CN120865105A - Fapirrevir-arginine salt hydrate and preparation method thereof - Google Patents

Abstract

This invention discloses a favipiravir-arginine salt hydrate and its preparation method. The favipiravir-arginine salt hydrate of this invention is prepared by controlling the molar ratio of favipiravir and L-arginine at 1:0.90~1.08. During preparation, favipiravir and L-arginine are used as raw materials and obtained by grinding and solution methods. The grinding method includes mixing favipiravir and L-arginine and then grinding, or adding a small amount of ethanol, water, or acetonitrile and grinding, using a grinding device. The solution method uses water or a mixture of water and an organic solvent as the solvent, dispersing or dissolving the mixed solid powder in the corresponding solvent, and obtaining the solution through a slurry stirring method, a low-temperature static crystallization method, or a volatilization crystallization method. This invention improves the physicochemical properties of favipiravir. Through research and screening, it provides a method that can significantly improve the solubility of favipiravir in aqueous solution, thereby improving its clinical efficacy and reducing drug toxicity and side effects, and therefore has good practical application value.

Description

Fapirrevir-arginine salt hydrate and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a fapirrevir-arginine salt hydrate and a preparation method thereof.

Background

Fapiravir (English name: favipiravir, chinese name: 6-fluoro-3-hydroxy pyrazine-2-carboxamide, CAS number 259793-96-9) is a broad spectrum anti-RNA virus drug whose mechanism of action is to inhibit viral RNA polymerase and thus block viral RNA synthesis, thereby playing an antiviral role. The research shows that the fampicevir has certain in vivo or in vitro antiviral effect on novel coronaviruses, HIV, SARS, ebola viruses, west Nile viruses, yellow fever viruses and the like. The existing commercial crystal form of the medicine is an alpha crystal form, the low solubility and the poor permeability lead to 1600mg of the medicine for oral administration, the dosage is large, side effects are easy to generate, the medicine effect is not high, and the medicine is not beneficial to patients to take. Therefore, how to improve the physicochemical properties of the fampicregion and solve the existing defects of the fampicregion is important, so that the wide application of the fampicregion is realized.

On the other hand, many methods for improving the dissolution of pharmaceutical compounds in water or formulations have been reported in the literature, such as changing the known crystalline form to amorphous form, and the present inventors have found that the commercially available crystalline form α is stable and amorphous form is difficult to obtain through previous studies and literature search. Original patent CN103209967A,

WO2017JP24032 and WO2018JP46126 both develop an amorphous lyophilized formulation of the fampicin salt type by optimizing the procedure and conditions of lyophilization after salification, thereby improving the dissolution of the formulation. While patent CN116283801a improves its solubility by forming a co-crystal with the fampicvir.

Disclosure of Invention

According to the research background, the invention provides a novel method for preparing the fampicin salt, which is simple and easy to obtain, can improve the solubility of the fampicin, and takes L-arginine as an efficient harmless aminoglycoside adjuvant, thereby being expected to improve the clinical curative effect of the fampicin and reduce the toxic and side effects of the medicine.

In order to achieve the above purpose, the invention adopts the following technical scheme:

in the first aspect, the faprasuavir-arginine salt hydrate is prepared from faprasuavir and L-arginine in a molar ratio of 1:0.90-1.08, wherein the angle of a powder XRD characteristic peak 2 theta is as follows:

7.30±0.02°、9.58±0.02°、11.02±0.02°、18.92±0.02°、19.88±0.02°、21.32±0.02°、23.80±0.02°、25.68±0.02°、26.44±0.02°、27.06±0.02°、28.94±0.02°、30.76±0.02°、33.24±0.02°;

in a second aspect, the invention provides a preparation method of the fapirrevir-arginine salt hydrate, which is characterized in that fapirrevir and L-arginine are taken as raw materials according to a molar ratio of 1:0.90-1.08 (weight ratio of 1:1.00-1.20) by adopting a grinding method and a solution method;

wherein the grinding method comprises mixing the fampicvir and the L-arginine and grinding or dripping a small amount of ethanol or water or acetonitrile for grinding, and can be carried out by adopting a grinding device, and in one specific embodiment of the invention, the grinding device comprises a grinding instrument, the grinding frequency is controlled to be 10-30 Hz, preferably 20Hz, the grinding time is controlled to be 10-50 min, preferably 30min, and the grinding process can be carried out at 5-30 ℃.

The solvent used in the solution method can be water or a mixed solvent formed by water and an organic solvent, wherein the organic solvent comprises any one of methanol, ethanol, acetonitrile, isopropanol, acetone, tetrahydrofuran and dimethyl maple, and the mixed solid powder is dispersed or dissolved in the corresponding solvent and is prepared by a crystal slurry stirring method, a low-temperature standing crystallization method or a volatile crystallization method. In a specific embodiment of the invention, the solvent is a mixed solution of water and acetonitrile, and the ratio of acetonitrile to water in the mixed solvent is 1:1-8, preferably 1:3.

In a third aspect, the present invention provides a comparative experiment of the solubility of the famprivir-arginine salt hydrate of the first aspect with a single famprivir.

The technical scheme of the invention has the following beneficial effects:

(1) The invention provides a novel salt forming mode of the fampicevir, compared with single-component fampicevir, the obtained fampicevir-arginine salt has higher solubility, and the combined action of the fampicevir and the L-arginine is expected to improve the clinical curative effect, reduce the clinical dosage and further reduce the toxic and side effects of medicines.

(2) According to the grinding method, the fampicevir and the arginine are fully and uniformly dispersed, the fampicevir-arginine salt hydrate crystal grows in a solution method, the preparation method is simple, convenient and quick, and the prepared crystal can be used as a seed crystal to induce the formation of the crystal in the solution in the process of expanding production.

Drawings

FIG. 1 is a diagram of the formulas of fampicvir (left) and L-arginine (right).

FIG. 2 is a powder X-ray diffraction pattern of the salt hydrate of famprivir and arginine prepared in example 1 of the present invention.

FIG. 3 is a Differential Scanning Calorimetric (DSC) chart of a salt hydrate of famprivir and arginine prepared in example 1 of the present invention.

FIG. 4 is a thermogravimetric analysis (TGA) of the famprivir-arginine salt hydrate prepared in example 1 of the present invention.

Fig. 5 is a graph showing the solubility comparison test of the fapirrevir-arginine salt hydrate prepared in example 1 of the present invention.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the detailed description and specific examples, while indicating the invention, are not intended to limit the invention. Modifications and equivalents will occur to those skilled in the art upon understanding the present teachings without departing from the spirit and scope of the present teachings. The raw materials used in the following embodiments are all commercially available.

Unless otherwise specified, room temperature is expressed as 25 °c

Example 1

As shown in figure 1, 1.00g of raw material fampicvir and 1.20g of L-arginine (molar ratio 1:1.08) are precisely weighed, a sample is placed in a grinding tank, a clean signal Tissuelyser grinding instrument is used, the frequency is 20Hz, the temperature is 20 ℃, 0.5ml of deionized water is added, and grinding is carried out for 30 minutes, so that the fampicvir and L-arginine solid mixed powder is obtained.

100Mg of the mixed powder is placed in a 10mL penicillin bottle, added into 4.0mL of deionized water, stirred and fully dissolved in a 50 ℃ water bath, slowly cooled to room temperature under stirring, placed in a4 ℃ constant temperature refrigerator for 3 days after standing for 4 hours, after crystals are separated out, the supernatant is removed, and placed in a40 ℃ vacuum drying oven for drying overnight, so that the fapirrevir-arginine salt hydrate crystals are obtained.

Using Rigaku Ultima IV X ray powder diffractometer, cu-ka, voltage 40kV, current 40mA,4 DEG/min, scanning range 3-40 DEG, detecting at room temperature, the obtained X ray powder diffractogram is shown in figure 2, wherein the characteristic peak 2 theta angle is:

7.30±0.02°、9.58±0.02°、11.02±0.02°、18.92±0.02°、19.88±0.02°、21.32±0.02°、23.80±0.02°、25.68±0.02°、26.44±0.02°、27.06±0.02°、28.94±0.02°、30.76±0.02°、33.24±0.02°;

And performing differential scanning thermal analysis and thermogravimetric analysis on the obtained fapirrevir-arginine salt hydrate, and acquiring data in METTLER TGA/DSC synchronous thermal analysis instruments. As shown in fig. 3 and 4. From the TGA plot, from the beginning to 160 ℃, the step weight loss was about 5.78%, about the total loss of one water, with a simultaneous comparison of exothermic peaks of water loss at the DSC corresponding positions, the fapirrevir-arginine salt was the monohydrate.

The obtained fapirrevir-arginine salt hydrate was subjected to a solubility test to obtain its solubility in a buffer solution of ph6.8 at a test temperature of 25 ℃. The test method comprises using liquid chromatography SHIMAZU LC2050,2050, detecting wavelength 225nm, mobile phase 0.1% trifluoroacetic acid water solution of acetonitrile 80:20, flow rate 1.0mL/min, and column temperature 30 deg.C. Excess sample was added to a vial containing 3.0mL of buffer solution, and the vial was then placed in a 25 ℃ thermostatic water bath and stirred with a magnetic stirrer at 300rpm for 24 hours. At 1, 2, 5, 10, 20, 30 and 60min and 2h, 4h, 8 h and 24h, saturated solution is taken by a pipette and filtered, filtrate is diluted 10 times, the content of the fampicvir in the solution is detected by using liquid chromatography, and the test result is shown in figure 5, so that the solubility of the fampicvir-arginine salt hydrate is obviously improved.

Example 2

Grinding method is the same as in example 1, 150mg of ground powder is weighed and placed in a 10mL penicillin bottle, 0.1mL of water and 2.0mL of ethanol are added, slurry is stirred for 4 days under a water bath of 30 ℃, supernatant is removed after centrifugation, and the mixture is placed in a vacuum drying oven of 40 ℃ and dried overnight, so that the fapirrevir-arginine salt hydrate is obtained.

Example 3

200.00Mg of fampicvir and 199.60mg of L-arginine (molar ratio 1:0.90) are weighed, a sample is placed in a grinding tank, a clean signal Tissuelyser grinding instrument is used, the frequency is 20Hz, grinding is carried out for 30min, the preparation temperature is 10 ℃, 0.5ml of ethanol solvent is added, and the mixture powder of fampicvir and L-arginine is obtained through grinding.

60Mg of the mixed powder is weighed and placed in a 10mL penicillin bottle, 3.0mL of water and 1.0mL of acetonitrile are added, the temperature is reduced to the room temperature after the solution is cleared at 50 ℃, no solid is separated out, the solution is filtered, the solution is stood at the room temperature for slow volatilization and crystallization, the fapirrevir-arginine salt hydrate obtained in the example 1 is taken as a seed crystal, and the fapirrevir-arginine salt hydrate is obtained after a period of volatilization.

Example 4

200.00Mg of fampicvir and 221.77mg of L-arginine (molar ratio 1:1.00) are weighed, a sample is placed in a grinding tank, a clean signal Tissuelyser grinding instrument is used, the frequency is 20Hz, grinding is carried out for 30min, the preparation temperature is 20 ℃, 0.5ml of water is added, and the fampicvir and L-arginine solid mixed powder is obtained through grinding.

80Mg of the mixed powder is weighed and placed in a 10mL penicillin bottle, 4.5mL of water is added, the temperature is slowly reduced to room temperature after stirring and clearing at 50 ℃, stirring is carried out for 24 hours, the mixture is placed at 4 ℃ and continuously stirred for 2 days to separate out white solid, the supernatant is removed after centrifugation, and the mixture is placed in a 40 ℃ vacuum drying oven for drying overnight, so that the fapirrevir-arginine salt hydrate is obtained.

Example 5

The grinding method is the same as in example 4, 80mg of the grinding mixed powder is weighed and placed in a 10mL penicillin bottle, 4.0mL of water and 1.5mL of tetrahydrofuran are added, the temperature is reduced to the room temperature after the dissolution at 50 ℃, no solid is separated out, the solution is filtered, the solution is left to stand at the room temperature for slow volatilization and crystallization, the fapirrevir-arginine salt hydrate obtained in example 1 is taken as a seed crystal, and the fapirrevir-arginine salt hydrate is obtained after a period of volatilization.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made by those skilled in the art. Modifications, equivalents, improvements, etc. within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (8)

1. A favipiravir-arginine salt hydrate, characterized in that it is prepared from favipiravir and arginine, and the molar ratio of favipiravir to arginine is controlled at 1:0.90~1:1.08; the 2θ angle of the powder XRD characteristic peak is: 7.30±0.02°, 9.58±0.02°, 11.02±0.02°, 18.92±0.02°, 19.88±0.02°, 21.32±0.02°, 23.80±0.02°, 25.68±0.02°, 26.44±0.02°, 27.06±0.02°, 28.94±0.02°, 30.76±0.02°, 33.24±0.02°. 2. The method for preparing favipiravir-arginine salt hydrate according to claim 1, characterized in that, after weighing the raw materials favipiravir and L-arginine, they are placed in a grinding jar and ground for 30 minutes using a Tissuelyser grinder at a frequency of 20 Hz; mixed solid powder can be obtained by directly grinding without adding solvent at a preparation temperature of 5-30°C. 3. The method for preparing favipiravir-arginine salt hydrate according to claim 1, characterized in that, after weighing the raw materials favipiravir and L-arginine, they are placed in a grinding jar and ground for 30 min using a Tissuelyser grinder at a frequency of 20 Hz; at a preparation temperature of 5-30°C, a specified amount of ethanol, water or acetonitrile is added, and grinding yields a mixed solid powder. 4. A method for preparing favipiravir-arginine salt hydrate according to claim 2 or 3, characterized in that the mixed solid powder is dispersed in water or a mixed solvent of water and organic solvent, and favipiravir-arginine salt hydrate is prepared by solution method. 5. The method for preparing favipiravir-arginine salt hydrate according to claim 4, characterized in that the organic solvent in the mixed solvent is any one or more of methanol, ethanol, acetonitrile, isopropanol, acetone, tetrahydrofuran, and dimethyl sulfoxide. 6. The method for preparing favipiravir-arginine salt hydrate according to claim 4, characterized in that the solution method involves dispersing or dissolving the mixed solid powder in a corresponding solvent and obtaining it by crystal slurry stirring, low-temperature static crystallization, or volatile crystallization. 7. The method for preparing favipiravir-arginine salt hydrate according to claim 4, characterized in that the solvent in the mixed solvent is acetonitrile, and the volume ratio of acetonitrile to water in the mixed solvent is 1:1~8. 8. The method for preparing favipiravir-arginine salt hydrate according to claim 4, characterized in that the solvent in the mixed solvent is acetonitrile, and the volume ratio of acetonitrile to water in the mixed solvent is 1:3.