CN112624985B

CN112624985B - Compound crystal, preparation method and application

Info

Publication number: CN112624985B
Application number: CN202011641416.3A
Authority: CN
Inventors: 何运良; 张阗; 王学重; 周浩宇
Original assignee: Beijing Institute of Petrochemical Technology
Current assignee: Beijing Institute of Petrochemical Technology
Priority date: 2020-12-31
Filing date: 2020-12-31
Publication date: 2022-05-24
Anticipated expiration: 2040-12-31
Also published as: CN112624985A

Abstract

The invention discloses a compound crystal, a preparation method and application, belonging to the technical field of chemical medicine. The compound crystal is a eutectic crystal of Favipiravir and P-aminobenzoic acid, a crystal cell of the eutectic crystal belongs to a monoclinic system, P21/c space group, and the parameters of the crystal cell are as follows:

Description

Compound crystal, preparation method and application

Technical Field

The invention belongs to the technical field of chemical medicine, and particularly relates to a compound crystal, a preparation method and application.

Background

The chemical structural formulas of 6-fluoro-3-hydroxypyrazine-2-formamide (favipiravir, cas259793-96-9, Chinese name Lavipiravir) and 4-aminobenzoic acid are shown as formula 1 and formula 2.

6-fluoro-3-hydroxypyrazine-2-carboxamide is a pyrazine analogue drug developed by Fushan Chemical Co.Ltd, Japan, and was originally approved for the treatment of drug-resistant influenza. The 6-fluoro-3-hydroxypyrazine-2-formamide can inhibit the replication of influenza A and influenza B, and the medicine has great hope in the treatment of avian influenza. Favipiravir is currently being investigated for the treatment of other fatal viral infections such as Ebola, Lassa and New coronavirus (COVID-19).

WO12043700a1 and WO12043696a1 describe hydrates and crystal forms of lyophilized crystals of sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide and meglumine salt thereof, which are invented by fushan chemical industries; in chinese patent CN102348458A, tablets and granulated powders containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, invented by fushan chemical industries, are described, but their formulation crystal forms are not reported; in patent CN 102977039B, its synthesis method and crystal form are reported, and crystal structure data are provided. A new crystal form is reported in the CN 107759529 a patent, but no crystal structure data is provided.

Disclosure of Invention

The invention aims to provide a compound crystal, a preparation method and application, and the specific technical scheme is as follows:

the invention provides a compound crystal, which is a eutectic crystal of Favipiravir and P-aminobenzoic acid, wherein a unit cell of the eutectic crystal belongs to a monoclinic system, P21/c space group, and unit cell parameters are as follows:

α＝γ＝90°，β＝92.578(3)°，Z＝4，Z'＝0。

further, it has characteristic peaks at 9.6 + -0.2 °, 13.3 + -0.2 °, 13.8 + -0.2 °, 15.3 + -0.2 °, 17.7 + -0.2 °, 22.8 + -0.2 °, 25.1 + -0.2 °, 27.0 + -0.2 °, and 28.2 + -0.2 ° in an X-ray powder diffraction pattern expressed by 2 θ angle.

Preferably, the X-ray powder diffraction pattern expressed by the angle of 2 theta also has a characteristic peak at one or more of 7.0 +/-0.2 degrees, 13.0 +/-0.2 degrees, 25.7 +/-0.2 degrees and 26.3 +/-0.2 degrees. The 2 theta angle may be shifted due to the influence of the test factors such as the thickness of the sample, the test temperature, etc.

Further, the characteristic peak at 15.3 ± 0.2 ° is the strongest peak, and the strongest diffraction peak varies depending on the crystallization condition, the test condition, and the preferred orientation of the crystal when tested.

Further, the X-ray powder diffraction pattern expressed by the angle of 2 theta also has characteristic peaks at 11.7 +/-0.2 degrees, 15.0 +/-0.2 degrees and 24.4 +/-0.2 degrees.

The second aspect of the present invention provides a method for preparing the complex crystal, comprising the step of preparing the complex crystal by wet grinding, suspension or solution crystallization of favipiravir, p-aminobenzoic acid and a solvent.

Further, the wet grinding process is specifically operative to: mixing Favipiravir and p-aminobenzoic acid, adding a solvent, grinding in a mortar, and drying at a drying temperature to obtain the eutectic of Favipiravir and p-aminobenzoic acid.

The suspension method comprises the following specific operations: mixing the Favipiravir and the p-aminobenzoic acid, adding a solvent, stirring and suspending for 72-96 h at room temperature by using magnetic stirring, and drying at a drying temperature to obtain the eutectic of the Favipiravir and the p-aminobenzoic acid.

The specific operation of the solution crystallization method is as follows: dissolving para aminobenzoic acid in a solvent, heating, dissolving, adding Favipiravir, stirring, filtering and drying to obtain a eutectic crystal of Favipiravir and para aminobenzoic acid; or dissolving part of para aminobenzoic acid and part of Favipiravir in the solvent, shaking uniformly, filtering out clear liquid, adding the rest Favipiravir and the rest para aminobenzoic acid, cooling after dissolving, and drying to obtain the eutectic crystal of Favipiravir and para aminobenzoic acid.

Further, the second aspect of the present invention provides the preparation method of the complex crystal, wherein the molar ratio of fapiravir to p-aminobenzoic acid is 1: 1; the solvent is more than one of ethyl acetate, methyl tert-butyl ether, acetonitrile, n-heptane or toluene.

Further, the drying temperature is 30-60 ℃.

In a third aspect, the invention provides a pharmaceutical composition comprising the crystal of the complex provided in the first aspect of the invention and a pharmaceutically acceptable excipient. Wherein the pharmaceutically acceptable auxiliary materials are selected from pharmaceutically acceptable carriers, diluents or excipients and the like.

The fourth aspect of the invention provides the use of the pharmaceutical composition of the compound crystal in the preparation of medicaments for treating human or mammal diseases. Further, the pharmaceutical dosage form is a tablet, a capsule, an injection, a microemulsion or a submicron emulsion.

The beneficial effects of the invention are as follows: compared with single-component solubility, the equivalent solubility of the Favipiravir in the compound crystal provided by the invention is reduced by 40-60%, which is beneficial to delaying the dissolution rate of the Favipiravir, prolonging the onset time of the Favipiravir and reducing the toxic and side effects of the Favipiravir.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of a Favipiravir-p-aminobenzoic acid eutectic obtained in example 1;

FIG. 2 is a crystal cell diagram of a Favipiravir-p-aminobenzoic acid eutectic provided by the present invention;

fig. 3 is a minimum asymmetric structure in the feprosan-p-aminobenzoic acid eutectic cell provided by the present invention;

FIG. 4 is a DSC chart of the eutectic of P-piravir and p-aminobenzoic acid obtained in example 1.

Detailed Description

The invention provides a composite crystal, a preparation method and application thereof, and the invention is further explained by combining the embodiment and the attached drawings.

Fig. 2 shows a diagram of a eutectic cell of fapiravir-p-aminobenzoic acid, and fig. 3 shows that the smallest asymmetric structure in the cell contains two different molecules and that there is a relatively strong interaction.

Adding Favipiravir and p-aminobenzoic acid into a solvent, heating to dissolve, standing, slowly cooling to room temperature, and precipitating to obtain a single crystal after 6-10 days. The crystal structure of the eutectic was determined by X-ray single crystal diffraction to obtain the cell parameters shown in table 1:

TABLE 1 eutectic cell parameters

Example 1

After fapiravir and p-aminobenzoic acid were mixed uniformly in a molar ratio of 1:1, about 2g of the solid was taken, added to about 0.5ml of ethyl acetate and ground manually in a mortar for 30 min. The sample was dried in a forced air oven at 30 ℃. The obtained product is a eutectic crystal of Favipiravir and para aminobenzoic acid through XRD analysis.

Example 2

After the Favipiravir and the p-aminobenzoic acid are uniformly mixed according to the molar ratio of 1:1, about 2g of solid is taken, 10ml of methyl tert-butyl ether is added, and the mixture is suspended and stirred for 72 to 96 hours at room temperature by magnetic stirring. After the sample was filtered, the solid was dried in a forced air drying oven at 60 ℃. XRD analysis of the obtained solid shows that the solid is eutectic of Favipiravir and para aminobenzoic acid.

Example 3

0.6g of p-aminobenzoic acid was taken, 50ml of ethyl acetate was added thereto, and the mixture was heated and dissolved. Then 0.456g Favipiravir is added and stirred for 2 h. After being filtered, the solid is dried by blowing at 40 ℃, and XRD analysis shows that the solid is eutectic of Favipiravir and para aminobenzoic acid.

Example 4

50g of p-aminobenzoic acid and 45g of Favipiravir are weighed and dissolved in 1L of ethyl acetate, after uniform oscillation, clear liquid is filtered out, 15.7g of Favipiravir and 14g of p-aminobenzoic acid are added, and after heating and dissolving, the temperature is slowly reduced. After the precipitated solid is filtered and dried, XRD analysis shows that the solid is eutectic of Favipiravir and para aminobenzoic acid.

Example 5

After fapiravir and p-aminobenzoic acid were mixed uniformly in a molar ratio of 1:1, about 1g of the solid was taken, about 0.3ml of acetonitrile was added and manually ground in a mortar for 30 min. The sample was dried in a forced air oven at 30 ℃. The obtained product is a eutectic crystal of Favipiravir and para aminobenzoic acid through XRD analysis.

Example 6

After Favipiravir and p-aminobenzoic acid are uniformly mixed according to a molar ratio of 1:1, about 2g of solid is taken, 10ml of n-heptane and 0.5ml of toluene are added, and the mixture is suspended and stirred for 72h +/-8 h at room temperature by magnetic stirring. After the sample was filtered, the solid was dried in a forced air drying oven at 60 ℃. XRD analysis of the obtained solid shows that the solid is eutectic of Favipiravir and para aminobenzoic acid.

Example 7

275mg of Favipiravir and 240mg of p-aminobenzoic acid were added to 8ml of ethyl acetate, and heated to be dissolved. The container was sealed and allowed to stand at room temperature in a fume hood. A yellow transparent large-particle single crystal is separated out after about one week. Taking out the crystal, washing with a small amount of solvent, and subjecting to X-ray single crystal diffraction to determine crystal structure.

The method for producing a single crystal described in example 7 does not mean that the production of a single crystal of fabrevir-p-aminobenzoic acid is limited thereto, and a single crystal obtained by a single crystal production method known in the art using a mixture of fabrevir and p-aminobenzoic acid at a molar ratio of 1:1 can be used to determine the crystal structure of the eutectic of fabrevir-p-aminobenzoic acid.

The eutectic crystals of aminobenzoic acid and fapirovir obtained in examples 1 to 6 were characterized by X-ray powder diffraction and DSC, and the single crystal obtained in example 7 was characterized by X-ray single crystal diffraction.

XRD analysis: x-ray powder diffraction analysis is carried out on the eutectic crystal prepared in the embodiment, a Marknpanedaceae Aeries desktop diffractometer is adopted, the X-ray is CuKa, the working voltage is 40kV, the working current is 7.5mA, the scanning step length is 0.01 degrees, the scanning speed is 10 degrees/min, the scanning range is 3-42 degrees, and an X-ray powder diffraction graph is obtained. Fig. 1 is an X-ray powder diffraction pattern of the co-crystal obtained in example 1, and table 2 is a list of the corresponding diffraction peaks in fig. 1.

Table 2 table of corresponding diffraction peaks of fig. 1

2θ	Peak height	H％	Area of	A％
					9.6	559	5.2	3078	4.7
11.7	298	2.8	1850	2.8
					13.3	728	6.8	5723	8.7
13.5	610	5.7	4878	7.4
					13.9	1043	9.7	6743	10.3
15.0	361	3.4	3501	5.3
					15.4	10734	100	65502	100
17.8	1058	9.9	7302	11.1
					19.0	262	2.4	4241	6.5
19.1	439	4.1	7528	11.5
					19.8	245	2.3	1948	3
21.9	405	3.8	2739	4.2
					22.9	1022	9.5	8851	13.5
23.5	904	8.4	7595	11.6
					24.1	329	3.1	1766	2.7
24.5	1063	9.9	8373	12.8
					25.1	2264	21.1	22347	34.1
25.8	247	2.3	1909	2.9
					26.7	289	2.7	4166	6.4
27.1	2909	27.1	24762	37.8
					27.7	684	6.4	10616	16.2
28.3	5277	49.2	48710	74.4
					28.8	488	4.6	5197	7.9
30.6	517	4.8	3978	6.1
					31.0	450	4.2	3386	5.2
31.6	196	1.8	2052	3.1
					32.2	362	3.4	2996	4.6
32.7	256	2.4	2088	3.2
					33.7	174	1.6	1557	2.4
34.6	255	2.4	2185	3.3
					35.7	286	2.7	3864	5.9
37.6	202	1.9	1549	2.4
					39.0	194	1.8	1942	3

DSC analysis: the eutectic obtained in example 1 was analyzed on a DSC 3 of Mettler-Torido using a disposable common aluminum crucible with a temperature rise rate of 30 ℃ to 200 ℃, a temperature rise rate of 10 ℃/min, a nitrogen flow rate of about 10ml/min, and the sample started to melt at about 157 ℃ as shown in FIG. 4. Both fapirovir and p-aminobenzoic acid start to melt at 187 ℃, and the melting point of the co-crystal is significantly lower than that of the single component.

Single crystal diffraction analysis: the single crystals prepared in example 7 were analyzed on a brookfield D8 single crystal X-ray diffractometer equipped with a Turbo X-ray source, using the direct drive rotating anode technique and a CMOS detector. Data frames were collected using the APEX3 program and processed using the SAINT method. The structure is solved by an eigenphase method of analysis software Shelkt, refined by OLEX2 and shelXL, and anisotropically refined by a full matrix program for all non-H atoms.

And (3) measuring the solubility: solubility was measured in a jacketed 100ml glass reactor, into which circulating water at 20 ℃ was passed. And adding 50ml of water into the reaction kettle, and adding 1-2 drops of Tween 80 aqueous solution to help the solid to disperse. The water in the reaction kettle was stirred magnetically at 600 rpm. Adding small amount of solid in batches, each time with an interval of about 30min, until insoluble particles exist in the reaction kettle, and observing the dissolution process by using a visual method. The solubility of the favipiravir single component crystal and the eutectic sample prepared in example 4 were examined separately. In the case where single-component crystals precipitate in the course of dissolution of the eutectic along with decomposition of the eutectic, the apparent solubility is at the maximum. For all experimental results, three measurements were averaged. The solubility of favipiravir was measured to be about 5.2 + -1 mg/mL, the solubility of the co-crystal was 4.5 + -1 mg/mL, and the equivalent solubility converted to favipiravir was 2.4 + -0.3 mg/mL, which was reduced by about 54%.

Claims

1. A compound crystal, wherein the compound crystal is a cocrystal of Favipiravir and P-aminobenzoic acid, the unit cell of the cocrystal belongs to a monoclinic system, P21/c space group, and the unit cell parameters are as follows:

α ═ γ ═ 90 °, β ═ 92.578(3) °; the X-ray powder diffraction pattern expressed by the 2 theta angle has characteristic peaks at 9.6 +/-0.2 degrees, 13.3 +/-0.2 degrees, 13.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.7 +/-0.2 degrees, 22.8 +/-0.2 degrees, 25.1 +/-0.2 degrees, 27.0 +/-0.2 degrees and 28.2 +/-0.2 degrees.

2. The composite crystal according to claim 1, characterized in that it further has characteristic peaks in one or more of 7.0 ± 0.2 °, 13.0 ± 0.2 °, 25.7 ± 0.2 °, 26.3 ± 0.2 ° in X-ray powder diffraction pattern expressed in terms of 2 Θ angles.

3. The composite crystal according to claim 1 or 2, characterized in that the characteristic peak at 15.3 ± 0.2 ° is the strongest peak.

4. A composite crystal according to claim 1 or 2, characterized in that it further has characteristic peaks in the X-ray powder diffraction pattern expressed in terms of 2 Θ angles at 11.7 ± 0.2 °, 15.0 ± 0.2 °, 24.4 ± 0.2 °.

5. A process for producing a complex crystal according to any one of claims 1 to 4, which comprises the step of subjecting Favipiravir, p-aminobenzoic acid and a solvent to wet grinding, suspension or solution crystallization to obtain a complex crystal,

the molar ratio of the Favipiravir to the para aminobenzoic acid is 1: 1; the solvent is more than one of ethyl acetate, methyl tert-butyl ether, acetonitrile, n-heptane or toluene;

and/or the drying temperature is 30-60 ℃.

6. A pharmaceutical composition comprising the crystal complex of any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

7. Use of a crystal of the complex of any one of claims 1 to 4 or the pharmaceutical composition of claim 6 for the preparation of a medicament for the treatment of a disease in a human or a mammal.

8. The use according to claim 7, wherein the pharmaceutical dosage form is a tablet, capsule, injection, microemulsion or submicron emulsion.