阅读说明：本技术 一种法匹拉韦药用结合物及在制备抗病毒药物制剂中的应用 (Favipiravir medicinal conjugate and application thereof in preparation of antiviral medicinal preparation ) 是由 王蕾 王新园 陶绪堂 谢冠英 宋淑虹 于 2020-12-11 设计创作，主要内容包括：本发明具体涉及一种法匹拉韦药用结合物及在制备抗病毒药物制剂中的应用。法匹拉韦是一种前景良好的广谱抗病毒药物,但法匹拉韦水溶性较差,生物利用度不高。本发明提供了法匹拉韦的药用结合物形式,采用茶碱和哌嗪作为共晶与盐的形成物,显著提高了法匹拉韦在水中的溶解性,为法匹拉韦药物联合应用方式及剂型的开发提供了新的研究思路。(The invention particularly relates to a favipiravir medicinal conjugate and application thereof in preparation of an antiviral medicinal preparation. Favipiravir is a broad-spectrum antiviral drug with good prospect, but the Favipiravir is poor in water solubility and low in bioavailability. The invention provides a medicinal combination form of Favipiravir, theophylline and piperazine are used as a formation of eutectic and salt, so that the solubility of Favipiravir in water is obviously improved, and a new research idea is provided for the development of a Favipiravir drug combined application mode and a dosage form.)

1. A favipiravir medicinal conjugate, which is characterized in that the medicinal conjugate is a salt crystal of favipiravir and piperazine;

the salt crystal is a triclinic system;

space group: p-1;

the molar ratio of the Favipiravir to the piperazine is 1: 0.9-1.1;

unit cell parameters:α＝99.480°β＝99.564°γ＝106.371°；

the salt crystal has characteristic peaks at diffraction angles 2 theta of 10.28 +/-1 degrees, 10.9 +/-1 degrees, 12.44 +/-1 degrees, 13.08 +/-1 degrees, 17.74 +/-1 degrees, 19.03 +/-1 degrees, 19.52 +/-1 degrees, 19.79 +/-1 degrees, 20.7 +/-1 degrees, 21.08 +/-1 degrees, 21.35 +/-1 degrees, 21.98 +/-1 degrees, 22.62 +/-1 degrees, 23.23 +/-1 degrees, 23.67 +/-1 degrees, 25.12 +/-1 degrees, 26.31 +/-1 degrees, 26.72 +/-1 degrees, 28.25 +/-1 degrees, 28.88 +/-1 degrees, 30.1 +/-1 degrees, 30.85 +/-1 degrees, 35.29 +/-1 degrees, 36.22 +/-1 degrees, 36.37 +/-1 degrees and 38.1 +/-1 degrees.

2. The favipiravir pharmaceutical conjugate of claim 1, wherein the salt crystals have XRD diffraction characteristic peaks as shown in figure 5.

3. The favipiravir medicinal conjugate according to claim 1, wherein the favipiravir and piperazine salt crystal is prepared by a grinding method, the grinding time is 25-35 min, and the grinding method comprises a method of grinding without adding a solvent and a method of grinding with adding a solvent; in the scheme of adding a solvent for grinding, the solvent is one or a combination of several of water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide.

4. The favipiravir pharmaceutical conjugate of claim 1, wherein the favipiravir and piperazine salt crystals are prepared by dissolving a sample in a solvent by a solvent method, wherein the solvent is one or a combination of water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, and N, N-dimethylformamide; then removing the solvent for crystallization; the crystallization mode comprises a volatilization crystallization mode and a cooling crystallization mode; preferably, the sample is subjected to ultrasonic assisted dissolution and then subjected to volatilization crystallization.

5. A pharmaceutical composition comprising the fapivoxil pharmaceutical conjugate of any of claims 1-4.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable conjugate is in a therapeutically effective amount of 0.01 to 10mg/kg body weight; preferably, the effective treatment amount is 0.01-5 mg/kg body weight.

7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is an aqueous composition comprising an effective amount of fapirovir and at least one pharmaceutically acceptable carrier or therapeutic agent or adjuvant in an aqueous medium.

8. The pharmaceutical composition of claim 5, further comprising an adjuvant or a carrier, wherein the adjuvant is: magnesium stearate, talc, polyethylene glycol, silica, a disintegrating agent and a moistening agent; the carrier comprises alumina, aluminum stearate, lecithin, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax or lanolin.

9. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is administered by oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intradermal, intraperitoneal, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intracranial, intranasal, or intraocular routes.

10. Use of a pharmaceutical composition as claimed in any one of claims 5 to 9 in the manufacture of an antiviral pharmaceutical formulation.

Technical Field

The invention belongs to the technical field of medicinal conjugates, and particularly relates to a common crystal of Favipiravir and theophylline, a salt of Favipiravir and piperazine, a preparation method of the medicinal conjugate, a medicinal composition containing the medicinal conjugate and application of the medicinal composition in an antiviral medicinal preparation.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Favipiravir (English name: favipiravir, Chinese name: 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a broad-spectrum antiviral pharmaceutical preparation developed by Fushan chemical Japan. In 3 months 2014, the drug is approved for treating new or recurrent influenza in Japan, and the existing research shows that the drug has good inhibition effect on various pathogenic viruses such as Ebola virus, West Nile virus, yellow fever virus, flavivirus, arenavirus, bunyavirus, alphavirus, enterovirus, rift valley fever virus and the like, is a broad-spectrum antiviral drug preparation, and has been used for treating and relevant research on new coronary pneumonia.

Theophylline (English name: theophylline, Chinese name: 2, 6-dioxo-1, 3-dimethylpurine) methylpurine medicine can reduce smooth muscle tension and dilate respiratory tract; can promote the release of endogenous adrenaline and noradrenaline and the relaxation of airway smooth muscle; inhibit the release of calcium ions from smooth muscle endoplasmic reticulum, and reduce the concentration of calcium ions in cells to generate respiratory tract expansion effect. Theophylline has a stronger relaxing effect on smooth muscle but is less potent than a beta receptor agonist. Therefore, has the effects of strengthening heart, promoting urination, dilating coronary artery, relaxing bronchial smooth muscle, exciting central channel system, etc. It is mainly used for treating bronchial asthma, emphysema, bronchitis, and cardiac dyspnea.

The physicochemical properties of drugs are one of the key factors affecting their clinical application. The crystal form drug is a solid dosage form, and has been the focus of research on the aspect of drug dosage forms. In recent years, with the progress of research on crystalline drugs, supramolecular chemical concepts have been introduced into the design of drug molecules, and eutectic molecules have been constructed with the participation of a series of weak interaction forces such as an ammonia bond and pi-pi conjugate stacking effect. In the clinical application aspect of the pharmaceutical co-crystal, the physicochemical properties of active drug molecules (API) determine the curative effect of the drug to a great extent. If the Δ pKa of the two components forming the co-crystal is > 3, it is referred to as a salt. If the co-crystal former is also an active pharmaceutical ingredient, the resulting pharmaceutical co-crystal is called a drug-drug co-crystal, which not only improves the physicochemical properties but may also be involved in the development of new clinical applications.

Since the Favipiravir is formally marketed in 2014, the main application form after being marketed is tablets, and the research on drug combination and crystal forms is relatively blank. And the Favipiravir can only reach slight solubility in an aqueous solution, which also obviously limits the bioavailability of Favipiravir and the development and application of related dosage forms. The predicted value of the permeability parameter LogP of the Favipiravir in a drug Bank database (https:// go. drug Bank. com /) is 0.25, and the low permeability is generally considered to be the low permeability when the permeability of the drug is lower than 1.72 in the field, so that the further improvement of the permeability of the Favipiravir is of great significance to the expansion of the drug form of the Favipiravir.

Disclosure of Invention

In view of the current research situation, the invention conjectures that the physicochemical properties of the favipiravir are improved by adopting the mode of the favipiravir medicinal combination. Through research and screening, the invention provides pharmaceutical co-crystals and salt forms which can obviously improve the solubility and permeability of Favipiravir, effectively improves the solubility of Favipiravir in an aqueous solution, and increases the membrane penetration capacity of Favipiravir on focus cells.

Based on the technical scheme, the invention provides the following technical scheme:

the invention firstly provides a Favipiravir medicinal combination, which is Favipiravir and theophylline or Favipiravir and piperazine.

In the medicinal combination, the Favipiravir and the theophylline are in a cocrystal, and the Favipiravir and the piperazine can form a salt. In the routine research thread in the art, it is often necessary to further explore the pharmaceutical forms of the compound entities during the study of compound formulations. In order to improve the water solubility of favipiravir, the present invention envisions the development of a pharmaceutical conjugate form of favipiravir that, by combination with other compounds, achieves an increase in the solubility of favipiravir. Research shows that the Favipiravir and the theophylline can form a co-crystal, the Favipiravir and the piperazine can form a salt form, and the two modes can effectively improve the solubility and permeability of the Favipiravir in water, so that the extended research and the bioavailability improvement of the Favipiravir pharmaceutical dosage form are facilitated. Besides, the method can also be applied to the pharmacological activity research work of Favipiravir.

In the co-crystal provided by the invention, Favipiravir is used as a broad-spectrum antiviral medicinal preparation and is usually used for treating influenza, theophylline is used for relieving wheezing and bronchospasm symptoms in respiratory diseases, and the two clinical applications are crossed to a certain extent.

And the salt formed by combining piperazine improves the solubility of Favipiravir more obviously, and the solubility in water is improved by 1.6 times.

The invention also provides a pharmaceutical composition comprising the co-crystal based on the co-crystal form of favipiravir and theophylline. Further, an application of the pharmaceutical composition in preparing an antiviral pharmaceutical preparation is provided.

Finally, the present invention provides a method of viral inhibition for use including, but not limited to, ebola, west nile, yellow fever, flavivirus, arenavirus, bunyavirus, alphavirus, enterovirus, or rift valley fever.

The beneficial effects of one or more technical schemes are as follows:

1. compared with a crystalline-state Lapivoxil medicament, the medicinal combination effectively improves the technical defects of low solubility and limited bioavailability of Lapivoxil in an aqueous solution, and provides a new research idea for Lapivoxil combined medication, dosage form development and clinical research.

2. The preparation method of the favipiravir medicinal conjugate provided by the invention comprises a solution method and a grinding method. The method has the advantages of simple operation, low production cost and strong operability, and is suitable for industrial expanded production.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.

FIG. 1 is an XRD (X-ray diffraction) spectrum of a Favipiravir-theophylline eutectic medicine powder prepared in example 3;

FIG. 2 is a molecular structure diagram of a Pilatavir-theophylline eutectic prepared by the preparation method in example 3;

FIG. 3 is a crystal cell structure of the P.pirillum-theophylline eutectic of example 3 preparation;

FIG. 4 is a test chart of the solubility of the F.piravir and F.piravir-theophylline eutectic prepared in example 3;

FIG. 5 is an XRD pattern of a fapirovir-piperazine salt medicament prepared in example 6;

FIG. 6 is a molecular structure diagram of a piravir-piperazine salt crystal according to example 6;

FIG. 7 is the unit cell structure of the Favipiravir-piperazine salt of example 6;

FIG. 8 is a graph of the solubility curves of each drug in buffer solution in example 6.

Fig. 9 shows permeability test results of favipiravir raw material and the cocrystals obtained in examples 3 and 6.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

As introduced in the background technology, aiming at the technical defects that the Favipiravir is poor in water solubility and limited in bioavailability, the invention provides the pharmaceutical cocrystal form of the Favipiravir, and the water solubility of the Favipiravir is effectively improved by introducing a cocrystal former.

In a first aspect of the invention, a favipiravir medicinal combination is provided, wherein the medicinal combination is favipiravir and theophylline or favipiravir and piperazine; wherein the Favipiravir and the theophylline are cocrystals, and the Favipiravir and the piperazine are salts

Preferably, the eutectic has characteristic peaks at diffraction angles 2 θ of 10.62 ± 1 °,12.46 ± 1 °,13.85 ± 1 °,15.57 ± 1 °,17.18 ± 1 °,17.91 ± 1 °,19.88 ± 1 °,21.96 ± 1 °,23.61 ± 1 °,24.75 ± 1 °,25.15 ± 1 °,27.30 ± 1 °,27.56 ± 1 °,27.99 ± 1 °,29.26 ± 1 °,30.18 ± 1 °,30.64 ± 1 °,34.56 ± 1 °,38.16 ± 1 °,40.54 ± 1 °, and 19.35 ± 1 °.

Further, the eutectic has characteristic peaks of XRD diffraction as shown in figure 1.

Further, the eutectic is monoclinic.

Furthermore, the mole ratio of the Favipiravir to the theophylline is 1: 0.9-1.1.

Preferably, the salt has characteristic peaks at diffraction angles 2 theta of 10.28 +/-1 degrees, 10.9 +/-1 degrees, 12.44 +/-1 degrees, 13.08 +/-1 degrees, 17.74 +/-1 degrees, 19.03 +/-1 degrees, 19.52 +/-1 degrees, 19.79 +/-1 degrees, 20.7 +/-1 degrees, 21.08 +/-1 degrees, 21.35 +/-1 degrees, 21.98 +/-1 degrees, 22.62 +/-1 degrees, 23.23 +/-1 degrees, 23.67 +/-1 degrees, 25.12 +/-1 degrees, 26.31 +/-1 degrees, 26.72 +/-1 degrees, 28.25 +/-1 degrees, 28.88 +/-1 degrees, 30.1 +/-1 degrees, 30.85 +/-1 degrees, 35.29 +/-1 degrees, 36.22 +/-1 degrees, 36.37 +/-1 degrees and 38.1 +/-1 degrees.

Further, the salt has characteristic peaks of XRD diffraction as shown in FIG. 5.

Further, the salt is triclinic.

Furthermore, the mole ratio of the Favipiravir to the piperazine is 1: 0.9-1.1.

Preferably, the pharmaceutically acceptable conjugate is prepared by methods including, but not limited to, milling or solution methods.

In a series of embodiments of the above preferred technical scheme, the preparation method of the common crystal of the Favipiravir and the theophylline adopts a grinding method, the grinding time is 25-35 min, and the grinding method comprises a method of grinding without adding a solvent and a method of grinding with adding a solvent.

In the scheme of adding a solvent for grinding, the solvent is one or a combination of more of water, methanol, ethanol, acetone, acetic acid, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, N-butanol, chloroform, dichloromethane, trichloromethane, carbon tetrachloride, hexane tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide; and dissolving the ground product in ethanol, and slowly volatilizing and crystallizing to obtain the co-crystal.

In some embodiments of the above preferred embodiments, the preparation of the cofrystal of favipiravir and theophylline uses a solvent method: dissolving a sample in a solvent, wherein the solvent is one or a combination of water, methanol, ethanol, acetone, acetic acid, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, N-butanol, chloroform, dichloromethane, chloroform, carbon tetrachloride, hexane tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide; then removing the solvent for crystallization.

In this series of embodiments, the crystallization mode includes a volatilization crystallization mode and a temperature reduction crystallization mode.

In some embodiments of the above preferred technical solution, the preparation of the fapiravir and piperazine salt is performed by a grinding method, the grinding time is 25-35 min, and the grinding method includes grinding without adding a solvent and grinding with adding a solvent.

In the scheme of adding a solvent for grinding, the solvent is one or a combination of several of water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide.

In still other embodiments of the above preferred technical solution, the preparation of the fapiravir and piperazine salt adopts a solvent method, and the sample is dissolved in a solvent, wherein the solution is one or a combination of several of water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide; then removing the solvent for crystallization.

In this series of embodiments, the crystallization mode includes a volatilization crystallization mode and a temperature reduction crystallization mode.

In this series of embodiments, the sample is subjected to volatilization crystallization with ultrasonic aid. In the research process of the invention, the method finds that in the solution method, the Favipiravir and the piperazine raw material are firstly dissolved in the solvent through ultrasonic waves and then volatilized, so that the crystallization can be carried out more easily.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a fapivoxil pharmaceutical conjugate of the first aspect.

Preferably, in the pharmaceutical composition, the pharmaceutically acceptable conjugate is in a therapeutically effective amount of about 0.01 to about 10mg/kg body weight.

Further, the therapeutically effective amount is about 0.01 to about 5mg/kg body weight.

Preferably, the pharmaceutical composition is an aqueous composition comprising an effective amount of fapiravir and at least one pharmaceutically acceptable carrier or therapeutic agent or adjuvant in an aqueous medium.

Preferably, the pharmaceutical composition further comprises an adjuvant or a carrier, wherein the adjuvant includes but is not limited to: magnesium stearate, talc, polyethylene glycol, silica, disintegrating agents (such as potato starch) and moistening agents (such as sodium lauryl sulfate); such carriers include, but are not limited to, alumina, aluminum stearate, lecithin, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, and the like.

Preferably, the mode of administration of the pharmaceutical composition is by oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, topical, nasal, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, orthotopic, intradermal, intraperitoneal, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intranasal or intraocular routes.

In a third aspect of the invention, there is provided the use of a pharmaceutical composition according to the second aspect in the preparation of an antiviral pharmaceutical formulation.

Preferably, the antiviral pharmaceutical preparation is used for treating influenza, bronchial asthma, acute bronchitis, asthmatic bronchitis, obstructive emphysema, chronic bronchitis, emphysema, cardiac asthma, cardiac edema, acute cardiac insufficiency and novel coronary pneumonia.

Preferably, in the pharmaceutical composition, the medicinal combination is a common crystal of favipiravir and theophylline.

In a fourth aspect of the invention, there is provided a method of viral inhibition, said method comprising the use of a pharmaceutical composition according to the second aspect.

Preferably, the inhibition method is for use including, but not limited to, ebola virus, west nile virus, yellow fever virus, flavivirus, arenavirus, bunyavirus, alphavirus, enterovirus, or rift valley fever virus.

In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.

Example 1

The embodiment provides a method for preparing a peravir-theophylline pharmaceutical co-crystal based on a solution method, which comprises the following steps: accurately weighing 15.71mg (0.1mmol) of favipiravir raw material and 18.016mg (0.1mmol) of theophylline raw material, putting the two weighed raw materials into a clean glass bottle (volume: 20ml) at room temperature, adding a proper amount of ethanol until the medicines are fully dissolved, clarifying the solution, putting an opening of the glass bottle into the glass bottle and volatilizing the glass bottle in a fume hood at room temperature, and obtaining the favipiravir and theophylline eutectic medicine after the solvent is completely volatilized.

Example 2

This example provides another method for preparing a peravir-theophylline pharmaceutical co-crystal based on a solution method: weighing 15.71mg (0.1mmol) of Favipiravir raw material and 18.016mg (0.1mmol) of theophylline raw material, putting the two weighed raw materials into a clean glass bottle (volume: 15mL) at room temperature, adding 5mL of ethanol (other solvents comprise water, methanol, ethanol, acetone, acetic acid, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, N-butanol, chloroform, dichloromethane, trichloromethane, carbon tetrachloride, hexane tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide or a combination thereof), putting the glass bottle filled with the solution into a 65 ℃ oil bath kettle, adding cleaned magnetons, fully dissolving the medicine at the rotating speed of 360r/m to obtain a clear solution, then putting the clear solution at room temperature, cooling and crystallizing after a period of time, and obtaining the Favipiravir and theophylline eutectic medicine.

Example 3

In the embodiment, a method for preparing a peravir-theophylline pharmaceutical co-crystal based on a grinding method is provided: accurately weighing 47.13mg (0.3mmol) of favipiravir raw material and 54.048mg (0.3mmol) of theophylline raw material, placing the sample in a grinding bowl, and a Retsch MM200 grinding instrument, wherein the frequency is 25Hz, grinding is carried out for 30 minutes, and grinding without adding a solvent or adding a solvent (comprising water, methanol, ethanol, acetone, acetic acid, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, N-butyl alcohol, chloroform, dichloromethane, trichloromethane, carbon tetrachloride, hexane tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide or a combination thereof can be used for grinding to obtain a eutectic product.

For the Favipiravir-theophylline eutectic obtained in this example, an X-ray powder diffractometer, manufactured by Bruker, Germany, was used, with the model number D8 Advance, Cu-k α, tube voltage 40kV, tube current 40mA, step size 0.08, scanning range 10-50 °, room temperature. The resulting diffraction pattern is shown in FIG. 1. The characteristic peak angles in the powder XRD pattern are as follows:

10.62±1°,12.46±1°,13.85±1°,15.57±1°,17.18±1°,17.91±1°,19.88±1°,21.96±1°,23.61±1°,24.75±1°,25.15±1°,27.30±1°,27.56±1°,27.99±1°,29.26±1°,30.18±1°,30.64±1°,34.56±1°,38.16±1°,40.54±1°,19.35±1°。

the single crystal with better quality can be directly obtained in the examples 1 and 2, and the ground product can be dissolved in ethanol for slow volatilization and crystallization in the example 3, so that the single crystal with better quality can be obtained. The structure of the obtained Favipiravir-theophylline single crystal by single crystal analysis is shown in FIG. 2 and FIG. 3.

For the farragvir-theophylline eutectic single crystal obtained in the example, a double-micro focal spot X-ray single crystal diffractometer was used for structural analysis, manufactured by bruker, germany, model D8 VENTURE, at room temperature. The information of the Pilatavir-theophylline eutectic crystallography can be known through single crystal analysis:

the chemical formula is as follows: c₂₄H₂₄F₂N₁₄O₈

Space group: p n

Crystal system: monoclinic system

Unit cell parameters:α＝90°β＝107.811°γ＝90°。

the obtained favipiravir and theophylline cocrystal drug was subjected to solubility test to obtain solubility in an aqueous solution having a pH of 6.8.

The test method comprises the following steps: and taking a proper amount of sample, and sieving the sample by a 100-mesh sieve to obtain sample powder with uniform particle size. 50mL of phosphate buffer solution with pH 6.8 was taken in the round-bottom flask, and the round-bottom flask was placed in an oil bath and kept at a constant temperature of 30 ℃. A weighed 77.5mg sample was added to the round bottom flask in the oil bath and stirred by a magnet at 500 r/min. Respectively taking clear liquid for 2min, 4min, 6min, 10min, 15min, 20min, 25min, 30min, 45min, 60min, 90min, 120min, 500min,1000min and 1500min, and filtering with 0.22 μm filter membrane.

The solubility test adopts High Performance Liquid Chromatography (HPLC), SHIMAZU, LC-20AT, 225nm as detection wavelength, and 0.01mol/L ammonium dihydrogen phosphate solution as mobile phase (pH 3.2 + -0.1 adjusted by trifluoroacetic acid): acetonitrile-methanol (50-50) ═ 80:20 (volume ratio), flow rate 1.0mL/min, column temperature 30 ℃.

The test results are shown in fig. 4, and the solubility of favipiravir in the co-crystal drug is significantly higher than that of crystalline favipiravir in an aqueous solution with a pH of 6.8.

Through the test results, the condition that the favipiravir and theophylline eutectic medicine obviously improves the poor solubility of the favipiravir in the aqueous solution with the pH value of 6.8 is shown, and the bioavailability of the favipiravir is favorably improved.

In this example, permeability tests were performed on a favipiravir and favipiravir-theophylline eutectic. The apparatus used was a vertical FRANZ diffusion cell, a PAMPA model was selected for the permeation model, and the faplataviv concentration in the test chamber was tested by high performance liquid chromatography HPLC at 30 ℃ and 1 hour intervals. The test results are shown in fig. 9. The permeability of the cocrystal drug is obviously superior to that of the single-component method Pilatavir.

Example 4

This example provides a process for preparing a valaciclovir-piperazine salt based on a milling process: accurately weighing 15.71mg (0.1mmol) of favipiravir raw material and 8.614mg (0.1mmol) of piperazine raw material, putting the two weighed raw materials into a clean glass bottle (volume: 20ml) at room temperature, adding a proper amount of methanol until the medicines are fully dissolved, clarifying the solution, placing the glass bottle at room temperature with an opening and volatilizing in a fume hood, and obtaining the favipiravir and piperazine salt medicine after the solvent is volatilized completely.

Example 5

This example provides a solution-based process for preparing a peravir-piperazine salt: precisely weighing 15.71mg (0.3mmol) of favipiravir raw material and 8.614mg (0.1mmol) of piperazine raw material, putting the two weighed raw materials into a clean glass bottle (volume: 15mL) at room temperature, adding 10mL of ethanol (which is not limited to ethanol and can be water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide or a combination thereof), putting the glass bottle filled with the solution into a 65 ℃ oil bath kettle, adding cleaned magnetons, fully dissolving the medicine at the rotating speed of 360r/m to obtain a clear light yellow solution, then putting the solution at room temperature, cooling and crystallizing after a period of time, and obtaining the eutectic medicine of the favipiravir and the piperazine.

Example 6

This example provides a solution-based process for preparing a peravir-piperazine salt: accurately weighing 47.13mg (0.3mmol) of Favipiravir raw material and 25.842mg (0.3mmol) of piperazine raw material, placing the sample in a grinding bowl, a Retsch MM200 grinding instrument, grinding for 30 minutes at the frequency of 25Hz, and grinding without adding a solvent or with a solvent (comprising water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide or a combination thereof) to obtain a eutectic product

For the fapirovir-piperazine salt obtained in this example, an X-ray powder diffractometer, manufactured by brueck, germany, model number D8 Advance, Cu — k α, tube voltage 40kV, tube current 40mA, step size 0.08, scan range 10-50 °, room temperature was used. The resulting diffraction pattern is shown in FIG. 5. The characteristic peak angles in the powder XRD pattern are as follows:

10.28±1°,10.9±1°,12.44±1°,13.08±1°,17.74±1°,19.03±1°,19.52±1°,19.79±1°,20.7±1°,21.08±1°,21.35±1°,21.98±1°,22.62±1°,23.23±1°,23.67±1°,25.12±1°,26.31±1°,26.72±1°,28.25±1°,28.88±1°,30.1±1°,30.85±1°35.29±1°,36.22±1°,36.37±1°,38.1±1°。

the single crystal with better quality can be directly obtained in the examples 4 and 5, and the ground product can be dissolved in methanol for slow volatilization and crystallization in the example 6, so that the single crystal with better quality can be obtained. The structure of the obtained favipiravir-piperazine single crystal by single crystal analysis is shown in fig. 7.

The single crystal of favipiravir-piperazine salt obtained in example 6 was subjected to structural analysis using a double-fine focal spot X-ray single crystal diffractometer, manufactured by brueck, germany, model D8 VENTURE, at room temperature. Crystallography information of the valacivir-piperazine salt can be known through single crystal analysis:

chemical molecular structure: c₁₈H₂₈F₂N₁₀O₄

Space group: p-1

Crystal system: triclinic system

Unit cell parameters:α＝99.480°β＝99.564°γ＝106.371°

the obtained favipiravir and piperazine cocrystal drug was subjected to solubility test, and the solubility in an aqueous solution having a pH of 6.8 was obtained.

The test method comprises the following steps: and taking a proper amount of sample, and sieving the sample by a 100-mesh sieve to obtain sample powder with uniform particle size. 50mL of phosphate buffer solution with pH 6.8 was taken in the round-bottom flask, and the round-bottom flask was placed in an oil bath and kept at a constant temperature of 30 ℃. A weighed 77.5mg sample was added to the round bottom flask in the oil bath and stirred by a magnet at 500 r/min. Respectively taking clear liquid at 2min, 4min, 6min, 10min, 15min, 20min, 25min, 30min, 45min, 60min, 90min, 120min, 500min,1000min 1500min, and filtering with 0.22 μm filter membrane.

The solubility test adopts High Performance Liquid Chromatography (HPLC), SHIMAZU, LC-20AT, 225nm as detection wavelength, and 0.01mol/L ammonium dihydrogen phosphate solution as mobile phase (pH 3.2 + -0.1 adjusted by trifluoroacetic acid): acetonitrile-methanol (50-50) ═ 80:20 (volume ratio), flow rate 1.0mL/min, column temperature 30 ℃.

The test results are shown in fig. 8, and the solubility of favipiravir in the co-crystal drug is significantly higher than that of crystalline favipiravir in an aqueous solution with a pH of 6.8. The solubility after dissolution equilibration was about 1.6 times the solubility of crystalline favipiravir.

From the test results, it can be seen that in the aqueous solution with the pH of 6.8, the favipiravir and piperazine salt drug obviously improves the poor solubility condition of the favipiravir, which is beneficial to improving the bioavailability of the favipiravir.

Based on the remarkable effect of piperazine on the solubility of the favipiravir, the favipiravir-piperazine salt is expected to be used as a pharmaceutical model preparation for the research work of the pharmacological properties of the favipiravir, such as the research situation of needing to increase the dosage in an acute toxicity experiment.

This example performed permeability tests on a fapivvir-theophylline co-crystal and a fapivir-piperazine salt. The apparatus used was a vertical FRANZ diffusion cell, a PAMPA model was selected for the permeation model, and the faplataviv concentration in the test chamber was tested by high performance liquid chromatography HPLC at 30 ℃ and 1 hour intervals. The test result is shown in fig. 9, and it can be seen from the figure that the pharmaceutical conjugate form of fapirovir can effectively improve the permeability of the drug, which is obviously superior to that of single-component fapirovir, wherein the permeability improvement effect of the salt form of fapirovir-piperazine is particularly obvious.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.