CN114075145A - A kind of favipiravir salt and its crystal form and preparation method - Google Patents

Abstract

The invention relates to favipiravir salt, a crystal form and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The salts of Favipiravir comprise Favipiravir L-lysine salt, Favipiravir L-arginine salt, Favipiravir L-histidine salt, Favipiravir tromethamine salt or Favipiravir piperazine salt, the salt form and the crystal form thereof have the advantages of high solubility, good solubility, high bioavailability, good stability and the like, and the preparation method has the advantages of simple operation, environmental protection, high yield and purity and the like.

Description

Favipiravir salt, crystal form and preparation method thereof

Technical Field

The invention belongs to the field of medicines, and relates to fapivoxil salt, a crystal form and a preparation method thereof.

Background

Favipiravir (T-705, Favipiravir, CAS No. 259793-96-9) has the chemical name 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, developed by fukushan chemical industry co.

The marketed preparation of favipiravir adopts a favipiravir crystal form alpha, the solubility of the crystal form is low, the preparation specification is large, the daily dosage is large, the preparation needs to be taken twice a day, each time is 1600mg (8 tablets), the preparation is very unfavorable for patients to take, and the compliance of the patients is not high.

CN201180055060.8 discloses Favipiravir sodium salt and a crystal form thereof, but the crystal form of the sodium salt has low solubility and low melting point, is not easy to crush during preparation, is easy to dehydrate and transform into crystal by heating, and is easy to soften and deteriorate. In general, the solubility of the amorphous form in water is better than that of the crystal, but the solubility of the freeze-dried preparation prepared by using the amorphous form of the salt is poor, and after a dissolving solution is added to the freeze-dried preparation, the freeze-dried cake becomes a difficultly soluble block and takes a long time to dissolve (see the description of the prior art of CN 111214446A).

CN201180055096.6 discloses meglumine salt and a crystal form thereof, but researches show that the hydrate of the meglumine salt is poor in stability, is easy to be converted into a crystal of an anhydrate, and the crystal form of the anhydrate is strong in hygroscopicity and poor in stability.

Therefore, there is still a need to research a pharmaceutically acceptable faviravir salt and a crystal form thereof of faviravir with high solubility and good stability, so as to obtain a salt and a crystal form with more convenience in use and a method with simple operation, easy implementation, high yield, high purity, low cost and environmental friendliness.

Disclosure of Invention

In order to solve the problems, the invention provides a favipiravir salt, a crystal form, a preparation method and an application thereof.

In a first aspect, the present invention provides a salt of favipiravir.

A salt of Favipiravir, said Favipiravir salt comprising Favipiravir tromethamine salt, Favipiravir L-lysine salt, Favipiravir L-arginine salt, Favipiravir L-histidine salt or Favipiravir piperazine salt.

The salt of favipiravir may be in crystalline form or in amorphous form. In some embodiments, the salts of favipiravir are in crystalline form, which is more advantageous for preparation and use. In some embodiments, the salt of favipiravir includes a crystalline form of favipiravir tromethamine salt, a crystalline form of favipiravir L-lysine salt, a crystalline form of favipiravir L-arginine salt, a crystalline form of favipiravir L-histidine salt, or a crystalline form of favipiravir piperazine salt.

According to embodiments of the present invention, the salts of favipiravir and/or the salts of favipiravir in crystalline form include: a Favipiravir tromethamine crystal form I, a Favipiravir L-lysine salt crystal form II, a Favipiravir L-arginine salt crystal form I, a Favipiravir L-histidine salt crystal form I or a Favipiravir piperazine salt crystal form I.

According to some embodiments of the invention, the crystalline form of fapirovir L-lysine salt comprises or is fapirovir L-lysine salt crystalline form I or fapirovir L-lysine salt crystalline form II.

The X-ray powder diffraction pattern of the Favipiravir L-lysine salt crystal form I is shown in the specification that the diffraction angle is 2 theta: characteristic peaks are present at 7.92 ° ± 0.2 °, 16.63 ° ± 0.2 ° and 20.72 ° ± 0.2 °. In some embodiments, the fapirovir L-lysine salt form I has an X-ray powder diffraction pattern that varies fromdiffraction angle 2 Θ: characteristic peaks are found at 7.92 ° ± 0.2 °, 13.36 ° ± 0.2 °, 14.39 ° ± 0.2 °, 16.63 ° ± 0.2 °, 20.72 ° ± 0.2 °, 25.17 ° ± 0.2 °, 26.85 ° ± 0.2 °, 28.52 ° ± 0.2 °, 29.88 ° ± 0.2 ° and 33.81 ° ± 0.2 °.

The crystalline form I of fapirovir L-lysine salt has an X-ray powder diffraction pattern substantially as shown in figure 1.

In a differential scanning calorimetry spectrum of the Lapirovir L-lysine salt crystal form I, an endothermic peak and an exothermic peak are arranged at the temperature of 150-250 ℃, the peak value of the endothermic peak is 185-195 ℃, and the peak value of the exothermic peak is 210-220 ℃.

The crystalline form I of fapirovir L-lysine salt has a differential scanning calorimetry pattern substantially as shown in figure 2.

The crystalline form I of fapirovir L-lysine salt has a thermogravimetric analysis profile substantially as shown in figure 3.

The X-ray powder diffraction pattern of the Favipiravir L-lysine salt crystal form II is shown in the specification that the diffraction angle is 2 theta: characteristic peaks are provided at 7.87 DEG +/-0.2 DEG, 15.88 DEG +/-0.2 DEG, 16.26 DEG +/-0.2 DEG, 18.07 DEG +/-0.2 DEG, 18.90 DEG +/-0.2 DEG, 20.52 DEG +/-0.2 DEG, 23.04 DEG +/-0.2 DEG, 27.94 DEG +/-0.2 DEG and 34.98 DEG +/-0.2 deg.

The X-ray powder diffraction pattern of the Favipiravir L-lysine salt crystal form II is shown in the specification that the diffraction angle is 2 theta: the angle of incidence of the light beam at the angles of incidence of the light beam at the angles of incidence of the light beam at the angles of incidence of the angles of the light beam at the angles of incidence of the angles of the light beam at the angles of incidence of the light beam at the angles of the light beam at the angles of incidence of the angles of the light beam at the angles of incidence of the light beam at the angles of incidence of the angles of incidence of the angles of incidence of the light beam at the angles of incidence of the angles of incidence of the angles of the light beam at the angles of incidence of the angles of the light beam at the angles of incidence of the angles of incidence of the angles of the light beam at the angles of incidence of the angles of the light beam at the angles of incidence of the angles of the.

The crystalline form II fapirovir L-lysine salt has an X-ray powder diffraction pattern substantially as shown in figure 4.

In a differential scanning calorimetry spectrum of the Lapirovir L-lysine salt crystal form II, an endothermic peak and an exothermic peak are arranged at the temperature of 150-250 ℃, the peak value of the endothermic peak is 175-185 ℃, and the peak value of the exothermic peak is 200-210 ℃.

The crystalline form II fapirovir L-lysine salt has a differential scanning calorimetry analysis pattern substantially as shown in figure 5.

The crystalline form II of fapirovir L-lysine salt has a thermogravimetric analysis profile substantially as shown in figure 6.

In some embodiments, the crystalline form of fapirovir L-arginine salt is fapirovir L-arginine salt form I.

The X-ray powder diffraction pattern of the crystalline form I of the Favipiravir L-arginine is shown in the specification that the diffraction angle is 2 theta: characteristic peaks are present at 7.13 ° ± 0.2 °, 9.42 ° ± 0.2 °, 10.87 ° ± 0.2 °, 18.77 ° ± 0.2 °, 18.97 ° ± 0.2 °, 19.75 ° ± 0.2 °, 23.65 ° ± 0.2 °, 28.80 ° ± 0.2 ° and 30.61 ° ± 0.2 °.

The X-ray powder diffraction pattern of the crystalline form I of the Favipiravir L-arginine is shown in the specification that the diffraction angle is 2 theta: the angle of 7.angle of the angle of 7.angle of the angle of the.

The crystalline form I of fapirovir L-arginine has an X-ray powder diffraction pattern substantially as shown in figure 7.

In a differential scanning calorimetry spectrum of the Lapiravir L-arginine crystal form I, an endothermic peak and an exothermic peak are arranged at the temperature of 150-.

The crystalline form I of fapirovir L-arginine has a differential scanning calorimetry analysis pattern substantially as shown in figure 8.

The crystalline form I of fapirovir L-arginine has a thermogravimetric analysis profile substantially as shown in figure 9.

In some embodiments, the crystalline form of fapirovir L-histidine salt is fapirovir L-histidine salt form I.

The X-ray powder diffraction pattern of the Favipiravir L-histidine salt crystal form I is shown in the specification that the diffraction angle is 2 theta: 11.59 DEG +/-0.2 DEG, 12.44 DEG +/-0.2 DEG, 13.34 DEG +/-0.2 DEG, 18.25 DEG +/-0.2 DEG, 20.32 DEG +/-0.2 DEG, 22.14 DEG +/-0.2 DEG, 26.40 DEG +/-0.2 DEG and 30.20 DEG +/-0.2 DEG.

The X-ray powder diffraction pattern of the Favipiravir L-histidine salt crystal form I is shown in the specification that the diffraction angle is 2 theta: 11.59 DEG + -0.2 DEG, 12.44 DEG + -0.2 DEG, 13.34 DEG + -0.2 DEG, 14.02 DEG + -0.2 DEG, 14.97 DEG + -0.2 DEG, 18.25 DEG + -0.2 DEG, 20.32 DEG + -0.2 DEG, 20.77 DEG + -0.2 DEG, 22.14 DEG + -0.2 DEG, 23.21 DEG + -0.2 DEG, 23.78 DEG + -0.2 DEG, 24.38 DEG + -0.2 DEG, 25.61 DEG + -0.2 DEG, 26.40 DEG + -0.2 DEG, 27.76 DEG + -0.2 DEG, 30.20 DEG + -0.2 DEG, 30.58 DEG + -0.2 DEG, 32.34 DEG + -0.2 DEG, 33.07 DEG + -0.2 DEG and 38.48 DEG + -0.2 DEG have characteristic peaks.

The crystalline form I of fapirovir L-histidine salt has an X-ray powder diffraction pattern substantially as shown in figure 10.

In a differential scanning calorimetry spectrum of the crystalline form I of the Lapiravir L-histidine salt, 2 endothermic peaks are formed at the temperature of 110-180 ℃, and the peak values of the endothermic peaks are respectively at the temperature of 120-135 ℃ and at the temperature of 160-170 ℃.

The crystalline form I of fapirovir L-histidine salt has a differential scanning calorimetry pattern substantially as shown in figure 11.

The crystalline form I of fapirovir L-histidine salt has a thermogravimetric analysis profile substantially as shown in figure 12.

In some embodiments, the crystalline form of fapivoxil salt is fapivoxil salt form I.

The X-ray powder diffraction pattern of the Favipiravir tromethamine salt crystal form I is characterized in that thediffraction angle 2 theta: characteristic peaks are present at 8.23 ° ± 0.2 °, 10.68 ° ± 0.2 °, 14.41 ° ± 0.2 °, 18.33 ° ± 0.2 °, 25.62 ° ± 0.2 °, 27.51 ° ± 0.2 °, 28.76 ° ± 0.2 °, 31.25 ° ± 0.2 ° and 33.46 ° ± 0.2 °.

The X-ray powder diffraction pattern of the Favipiravir tromethamine salt crystal form I is characterized in that thediffraction angle 2 theta: the peak characteristics of the angles at 8.23 +/-0.2 DEG, 10.68 +/-0.2 DEG, 12.48 +/-0.2 DEG, 14.41 +/-0.2 DEG, 16.47 +/-0.2 DEG, 17.34 +/-0.2 DEG, 18.33 +/-0.2 DEG, 19.69 +/-0.2 DEG, 21.00 +/-0.2 DEG, 21.47 +/-0.2 DEG, 21.84 +/-0.2 DEG, 24.12 +/-0.2 DEG, 24.81 +/-0.2 DEG, 25.17 +/-0.2 DEG, 25.62 +/-0.2 DEG, 26.12 +/-0.2 DEG, 27.51 +/-0.2 DEG, 28.76 +/-0.2 DEG, 30.34 +/-0.2 DEG, 31.25 +/-0.2 DEG, 32.01 +/-0.2 DEG, 32.45 +/-0.2 DEG, 33.46 +/-0.2 DEG and 34.23 +/-0.2 DEG.

The fapirovir tromethamine salt form I has an X-ray powder diffraction pattern substantially as shown in figure 13.

In a differential scanning calorimetry spectrum of the valaciclovir tromethamine salt crystal form I, an endothermic peak and an exothermic peak are arranged at the temperature of 190-230 ℃, the peak value of the endothermic peak is 195-205 ℃, and the peak value of the exothermic peak is 205-215 ℃.

The fapirovir tromethamine salt form I has a differential scanning calorimetry analysis pattern substantially as shown in figure 14.

The crystalline form I of fapirovir tromethamine salt has a thermogravimetric analysis profile substantially as shown in figure 15.

In some embodiments, the crystalline form of fapivoxil is fapivoxil salt form I.

The X-ray powder diffraction pattern of the Favipiravir piperazine salt crystal form I is shown in the specification that the diffraction angle is 2 theta: characteristic peaks are found at 10.96 ° ± 0.2 °, 12.51 ° ± 0.2 °, 21.40 ° ± 0.2 °, 23.30 ° ± 0.2 ° and 26.36 ° ± 0.2 °.

The X-ray powder diffraction pattern of the Favipiravir piperazine salt crystal form I is shown in the specification that the diffraction angle is 2 theta: characteristic peaks are provided at 10.32 ° ± 0.2 °, 10.96 ° ± 0.2 °, 12.51 ° ± 0.2 °, 17.83 ° ± 0.2 °, 19.07 ° ± 0.2 °, 19.57 ° ± 0.2 °, 19.85 ° ± 0.2 °, 20.79 ° ± 0.2 °, 21.40 ° ± 0.2 °, 22.65 ° ± 0.2 °, 23.30 ° ± 0.2 °, 23.72 ° ± 0.2 °, 25.21 ° ± 0.2 °, 26.36 ° ± 0.2 °, 27.31 ° ± 0.2 °, 28.31 ° ± 0.2 °, 28.94 ° ± 0.2 °, 30.19 ° ± 0.2 °, 30.97 ° ± 0.2 °, 35.36 ° ± 0.2 ° and 36.40 ° ± 0.2 °.

In a differential scanning calorimetry spectrum of the crystal form I of the Favipiravir piperazine salt, an endothermic peak and an exothermic peak are arranged at the temperature of 150-250 ℃, the peak value of the endothermic peak is 185-195 ℃, and the peak value of the exothermic peak is 210-220 ℃.

In a second aspect, the present invention provides a process for preparing the aforementioned fapirovir L-lysine salt, fapirovir L-arginine salt or fapirovir L-histidine salt.

A process for preparing the aforementioned favipiravir L-lysine salt, favipiravir L-arginine salt, or favipiravir L-histidine salt, comprising: dissolving Favipiravir in a solvent A to obtain a Favipiravir solution; dissolving a salt forming agent in water to obtain a salt forming agent solution; mixing the salifying agent solution with the Favipiravir solution, stirring to form a solid, and filtering to obtain the Favipiravir L-lysine salt, the Favipiravir L-arginine salt or the Favipiravir L-histidine salt; the salt forming agent comprises L-lysine, L-arginine or L-histidine.

In some embodiments, the mixing mode is to add the salt forming agent solution into the favipiravir solution for mixing, and by adopting the mixing mode, the favipiravir and the salt forming agent can be fully combined, and the yield of the obtained product is high. In some embodiments, the mixing is performed by adding the salt forming agent solution to the favipiravir solution in batches, and the favipiravir and the salt forming agent can be fully combined by adopting the mixing mode, so that the yield of the obtained product is higher.

The solvent A comprises at least one of methanol, ethanol, n-propanol or isopropanol.

The mass-volume ratio of the fapirovir to the solvent A can be 10-100 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 15 to 80 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 20-60 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 20-40 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 25 to 35 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 10 to 30 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 10-20 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 20-50 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent a is 30-50 mg/ml.

The feeding molar ratio of the salt forming agent to the Favipiravir can be 0.5:1-2: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.8:1 to 1.5: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.9:1 to 1.2: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is 1: 1.

The dissolution temperature of the favipiravir can be 0-80 ℃. In some embodiments, the favipiravir has a dissolution temperature of 10 to 70 ℃. In some embodiments, the favipiravir has a dissolution temperature of 20 to 60 ℃. In some embodiments, the favipiravir has a dissolution temperature of 25 to 50 ℃. In some embodiments, the favipiravir has a dissolution temperature of 25 to 40 ℃. In some embodiments, the favipiravir has a dissolution temperature of 25 to 30 ℃.

The mass volume ratio of the salt forming agent to the water can be 10-150 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 10-100 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 15-90 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 20-80 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 30-80 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 40-80 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 50-70 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 55-65 mg/ml. In some embodiments, the mass to volume ratio of the salt forming agent to water is 60 mg/ml.

The dissolution temperature of the salt forming agent may be 20-40 ℃. In some embodiments, the salt forming agent has a dissolution temperature of 20-30 ℃. In some embodiments, the salt forming agent has a dissolution temperature of 25-35 ℃. In some embodiments, the salt forming agent has a dissolution temperature of 25-35 ℃. In some embodiments, the salt forming agent has a dissolution temperature of 30-35 ℃.

The temperature of the stirring may be 20-40 ℃. In some embodiments, the temperature of the agitation is 20-30 ℃. In some embodiments, the dissolution temperature of the salt forming agent and/or the temperature of the agitation is 25-35 ℃. In some embodiments, the temperature of the agitation is 25-35 ℃. In some embodiments, the temperature of the agitation is 30-35 ℃.

The stirring time can be 2.0-24.0 h. In some embodiments, the stirring time is 3.0 to 20.0 hours. In some embodiments, the stirring time is 4.0 to 18.0 hours. In some embodiments, the stirring time is from 5.0 to 16.0 hours. In some embodiments, the stirring time is 8.0 to 16.0 hours. In some embodiments, the stirring time is 10.0-14.0 hours. In some embodiments, the stirring time is 10.0 to 12.0 hours.

According to some embodiments of the invention, the mass to volume ratio of favipiravir to solvent a is 15-27mg/ml and the mass to volume ratio of the salifying agent to water is 30-50mg/ml, the crystalline form of the resulting favipiravir L-lysine salt is favipiravir L-lysine salt crystalline form I.

According to some embodiments of the invention, the mass to volume ratio of favipiravir to solvent a is 28-50mg/ml and the mass to volume ratio of the salifying agent to water is 60-100mg/ml, the crystalline form of the resulting favipiravir L-lysine salt is favipiravir L-lysine salt crystalline form II.

In some embodiments, a process for preparing the aforementioned fapirovir L-lysine salt, fapirovir L-arginine salt, or fapirovir L-histidine salt, comprises: dissolving Favipiravir in a solvent A to obtain a Favipiravir solution, dissolving a salt forming agent in water to obtain a salt forming agent solution, adding the salt forming agent solution into the Favipiravir solution, mixing, stirring, crystallizing, and filtering to obtain the Favipiravir salt, wherein the salt forming agent comprises L-lysine, L-arginine or L-histidine; the solvent A comprises at least one of methanol, ethanol, n-propanol or isopropanol; the mass volume ratio of the Favipiravir to the solvent A is 10-100 mg/ml; the feeding molar ratio of the salt forming agent to the Favipiravir is 0.5:1-2: 1; the dissolving temperature of the Favipiravir is 0-80 ℃; the mass volume ratio of the salt forming agent to water is 10-150 mg/ml; the dissolving temperature of the salt forming agent is 20-40 ℃, and the stirring temperature is 20-40 ℃; the stirring time is 2.0-24.0 h; the obtained salt of the Favipiravir is Favipiravir L-lysine salt in a crystal form, Favipiravir L-arginine salt in a crystal form or Favipiravir L-histidine salt in a crystal form.

In some embodiments, a process for preparing the aforementioned crystalline form I of fapirovir L-lysine salt, comprises: dissolving Favipiravir in a solvent A to obtain a Favipiravir solution, dissolving a salt forming agent in water to obtain a salt forming agent solution, adding the salt forming agent solution into the Favipiravir solution, mixing, stirring, crystallizing, and filtering to obtain the Favipiravir L-lysine salt crystal form I, wherein the salt forming agent is L-lysine; the solvent A comprises at least one of methanol, ethanol, n-propanol or isopropanol; the mass volume ratio of the Favipiravir to the solvent A is 15-27mg/ml, the mass volume ratio of the salifying agent to water is 30-50mg/ml, and the obtained crystal form of the Favipiravir L-lysine salt is a Favipiravir L-lysine salt crystal form I; the feeding molar ratio of the salt forming agent to the Favipiravir is 0.5:1-2: 1; the dissolving temperature of the Favipiravir is 0-80 ℃; the mass volume ratio of the salt forming agent to water is 10-150 mg/ml; the dissolving temperature of the salt forming agent is 20-40 ℃; the stirring temperature is 20-40 ℃; the stirring time is 2.0-24.0 h.

In some embodiments, a process for preparing the aforementioned crystalline form II of fapirovir L-lysine salt, comprises: dissolving Favipiravir in a solvent A to obtain a Favipiravir solution, dissolving a salt forming agent in water to obtain a salt forming agent solution, adding the salt forming agent solution into the Favipiravir solution, mixing, stirring, crystallizing, and filtering to obtain the Favipiravir L-lysine salt crystal form II, wherein the salt forming agent is L-lysine; the solvent comprises at least one of methanol, ethanol, n-propanol or isopropanol; the mass-volume ratio of the Favipiravir to the solvent A is 28-50mg/ml, and the mass-volume ratio of the salt forming agent to the water is 60-100 mg/ml; the feeding molar ratio of the salt forming agent to the Favipiravir is 0.5:1-2: 1; the dissolving temperature of the Favipiravir is 0-80 ℃; the dissolving temperature of the salt forming agent is 20-40 ℃; the stirring temperature is 20-40 ℃; the stirring time is 2.0-24.0 h.

In a third aspect, the invention provides a preparation method of the fapivoxil salt or the fapivoxil piperazine salt.

A method for preparing Favipiravir tromethamine salt or Favipiravir piperazine salt comprises the steps of mixing Favipiravir, a salt forming agent and a solvent B, stirring and filtering to obtain Favipiravir salt; the salt forming agent comprises tromethamine or piperazine.

The solvent B comprises at least one of methanol, ethanol, n-propanol or isopropanol.

The mass-volume ratio of the Favipiravir to the solvent B can be 10-100 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 10 to 100 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 10 to 100 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 15 to 80 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 20-60 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 20-50 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 20-40 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 25-35 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to solvent B is 30 mg/ml.

The feeding molar ratio of the salt forming agent to the Favipiravir can be 0.5:1-2: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.6:1 to 1.9: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.7:1 to 1.8: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.8:1 to 1.7: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.8:1 to 1.6: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.8:1 to 1.5: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.9:1 to 1.3: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is from 0.9:1 to 1.2: 1. In some embodiments, the dosing molar ratio of the salt forming agent to favipiravir is 1.0:1 to 1.1: 1.

The temperature of the stirring may be 20-40 ℃. In some embodiments, the temperature of the agitation is 20-30 ℃. In some embodiments, the temperature of the agitation is 25-35 ℃. In some embodiments, the temperature of the agitation is 25-35 ℃. In some embodiments, the temperature of the agitation is 30-35 ℃.

The stirring time can be 2.0-24.0 h. In some embodiments, the stirring time is 3.0 to 20.0 hours. In some embodiments, the stirring time is 4.0 to 18.0 hours. In some embodiments, the stirring time is from 5.0 to 16.0 hours. In some embodiments, the stirring time is 8.0 to 16.0 hours. In some embodiments, the stirring time is 10.0-14.0 hours. In some embodiments, the stirring time is 10.0 to 12.0 hours.

In some embodiments, a process for preparing the aforementioned crystalline form I of fapirovir tromethamine salt comprises mixing fapirovir and tromethamine with solvent B, stirring, filtering to obtain said crystalline form I of fapirovir tromethamine salt; the solvent B comprises at least one of methanol, ethanol, n-propanol or isopropanol; the mass volume ratio of the Favipiravir to the solvent B is 10-100 mg/ml; the feeding molar ratio of the tromethamine to the Favipiravir is 0.5:1-2: 1; the stirring temperature is 20-40 ℃; the stirring time is 2.0-24.0 h.

In some embodiments, a process for preparing fapirovir tromethamine salt form I as described above, comprises mixing fapirovir and tromethamine with solvent B, stirring, and filtering to obtain the fapirovir salt; the solvent comprises at least one of methanol, ethanol, n-propanol or isopropanol; the mass volume ratio of the Favipiravir to the solvent B is 25-35 mg/ml; the feeding molar ratio of the tromethamine to the Favipiravir is 1.0:1-1.1: 1; the stirring temperature is 20-40 ℃; the stirring time is 8.0-16.0 h.

In a fourth aspect, the present invention provides a composition comprising a salt of any of the foregoing fapivoxil.

A pharmaceutical composition comprising at least one of a salt of favipiravir of the first aspect, a salt of favipiravir of the second aspect or the third aspect, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

The composition can be prepared into pharmaceutically acceptable preparations such as injection, powder, tablets, capsules, granules or dry suspension and the like.

In a fifth aspect, the present invention provides a use of a salt of fapivoxil or a pharmaceutical composition as described above.

Use of a salt of favipiravir according to the first aspect, a salt of favipiravir according to the second or third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for preventing, treating, or ameliorating a disease or infection caused by influenza virus, coronavirus (including COVID-19 and SARS), hepatitis c, or bovine diarrhea virus.

Advantageous effects

Compared with the prior art, the invention has the following beneficial technical effects:

(1) the favipiravir salt provided by the invention has high solubility and good crystal form stability;

(2) the Favipiravir tromethamine salt crystal form I provided by the invention has the advantages of high solubility, high bioavailability, good crystal form stability, good stability of related substances and the like, and a preparation prepared by using the Favipiravir tromethamine salt crystal form I has the advantages of high bioavailability, small preparation specification, convenience in taking, good stability, long validity period and the like;

(3) the preparation method provided by the invention has the advantages of good reproducibility, simple operation, environmental protection, high yield and purity and the like;

(4) the pharmaceutical composition provided by the invention has the advantages of high bioavailability, small preparation specification, convenience in taking, good stability, long validity period and the like.

Description of the terms

In the present invention, mmol means mmol, h means hour, g means g, μ l means microliter, ml means ml, deg.C means centigrade, mg means milligram, rpm means rpm.

"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to a temperature of from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" refers to 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, and the like.

The term "pharmaceutically acceptable" as used herein refers to a substance that is acceptable from a toxicological point of view for pharmaceutical applications and does not adversely interact with the active ingredient.

"crystalline form" or "crystal form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.

"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, and is characterized by a diffuse, non-peaked, X-ray powder diffraction pattern. Amorphous is a particular physical form of solid material, with locally ordered structural features suggesting a myriad of connections to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.

"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).

By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"solvate" means having a solvent on the surface, in the crystal lattice, or both, which solvent may be water, … …, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.

Crystalline forms or amorphous forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program₂O₃) The energy difference therebetween varies with temperature. 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. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The melting peak has a tolerance of + -3 deg.C depending on the condition of the instrument used in the test.

Glass transition refers to the transition of an amorphous substance between a high elastic state and a glassy state, and is the inherent property of the substance; the transition temperature corresponds to the glass transition temperature (Tg), which is an important physical property of an amorphous substance. Glass transition is a phenomenon related to molecular motion, and thus, the glass transition temperature (Tg) is mainly dependent on the structure of a substance, and is relatively insensitive to experimental details and the like. The melting peak has a tolerance of + -3 deg.C depending on the condition of the instrument used in the test.

Differential Scanning Calorimetry (DSC) can also be used for detecting and analyzing whether the crystal form has crystal transformation or crystal mixing phenomenon.

Solids of the same chemical composition often form isomeric, or referred to as metamorphosis, isomers of different crystal structures under different thermodynamic conditions, and this phenomenon is called polymorphism or homomultiphase phenomenon. When the temperature and pressure conditions are changed, the variants are transformed into each other, and the phenomenon is called crystal transformation. Due to the crystal form transformation, the mechanical, electrical, magnetic and other properties of the crystal can be changed greatly. When the temperature of crystal form transformation is in a measurable range, the transformation process can be observed on a Differential Scanning Calorimetry (DSC) chart, and the DSC chart is characterized in that the DSC chart has an exothermic peak reflecting the transformation process and simultaneously has two or more endothermic peaks which are respectively characteristic endothermic peaks of different crystal forms before and after transformation.

Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.

In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).

The term "substantially 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 in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.

When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.

"relative intensity" refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in an X-ray powder diffraction pattern (XRPD).

In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.

Drawings

Figure 1 shows an XRPD spectrum of favipiravir L-lysine salt form I;

figure 2 shows a DSC profile of favipiravir L-lysine salt form I;

figure 3 shows a TGA profile of crystalline form I of valprazvir L-lysine salt;

figure 4 shows an XRPD spectrum of favipiravir L-lysine salt form II;

FIG. 5 shows a DSC spectrum of crystalline form II of Favipiravir L-lysine salt;

figure 6 shows a TGA profile of crystalline form II of valprazvir L-lysine salt;

figure 7 shows an XRPD spectrum of favipiravir L-arginine salt form I;

figure 8 shows a DSC profile of valprazvir L-arginine salt form I;

figure 9 is a TGA profile of valprazvir L-arginine salt form I;

FIG. 10 is an XRPD spectrum of Favipiravir L-histidine salt form I;

FIG. 11 is a DSC spectrum of Favipiravir L-histidine salt form I;

FIG. 12 is a TGA spectrum of morpheme of pyrroside L-histidine salt form I;

FIG. 13 is an XRPD spectrum of Favipiravir tromethamine salt form I;

FIG. 14 is a DSC spectrum of favipiravir tromethamine salt form I;

figure 15 shows a TGA profile of valprazvir tromethamine salt form I.

Detailed Description

Instrument parameters, test conditions and characterization results

All analyses below were performed at room temperature unless otherwise specified in the parameters.

X-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with anautomated 3X 15 zero background sample holder. The radiation source used was a source of radiation of (Cu, k α,

1.540598；

1.544426, respectively; theK alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10mm, with a theta-theta continuous scanning mode, yielding an effective 2 theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate is diffraction intensity expressed in counts (counts), and the abscissa isdiffraction angle 2 θ expressed in degrees (°).

Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter Q2000. The sample (about 1mg to 3mg) was placed in an aluminum pan and the weight was accurately recorded. The pan was covered with a lid and then crimped and the sample was transferred to the instrument for measurement. The sample cell was equilibrated at 30 deg.C and heated to a final temperature of 300 deg.C at a rate of 10 deg.C/min under a nitrogen purge. In the DSC chart, the abscissa represents Temperature (DEG C) and the ordinate represents the Heat Flow (W/g) released per unit mass of a substance.

Thermogravimetric analysis (TGA)

Thermogravimetric analysis was performed using a TA Instruments thermogravimetric analyzer Q500, placing the appropriate amount of sample in a platinum sample pan, and increasing the temperature at a rate of 10 ℃/min under nitrogen atmosphere, with a temperature range of 30 to 300 ℃. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents mass percent (Weight%). In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.

Method for detecting substance concerned

The method adopts high performance liquid chromatography to detect the related substances of the Pilarvir, and the chromatographic conditions are as follows: a chromatographic column: octadecylsilane chemically bonded silica gel column (Agela MP C18(2) (4.6 x 250mm,5 μm),column temperature 25 deg.C, mobile phase 0.6% trifluoroacetic acid aqueous solution (pH adjusted to 2.6 with triethylamine) -acetonitrile (92:8), flow rate 1.0ml/min,injection volume 20 μ l, detector UV detector (wavelength 323nm), system applicability that separation degree between chromatographic peak of impurity E (6-fluoro-3-hydroxypyrazinyl-2-carboxylic acid) and chromatographic peak of Favipiravir should not be less than 4.0, theoretical plate number is not less than 3000 according to Favipiravir peak, Favipiravir with purity more than 99.5% and its impurity as reference substance can be used for determination, known impurity and unknown impurity in composition or crude drug can be quantitatively calculated according to main component self dilution control method.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

The crystal form alpha of favipiravir is prepared according to the method disclosed in the patent application CN 102977039B.

Example 1

Taking 94.2mg of favipiravir and 4.0ml of methanol, mixing, and stirring under the conditions of about 35.0 ℃ and magnetic stirring at 200rpm until the mixture is completely dissolved to obtain a methanol solution of the favipiravir. 87.8mg of L-lysine and 2.0mL of purified water were mixed, and stirred at 25.0 ℃ under magnetic stirring at 200rpm until completely dissolved to obtain an aqueous solution of L-lysine. Dropwise adding an aqueous solution of L-lysine into a methanol solution of Favipiravir, stirring for 12h, filtering to obtain 94.0mg Favipiravir L-lysine salt (light brown solid), and performing XRPD (X-ray diffraction pattern), DSC (differential scanning calorimetry) and TGA (TGA) detection on the obtained Favipiravir L-lysine salt respectively, wherein the XRPD spectrum is basically shown in the attached figure 1, the DSC spectrum is basically shown in the attached figure 2, and the TGA spectrum is basically shown in the attached figure 3, and is the Favipiravir L-lysine salt crystal form I.

Example 2

Taking 94.2mg of favipiravir and 3.0ml of methanol, mixing, and stirring under the conditions of 40.0 ℃ and 200rpm magnetic stirring until the mixture is completely dissolved to obtain a methanol solution of the favipiravir. 87.8mg of L-lysine and 1.0mL of purified water were mixed, and stirred at 25.0 ℃ under magnetic stirring at 200rpm until completely dissolved to obtain an aqueous solution of L-lysine. Dropwise adding an aqueous solution of L-lysine into a methanol solution of Favipiravir, stirring for 12h, filtering to obtain 92.5mg Favipiravir L-lysine salt (light brown solid), and performing XRPD (X-ray diffraction pattern), DSC (differential scanning calorimetry) and TGA (TGA) detection on the obtained Favipiravir L-lysine salt respectively, wherein the XRPD spectrum is basically shown in figure 4, the DSC spectrum is basically shown in figure 5, and the TGA spectrum is basically shown in figure 6, and is the Favipiravir L-lysine salt crystal form II.

Example 3

Taking 94.2mg of favipiravir and 4.0ml of methanol, mixing, and stirring under the conditions of 35.0 ℃ and 200rpm magnetic stirring until the mixture is completely dissolved to obtain a methanol solution of the favipiravir. Mixing 104.6mg of L-arginine with 2.0mL of purified water, and stirring at 25.0 ℃ and 200rpm under magnetic stirring until the L-arginine is completely dissolved to obtain an L-arginine aqueous solution. Dropwise adding an aqueous solution of L-arginine into a methanol solution of Favipiravir, stirring for 12h, filtering to obtain 81.1mg Favipiravir L-arginine salt (white solid), and performing XRPD (X-ray diffraction pattern), DSC (differential scanning calorimetry) and TGA (TGA) detection on the obtained Favipiravir L-arginine salt respectively, wherein the XRPD spectrum is basically shown in the attached figure 7, the DSC spectrum is basically shown in the attached figure 8, and the TGA spectrum is basically shown in the attached figure 9, so that the Favipiravir L-arginine salt crystal form I is obtained.

Example 4

Taking 94.2mg of favipiravir and 4.0ml of methanol, mixing, and stirring under the conditions of 35.0 ℃ and 200rpm magnetic stirring until the mixture is completely dissolved to obtain a methanol solution of the favipiravir. 93.0mg of L-histidine and 2.0mL of purified water were mixed, and stirred at 25.0 ℃ under magnetic stirring at 200rpm until the mixture was completely dissolved to obtain an L-histidine aqueous solution. Dropwise adding an aqueous solution of L-histidine into a methanol solution of Favipiravir, stirring for 12h, filtering to obtain 166.1mg Favipiravir L-histidine salt (white solid), and respectively carrying out XRPD, DSC and TGA detection on the obtained Favipiravir L-histidine salt, wherein the XRPD spectrum is basically shown in the attached figure 10, the DSC spectrum is basically shown in the attached figure 11, and the TGA spectrum is basically shown in the attached figure 12, and is the Favipiravir L-histidine salt crystal form I.

Example 5

94.2mg of Favipiravir, 72.6mg of tromethamine and 3.0ml of methanol are mixed, stirred under the magnetic stirring condition of 25.0 ℃ and 200rpm for 12 hours and then filtered to obtain 144.4mg of Favipiravir tromethamine salt (light yellow solid), and XRPD (X-ray diffraction pattern), DSC (DSC) and TGA (thermo-gravimetric analysis) detection are respectively carried out on a sample, wherein the XRPD spectrum is basically shown in figure 13, the DSC spectrum is basically shown in figure 14, and the TGA spectrum is basically shown in figure 15, and is Favipiravir tromethamine salt crystal form I.

Example 6

94.2mg of favipiravir, 116.5mg of piperazine hexahydrate and 4.0ml of methanol were mixed, stirred at 29.0 ℃ for 12 hours under magnetic stirring at 200rpm, and then filtered to obtain 129.4mg of favipiravir piperazine salt form I (light yellow solid).

Example 7: preparation of Favipiravir meglumine salt monohydrate crystal

A suspension of 10.0g of Favipiravir and 15.0g of meglumine in 30mL of water was heated to 50 ℃ and allowed to dissolve. After 120mL of 2-propanol was added dropwise at 40 ℃, it was cooled to 5 ℃ and stirred at the same temperature for 1 hour. The solid material was filtered to obtain 20.9g of monohydrate crystals (pale yellow crystals) of fapivoxil meglumine salt.

Example 8: preparation of favipiravir meglumine salt anhydrous crystal

1.35g of the crystals obtained in example 7 were allowed to stand at 40 ℃ under vacuum (50Pa or less) for 64 hours to obtain anhydrous crystals.

Example 9: preparation of Favipiravir Crystal alpha (reference CN102977039B preparation)

4.0g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is dissolved in 20ml of methanol, heated and refluxed in a water bath for 10 minutes, cooled, and then placed in a thermostatic water bath at 25 ℃ for standing, when crystals begin to precipitate, the solution is placed atminus 15 ℃ for crystallization, filtered, and dried in vacuum at 60 ℃ for 7 hours, and then 3.6g of Favipiravir crystal alpha is obtained.

Example 10: investigation of influence factors

According to the guiding principle of the stability test of the pharmaceutical preparation, the salt forms of the Favipiravir obtained in the examples 1-8 and the Favipiravir crystal alpha obtained in the example 9 are subjected to influence factor experiments, including a high temperature test, a high humidity test and a strong light irradiation test, and the stability conditions influencing the crystal forms of the Favipiravir are examined.

High-temperature test: taking appropriate amount of the salt forms of the Favipiravir obtained in the examples 1-8 and the Favipiravir crystal alpha obtained in the example 9, respectively spreading the salt forms and the Favipiravir crystal alpha into weighing bottles, placing the bottles in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5%, respectively taking about 10mg of the samples in 5 days, 10 days and 15 days, and testing the crystal forms of the samples.

High humidity test: taking appropriate amount of the salt forms of the Favipiravir obtained in the examples 1-8 and the Favipiravir crystal alpha obtained in the example 9, respectively spreading the salt forms and the Favipiravir crystal alpha into weighing bottles, placing the bottles in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5%, then respectively taking about 10mg of the samples in 5 days, 10 days and 15 days, and testing the crystal forms of the samples.

And (3) illumination test: taking appropriate amount of the salt forms of the Favipiravir obtained in examples 1-8 and the crystals alpha of the Favipiravir obtained in example 9, spreading the salt forms and the crystals alpha into weighing bottles respectively, placing the bottles under the conditions of a constant temperature and humidity box (25 ℃, RH60 +/-5%) with visible light 4500Lux +/-500 Lux and ultraviolet light 1.7W x h/m2, taking about 10mg of each sample in 5, 10 and 15 days respectively, and testing the crystal forms.

The crystal form of each favipiravir salt and the test results of the influence factors of the favipiravir crystal alpha are shown in table 1.

Table 1: the invention discloses a test result of influencing factors of Favipiravir salt

And (4) conclusion: the crystal form of the favipiravir salt disclosed by the invention keeps the original crystal form under the conditions of high temperature, high humidity and illumination, and the stability of the crystal form of the favipiravir salt under the condition of influencing factors is proved. The crystal of the Favipiravir meglumine salt monohydrate is easy to be subjected to crystal transformation under the high-temperature condition, and the crystal of the Favipiravir meglumine salt anhydrate is easy to be subjected to crystal transformation under the high-humidity environment and is relatively unstable.

Example 11

And (3) testing the solubility: a flask and a stirrer are weighed in advance, the crystal form alpha of the Favipiravir obtained in the example 9 and the salt of the Favipiravir obtained in the examples 1 to 8 are respectively and accurately weighed, the Favipiravir and the salt are respectively added into the flask, water is dripped, magnetic stirring is carried out at 200rpm, and the water is stopped being added until solid is dissolved. No visually visible particles were considered to be completely dissolved. Weighing the total weight of the test tube, the stirrer and the solution after dissolution, calculating the weight of the added water, and then calculating the solubility; the water density was calculated as 1.00g/mL and the solubility of these salts in water at 37 ℃ was tested separately, and the results of the solubility test are shown in Table 2.

The solubility testing process can find that compared with the Favipiravir crystal form alpha, each salt has better wettability and solubility in water and can be quickly mixed and dissolved with water, and the Favipiravir crystal form alpha partially floats on the surface and is difficult to mix and dissolve with water.

Table 2: solubility test experimental result of favipiravir salt

To summarize: the salts have better solubility and dissolution speed than a Favipiravir crystal form alpha used in a commercially available preparation, wherein the solubility and dissolution speed of an L-lysine salt crystal form I, L-lysine salt crystal form II and an L-histidine salt crystal form I, L-tromethamine salt crystal form I are better.

Example 12

Taking 50.0mg of each Favipiravir salt and 400 mu l of purified water, mixing, respectively stirring for a certain time (1.0h, 4.0h and 12.0h) at 37.0 ℃ under the condition of magnetic stirring at 200rpm, sampling, filtering and detecting the crystal form condition of a sample; the results are shown in Table 3.

Table 3: stability results of Favipiravir salts in purified water at 37 deg.C

To summarize: five salts were tested for stability in a purified water system at 37.0 ℃. The result shows that the crystal form II of the Favipiravir L-lysine salt is very easy to be converted into the crystal form I of the Favipiravir lysine salt in a purified water system at 37.0 ℃, and the rest salts are kept as the original crystal form under the condition. It is shown that in a purified water system at 37.0 ℃, only the L-lysine salt crystal form II is unstable, and the rest salt and crystal form are stable.

Example 13: preparation of injection

Dissolving Favipiravir tromethamine salt crystal form I (13.8 g in terms of Favipiravir) in 480mL of water for injection, filtering with a 0.22-micron filter membrane, filling the solution into a small bottle in an amount of 8mL per bottle, and freeze-drying to obtain a freeze-dried preparation of the Favipiravir tromethamine salt crystal form I.

Dissolving the Favipiravir meglumine salt monohydrate crystal (13.8 g in terms of Favipiravir) in 480mL of water for injection, filtering with a 0.22-micron filter membrane, filling the filter membrane into a small bottle in an amount of 8mL per bottle, and freeze-drying to obtain the freeze-dried preparation of the Favipiravir meglumine salt monohydrate crystal.

Example 14: dissolution time

10mL of water for injection was added to each of 5 bottles of the lyophilized preparation of form I of fapiviror tromethamine salt and the lyophilized preparation of the crystal of fapiviror meglumine salt monohydrate obtained in example 13, and the time required for complete dissolution was measured by shaking with a hand, and the results are shown in Table 4.

Table 4: dissolution time results

And (4) conclusion: compared with the freeze-dried preparation of the Favipiravir meglumine salt monohydrate crystal, the freeze-dried preparation of the Favipiravir tromethamine salt crystal form I has faster dissolution time, and can be completely dissolved in 3 seconds at shortest.

Example 15: investigation of stability of related substances

The lyophilized preparation of the crystal form I of fapivoxil tromethamine salt obtained in example 13 and the lyophilized preparation of the crystal form I of fapivoxil meglumine salt monohydrate were subjected to stability test under accelerated conditions (40 ℃, 75% RH), respectively, and the results are shown in table 5.

Table 5: accelerated stability investigation results

Note: impurity E is a degradation product of Favipiravir, chemically known as 6-fluoro-3-hydroxypyrazinyl-2-carboxylic acid.

And (4) conclusion: the impurity E and the total impurity of the freeze-dried preparation prepared by adopting the Favipiravir tromethamine salt crystal form I have no obvious change within 6 months, and the stability of the related substances of the freeze-dried preparation prepared by adopting the Favipiravir tromethamine salt crystal form I is proved to be good.

While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (10)

Translated fromChinese

1.一种法匹拉韦的盐，其特征在于，所述法匹拉韦的盐为晶体形式的法匹拉韦氨丁三醇盐、晶体形式的法匹拉韦L-赖氨酸盐或晶体形式的法匹拉韦L-组氨酸盐。1. a salt of favipiravir, is characterized in that, the salt of described favipiravir is the favipiravir tromethamine salt of crystalline form, the favipiravir L-lysine salt of crystalline form or Favipiravir L-histidine in crystalline form.2.根据权利要求1所述的盐，其特征在于，所述晶体形式的法匹拉韦氨丁三醇盐为法匹拉韦氨丁三醇盐晶型I，所述法匹拉韦氨丁三醇盐晶型I的X射线粉末衍射图谱在衍射角2θ：8.23°±0.2°、10.68°±0.2°、14.41°±0.2°、18.33°±0.2°、25.62°±0.2°、27.51°±0.2°、28.76°±0.2°、31.25°±0.2°和33.46°±0.2°处具有特征峰；所述晶体形式的法匹拉韦L-赖氨酸盐包括法匹拉韦L-赖氨酸盐晶型I或法匹拉韦L-赖氨酸盐晶型II，所述法匹拉韦L-赖氨酸盐晶型I的X射线粉末衍射图谱在衍射角2θ：7.92°±0.2°、16.63°±0.2°和20.72°±0.2°处具有特征峰；所述法匹拉韦L-赖氨酸盐晶型II的X射线粉末衍射图谱在衍射角2θ：7.87°±0.2°、15.88°±0.2°、16.26°±0.2°、18.07°±0.2°、18.90°±0.2°、20.52°±0.2°、23.04°±0.2°、27.94°±0.2°和34.98°±0.2°处具有特征峰；所述晶体形式的法匹拉韦L-组氨酸盐为法匹拉韦L-组氨酸盐晶型I，所述法匹拉韦L-组氨酸盐晶型I的X射线粉末衍射图谱在衍射角2θ：11.59°±0.2°、12.44°±0.2°、13.34°±0.2°、18.25°±0.2°、20.32°±0.2°、22.14°±0.2°、26.40°±0.2°和30.20°±0.2°处具有特征峰。2. The salt according to claim 1, wherein the favipiravir tromethamine salt in the crystalline form is favipiravir tromethamine salt crystal form I, and the favipiravir tromethamine salt is X-ray powder diffraction pattern of butanetrioxide crystal form I at diffraction angles 2θ: 8.23°±0.2°, 10.68°±0.2°, 14.41°±0.2°, 18.33°±0.2°, 25.62°±0.2°, 27.51° There are characteristic peaks at ±0.2°, 28.76°±0.2°, 31.25°±0.2° and 33.46°±0.2°; the crystalline form of favipiravir L-lysine salt includes favipiravir L-lysine Salt crystal form I or favipiravir L-lysine salt crystal form II, the X-ray powder diffraction pattern of the favipiravir L-lysine salt crystal form I at diffraction angle 2θ: 7.92°±0.2 °, 16.63°±0.2° and 20.72°±0.2° have characteristic peaks; the X-ray powder diffraction pattern of the Favipiravir L-lysine salt form II is at diffraction angle 2θ: 7.87°±0.2°, Featured at 15.88°±0.2°, 16.26°±0.2°, 18.07°±0.2°, 18.90°±0.2°, 20.52°±0.2°, 23.04°±0.2°, 27.94°±0.2° and 34.98°±0.2° Peak; the crystalline form of Favipiravir L-histidine salt is Favipiravir L-histidine salt form I, the X-ray of the Favipiravir L-histidine salt form I Powder diffraction patterns at diffraction angles 2θ: 11.59°±0.2°, 12.44°±0.2°, 13.34°±0.2°, 18.25°±0.2°, 20.32°±0.2°, 22.14°±0.2°, 26.40°±0.2° and There is a characteristic peak at 30.20°±0.2°.3.根据权利要求1-2任一项所述的盐，其特征在于，所述法匹拉韦氨丁三醇盐晶型I的X射线粉末衍射图谱在衍射角2θ：8.23°±0.2°、10.68°±0.2°、12.48°±0.2°、14.41°±0.2°、16.47°±0.2°、17.34°±0.2°、18.33°±0.2°、19.69°±0.2°、21.00°±0.2°、21.47°±0.2°、21.84°±0.2°、24.12°±0.2°、24.81°±0.2°、25.17°±0.2°、25.62°±0.2°、26.12°±0.2°、27.51°±0.2°、28.76°±0.2°、30.34°±0.2°、31.25°±0.2°、32.01°±0.2°、32.45°±0.2°、33.46°±0.2°和34.23°±0.2°处具有特征峰；所述法匹拉韦L-赖氨酸盐晶型I的X射线粉末衍射图谱在衍射角2θ：7.92°±0.2°、13.36°±0.2°、14.39°±0.2°、16.63°±0.2°、20.72°±0.2°、25.17°±0.2°、26.85°±0.2°、28.52°±0.2°、29.88°±0.2°和33.81°±0.2°处具有特征峰；所述法匹拉韦L-赖氨酸盐晶型II的X射线粉末衍射图谱在衍射角2θ：6.84°±0.2°、7.87°±0.2°、8.58°±0.2°、11.94°±0.2°、12.46°±0.2°、14.20°±0.2°、15.88°±0.2°、16.26°±0.2°、18.07°±0.2°、18.90°±0.2°、20.52°±0.2°、20.97°±0.2°、22.13°±0.2°、22.46°±0.2°、23.04°±0.2°、24.26°±0.2°、25.17°±0.2°、26.20°±0.2°、27.36°±0.2°、27.56°±0.2°、27.94°±0.2°、28.78°±0.2°和34.98°±0.2°处具有特征峰；所述法匹拉韦L-组氨酸盐晶型I的X射线粉末衍射图谱在衍射角2θ：11.59°±0.2°、12.44°±0.2°、13.34°±0.2°、14.02°±0.2°、14.97°±0.2°、18.25°±0.2°、20.32°±0.2°、20.77°±0.2°、22.14°±0.2°、23.21°±0.2°、23.78°±0.2°、24.38°±0.2°、25.61°±0.2°、26.40°±0.2°、27.76°±0.2°、30.20°±0.2°、30.58°±0.2°、32.34°±0.2°、33.07°±0.2°和38.48°±0.2°处具有特征峰。3. The salt according to any one of claims 1-2, wherein the X-ray powder diffraction pattern of the favipiravir tromethamine salt form I is at diffraction angle 2θ: 8.23°±0.2° , 10.68°±0.2°, 12.48°±0.2°, 14.41°±0.2°, 16.47°±0.2°, 17.34°±0.2°, 18.33°±0.2°, 19.69°±0.2°, 21.00°±0.2°, 21.47 °±0.2°, 21.84°±0.2°, 24.12°±0.2°, 24.81°±0.2°, 25.17°±0.2°, 25.62°±0.2°, 26.12°±0.2°, 27.51°±0.2°, 28.76°± 0.2°, 30.34°±0.2°, 31.25°±0.2°, 32.01°±0.2°, 32.45°±0.2°, 33.46°±0.2° and 34.23°±0.2° have characteristic peaks; the Favipiravir L - X-ray powder diffraction pattern of lysine salt form I at diffraction angles 2θ: 7.92°±0.2°, 13.36°±0.2°, 14.39°±0.2°, 16.63°±0.2°, 20.72°±0.2°, 25.17 There are characteristic peaks at °±0.2°, 26.85°±0.2°, 28.52°±0.2°, 29.88°±0.2° and 33.81°±0.2°; X of the Favipiravir L-lysine salt form II Ray powder diffraction pattern at diffraction angles 2θ: 6.84°±0.2°, 7.87°±0.2°, 8.58°±0.2°, 11.94°±0.2°, 12.46°±0.2°, 14.20°±0.2°, 15.88°±0.2° , 16.26°±0.2°, 18.07°±0.2°, 18.90°±0.2°, 20.52°±0.2°, 20.97°±0.2°, 22.13°±0.2°, 22.46°±0.2°, 23.04°±0.2°, 24.26 Characteristic peaks at °±0.2°, 25.17°±0.2°, 26.20°±0.2°, 27.36°±0.2°, 27.56°±0.2°, 27.94°±0.2°, 28.78°±0.2° and 34.98°±0.2° ; The X-ray powder diffraction pattern of the Favipiravir L-histidine salt crystal form I at diffraction angles 2θ: 11.59°±0.2°, 12.44°±0.2°, 13.34°±0.2°, 14.02°±0.2° , 14.97°±0.2°, 18.25°±0.2°, 20.32°±0.2°, 20.77°±0.2°, 22.14°±0.2°, 23.21°±0.2°, 23.78°±0.2°, 24.38°±0.2°, 25.61 ° There are characteristic peaks at ±0.2°, 26.40°±0.2°, 27.76°±0.2°, 30.20°±0.2°, 30.58°±0.2°, 32.34°±0.2°, 33.07°±0.2° and 38.48°±0.2°.4.根据权利要求1-3任一项所述的盐，其特征在于，所述法匹拉韦氨丁三醇盐晶型I具有基本上如图13所示的X-射线粉末衍射图谱；所述法匹拉韦L-赖氨酸盐晶型I具有基本上如图1所示的X-射线粉末衍射图谱；所述法匹拉韦L-赖氨酸盐晶型II具有基本上如图4所示的X-射线粉末衍射图谱；所述法匹拉韦L-组氨酸盐晶型I具有基本上如图10所示的X-射线粉末衍射图谱。4. The salt according to any one of claims 1-3, wherein the favipiravir tromethamine salt crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 13; The Favipiravir L-Lysine salt crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1 ; the Favipiravir L-Lysine salt crystalline form II has substantially the same The X-ray powder diffraction pattern shown in FIG. 4 ; the Favipiravir L-histidine salt form I has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .5.根据权利要求1-4任一项所述的盐，其特征在于，所述法匹拉韦氨丁三醇盐晶型I的差示扫描量热图谱中，在190-230℃具有吸热峰和放热峰，吸热峰的峰值在195-205℃和放热峰的峰值在205-215℃；所述法匹拉韦L-赖氨酸盐晶型I的差示扫描量热图谱中，在150-250℃具有吸热峰和放热峰，吸热峰的峰值在185-195℃和放热峰的峰值在210-220℃；所述法匹拉韦L-赖氨酸盐晶型II的差示扫描量热图谱中，在150-250℃具有吸热峰和放热峰，吸热峰的峰值在175-185℃和放热峰的峰值在200-210℃；所述法匹拉韦L-组氨酸盐晶型I的差示扫描量热图谱中，在110-180℃具有2个吸热峰，吸热峰的峰值温度分别在120-135℃和160-170℃。5. The salt according to any one of claims 1-4, characterized in that, in the differential scanning calorimetry spectrum of the favipiravir tromethamine salt crystal form I, it has absorption at 190-230° C. Thermal peaks and exothermic peaks, the peak of the endothermic peak is at 195-205 °C and the peak of the exothermic peak is at 205-215 °C; the differential scanning calorimetry of the Favipiravir L-lysine salt form I In the spectrum, there are endothermic and exothermic peaks at 150-250 °C, the peak of the endothermic peak is at 185-195 °C and the peak of the exothermic peak is at 210-220 °C; the Favipiravir L-Lysine In the differential scanning calorimetry spectrum of salt crystal form II, there are endothermic and exothermic peaks at 150-250 °C, the peak of the endothermic peak is at 175-185 °C and the peak of the exothermic peak is at 200-210 °C; In the differential scanning calorimetry spectrum of the Favipiravir L-histidine salt crystal form I, there are 2 endothermic peaks at 110-180 °C, and the peak temperatures of the endothermic peaks are at 120-135 °C and 160- 170°C.6.根据权利要求1-5任一项所述的盐，其特征在于，所述法匹拉韦氨丁三醇盐晶型I具有基本上如图14所示的差示扫描量热分析图谱；所述法匹拉韦L-赖氨酸盐晶型I具有基本上如图2所示的差示扫描量热分析图谱；所述法匹拉韦L-赖氨酸盐晶型II具有基本上如图5所示的差示扫描量热分析图谱；所述法匹拉韦L-组氨酸盐晶型I具有基本上如图11所示的差示扫描量热分析图谱。6. The salt according to any one of claims 1-5, wherein the favipiravir tromethamine salt crystal form I has a differential scanning calorimetry analysis pattern substantially as shown in Figure 14 ; The Favipiravir L-Lysine salt crystal form I has a differential scanning calorimetry analysis pattern substantially as shown in FIG. 2 ; The Favipiravir L-Lysine salt crystal form II has the basic The differential scanning calorimetry analysis pattern shown in FIG. 5 above; the Favipiravir L-histidine salt crystal form I has a differential scanning calorimetry analysis pattern substantially as shown in FIG. 11 .7.根据权利要求1-6任一项所述的盐，其特征在于，所述法匹拉韦氨丁三醇盐晶型I具有基本上如图15所示的热重分析图谱；所述法匹拉韦L-赖氨酸盐晶型I具有基本上如图3所示的热重分析图谱；所述法匹拉韦L-赖氨酸盐晶型II具有基本上如图6所示的热重分析图谱；所述法匹拉韦L-组氨酸盐晶型I具有基本上如图12所示的热重分析图谱。7. The salt according to any one of claims 1-6, wherein the favipiravir tromethamine salt crystal form I has a thermogravimetric analysis pattern substantially as shown in Figure 15; the Favipiravir L-lysine salt crystal form I has a thermogravimetric analysis pattern substantially as shown in Figure 3; said Favipiravir L-lysine salt crystal form II has substantially as shown in Figure 6 The thermogravimetric analysis pattern of ; the Favipiravir L-histidine salt crystal form I has a thermogravimetric analysis pattern substantially as shown in FIG. 12 .8.一种制备权利要求1-7任一项所述法匹拉韦的盐的方法，其特征在于，包括：将法匹拉韦溶解于溶剂A中，得法匹拉韦溶液；将成盐剂溶解于水中，得成盐剂溶液；将成盐剂溶液与法匹拉韦溶液混合，搅拌，析出固体，过滤，得到所述法匹拉韦的盐；所述成盐剂包括L-赖氨酸或L-组氨酸，所述溶剂A包括甲醇、乙醇、正丙醇或异丙醇中的至少一种。8. A method for preparing the salt of Favipiravir according to any one of claims 1-7, characterized in that, comprising: dissolving Favipiravir in solvent A to obtain Favipiravir solution; Dissolve in water to obtain a salt-forming agent solution; mix the salt-forming agent solution with the favipiravir solution, stir, separate out solids, and filter to obtain the salt of the favipiravir; the salt-forming agent includes L-lysine or L-histidine, the solvent A includes at least one of methanol, ethanol, n-propanol or isopropanol.9.根据权利要求8所述的方法，所述法匹拉韦与溶剂A的质量体积比为15-27mg/ml，且所述成盐剂与水的质量体积比为30-50mg/ml，所得法匹拉韦L-赖氨酸盐的晶型为法匹拉韦L-赖氨酸盐晶型I；或所述法匹拉韦与溶剂A的质量体积比为28-50mg/ml，且所述成盐剂与水的质量体积比为60-100mg/ml，所得法匹拉韦L-赖氨酸盐的晶型为法匹拉韦L-赖氨酸盐晶型II。9. method according to claim 8, the mass volume ratio of described Favipiravir and solvent A is 15-27mg/ml, and the mass volume ratio of described salt-forming agent and water is 30-50mg/ml, The crystal form of the obtained favipiravir L-lysine salt is favipiravir L-lysine salt crystal form I; or the mass volume ratio of the favipiravir to solvent A is 28-50 mg/ml, And the mass-volume ratio of the salt-forming agent to water is 60-100 mg/ml, and the crystal form of the obtained favipiravir L-lysine salt is favipiravir L-lysine salt crystal form II.10.一种制备根据权利要求1-7任一项所述法匹拉韦的盐的方法，包括将法匹拉韦、氨丁三醇和溶剂B混合，搅拌，过滤，得到所述法匹拉韦的盐；其中，所述溶剂B包括甲醇、乙醇、正丙醇或异丙醇中的至少一种；所述法匹拉韦与溶剂B的质量体积比为10-100mg/ml；所述氨丁三醇与法匹拉韦的投料摩尔比为0.5:1-2:1；所述搅拌的温度为20-40℃和所述搅拌的时间为2.0-24.0h。10. A method for preparing the salt of Favipiravir according to any one of claims 1-7, comprising mixing Favipiravir, tromethamine and solvent B, stirring, and filtering to obtain the Favipiravir Wei salt; wherein, the solvent B includes at least one of methanol, ethanol, n-propanol or isopropanol; the mass volume ratio of the favipiravir to the solvent B is 10-100 mg/ml; the The molar ratio of tromethamine to favipiravir is 0.5:1-2:1; the stirring temperature is 20-40° C. and the stirring time is 2.0-24.0h.

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