: oral administration, inhalation spray, local administration, rectal administration, nasal administration, local administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, or intracranial injection or infusion, or administration via an external reservoir. Preferred methods are oral administration, intramuscular injection, intraperitoneal administration, or intravenous injection.

[0081] The compounds of this invention, or pharmaceutically acceptable compositions, can be administered in unit doses. The dosage form can be a liquid or a solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders for injection, inclusion complexes, implants, patches, and liniments.

[0082] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0083] Oral liquids can be formulated as suspensions, solutions, emulsions, syrups, or elixirs of hydrated oils, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous carriers (which may contain edible oils such as almond oil), oils such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0084] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0085] For external administration, liquid dosage forms are typically made from a compound and a sterilized carrier. Water is the preferred carrier. Depending on the chosen carrier and drug concentration, the compound can be either dissolved in the carrier or prepared as a suspension. When preparing an injectable solution, the compound is first dissolved in water, filtered, sterilized, and then packaged into sealed bottles or ampoules.

[0086] When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointments, lotions, or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified wax, and water. Carriers that can be used in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. Attached Figure Description

[0087] Figure 1 XRPD spectrum of favipiravir-isonin eutectic;

[0088] Figure 2 DSC spectrum of favipiravir-isonin eutectic;

[0089] Figure 3 TGA spectrum of favipiravir-isonin eutectic;

[0090] Figure 4 XRPD spectrum of favipiravir-urea eutectic;

[0091] Figure 5 DSC spectrum of favipiravir-urea eutectic;

[0092] Figure 6 TGA spectrum of favipiravir-urea eutectic;

[0093] Figure 7 XRPD spectrum of favipiravir-o-aminobenzoic acid eutectic;

[0094] Figure 8 DSC spectrum of favipiravir-o-aminobenzoic acid eutectic;

[0095] Figure 9 TGA spectrum of favipiravir-o-aminobenzoic acid eutectic. Detailed Implementation

[0096] Instrument parameters, test conditions and characterization results

[0097] Unless otherwise specified in the parameters, all the following analyses are performed at room temperature.

[0098] X-ray powder diffraction (XRPD)

[0099] 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°–60°. An appropriate amount of sample was placed in the circular groove of the zero-background sample holder under ambient conditions (approximately 18°–32°C), and gently pressed with a clean glass slide to create a flat surface. The zero-background sample holder was then fixed in place. A conventional XRPD pattern was generated within the range of 3–60°2θ ± 0.2° using a scanning step of 0.0167°. Data collection was performed using Data Collector, and the data was analyzed and displayed using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the vertical axis represents the diffraction intensity expressed in counts, and the horizontal axis represents the diffraction angle 2θ expressed in degrees (°).

[0100] Differential scanning calorimetry (DSC)

[0101] Differential scanning calorimetry (DSC) was performed using a TA Instruments Q2000 differential scanning calorimeter. The sample (approximately 1 mg to 3 mg) was placed in an aluminum pan, and the weight was accurately recorded. The pan was covered with a lid, then pressed shut, and the sample was transferred to the instrument for measurement. The sample cell was equilibrated at 30°C and heated to a final temperature of 300°C at a rate of 10°C / min under nitrogen purging. In the DSC plot, the horizontal axis represents temperature (°C), and the vertical axis represents the heat flow per unit mass of the substance (W / g).

[0102] Thermogravimetric Analysis (TGA)

[0103] Thermogravimetric analysis (TGA) was performed using a TA Instruments Q500 thermogravimetric analyzer. An appropriate amount of sample was placed in a platinum sample pan, and the temperature was increased at a rate of 10 °C / min under a nitrogen atmosphere, ranging from 30 to 300 °C. In the TGA graph, the horizontal axis represents temperature (°C), and the vertical axis represents mass percentage (%).

[0104] 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.

[0105] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0106] The favipiravir crystal form α described in this invention is the 6-fluoro-3-hydroxy-2-pyrazinamide crystal form α described in CN201210535512.9 (in this invention, favipiravir crystal form α is used as a substitute).

[0107] Example 1: Preparation of favipiravir-isonin eutectic

[0108] Add favipiravir (100.0 mg) and 8.00 ml methanol to a 10 ml centrifuge tube. Add isonicotinic acid (1.0 g) and 3.00 ml methanol to a 5 ml centrifuge tube. Stir both at 25 °C and 200 rpm magnetically for approximately 6.0 h to obtain saturated suspensions of favipiravir and isonicotinic acid. Allow to separate into layers. Take 2.0 ml of the upper layer of the favipiravir saturated suspension and 2.0 ml of the upper layer of the isonicotinic acid saturated suspension and place them into 5 ml centrifuge tubes, respectively. Mix with magnetic stirring (200 rpm) and allow to stand at room temperature to evaporate the solvent, yielding 67.0 mg of favipiravir-isonicotinic acid eutectic solid. Samples were analyzed by XRPD, DSC, and TGA. The XRPD spectrum is shown in the attached figure. Figure 1 As shown, its DSC spectrum is basically as attached. Figure 2 As shown, its TGA spectrum and attached Figure 3 As shown.

[0109] Example 2: Preparation of favipiravir-urea eutectic

[0110] Favipiravir (100.0 mg) and 8.00 ml of methanol were added to a 10 ml centrifuge tube, and urea (1.0 g) and 3.00 ml of methanol were added to a 5 ml centrifuge tube. Both were stirred magnetically at 25°C and 200 rpm for approximately 6.0 h to obtain saturated suspensions of favipiravir and urea. After standing and separating the layers, 2.0 ml of the upper layer of the favipiravir saturated suspension and 2.0 ml of the upper layer of the urea saturated suspension were placed in separate 5 ml centrifuge tubes and mixed magnetically (200 rpm). The mixture was then allowed to stand at room temperature to evaporate the solvent, yielding 40.1 mg of favipiravir-urea eutectic solid. Samples were analyzed by XRPD, DSC, and TGA. The XRPD spectrum is shown in the attached figure. Figure 4 As shown, its DSC spectrum is basically as attached. Figure 5 As shown, its TGA spectrum is basically as attached. Figure 6 As shown.

[0111] Example 3: Preparation of favipiravir-o-aminobenzoic acid eutectic

[0112] Add 94.3 mg (0.60 mmol) of favipiravir and 4.0 ml of purified water to a 25 ml beaker. Stir at 80.0 °C and 200 rpm until completely dissolved. Then add 82.3 mg (0.60 mmol) of anthranilic acid and stir at 80.0 °C and 200 rpm until completely dissolved. Stop heating and allow the solution to cool to room temperature naturally. After stirring magnetically (200 rpm) for about 12 hours, filter to obtain 127.6 mg of favipiravir-anthranilic acid eutectic solid. Samples were taken for XRPD, DSC, and TGA analysis. The XRPD spectrum is shown in the attached figure. Figure 7 As shown, its DSC spectrum is basically as attached. Figure 8 As shown, its TGA spectrum is basically as attached. Figure 9 As shown.

[0113] Example 4: Preparation of favipiravir-isonin eutectic

[0114] Favipiravir (314.2 mg) and 13.5 ml of methanol were added to a 25 ml beaker. Isonicotinic acid (6.0 g) and 20.0 ml of methanol were added to the same 25 ml beaker. Both were stirred at 25°C and 200 rpm magnetically for approximately 6.0 h to obtain saturated suspensions of favipiravir and isonicotinic acid. After standing and separating the layers, 13.5 ml of the upper layer of the favipiravir saturated suspension and 13.5 ml of the upper layer of the isonicotinic acid saturated suspension were placed in 50 ml centrifuge tubes and mixed with magnetic stirring (200 rpm). The solvent was allowed to evaporate at room temperature, yielding 453.2 mg of favipiravir-isononicotinic acid eutectic solid. Samples were analyzed by XRPD, DSC, and TGA. The XRPD, DSC, and TGA spectra are consistent with the attached... Figure 1 -Appendix Figure 3 Consistent.

[0115] Example 5: Preparation of favipiravir-urea eutectic

[0116] Favipiravir (314.2 mg) and 13.5 ml of methanol were added to a 25 ml beaker, and urea (6.0 g) and 20.0 ml of methanol were added to another 25 ml beaker. Both were magnetically stirred at 25°C and 200 rpm for approximately 6.0 h to obtain saturated suspensions of favipiravir and urea. After standing and separating the layers, 13.5 ml of the supernatant from each of the favipiravir and urea suspensions was placed in 50 ml centrifuge tubes and mixed with magnetic stirring (200 rpm). The mixture was then allowed to stand at room temperature to evaporate the solvent, yielding 272.5 mg of favipiravir-urea eutectic solid. Samples were analyzed by XRPD, DSC, and TGA. The XRPD, DSC, and TGA spectra are consistent with the attached... Figure 4 -Appendix Figure 6 Consistent.

[0117] Example 6: Preparation of favipiravir-o-aminobenzoic acid

[0118] 314.2 mg (2.0 mmol) of favipiravir and 13.5 ml of purified water were added to a 25 ml beaker and completely dissolved under magnetic stirring at 80.0 °C and 200 rpm. Then, 274.3 mg (2.0 mmol) of anthranilic acid was added and thoroughly mixed and dissolved under magnetic stirring at 80.0 °C and 200 rpm. Heating was then stopped, and the solution was allowed to cool naturally to room temperature. After stirring magnetically (200 rpm) for approximately 12 hours, the mixture was filtered to obtain 425.4 mg of favipiravir-anthranilic acid eutectic solid. Samples were analyzed by XRPD, DSC, and TGA. The XRPD, DSC, and TGA spectra were consistent with those of the attached... Figure 7 -Appendix Figure 9 Consistent.

[0119] Comparative Example 1: Preparation of the novel favipiravir crystal form described in CN201711103203.3

[0120] Dissolve 7g of favipiravir in 100ml of ethanol, filter, and adjust the pH of the filtrate to 6 with 0.1mol / L hydrochloric acid or 0.1mol / L sodium hydroxide. Cool to -15℃ with stirring, at which point crystals precipitate. Add 300ml of ethanol to the solution at a flow rate of 1.8ml / min. After the addition is complete, adjust the pH of the solution to 6 again with 0.1mol / L hydrochloric acid or 0.1mol / L sodium hydroxide. Continue stirring at this temperature for 2 hours to allow crystals to grow for 2 hours. Filter to obtain the new crystal form of favipiravir described in CN201711103203.3.

[0121] Comparative Example 2: Preparation of favipiravir α crystal form in CN201210535512.9

[0122] Dissolve 4.0 g favipiravir in 20 ml methanol, heat under reflux in a water bath for 10 minutes, cool, and then place the solution in a constant temperature water bath at 25 °C. When crystals begin to precipitate, place the solution at -15 °C to crystallize. After filtration, dry under vacuum at 60 °C for 7 hours to obtain 3.6 g favipiravir α crystal form.

[0123] Example 7: Preparation of Favipiravir Tablets

[0124] Prescription: 200g (calculated as favipiravir) favipiravir crystal form (the new favipiravir crystal form obtained in Comparative Example 1 or favipiravir crystal form α obtained in Comparative Example 2) or favipiravir cocrystal (favipiravir-isonicotinic acid cocrystal, favipiravir-urea cocrystal or favipiravir-o-aminobenzoic acid cocrystal obtained in Examples 1-6), 35g microcrystalline cellulose, 15g lactose, 12g polyethylene glycol 6000, 1.0g sodium dodecyl sulfate, 1.8g magnesium stearate.

[0125] Favipiravir cocrystals (favipiravir-isonicotinic acid cocrystals, favipiravir-urea cocrystals, or favipiravir-o-aminobenzoic acid cocrystals obtained in Examples 1-6) and favipiravir crystal forms (the new favipiravir crystal form obtained in Comparative Example 1 or favipiravir crystal form α obtained in Comparative Example 2) were taken separately and favipiravir tablets were prepared according to the following method:

[0126] Step 1: Favipiravir crystal form or favipiravir eutectic is passed through a 100-mesh sieve, and microcrystalline cellulose, lactose, polyethylene glycol 6000, sodium dodecyl sulfate, and magnesium stearate are passed through an 80-mesh sieve.

[0127] Step 2: Weigh out the prescribed amount of favipiravir crystal form or favipiravir cocrystal, sodium dodecyl sulfate, polyethylene glycol 6000, half the prescribed amount of microcrystalline cellulose and half the prescribed amount of lactose, mix them well, granulate them with 30-40% ethanol solution as a wetting agent, dry them at 50℃, and pulverize them to pass through a 100-mesh sieve.

[0128] Step 3: The granules obtained in step 2 are mixed with the remaining half of the prescription amount of microcrystalline cellulose and the remaining half of the prescription amount of lactose, granulated with 30-40% ethanol solution as a wetting agent, dried at 50°C, and passed through an 80-mesh sieve.

[0129] Step 4: Add the prescribed amount of magnesium stearate to the granules obtained in step 3, mix well, and compress into tablets.

[0130] Example 8: Influencing Factor Experiment

[0131] In accordance with the guidelines for drug formulation stability testing, the favipiravir cocrystals (favipiravir-isonicotinic acid cocrystal, favipiravir-urea cocrystal, or favipiravir-o-aminobenzoic acid cocrystal) obtained in Examples 1-6 were subjected to influencing factor experiments, including high temperature test, high humidity test, and strong light irradiation test, to investigate the conditions affecting the stability of their crystal form.

[0132] High temperature test: Take an appropriate amount of favipiravir eutectic (favipiravir-isonicotinic acid eutectic, favipiravir-urea eutectic or favipiravir-o-aminobenzoic acid eutectic obtained in Examples 1-6), spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber at 60±5℃ and RH75±5%. Then, take about 10mg of the above sample at 5, 10 and 15 days respectively to test its crystal form.

[0133] High humidity test: Take an appropriate amount of favipiravir cocrystal (favipiravir-isonicotinic acid cocrystal, favipiravir-urea cocrystal or favipiravir-o-aminobenzoic acid cocrystal obtained in Examples 1-6), spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber at 25℃ and RH 92.5±5%. Then, take about 10mg of the above sample at 5, 10 and 15 days respectively to test its crystal form.

[0134] Light exposure test: Take an appropriate amount of favipiravir eutectic (favipiravir-isonicotinic acid eutectic, favipiravir-urea eutectic, or favipiravir-o-aminobenzoic acid eutectic obtained in Examples 1-6), spread it evenly in a weighing bottle, and expose it to visible light (4500 Lux ± 500 Lux) and ultraviolet light (1.7 W*h / m). 2 The samples were placed in a constant temperature and humidity chamber (25℃, RH 60±5%), and then approximately 10 mg of the samples were collected at 5, 10, and 15 days to test their crystal form. The results of the test on the influencing factors of favipiravir eutectic are shown in Table 1.

[0135] Table 1: Experimental Results of Factors Affecting Favipiravir Eutectic

[0136]

[0137]

[0138] Conclusion: Favipiravir-isonicotinic acid eutectic and favipiravir-o-aminobenzoic acid eutectic are stable under high temperature, high humidity and light conditions. Favipiravir-urea eutectic is stable under light conditions, but unstable under high temperature and high humidity conditions.

[0139] Example 9: Solubility Test in Water

[0140] Solubility test: Pre-weigh the flasks and stir bar. Accurately weigh each favipiravir eutectic or favipiravir α crystal form and add them separately to the flasks. Add water dropwise and stir magnetically at 200 rpm until the solid dissolves. Stop adding water. Complete dissolution is considered complete when no visible particles remain. After dissolution, weigh the total weight of the test tubes, stir bar, and aqueous solution. Calculate the weight of the added water and then calculate the solubility. The density of water is calculated as 1.00 g / mL. Test the solubility of the three eutectic samples and favipiravir α crystal form in water at 37℃. The results of the solubility test are shown in Table 2. The solubility test revealed that, compared to favipiravir α, the three cocrystals exhibited better wettability in water and could quickly and evenly mix with water, while favipiravir α partially floated on the water surface. In pure water at 37°C, the solubility of the favipiravir-isonicotinic acid cocrystal was approximately twice that of favipiravir α (calculated based on free favipiravir base), and the solubility of the favipiravir-urea cocrystal was also greater than that of favipiravir α (calculated based on free favipiravir base). The solubility results of each favipiravir cocrystal in purified water at 37.0°C are shown in Table 2.

[0141] Table 2: Experimental results of water solubility tests for favipiravir eutectic and favipiravir α-crystal.

[0142]

[0143] Conclusion: The three favipiravir cocrystals described in this invention exhibit better wettability than favipiravir crystal form α. In water at 37°C, the solubility of the favipiravir-isonicotinic acid cocrystal is approximately twice that of favipiravir crystal form α, and the solubility of the favipiravir-urea cocrystal is also greater than that of favipiravir crystal form α.

[0144] Example 10: Stability Study in Water

[0145] Stability study in water: 50.0 mg of each favipiravir cocrystal and 400 μl of purified water were added to 5 ml centrifuge tubes, respectively. The mixture was stirred at 37.0 ℃ and 200 rpm with magnetic stirring. Approximately 100 μl of each sample was taken at 1.0 h, 4.0 h and 12.0 h, filtered, and the crystal form of each sample was determined. The stability study results of each favipiravir cocrystal in purified water at 37.0 ℃ are shown in Table 3.

[0146] Table 3: Stability of various favipiravir cocrystals in purified water at 37.0℃

[0147]

[0148] Conclusion: The favipiravir-isonin cocrystal and the favipiravir-o-aminobenzoic acid cocrystal are stable in purified water at 37.0℃ for 12 hours, while the urea cocrystal readily transforms into the favipiravir α crystal form. This indicates that the favipiravir-isonin cocrystal and the favipiravir-o-aminobenzoic acid cocrystal have good water stability.

[0149] Example 11: Dissolution Test

[0150] According to the dissolution test method for tablets specified in the pharmacopoeia, the dissolution of each favipiravir tablet obtained in Example 7 was determined. 900 ml of 0.12 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 75 rpm. The dissolution was measured at 5 min, 10 min, 20 min, 30 min and 60 min. The results are shown in Table 4.

[0151] Table 4: Dissolution data of each favipiravir tablet obtained in Example 7

[0152]

[0153] Conclusion: Comparison of dissolution rates in 0.12 mol / L hydrochloric acid solution showed that the dissolution rate of the favipiravir-isonicotinic acid cocrystal tablets was significantly improved compared to the favipiravir α crystal form tablets, the anthranilic acid cocrystal tablets, the favipiravir-anthranilic acid cocrystal tablets, and the new favipiravir crystal form tablets of Comparative Example 1. The dissolution rate of the favipiravir-urea cocrystal tablets was comparable to that of the favipiravir α crystal form tablets and the new favipiravir crystal form tablets of Comparative Example 1. The dissolution rate of the anthranilic acid cocrystal tablets was lower than that of the other crystal forms and cocrystal tablets.

[0154] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A eutectic, characterized in that, The eutectic is a favipiravir-isonicotinic acid eutectic, and the X-ray powder diffraction pattern of the favipiravir-isonicotinic acid eutectic has characteristic peaks at diffraction angles 2θ: 7.10°±0.2°, 13.94°±0.2°, 14.16°±0.2°, 19.44°±0.2°, 21.26°±0.2°, 23.58°±0.2°, 27.09°±0.2° and 29.16°±0.2°.

2. The eutectic according to claim 1, characterized in that, The molar ratio of favipiravir to isonicotinic acid in the favipiravir-isonicotinic acid eutectic is 1:

1.

3. The eutectic according to claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 150–175 °C.

4. The eutectic according to claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 155–165 °C.

5. The eutectic according to claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of the favipiravir-isonicotinic acid eutectic exhibits an endothermic peak at 158–162 °C.

6. The eutectic according to claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of the favipiravir-isonicotinic acid eutectic showed an endothermic peak at 160 °C.

7. The eutectic according to claim 1, characterized in that, The favipiravir-isonicotinic acid eutectic has the differential scanning calorimetry spectrum shown in Figure 2.

8. The eutectic according to claim 1, characterized in that, The favipiravir-isonicotinic acid eutectic has the thermogravimetric analysis spectrum shown in Figure 3.

9. A method for preparing the eutectic as described in any one of claims 1-8, characterized in that, include: Favipiravir and the co-crystal ligand, wherein the co-crystal ligand is isonicotinic acid, are mixed with solvent and stirred to form a saturated suspension of favipiravir and a saturated suspension of the co-crystal ligand, respectively. After standing and separating into layers, equal volumes of the upper layer of the favipiravir saturated suspension and the upper layer of the co-crystal ligand saturated suspension are taken and mixed evenly. After standing and allowing the solvent to evaporate, the co-crystal is obtained.

10. The method according to claim 9, characterized in that, The solvent includes at least one selected from methanol, ethanol, n-propanol, and isopropanol.

11. The method according to claim 9, characterized in that, The stirring time is 2-12 hours; and / or the evaporation temperature is 10-40°C.

12. A pharmaceutical composition comprising the cocrystal of any one of claims 1-8 or the cocrystal obtained by the method of any one of claims 9-11, and Pharmaceutically acceptable carriers, diluents, or combinations thereof.

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