A crystalline form of favipiravir hydrate, its preparation method and application

Abstract

The application belongs to the technical field of medicine crystal form, and particularly relates to a crystalline form of favipiravir hydrate, a preparation method and application thereof. The molar ratio of favipiravir to water molecules in the crystal structure of the crystalline form of favipiravir hydrate is 5:2, and the X-ray powder diffraction diagram has diffraction peaks at 13.12+ / -1 degree, 13.84+ / -1 degree, 14.16+ / -1 degree, 14.68+ / -1 degree, 16.06+ / -1 degree, 16.66+ / -1 degree, 16.96+ / -1 degree, 18.32+ / -1 degree, 19.28+ / -1 degree, 22.2+ / -1 degree, 22.58+ / -1 degree, 23.78+ / -1 degree, 24.98+ / -1 degree, 26.46+ / -1 degree, 27.2+ / -1 degree, 28.26+ / -1 degree, 28.56+ / -1 degree, 29.18+ / -1 degree, 29.62+ / -1 degree, 34.92+ / -1 degree, 36.26+ / -1 degree, and 37.94+ / -1 degree. The crystalline form of favipiravir hydrate provided in the application has similar humidity stability and better solubility compared with single-component favipiravir, and the stability of the prior art favipiravir is improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug crystal forms, and particularly relates to a favipiravir hydrate crystal and a preparation method and application thereof. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing an understanding of the general background of the application and does not necessarily constitute an admission or a recognition that the information forms part of the prior art already known to a person of ordinary skill in the art.

[0003] Favipiravir (English name: Favipiravir, FPV, Chinese name: 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a broad-spectrum antiviral drug with activity against multiple pathogens, including Ebola virus, norovirus, RSV, rhinovirus, poliovirus, yellow fever virus and influenza virus. Favipiravir can selectively inhibit the RNA polymerase associated with influenza virus replication, and is an antiviral drug with a completely new mechanism of action. The drug was launched in Japan in 2014 for the treatment of new and recurrent influenza. Favipiravir has been used in emergency in Japan, India, Russia and other countries. In China, favipiravir was approved for clinical trials in 2019, and the results showed that the bioavailability of the drug was low, resulting in a large oral dose and weak efficacy. Moreover, favipiravir has strict requirements for environmental conditions during storage.

[0004] Crystal form can affect the physicochemical properties of the drug, such as solubility, machinability, etc., and thus affect the bioavailability and stability of the drug, so the development of crystal drug becomes particularly important. As an antiviral drug, the lower solubility of favipiravir limits its bioavailability, resulting in a large oral daily dose (1600 mg / day). There are many reports on patents and literatures on the preparation of favipiravir pharmaceutical cocrystals to improve its solubility, but there is only one article on the crystal form of favipiravir, and its physicochemical properties are not reported. The present application aims to prepare a favipiravir hydrate crystal to improve the solubility of favipiravir while maintaining good physical stability, and the hydrate crystal can be used as a prodrug, which is beneficial to the subsequent research on the polymorphs of favipiravir. SUMMARY

[0005] In order to solve the problems of the prior art, the present application aims to provide a favipiravir hydrate crystal and a preparation method and application thereof. The favipiravir hydrate crystal provided by the present application has high solubility and good humidity stability compared with single-component favipiravir, which makes up for the shortcomings of the prior art.

[0006] In order to achieve the above-mentioned purpose, the present application is realized by the following technical scheme:

[0007] In a first aspect, the present application provides a crystalline form of a ribavirin hydrate, wherein the molar ratio of ribavirin to water in the crystal structure is 5:2, and the X-ray powder diffraction pattern has diffraction peaks at 13.12±1°, 13.84±1°, 14.16±1°, 14.68±1°, 16.06±1°, 16.66±1°, 16.96±1°, 18.32±1°, 19.28±1°, 22.2±1°, 22.58±1°, 23.78±1°, 24.98±1°, 26.46±1°, 27.2±1°, 28.26±1°, 28.56±1°, 29.18±1°, 29.62±1°, 34.92±1°, 36.26±1°, 37.94±1°.

[0008] In a second aspect, the present application provides a preparation method of the ribavirin hydrate crystal according to the first aspect, characterized in that ribavirin is mixed with a solution containing an additive, stirred until the solution is clear, and the solvent is volatilized at room temperature to obtain the ribavirin hydrate crystal.

[0009] In a third aspect, the present application provides use of the ribavirin hydrate crystal according to the first aspect in the preparation of an antiviral drug.

[0010] In a fourth aspect, the present application provides a pharmaceutical composition comprising the ribavirin hydrate crystal according to the first aspect.

[0011] In a fifth aspect, the present application provides a pharmaceutical preparation comprising the ribavirin hydrate crystal according to the first aspect and a pharmaceutically acceptable excipient and / or carrier.

[0012] The beneficial effects achieved by one or more technical solutions of the present application are as follows:

[0013] The ribavirin hydrate crystal is obtained by adding ribavirin to a solution containing an additive and then volatilizing the solvent. The Cu-kα is used for structure characterization and physicochemical property testing, and the X-ray diffraction spectrum has sharp diffraction peaks, which characterize the specific parameters of the crystal.

[0014] The dynamic water adsorption test shows that the ribavirin hydrate crystal has low moisture absorption and good humidity stability, which is beneficial to the subsequent preparation of high-stability ribavirin drugs.

[0015] The solubility of the ribavirin hydrate in the simulated human intestinal fluid buffer solution at pH=6.8 is tested by high performance liquid chromatography, and the results show that the solubility of the ribavirin hydrate is significantly improved, which is twice that of ribavirin under the same conditions. BRIEF DESCRIPTION OF DRAWINGS

[0016] The accompanying drawings, which form a part of this specification, are included to provide a further understanding of the application and are incorporated herein by reference. The embodiments illustrated in the drawings are exemplary embodiments of the application and, therefore, not limiting of the scope of the application.

[0017] Figure 1 X-ray powder diffraction pattern of the favipiravir hydrate prepared in the present application;

[0018] Figure 2 The minimum asymmetric unit of the favipiravir hydrate crystal prepared in the present application;

[0019] Figure 3 The unit cell structure of the favipiravir hydrate crystal prepared in the present application;

[0020] Figure 4 Differential scanning calorimetry pattern of the favipiravir hydrate crystal prepared in the present application;

[0021] Figure 5 Raman spectrogram of the favipiravir hydrate crystal prepared in the present application;

[0022] Figure 6 Dynamic water vapor adsorption test pattern of the favipiravir hydrate crystal prepared in the present application;

[0023] Figure 7 Solubility curve of the favipiravir hydrate crystal prepared in the present application. DETAILED DESCRIPTION

[0024] In a first exemplary embodiment of the present application, a favipiravir hydrate crystal has a crystal structure with a molar ratio of favipiravir to water molecules of 5:2, and an X-ray powder diffraction pattern with diffraction peaks at 13.12±1°, 13.84±1°, 14.16±1°, 14.68±1°, 16.06±1°, 16.66±1°, 16.96±1°, 18.32±1°, 19.28±1°, 22.2±1°, 22.58±1°, 23.78±1°, 24.98±1°, 26.46±1°, 27.2±1°, 28.26±1°, 28.56±1°, 29.18±1°, 29.62±1°, 34.92±1°, 36.26±1°, 37.94±1°.

[0025] In one or more embodiments of this embodiment, the space group is P 21 / c, and the unit cell parameters are: a = 13.12±0.1 A, b = 16.06±0.1 A, c = 37.94±0.1 A, α = 90°, β = 112.93±0.1°, γ = 90°,

[0026] In a second typical embodiment of the present application, a method for preparing the crystalline form of the fapiavir hydrate as described in the first typical embodiment, the fapiavir is mixed with a solution containing an additive, the solution is stirred until it is clear, and the solvent is evaporated at room temperature to obtain the crystalline form of the fapiavir hydrate.

[0027] In one or more embodiments of this embodiment, the additive is polyvinylpyrrolidone or succinic acid, and the mass ratio of the fapiavir to the additive is 100:24-40.

[0028] In one or more embodiments of this embodiment, the solvent of the solution containing the additive is a mixture of acetonitrile and water, and the volume ratio of acetonitrile to water is 2.9-3.1:1.

[0029] In one or more embodiments of this embodiment, the mass-to-volume ratio of the fapiavir to the solution containing the additive is 50mg:3-5mL.

[0030] In one or more embodiments of this embodiment, the solvent is evaporated at room temperature for 3-4 days.

[0031] In a third typical embodiment of the present application, the crystalline form of the fapiavir hydrate as described in the first typical embodiment is used in the preparation of an antiviral drug.

[0032] In a fourth typical embodiment of the present application, a pharmaceutical composition comprises the crystalline form of the fapiavir hydrate as described in the first typical embodiment.

[0033] In a fifth typical embodiment of the present application, a pharmaceutical preparation comprises the crystalline form of the fapiavir hydrate as described in the first typical embodiment and a pharmaceutically acceptable excipient and / or carrier.

[0034] In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below with specific examples and comparative examples.

[0035] Example 1

[0036] Accurately weigh 50mg (0.32mol) of the raw material fapiavir into a clean glass vial, and add 3-5ml of the previously prepared 4mg / ml succinic acid (solvent: acetonitrile: water = 3:1) mixed solution. Stir the solution using a magnetic stirrer until it is clear, then place the glass vial in a fume hood, and evaporate the solvent at room temperature for 3-4 days to obtain the crystalline form of the fapiavir hydrate.

[0037] Example 2

[0038] Accurately weigh 50 mg of the raw material of favipiravir 50 mg (0.32 mol) into a clean glass vial, add 3-5 ml of the prepared 4 mg / ml polyvinylpyrrolidone (solvent acetonitrile-water = 3:1) mixed solution. Use a magnetic stirrer to stir the solution to clarify, then place the glass vial in a fume hood, and volatilize the solvent at room temperature for 3-4 days to obtain favipiravir hydrate crystals.

[0039] Comparative Example

[0040] Accurately weigh 100 mg of the raw material of favipiravir 100 mg (0.64 mol) into a clean glass vial, add 5 ml of acetonitrile solution, use a magnetic stirrer to stir the solution to clarify, then place the glass vial in a fume hood, and volatilize the solvent at room temperature for 3-4 days to obtain favipiravir crystals.

[0041] The favipiravir hydrate crystals obtained in Examples 1 and 2 were subjected to powder diffraction analysis using a D8 Advance X-ray powder diffractometer produced by Bruker, Cu-kα, tube voltage 40 kV, tube current 40 mA, step size 0.1, scanning range 10-50°, and room temperature.

[0042] The obtained powder X-ray diffraction pattern is shown in Figure 1 , wherein the characteristic peak angles are:

[0043] 13.12±1°, 13.84±1°, 14.16±1°, 14.68±1°, 16.06±1°, 16.66±1°, 16.96±1°, 18.32±1°, 19.28±1°, 22.2±1°, 22.58±1°, 23.78±1°, 24.98±1°, 26.46±1°, 27.2±1°, 28.26±1°, 28.56±1°, 29.18±1°, 29.62±1°, 34.92±1°, 36.26±1°, 37.94±1°.

[0044] Examples 1 and 2 can obtain single crystals with good quality suitable for single crystal analysis. Structure analysis was performed at room temperature using a D8 VENTURE double microfocus X-ray single crystal diffractometer produced by Bruker, Germany, and the structure of the favipiravir hydrate crystal obtained by single crystal structure analysis is shown in Figure 2 (minimal asymmetric unit) and Figure 3 (unit cell structure), and the crystallographic information is shown in Table 1, wherein the values in the brackets in Table 1 are the error of the last digit of the corresponding value.

[0045] Table 1: Crystal structure information of favipiravir hydrate crystal

[0046]

[0047]

[0048] DSC analysis of the crystalline form of favipiravir hydrate was performed on a Mettler DSC 214 Polyma thermal analyzer in Germany. The sample was heated from room temperature to 220°C at a rate of 10°C / min under nitrogen atmosphere. The heat flow of the sample was recorded during the heating process using software. The results are shown in Figure 2. The first endothermic peak appeared at 69°C and the second endothermic peak appeared at 189°C. The first peak in the differential thermal curve is the water vaporization, i.e. dehydration peak, and the second endothermic peak is the endothermic peak of favipiravir after dehydration, indicating that dehydration has no effect on the thermal stability of favipiravir. Figure 4

[0049] Raman spectrum analysis of the crystalline form of favipiravir hydrate was performed on a HORIBA LabRAM HR800 Raman spectrometer in Japan at room temperature. The wave number was 500-2000 cm -1 , and the resolution was 1 cm -1 . The results are shown in Figure 3. Figure 5

[0050] The adsorption and desorption of water of the crystalline form of favipiravir hydrate and favipiravir were tested using a dynamic water vapor adsorption instrument under conditions of 0-95% relative humidity. The mass change of the sample under different humidity conditions was recorded. The final results are shown in Figure 4. The results show that the mass change of favipiravir hydrate during the cycle does not exceed 0.5%, and no mass mutation occurs, indicating that the favipiravir hydrate crystal has low hygroscopicity and good humidity stability. Figure 6

[0051] ​​​The solubility of the compound was tested by using a high performance liquid chromatograph, and the solubility of the compound in a simulated human intestinal fluid buffer solution with pH = 6.8 was obtained. The high performance liquid chromatograph was a Shimadzu LC-20AT model, equipped with a diode array detector and a Shimi-pack VP-ODS chromatographic column. The mobile phase was a mixture of methanol-acetonitrile (1:1, v / v) and 0.01 mol / ml ammonium dihydrogen phosphate solution (pH 3.2 adjusted by trifluoroacetic acid) with a volume ratio of 20:80. The detection wavelength was 225 nm, the column temperature was 35°C, the flow rate of the mobile phase was 1 ml / min, and the single sample injection amount was 20 μl. The sample was sieved to have a particle size range of 80-150 μm, and an excess of the sample with uniform particle size was added to a round-bottom flask containing 10 ml of the buffer solution. Then, the round-bottom flask containing the saturated solution was placed in an oil bath at 35±0.1°C, and stirred by a magnetic stirrer at 500 rpm for 60 minutes. At 2, 5, 10, 20, 30, 40, 60 min, 100 μL of the saturated solution was taken by using a 1 ml pipette and diluted 10 times with the buffer solution, filtered by using a filter membrane with a pore size of 0.22 μm, and 20 μL of the filtrate was used to determine the content of the compound in the solution by high performance liquid chromatography. The concentration at each time point was determined three times to determine the error and the mean value. The test results are shown in Table 1. Figure 7 As shown in Table 1, the solubility of the compound is significantly improved, and is about twice that of the compound.

[0052] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. The present application can have various modifications and changes for those skilled in the art. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing favipiravir hydrate crystals, characterized in that, Favipiravir was mixed with a solution containing additives and stirred until the solution became clear. The solvent was then evaporated at room temperature to obtain the favipiravir hydrate crystals. The additive is polyvinylpyrrolidone or succinic acid, and the mass ratio of favipiravir to the additive is 100:24-40. The solvent of the solution containing the additive is a mixture of acetonitrile and water, with a volume ratio of acetonitrile to water of 2.9-3.1:1; The mass-to-volume ratio of favipiravir to the solution containing the additive is 50 mg: 3-5 mL; In the crystal structure, the molar ratio of favipiravir to water molecules is 5:

2. The X-ray powder diffraction pattern shows diffraction peaks at positions 13.12±1°, 13.84±1°, 14.16±1°, 14.68±1°, 16.06±1°, 16.66±1°, 16.96±1°, 18.32±1°, 19.28±1°, 22.2±1°, 22.58±1°, 23.78±1°, 24.98±1°, 26.46±1°, 27.2±1°, 28.26±1°, 28.56±1°, 29.18±1°, 29.62±1°, 34.92±1°, 36.26±1°, and 37.94±1°.

2. The method for preparing favipiravir hydrate crystals as described in claim 1, characterized in that, The crystal space group is P. 2 1 / c The unit cell parameters are: α =90°, β =112.93±0.1°, γ =90°, a=7.1462±0.0002Å, b=60.2551±0.0013 Å, c=8.1657±0.0002 Å.

3. The method for preparing favipiravir hydrate crystals as described in claim 1, characterized in that, Solvent evaporates at room temperature in 3-4 days.

Images