CN114057656A - Favipiravir eutectic crystal and preparation method thereof - Google Patents

Favipiravir eutectic crystal and preparation method thereof Download PDF

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CN114057656A
CN114057656A CN202110891257.0A CN202110891257A CN114057656A CN 114057656 A CN114057656 A CN 114057656A CN 202110891257 A CN202110891257 A CN 202110891257A CN 114057656 A CN114057656 A CN 114057656A
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crystal
favipiravir
eutectic
isonicotinic
fapirovir
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张�杰
廖伟龙
徐巾超
张鹏伟
陈勇
罗忠华
黄芳芳
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Sunshine Lake Pharma Co Ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention relates to a Favipiravir eutectic crystal and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The Favipiravir co-crystal comprises a Favipiravir-isonicotinic co-crystal, a Favipiravir-urea co-crystal or a Favipiravir-anthranilic acid co-crystal, and the Favipiravir co-crystal has good solubility and stability.

Description

Favipiravir eutectic crystal and preparation method thereof
Technical Field
The invention belongs to the field of medicines, and relates to a Favipiravir eutectic crystal and a preparation method thereof.
Background
Favipiravir (T-705, Favipiravir, CAS number 259793-96-9) chemical name is 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, and is used for the treatment of both new and recurrent influenza.
Patent application CN201210535512.9 discloses a crystalline form alpha of fapiroviru, but researches show that the crystalline form alpha has low solubility and low bioavailability, the size of a commercially available dosage form using the crystalline form is large, the daily dosage is large, the dosage needs to be taken twice every day, each time 1600mg (8 tablets) is very unfavorable for patients to take, and the compliance of the patients is not high.
CN201711103203.3 discloses a new crystal form, but the crystal form has poor reproducibility of the preparation process, the preparation of the crystal form cannot be reproduced according to the preparation process, and the crystal form is not suitable for industrial production, and in addition, the water solubility and dissolution rate of the crystal form are still poor.
Therefore, there is still a need to research a solid form of faviravir with high solubility and a preparation method with good reproducibility so as to obtain a faviravir solid form with more convenient 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 eutectic crystal, a preparation method thereof, a pharmaceutical composition and application.
In a first aspect, the invention provides a favipiravir co-crystal.
The Favipiravir eutectic comprises Favipiravir-isonicotinic eutectic, Favipiravir-urea eutectic or Favipiravir-anthranilic acid eutectic.
The molar ratio of the Favipiravir to the isonicotinic in the Favipiravir-isonicotinic eutectic is 1: 1.
The X-ray powder diffraction pattern of the faperavir-isonicotinic co-crystal is shown in the diffraction angle 2 theta: characteristic peaks are present at 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 fapirovir-isonicotinic co-crystal has an X-ray powder diffraction pattern that varies from diffraction angle 2 Θ: characteristic peaks are present at 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 fapirovir-isonicotinib co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 1.
In a differential scanning calorimetry analysis map of the common crystal of the pyrrosia piriflora and the isonicotinib, an endothermic peak is formed at the temperature of 150-175 ℃. In some embodiments, the Favipiravir-isonicotinic eutectic has an endothermic peak at 155-165 ℃ in a differential scanning calorimetry analysis spectrum. In some embodiments, the Favipiravir-isonicotinic eutectic has an endothermic peak at 158-162 ℃ in a differential scanning calorimetry analysis spectrum. In some embodiments, the fapirovir-isonicotinib co-crystal has a differential scanning calorimetry analysis profile with an endothermic peak at 160 ℃. In some embodiments, the fapirovir-isonicotinib co-crystal has a differential scanning calorimetry pattern substantially as shown in figure 2.
The Favipiravir-isonicotinic eutectic has small weight loss within the temperature range of 30-125 ℃. In some embodiments, the fapirovir-isonicotinic co-crystal loses less than 0.2% weight over the range of 30-125 ℃. In some embodiments, the fapirovir-isonicotinic co-crystal loses about 0.1% weight over a range of 30-125 ℃. In some embodiments, the fapirovir-isonicotinic co-crystal has a thermogravimetric analysis profile substantially as shown in figure 3.
The molar ratio of the Favipiravir to the urea in the Favipiravir-urea eutectic is 2: 1.
The X-ray powder diffraction pattern of the Favipiravir-urea eutectic is shown in the diffraction angle 2 theta: characteristic peaks are present at 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 fapirovir-urea co-crystal has an X-ray powder diffraction pattern that varies from diffraction angle 2 θ: characteristic peaks are provided at 9.02 DEG +/-0.2 DEG, 9.91 DEG +/-0.2 DEG, 11.85 DEG +/-0.2 DEG, 15.17 DEG +/-0.2 DEG, 15.40 DEG +/-0.2 DEG, 15.70 DEG +/-0.2 DEG, 16.45 DEG +/-0.2 DEG, 17.84 DEG +/-0.2 DEG, 19.64 DEG +/-0.2 DEG, 19.84 DEG +/-0.2 DEG, 21.18 DEG +/-0.2 DEG, 23.59 DEG +/-0.2 DEG, 25.20 DEG +/-0.2 DEG, 27.15 DEG +/-0.2 DEG, 27.88 DEG +/-0.2 DEG and 36.09 DEG +/-0.2 deg. In some embodiments, the fapirovir-urea co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 4.
In a differential scanning calorimetry analysis map of the Favipiravir-urea eutectic, an endothermic peak is formed at the temperature of 100-150 ℃. In some embodiments, the fapiravir-urea eutectic has an endothermic peak at 125-. In some embodiments, the fapirovir-urea co-crystal has a differential scanning calorimetry analysis profile with an endothermic peak at 128 ℃. In some embodiments, the fapirovir-urea co-crystal has a differential scanning calorimetry pattern substantially as shown in figure 5.
The Favipiravir-urea eutectic has small weight loss within the range of 30-100 ℃. In some embodiments, the fapirovir-urea co-crystal loses less than 0.3% weight over a temperature range of 30-100 ℃. In some embodiments, the fapirovir-urea co-crystal loses about 0.2% weight in the range of 30-100 ℃. In some embodiments, the fapirovir-urea co-crystal has a thermogravimetric analysis profile substantially as shown in figure 6.
The molar ratio of the pyrroside to the anthranilic acid in the pyrroside-anthranilic acid eutectic is 1: 1.
The X-ray powder diffraction pattern of the Favipiravir-anthranilic acid eutectic is shown in the diffraction angle 2 theta: characteristic peaks are present at 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 fapirovir-anthranilic acid co-crystal has an X-ray powder diffraction pattern that varies from diffraction angle 2 θ: characteristic peaks are present at 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 °, 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 fapirovir-anthranilic acid co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 7.
In a differential scanning calorimetry analysis map of the Lapirovir-anthranilic acid eutectic, an endothermic peak is formed at the temperature of 130-160 ℃. In some embodiments, the fapirovir-anthranilic acid co-crystal has an endothermic peak at 140 ℃. — -150 ℃ in a differential scanning calorimetry analysis profile. In some embodiments, the Favipiravir-anthranilic acid co-crystal has an endothermic peak at 144-. In some embodiments, the fapirovir-anthranilic acid co-crystal has a differential scanning calorimetry pattern substantially as shown in figure 8.
The fapirovir-anthranilic acid co-crystal has a thermogravimetric analysis profile substantially as shown in figure 9. In some embodiments, the fapirovir-anthranilic acid co-crystal has a small weight loss in the range of 30-100 ℃. In some embodiments, the fapirovir-anthranilic acid co-crystal loses less than 0.4% weight over a range of 30-100 ℃. In some embodiments, the fapirovir-anthranilic acid co-crystal loses about 0.3% weight over a range of 30-100 ℃.
In a second aspect, the invention provides a preparation method of the Favipiravir-isonicotinic eutectic and the Favipiravir-urea eutectic.
A method of making a co-crystal comprising: mixing Favipiravir and a eutectic ligand with a solvent respectively, wherein the eutectic ligand is selected from isonicotin and urea, stirring, and forming Favipiravir saturated suspension and eutectic ligand saturated suspension respectively; standing for layering, and respectively taking an upper solution of the Favipiravir saturated suspension and an upper solution of the eutectic ligand saturated suspension with the same volume, and uniformly mixing; standing to volatilize the solvent to obtain the eutectic.
The solvent includes at least one selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.
The stirring time is 2-12 hours. In some embodiments, the time of stirring is 3-10 hours; in some embodiments, the time of stirring is 5 to 8 hours; in some embodiments, the time of stirring is 6 to 7 hours.
The volatilization temperature is 10-40 ℃. In some embodiments, the temperature of the volatilization is 15-40 ℃; in some embodiments, the temperature of the volatilization is 20-35 ℃; in some embodiments, the temperature of the volatilization is from 25 ℃ to 30 ℃.
In some embodiments of the present invention, a method of preparing the aforementioned copperavir-isonicotinib cocrystal or copperavir-urea cocrystal comprises: mixing Favipiravir and a eutectic ligand with a solvent respectively, stirring for 2-12 hours, and forming Favipiravir saturated suspension and eutectic ligand saturated suspension respectively; standing for layering, and respectively taking an upper solution of the Favipiravir saturated suspension and an upper solution of the eutectic ligand saturated suspension with the same volume, and uniformly mixing; then standing at 10-40 ℃ to volatilize the solvent to obtain the eutectic crystal; wherein the eutectic ligand is selected from isonicotin and urea, and the solvent is selected from at least one of methanol, ethanol, n-propanol and isopropanol.
In some embodiments of the present invention, a method of preparing the fapirovir-isonicotinic co-crystal comprises: mixing Favipiravir and a eutectic ligand with a solvent respectively, stirring for 2-12 hours, and forming Favipiravir saturated suspension and eutectic ligand saturated suspension respectively; standing for layering, and respectively taking an upper solution of the Favipiravir saturated suspension and an upper solution of the eutectic ligand saturated suspension with the same volume, and uniformly mixing; then standing at 10-40 ℃ to volatilize the solvent to obtain the eutectic crystal; wherein the eutectic ligand is isonicotin, and the solvent is at least one selected from methanol, ethanol, n-propanol and isopropanol.
In a third aspect, the invention provides a method for preparing a Favipiravir-anthranilic acid eutectic.
A method for preparing a Favipiravir-anthranilic acid eutectic comprises the following steps: dissolving Favipiravir and anthranilic acid in water, stirring, naturally cooling, and crystallizing to obtain the eutectic crystal.
In some embodiments, the order of dissolution is that of dissolving the pyrroside first and then the anthranilic acid, and dissolving the pyrroside and the anthranilic acid separately in this order, the combination of the pyrroside and anthranilic acid being more complete and the resulting eutectic yield of pyrroside-anthranilic acid being higher.
The feeding molar ratio of the Favipiravir to the anthranilic acid can be 0.5: 1-2.1. In some embodiments, the feed molar ratio of fapirovir to anthranilic acid is from 1:1 to 1.5: 1. In some embodiments, the molar feed ratio of fapirovir to anthranilic acid is from 0.8:1 to 1.5: 1.
The mass-to-volume ratio of fapirovir to water may be 10.0 to 50.0 mg/ml. In some embodiments, the mass to volume ratio of favipiravir to water is 15.0 to 45.0 mg/ml; in some embodiments, the mass to volume ratio of favipiravir to water is 20.0 to 40.0 mg/ml; in some embodiments, the mass to volume ratio of favipiravir to water is 25.0 to 35.0 mg/ml; in some embodiments, the mass to volume ratio of favipiravir to water is 20.0 to 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.
The temperature of the dissolution is 60.0-100.0 ℃. In some embodiments, the temperature of the dissolution is 65.0-95.0 ℃; in some embodiments, the temperature of the dissolution is 70.0-90.0 ℃; in some embodiments, the temperature of the dissolution is 75.0-85.0 ℃; in some embodiments, the temperature of the dissolution is 80.0 ℃.
In some embodiments, fapiravir and anthranilic acid are dissolved in water at 60.0 to 100.0 ℃.
The time for the crystallization may be 4 to 24 hours. In some embodiments, the time for the devitrification is 6 to 20 hours; in some embodiments, the time for crystallization is 8 to 15 hours; in some embodiments, the time for crystallization is 10-15 hours.
The temperature of the crystallization may be 10-40 ℃. In some embodiments, the temperature of the devitrification is 15-40 ℃; in some embodiments, the temperature of the devitrification is 20-35 ℃; in some embodiments, the temperature of the devitrification is from 25 to 30 ℃.
In some embodiments, the foregoing method for preparing a copoite of peravir and anthranilic acid comprises: dissolving Favipiravir and anthranilic acid in water at the temperature of 60.0-100.0 ℃, stirring, naturally cooling, and crystallizing at the temperature of 10-40 ℃ for 4-24 hours to obtain the eutectic crystal; wherein the feeding molar ratio of the Favipiravir and the anthranilic acid is 1:1-1.5:1, and the mass-volume ratio of the Favipiravir and the water is 10.0-50.0 mg/ml.
In a fourth aspect, the present invention also provides a pharmaceutical composition comprising at least one co-crystal as described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
In some embodiments, a pharmaceutical composition comprising a fapirovir-isonicotinic co-crystal of the first aspect or a fapirovir-isonicotinic co-crystal obtained by the method of the second aspect, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
The pharmaceutical composition can be prepared into pharmaceutically acceptable preparations such as injection, tablets, capsules, granules or dry suspension.
In a fifth aspect, the co-crystal or pharmaceutical composition of the present invention can be used for preparing a medicament for preventing, treating or alleviating diseases or infections 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-isonicotinic eutectic disclosed by the invention has good solubility, the solubility of the Favipiravir-isonicotinic eutectic is twice of that of a Favipiravir crystal form alpha used in a commercially available preparation, the specification of the preparation can be reduced, the bioavailability is improved, the dosage is reduced, and the use compliance of a patient is improved.
(2) The Favipiravir-isonicotinic eutectic disclosed by the invention has good stability in water and stability of influencing factors (high temperature, high humidity and illumination), so that the stability of a preparation containing the eutectic can be improved, and the effective periods of raw material medicines and the preparation are prolonged.
(3) The preparation method has the advantages of good reproducibility, simple operation, environmental protection, high yield and purity and the like.
(4) The pharmaceutical composition containing the fapivoxil eutectic has the beneficial technical effects of high solubility, high bioavailability, small preparation specification, convenience in taking and the like.
Description of the terms
In the present invention, mmol means mmol, h means hour, g means g, ml means ml, μ l means μ l, ° c means celsius, mg means mg, rpm means rpm, RH means humidity, lux means illuminance measurement unit "lux", W means watt, m2Representing square meters.
"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 "crystalline 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. According to the instrument used in the testIn this case, the melting peak has a margin of error of + -3 deg.C.
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.
Raman spectroscopy (Roman) is a spectroscopic technique used to study vibrational modes, rotational modes, and other low frequency modes of molecules in a system. Different spatial structures of the same molecule (not)Isomorphous or amorphous) having different raman activities, and thus the crystal form or amorphous can be determined and identified using raman spectroscopy. The peak position of the raman spectrum is primarily related to the structure of the material and is relatively insensitive to experimental details, while the peak intensity depends on factors such as sample preparation and instrumentation. Thus, the crystalline form or amorphous form of the invention is characterized by a raman spectrum having characteristic peak positions substantially as provided in the figures of the invention. Meanwhile, the raman spectrum may have experimental errors, and the peak position and the peak value of the raman spectrum may be slightly different between different instruments and different samples, so that the value of the peak position or the peak intensity of the raman spectrum cannot be regarded as absolute. According to the condition of the instrument used in the test, the absorption peak exists at + -2 cm-1Error tolerance of (2).
In different space structures of the same molecule, the bond length and bond angle of some chemical bonds are different, so that the vibration-rotation transition energy levels are different, and some main characteristics of the infrared spectrum, such as absorption band frequency, peak shape, peak position, peak intensity and the like, are different from those of the corresponding infrared spectrum, so that the infrared spectrum can be used for research on drug polymorphism. The crystalline form or amorphous form of the present invention is characterized by a fourier infrared (FT-IR) spectrum having characteristic peak positions substantially as shown in the fourier IR spectrum provided in the accompanying drawings of the invention. Meanwhile, the fourier infrared spectrum may have experimental errors, and the peak position and the peak value of the fourier infrared spectrum may be slightly different between different instruments and different samples, so the value of the peak position or the peak intensity of the fourier infrared spectrum cannot be regarded as absolute. According to the condition of the instrument used in the test, the absorption peak exists at + -2 cm-1Error tolerance of (2).
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.
By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline 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% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline 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%.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is 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%.
"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%, particularly within 1%, for example "about 0.3%" means 0.27% -0.33% 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.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms. Isotopically enriched compounds have the structure given in the present invention, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine … …, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl、125I……。
In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H、14C and18compounds of F, or in which non-radioactive isotopes are present, e.g.2H and13a compound of C. The isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (Ia) can be prepared by conventional techniques known to those skilled in the art or by the procedures and procedures described in the examples and preparations of this invention using suitable isotopically labelled reagents in place of the original unlabeled formThe reagents were used.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I) or (Ia). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: 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. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of The references herein, indicate that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.
Materials 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; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures 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; polyacrylate esters; a wax; 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 sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.
Pharmaceutical compositions of the compounds of the present invention may be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an explanted reservoir. Preferred modes of administration are oral, intramuscular, intraperitoneal or intravenous.
The compounds of the present invention or compositions containing them which are pharmaceutically acceptable may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, etc.
Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.
Oral liquids may be in the form of suspensions, solutions, emulsions, syrups or elixirs containing hydrated oils, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gelatin, hydrogenated edible fats and oils, emulsifying agents, such as lecithin, sorbitan monooleate, acacia; or a non-aqueous carrier (which may comprise an edible oil), such as almond oil, an oil such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoate, sorbic acid. Flavoring or coloring agents may be added if desired.
Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
For parenteral administration, the liquid dosage forms are generally prepared from the compound and a sterile vehicle. The carrier is preferably water. The compound can be dissolved in the carrier or made into suspension solution according to the concentration of the carrier and the drug, and the compound is firstly dissolved in water when made into the solution for injection, filtered and sterilized and then filled into a sealed bottle or ampoule.
When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers, which may be used in ointment formulations including, but not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams may employ carriers including, but not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Drawings
Figure 1 shows an XRPD spectrum of a valacivir-isonicotinic co-crystal;
FIG. 2 shows a DSC spectrum of a valacivir-isonicotinic co-crystal;
FIG. 3 is a TGA spectrum of a valacivir-isonicotinic co-crystal;
FIG. 4 shows an XRPD spectrum of a valprazvir-urea cocrystal;
FIG. 5 shows a DSC spectrum of a valaciclovir-urea co-crystal;
FIG. 6 is a TGA spectrum of a Laplacvir-urea co-crystal;
FIG. 7 shows an XRPD spectrum of a farragavir-anthranilic acid co-crystal;
FIG. 8 shows a DSC spectrum of a valaciclovir-anthranilic acid eutectic;
figure 9 shows a TGA spectrum of a farragavir-anthranilic acid co-crystal.
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 an automated 3X 15 zero background sample holder. The radiation source used was a source of radiation of (Cu, k α,
Figure BDA0003196176010000101
the K 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 for Data collection is Data Collector, Data Viewer and HighScore Plus analysis and display. In the X-ray powder diffraction pattern, the ordinate is diffraction intensity expressed in counts (counts), and the abscissa is diffraction 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.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
The favipiravir crystal form alpha is the 6-fluoro-3-hydroxy-2-pyrazinecarboxamide crystal form alpha described in CN201210535512.9 (the favipiravir crystal form alpha is referred to in the invention).
Example 1: preparation of Favipiravir-isonicotinic eutectic
Favipiravir (100.0mg) and 8.00ml methanol were added to 10ml centrifuge tubes. Isonicotine (1.0g) and 3.00ml methanol are added into a 5ml centrifuge tube, and the mixture is respectively stirred for about 6.0 hours under the conditions of 25 ℃ and 200rpm magnetic stirring, thus obtaining the Favipiravir saturated suspension and the isonicotin saturated suspension. Standing for layering, respectively taking 2.0ml of upper solution of the Laura virens saturated suspension and 2.0ml of upper solution of the isonicotinic saturated suspension, placing the obtained mixture in a 5ml centrifuge tube, mixing the obtained mixture by magnetic stirring (200rpm), standing for volatilizing the solvent at room temperature to obtain 67.0mg of Laura virens-isonicotinic eutectic solid, and sampling for respectively carrying out XRPD, DSC and TGA detection, wherein the XRPD spectrum is basically shown as the attached figure 1, the DSC spectrum is basically shown as the attached figure 2, and the TGA spectrum is basically shown as the attached figure 3.
Example 2: preparation of Favipiravir-urea eutectic
Favipiravir (100.0mg) and 8.00ml of methanol are added into a 10ml centrifuge tube, urea (1.0g) and 3.00ml of methanol are added into a 5ml centrifuge tube, and the mixture is respectively stirred for about 6.0 hours under the conditions of magnetic stirring at 200rpm and 25 ℃ to obtain a Favipiravir saturated suspension and a urea saturated suspension. Standing for layering, respectively taking 2.0ml of upper solution of the Laura virens saturated suspension and 2.0ml of upper solution of the urea saturated suspension, placing the obtained mixture in a 5ml centrifuge tube, mixing the obtained mixture by magnetic stirring (200rpm), standing at room temperature for volatilizing the solvent to obtain 40.1mg of Laura virens-urea eutectic solid, and sampling for XRPD, DSC and TGA detection 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.
Example 3: preparation of Favipiravir-anthranilic acid eutectic
94.3mg (0.60mmol) of Favipiravir and 4.0ml of purified water are added into a 25ml beaker, the mixture is stirred under the magnetic stirring condition of 80.0 ℃ and 200rpm until the mixture is completely dissolved, 82.3mg (0.60mmol) of anthranilic acid is added, the stirring under the magnetic stirring condition of 80.0 ℃ and 200rpm means complete dissolution, then the heating is stopped, the solution is naturally cooled to the room temperature, the mixture is filtered after magnetic stirring (200rpm) for about 12 hours, 127.6mg of Favipiravir-anthranilic acid eutectic solid is obtained, and samples are respectively subjected to XRPD, DSC and TGA detection, wherein the XRPD spectrum is basically shown in figure 7, the DSC spectrum is basically shown in figure 8, and the TGA spectrum is basically shown in figure 9.
Example 4: preparation of Favipiravir-isonicotinic eutectic
Favipiravir (314.2mg) and 13.5ml methanol were added to a 25ml beaker. Isonicotine (6.0g) and 20.0ml methanol were added to a 25ml beaker, and stirred at 25 ℃ for about 6.0 hours under magnetic stirring at 200rpm, respectively, to give a Favipiravir saturated suspension and an isonicotin saturated suspension. Standing for layering, respectively taking 13.5ml of upper solution of the Favipiravir saturated suspension and 13.5ml of upper solution of the isonicotinic saturated suspension, placing the upper solutions in a 50ml centrifuge tube, mixing by magnetic stirring (200rpm), standing at room temperature for volatilizing the solvent to obtain 453.2mg of Favipiravir-isonicotinic eutectic solid, sampling, and respectively carrying out XRPD, DSC and TGA detection, wherein XRPD, DSC and TGA spectrograms are consistent with those of attached figures 1-3.
Example 5: preparation of Favipiravir-urea eutectic
Favipiravir (314.2mg) and 13.5ml of methanol were added to a 25ml beaker, urea (6.0g) and 20.0ml of methanol were added to a 25ml beaker, and magnetic stirring was carried out at 25 ℃ and 200rpm for about 6.0 hours to give a saturated suspension of Favipiravir and a saturated suspension of urea, respectively. Standing for layering, respectively taking 13.5ml of upper solution of the Favipiravir saturated suspension and 13.5ml of upper solution of the urea saturated suspension, placing the upper solutions in a 50ml centrifuge tube, mixing the solutions by magnetic stirring (200rpm), standing for volatilizing the solvent at room temperature to obtain 272.5mg of Favipiravir-urea eutectic solid, sampling, and respectively carrying out XRPD, DSC and TGA detection, wherein XRPD, DSC and TGA spectrograms of the eutectic solid are consistent with those in the attached figures 4-6.
Example 6: preparation of Favipiravir-anthranilic acid
314.2mg (2.0mmol) of Favipiravir and 13.5ml of purified water are added into a 25ml beaker, and completely dissolved under the magnetic stirring condition of 200rpm at 80.0 ℃; 274.3mg (2.0mmol) of anthranilic acid was added, and the mixture was dissolved by mixing well under magnetic stirring at 200rpm at 80.0 ℃. And then stopping heating, naturally cooling the solution to room temperature, stirring for about 12 hours by magnetic stirring (200rpm), and filtering to obtain 425.4mg Favipiravir-anthranilic acid eutectic solid, sampling, and performing XRPD, DSC and TGA detection respectively, wherein the XRPD, DSC and TGA spectrums are consistent with that of the attached figures 7-9.
Comparative example 1: preparation of new Favipiravir crystal form described in CN201711103203.3
Dissolving 7g of Laevir in 100ml of ethanol, filtering, adjusting the pH of the filtrate to 6 by using 0.1mol/l hydrochloric acid or 0.1mol/l sodium hydroxide, cooling to-15 ℃ under stirring, separating out crystals at the moment, adding 300ml of ethanol into the solution at the feeding rate of 1.8ml/min, adjusting the pH of the solution to 6 by using 0.1mol/l hydrochloric acid or 0.1mol/l sodium hydroxide after the dropwise addition is finished, continuing stirring for 2 hours at the temperature, growing the crystals for 2 hours, and filtering to obtain the new Laevir crystal form of CN 201711103203.3.
Comparative example 2: preparation of Favipiravir crystal form alpha in CN201210535512.9
Dissolving 4.0g of Favipiravir in 20ml of methanol, heating and refluxing in a water bath for 10 minutes, cooling, placing the solution in a constant-temperature water bath at 25 ℃, standing, when crystals begin to precipitate, then placing at-15 ℃ for crystallization, filtering, and drying in vacuum at 60 ℃ for 7 hours to obtain the 3.6g of Favipiravir alpha crystal form.
Example 7: preparation of favipiravir tablets
Prescription: 200g (calculated as Favipiravir) of a Favipiravir crystal form (new Favipiravir crystal form obtained in comparative example 1 or Favipiravir crystal form alpha obtained in comparative example 2) or a Favipiravir co-crystal (Favipiravir-isonicotin co-crystal, Favipiravir-urea co-crystal or Favipiravir-anthranilate co-crystal obtained in examples 1-6), 35g of microcrystalline cellulose, 15g of lactose, 12g of polyethylene glycol 6000, 1.0g of sodium lauryl sulfate, 1.8g of magnesium stearate.
Taking Favipiravir eutectic (Favipiravir-isonicotinic eutectic, Favipiravir-urea eutectic or Favipiravir-anthranilic acid eutectic obtained in examples 1-6) and Favipiravir crystal form (Favipiravir new crystal form obtained in comparative example 1 or Favipiravir crystal form alpha obtained in comparative example 2), respectively, preparing Favipiravir tablets according to the following methods:
the first step is as follows: sieving Favipiravir crystal form or Favipiravir eutectic through a 100-mesh sieve, and sieving microcrystalline cellulose, lactose, polyethylene glycol 6000, sodium dodecyl sulfate and magnesium stearate through a 80-mesh sieve;
the second step is that: weighing a Favipiravir crystal form or Favipiravir eutectic crystal, sodium dodecyl sulfate, polyethylene glycol 6000, microcrystalline cellulose and lactose, uniformly mixing, granulating by using 30-40% ethanol solution as a wetting agent, drying at 50 ℃, and crushing to pass through a 100-mesh sieve;
the third step: mixing the granules obtained in the second step with the rest microcrystalline cellulose and the rest lactose in the half prescription, granulating with 30-40% ethanol solution as wetting agent, oven drying at 50 deg.C, and sieving with 80 mesh sieve;
the fourth step: and thirdly, adding magnesium stearate with the prescription amount into the granules obtained in the third step, uniformly mixing and tabletting.
Example 8: test for influencing factor
According to the guiding principle of the stability test of the pharmaceutical preparation, influencing factor experiments are carried out on the Favipiravir eutectic (Favipiravir-isonicotinic eutectic, Favipiravir-urea eutectic or Favipiravir-anthranilic acid eutectic) obtained in the examples 1-6, wherein the influencing factor experiments comprise a high-temperature test, a high-humidity test and a strong light irradiation test, and the stability conditions influencing the crystal form of the Favipiravir eutectic are examined.
High-temperature test: taking a proper amount of Favipiravir eutectic (Favipiravir-isonicotinic eutectic, Favipiravir-urea eutectic or Favipiravir-anthranilic acid eutectic obtained in examples 1-6), flatly spreading the Favipiravir-isonicotinic eutectic in a weighing bottle, placing the Favipiravir-urea eutectic in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5%, then taking about 10mg of the sample in 5, 10 and 15 days respectively, and testing the crystal form condition of the sample.
High humidity test: taking a proper amount of Favipiravir eutectic (Favipiravir-isonicotinic eutectic, Favipiravir-urea eutectic or Favipiravir-anthranilic acid eutectic obtained in examples 1-6), flatly spreading the Favipiravir-isonicotinic eutectic in a weighing bottle, placing the bottle in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5%, then taking about 10mg of the sample in 5, 10 and 15 days respectively, and testing the crystal form condition of the sample.
And (3) illumination test: taking a proper amount of Favipiravir eutectic (Favipiravir-isonicotinic eutectic, Favipiravir-urea eutectic or Favipiravir-anthranilic acid eutectic obtained in examples 1-6), spreading the Favipiravir eutectic in a weighing bottle, and placing the Favipiravir eutectic in a visible light of 4500Lux +/-500 Lux and an ultraviolet light of 1.7W h/m2The sample was placed in a constant temperature and humidity chamber (25 ℃, RH60 + -5%), and about 10mg of the sample was taken at 5, 10 and 15 days, respectively, to test the crystal form. The influence factor test results of favipiravir co-crystal are shown in table 1.
Table 1: influence factor test result of Favipiravir eutectic
Figure BDA0003196176010000141
Figure BDA0003196176010000151
And (4) conclusion: the Favipiravir-isonicotinic eutectic and the Favipiravir-anthranilic acid eutectic are stable under high temperature, high humidity and illumination conditions, and the Favipiravir-urea eutectic is stable under illumination conditions but unstable under high temperature and high humidity conditions.
Example 9: solubility in Water test
And (3) testing the solubility: weighing a flask and a stirrer in advance, accurately weighing each Favipiravir eutectic crystal or Favipiravir crystal form alpha, respectively adding the Favipiravir eutectic crystal or Favipiravir crystal form alpha into the flask, dripping water, respectively magnetically stirring at 200rpm until the solid is dissolved, and stopping adding the water. No visually visible particles were considered to be completely dissolved. Weighing the total weight of the test tube, the stirrer and the aqueous 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 the three eutectic samples and the favipiravir crystal form alpha in water at 37 ℃ was tested, with the results of the solubility test shown in table 2. The solubility testing process can find that, compared with the Favipiravir crystal form alpha, the three eutectics have better wettability in water and can be quickly and uniformly mixed with the water, and part of the Favipiravir crystal form alpha floats on the water surface; in pure water at 37 ℃, the solubility of the Favipiravir-isonicotinic eutectic is about twice that of the Favipiravir crystal form alpha (calculated as Favipiravir free base), and the solubility of the Favipiravir-urea eutectic is also greater than that of the Favipiravir crystal form alpha (calculated as Favipiravir free base); the solubility results of the favipiravir co-crystals in purified water at 37.0 ℃ are shown in table 2.
Table 2: experimental results of solubility test in water of Favipiravir eutectic crystal and Favipiravir crystal form alpha
Figure BDA0003196176010000152
And (4) conclusion: the three Favipiravir eutectic phases have better wettability than the Favipiravir crystal form alpha. In water at 37 ℃, the solubility of the Favipiravir-isonicotinic eutectic is about twice that of the Favipiravir crystal form alpha, and the solubility of the Favipiravir-urea eutectic is also greater than that of the Favipiravir crystal form alpha.
Example 10: investigation of stability in Water
And (3) investigating stability in water: respectively adding 50.0mg of Favipiravir eutectic and 400 mu l of purified water into a 5ml centrifuge tube, stirring at 37.0 ℃ under the condition of magnetic stirring at 200rpm, filtering about 100 mu l of the Favipiravir eutectic and the purified water at 1.0h, 4.0h and 12.0h respectively, and detecting the crystal forms of the Favipiravir eutectic and the purified water; the stability test results of the favipiravir co-crystals in purified water at 37.0 ℃ are shown in table 3.
Table 3: stability of Favipiravir co-crystals in purified water at 37.0 ℃
Figure BDA0003196176010000161
And (4) conclusion: the Favipiravir-isonicotinic eutectic and the Favipiravir-anthranilic acid eutectic can stably exist in purified water at 37.0 ℃ for 12 hours, and the urea eutectic is easy to be transformed into the Favipiravir crystal form alpha. The method shows that the Favipiravir-isonicotinic eutectic and the Favipiravir-anthranilic acid eutectic have good water stability.
Example 11: dissolution testing
The dissolution rates of the respective faravir tablets obtained in example 7 were measured according to the dissolution rate measurement method for tablets prescribed in pharmacopoeia, using 900ml of 0.12mol/L hydrochloric acid solution as a dissolution medium and 75 rotations per minute, and the dissolution rates were measured for 5min, 10min, 20min, 30min and 60min, and the results are shown in table 4.
Table 4: dissolution data for each favipiravir tablet obtained in example 7
Figure BDA0003196176010000162
And (4) conclusion: compared with dissolution rates in a 0.12mol/L hydrochloric acid solution dissolution medium, the dissolution rate of the Favipiravir-isonicotinic acid eutectic tablet is remarkably improved compared with the Favipiravir crystalline form alpha tablet, the anthranilic acid eutectic tablet, the Favipiravir-anthranilic acid eutectic tablet and the Favipiravir new crystalline form tablet in the comparative example 1; the dissolution rate of the Favipiravir-urea eutectic tablet is equivalent to that of the Favipiravir crystal form alpha tablet and the Favipiravir new crystal form tablet in the comparative example 1; compared with other crystal forms and tablets of the co-crystal, the dissolution rate of the tablets of the co-crystal of the anthranilic acid is lower.
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)

1. A co-crystal, wherein the co-crystal is a fapirovir-isonicotinic co-crystal.
2. The co-crystal of claim 1, wherein the molar ratio of favipiravir to isonicotin in the favipiravir-isonicotinic co-crystal is 1: 1.
3. The co-crystal according to any one of claims 1-2, wherein the fapiravir-isonicotinib co-crystal has an X-ray powder diffraction pattern at diffraction angles 2 Θ: characteristic peaks are provided at 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 °; or the X-ray powder diffraction pattern of the fapiravir-isonicotinib co-crystal is determined at diffraction angles 2 theta: characteristic peaks at 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 °; and/or the fapirovir-isonicotinic co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 1.
4. The co-crystal according to any one of claims 1 to 3, wherein the Favipiravir-isonicotinic co-crystal has an endothermic peak at 150 to 175 ℃ in a differential scanning calorimetry analysis spectrum; or has an endothermic peak at 155 to 165 ℃; or has an endothermic peak at 158 to 162 ℃; or has an endothermic peak at 160 ℃; or the fapirovir-isonicotinic co-crystal has a differential scanning calorimetry pattern substantially as shown in figure 2.
5. The co-crystal of any one of claims 1 to 4, wherein the Favipiravir-isonicotinic co-crystal has a thermogravimetric analysis profile substantially as shown in figure 3.
6. A method of making the co-crystal of any one of claims 1-5, comprising: mixing Favipiravir and a eutectic ligand with a solvent respectively, wherein the eutectic ligand is isonicotin, stirring, and forming a Favipiravir saturated suspension and a eutectic ligand saturated suspension respectively;
standing for layering, and respectively taking an upper solution of the Favipiravir saturated suspension and an upper solution of the eutectic ligand saturated suspension with the same volume, and uniformly mixing; standing to volatilize the solvent to obtain the eutectic.
7. The method according to claim 6, wherein the solvent comprises at least one selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.
8. The method according to any one of claims 6 to 7, wherein the stirring time is 2 to 12 hours; and/or the temperature of the volatilization is 10-40 ℃.
9. A pharmaceutical composition comprising the co-crystal of any one of claims 1 to 5 or the co-crystal obtained by the method of any one of claims 7 to 9, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
10. Use of the co-crystal of any one of claims 1 to 5, the co-crystal obtained by the method of any one of claims 6 to 8 or the pharmaceutical composition of claim 9 for the manufacture of a medicament for the prevention, treatment or alleviation of diseases or infections caused by influenza virus, coronavirus, hepatitis c or bovine diarrhea virus.
CN202110891257.0A 2020-08-05 2021-08-04 Favipiravir eutectic crystal and preparation method thereof Pending CN114057656A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114436977A (en) * 2022-02-22 2022-05-06 山东大学 Favipiravir multi-component medicine and preparation method and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114436977A (en) * 2022-02-22 2022-05-06 山东大学 Favipiravir multi-component medicine and preparation method and application thereof
CN114436977B (en) * 2022-02-22 2024-01-05 山东大学 Fapirrevir multicomponent drug and preparation method and application thereof

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