Novel cocrystal

Abstract

The purpose of the present invention is to provide a novel cocrystal of Amenamevir having excellent solubility.　The present invention provides a cocrystal comprising Amenamevir and a coformer, in which the coformer is one or more selected from the group consisting of succinic acid, L-malic acid, D-malic acid, L-tartaric acid, D-tartaric acid, fumaric acid, maleic acid, phenol, salicylic acid, D-camphor, 1-naphthol, 2-naphthol, benzotriazole, vanillin, anthranilic acid, thiomalic acid, pyrogallol, hydroquinone lidocaine, chlorocresol, chlorobutanol, catechol, resorcinol, o-cresol, m-cresol, p-cresol, 1,2,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, and 4-methylcatechol.

Description

New cocrystals

[0001] The present invention relates to novel cocrystals of amenamevir.

[0002] Amenamevir is known to be useful as an antiviral agent (a therapeutic agent for shingles) (Patent Document 1). Amenamevir is a poorly water-soluble compound, and pharmaceutical ingenuity was required to make it into a commercially available formulation.

[0003] Patent No. 5011739

[0004] The object of the present invention is to provide a novel cocrystal of amenamevir that has excellent solubility.

[0005] As a result of intensive research to solve the above problems, the present inventors have found that excellent solubility can be achieved by forming a cocrystal consisting of a combination of amenamevir and a coformer described below. The present inventors have further pursued their research and have completed the present invention.

[0006] That is, the present invention is as follows: [1] A cocrystal consisting of amenamevir and a coformer, wherein the coformer is one or more selected from the group consisting of succinic acid, L-malic acid, D-malic acid, L-tartaric acid, D-tartaric acid, fumaric acid, maleic acid, phenol, salicylic acid, D-camphor, 1-naphthol, 2-naphthol, benzotriazole, vanillin, anthranilic acid, thiomalic acid, pyrogallol, hydroquinone, lidocaine, chlorocresol, chlorobutanol, catechol, resorcinol, o-cresol, m-cresol, p-cresol, 2,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, and 4-methylcatechol. [1'] A cocrystal consisting of amenamevir and a coformer, wherein the coformer is one or more selected from the group consisting of succinic acid, malic acid, tartaric acid, fumaric acid, maleic acid, phenol, salicylic acid, D-camphor, 2-naphthol, benzotriazole, vanillin, anthranilic acid, thiomalic acid, pyrogallol, and hydroquinone. [2] The cocrystal according to [1] above, consisting of amenamevir and succinic acid, having characteristic peaks at diffraction angles (2θ) of 8.207°±0.2°, 9.566°±0.2°, 10.024°±0.2°, 11.225°±0.2°, and 11.990°±0.2° in a powder X-ray diffraction pattern. [3] The cocrystal according to [1] above, which consists of amenamevir and L-malic acid and has characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.658°±0.2°, 10.065°±0.2°, 11.281°±0.2°, and 11.836°±0.2° in its powder X-ray diffraction pattern. [4] The cocrystal according to [1] above, which consists of amenamevir and D-malic acid and has characteristic peaks at diffraction angles (2θ) of 8.151°±0.2°, 9.650°±0.2°, 10.065°±0.2°, 11.278°±0.2°, and 11.834°±0.2° in its powder X-ray diffraction pattern. [5] The cocrystal according to the above-mentioned [1], which consists of amenamevir and L-tartaric acid and has characteristic peaks at diffraction angles (2θ) of 8.093°±0.1°, 8.778°±0.1°, 9.758°±0.1°, and 10.122°±0.1° in a powder X-ray diffraction pattern.[6] The cocrystal according to [1] above, which consists of amenamevir and D-tartaric acid and has characteristic peaks at diffraction angles (2θ) of 8.100°±0.1°, 8.761°±0.1°, 9.742°±0.1°, and 10.123°±0.1° in a powder X-ray diffraction pattern. [7] The cocrystal according to [1] above, which consists of amenamevir and fumaric acid and has characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.618°±0.2°, 10.045°±0.2°, 11.261°±0.2°, and 11.866°±0.2° in a powder X-ray diffraction pattern. [8] The cocrystal according to [1] above, which consists of amenamevir and maleic acid and has characteristic peaks at diffraction angles (2θ) of 8.492°±0.2°, 9.172°±0.2°, 10.709°±0.2°, and 11.131°±0.2° in its powder X-ray diffraction pattern. [9] The cocrystal according to [1] above, which consists of amenamevir and phenol and has characteristic peaks at diffraction angles (2θ) of 8.610°±0.2°, 10.680°±0.2°, and 13.688°±0.2° in its powder X-ray diffraction pattern.

[10] The cocrystal according to the above item [1], which consists of amenamevir and salicylic acid and has characteristic peaks at diffraction angles (2θ) of 6.403°±0.1°, 8.557°±0.1°, 8.871°±0.1°, and 10.781°±0.1° in a powder X-ray diffraction pattern.

[11] The cocrystal according to the above item [1], which consists of amenamevir and D-camphor and has characteristic peaks at diffraction angles (2θ) of 7.341°±0.2°, 8.087°±0.2°, 11.747°±0.2°, and 13.602°±0.2° in a powder X-ray diffraction pattern.

[12] The cocrystal according to [1] above, which consists of amenamevir and 1-naphthol and has characteristic peaks at diffraction angles (2θ) of 8.118°±0.1°, 8.820°±0.1°, 9.166°±0.1°, 10.821°±0.1°, and 12.494°±0.1° in a powder X-ray diffraction pattern.

[13] The cocrystal according to [1] above, which consists of amenamevir and 2-naphthol and has characteristic peaks at diffraction angles (2θ) of 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, and 11.260°±0.2° in a powder X-ray diffraction pattern.

[14] The cocrystal according to [1], which consists of amenamevir and benzotriazole and has characteristic peaks at diffraction angles (2θ) of 8.284°±0.1°, 9.228°±0.1°, 9.585°±0.1°, 12.277°±0.1°, and 12.871°±0.1° in a powder X-ray diffraction pattern.

[15] The cocrystal according to [1], which consists of amenamevir and vanillin and has characteristic peaks at diffraction angles (2θ) of 8.406°±0.05°, 10.643°±0.05°, 10.832°±0.05°, and 13.067°±0.05° in a powder X-ray diffraction pattern.

[16] The cocrystal according to [1] above, which consists of amenamevir and anthranilic acid and has characteristic peaks at diffraction angles (2θ) of 8.345°±0.1°, 9.297°±0.1°, 11.865°±0.1°, 14.516°±0.1°, and 15.092°±0.1° in its powder X-ray diffraction pattern.

[17] The cocrystal according to [1] above, which consists of amenamevir and thiomalic acid and has characteristic peaks at diffraction angles (2θ) of 8.137°±0.2°, 9.536°±0.2°, 10.102°±0.2°, 11.321°±0.2°, and 11.815°±0.2° in its powder X-ray diffraction pattern.

[18] The cocrystal according to [1], which consists of amenamevir and pyrogallol and has characteristic peaks at diffraction angles (2θ) of 8.174°±0.05°, 8.521°±0.05°, 8.707°±0.05°, 10.613°±0.05°, and 13.511°±0.05° in a powder X-ray diffraction pattern.

[19] The cocrystal according to [1], which consists of amenamevir and hydroquinone and has characteristic peaks at diffraction angles (2θ) of 8.645°±0.1°, 10.655°±0.1°, 13.723°±0.1°, and 14.898°±0.1° in a powder X-ray diffraction pattern.

[20] The cocrystal according to the above-mentioned [1], which consists of amenamevir and lidocaine and has characteristic peaks at diffraction angles (2θ) of 6.921°±0.05°, 7.071°±0.05°, 12.917°±0.05°, and 13.648°±0.05 in a powder X-ray diffraction pattern.

[21] The cocrystal according to [1] above, which consists of amenamevir and chlorocresol and has characteristic peaks at diffraction angles (2θ) of 8.267°±0.2°, 8.730°±0.2°, 10.384°±0.2°, 12.879°±0.2°, and 15.580°±0.2° in a powder X-ray diffraction pattern.

[22] The cocrystal according to [1] above, which consists of amenamevir and chlorobutanol and has characteristic peaks at diffraction angles (2θ) of 8.082°±0.1°, 8.571°±0.1°, 11.391°±0.1°, 13.649°±0.1°, and 15.216°±0.1° in a powder X-ray diffraction pattern.

[23] The cocrystal according to [1], which consists of amenamevir and catechol and has characteristic peaks at diffraction angles (2θ) of 8.481°±0.1°, 8.729°±0.1°, 10.917°±0.1°, 11.079°±0.1°, and 15.154°±0.1° in a powder X-ray diffraction pattern.

[24] The cocrystal according to [1], which consists of amenamevir and resorcinol and has characteristic peaks at diffraction angles (2θ) of 8.518°±0.05°, 8.649°±0.05°, 10.652°±0.05°, 13.535°±0.05°, and 16.091°±0.05° in a powder X-ray diffraction pattern.

[25] The cocrystal according to [1] above, which consists of amenamevir and o-cresol and has characteristic peaks at diffraction angles (2θ) of 8.538°±0.1°, 10.629°±0.1°, 11.015°±0.1°, 13.686°±0.1°, and 16.203°±0.2° in its powder X-ray diffraction pattern.

[26] The cocrystal according to [1] above, which consists of amenamevir and m-cresol and has characteristic peaks at diffraction angles (2θ) of 7.306°±0.2°, 8.827°±0.2°, 10.686°±0.2°, 12.736°±0.2°, and 14.640°±0.2° in its powder X-ray diffraction pattern.

[27] The cocrystal according to the above-mentioned [1], which consists of amenamevir and p-cresol and has characteristic peaks at diffraction angles (2θ) of 7.300°±0.2°, 8.159°±0.2°, 8.607°±0.2°, 10.966°±0.2°, and 14.540°±0.2° in a powder X-ray diffraction pattern.

[28] The cocrystal according to [1] above, which consists of amenamevir and 1,2,4-trihydroxybenzene and has characteristic peaks at diffraction angles (2θ) of 8.663°±0.05°, 10.593°±0.05°, 13.432°±0.05°, 14.919°±0.05°, and 16.029°±0.05° in a powder X-ray diffraction pattern.

[29] The cocrystal according to [1] above, which consists of amenamevir and 1,3,5-trihydroxybenzene and has characteristic peaks at diffraction angles (2θ) of 6.174°±0.1°, 9.804°±0.1°, 12.006°±0.1°, 12.203°±0.1°, and 15.247°±0.1° in a powder X-ray diffraction pattern.

[30] The cocrystal according to the above item [1], which consists of amenamevir and 4-methylcatechol and has characteristic peaks at diffraction angles (2θ) of 6.823°±0.1°, 7.162°±0.1°, 9.311°±0.1°, 14.377°±0.1°, and 14.685°±0.1° in a powder X-ray diffraction pattern.

[0007] According to the present invention, a novel cocrystal of amenamevir having excellent solubility can be provided.

[0008] FIG. 1 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and succinic acid obtained in Example 1. FIG. 2 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and L-malic acid obtained in Example 2. FIG. 3 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and D-malic acid obtained in Example 3. FIG. 4 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and L-tartaric acid obtained in Example 4. FIG. 5 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and D-tartaric acid obtained in Example 5. FIG. 6 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and fumaric acid obtained in Example 6. FIG. 7 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and maleic acid obtained in Example 7. FIG. 8 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and phenol obtained in Example 8. FIG. 9 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and salicylic acid obtained in Example 9. FIG. 10 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and D-camphor obtained in Example 10. FIG. 11 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and 2-naphthol obtained in Example 11. FIG. 12 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and benzotriazole obtained in Example 12. FIG. 13 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and vanillin obtained in Example 13. FIG. 14 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and anthranilic acid obtained in Example 14. FIG. 15 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and thiomalic acid obtained in Example 15. FIG. 16 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and pyrogallol obtained in Example 16. Figure 17 shows a powder X-ray diffraction pattern for the cocrystal of amenamevir and hydroquinone obtained in Example 17. Figure 18 shows a powder X-ray diffraction pattern for the cocrystal of amenamevir and 1-naphthol obtained in Example 18. Figure 19 shows a powder X-ray diffraction pattern for the cocrystal of amenamevir and lidocaine obtained in Example 19. Figure 20 shows a powder X-ray diffraction pattern for the cocrystal of amenamevir and chlorocresol obtained in Example 20. Figure 21 shows a powder X-ray diffraction pattern for the cocrystal of amenamevir and chlorobutanol obtained in Example 21.Figure 22 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and catechol obtained in Example 22. Figure 23 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and resorcinol obtained in Example 23. Figure 24 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and o-cresol obtained in Example 24. Figure 25 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and m-cresol obtained in Example 25. Figure 26 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and p-cresol obtained in Example 26. Figure 27 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and 1,2,4-trihydroxybenzene obtained in Example 27. Figure 28 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and 1,3,5-trihydroxybenzene obtained in Example 28. FIG. 29 shows the powder X-ray diffraction pattern of the cocrystal of amenamevir and 4-methylcatechol obtained in Example 29.

[0009] The cocrystal of the present invention is a cocrystal consisting of amenamevir and a coformer, wherein the coformer is one or more selected from the group consisting of succinic acid, malic acid (e.g., L-malic acid, D-malic acid), tartaric acid (e.g., L-tartaric acid, D-tartaric acid), fumaric acid, maleic acid, phenol, salicylic acid, D-camphor, 1-naphthol, 2-naphthol, benzotriazole, vanillin, anthranilic acid, thiomalic acid, pyrogallol, hydroquinone, lidocaine, chlorocresol, chlorobutanol, catechol, resorcinol, o-cresol, m-cresol, p-cresol, 2,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, and 4-methylcatechol.

[0010] In the present invention, the term "cocrystal" refers to a crystalline solid in which two or more different molecules form a crystal structure in a single crystal lattice at a certain stoichiometric ratio. The intermolecular bonding form within a cocrystal distinguishes it from salts and mixtures. Furthermore, a cocrystal refers to a crystalline solid that has a new crystal structure formed by bonding with a coformer at a regular ratio through intermolecular forces, such as hydrogen bonds. The cocrystal in the present invention may also be a solvate. Examples of solvents that form solvates include water, acetonitrile, acetone, ethanol, isopropanol, chloroform, and diethyl ether. In the present invention, the term "solvate" refers to a compound containing a solvent in a crystal at a certain stoichiometric ratio. A hydrate is a compound in which the solvating solvent is water. In the present invention, the term "coformer" refers to a molecule other than amenamevir that constitutes the crystal of a cocrystal pharmaceutical. In the present invention, whether a compound is a cocrystal can be characterized by analytical methods known in the pharmaceutical industry for characterizing crystalline solids. These methods include, but are not limited to, powder X-ray diffraction and single crystal X-ray structure analysis, infrared spectroscopy, Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and differential thermal analysis (DTA). The cocrystal of the present invention can be characterized by one of the above-mentioned analytical methods or by combining two or more of them. In particular, the cocrystal of the present invention can be confirmed by one of the following embodiments or by combining two or more of the following embodiments. In powder X-ray diffraction, the 2θ values ​​of a powder X-ray diffraction pattern can generally vary due to differences in the measurement device, sample preparation, etc.; therefore, when examining powder X-ray diffraction data, a measurement error of about diffraction angle (2θ) ±0.2° (or diffraction angle (2θ) ±0.1°, diffraction angle (2θ) ±0.05°) should be taken into consideration. Therefore, not only crystals whose diffraction angles (2θ) in powder X-ray diffraction are perfectly identical, but also crystals whose diffraction angles (2θ) are identical within a range of ±0.2°, ±0.1°, or ±0.05° are included in the scope of the present invention.

[0011] The cocrystals of the present invention include the following (1) to (27): (1) Cocrystal of amenamevir and succinic acid As the cocrystal of amenamevir and succinic acid, when powder X-ray diffraction measurement is performed under the conditions described in the Examples below, a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.207°±0.2°, 9.566°±0.2°, 10.024°±0.2°, 11.225°±0.2°, and 11.990°±0.2° in the powder X-ray diffraction pattern is preferred; a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.207°±0.2°, 9.566°±0.2°, 10.024°±0.2°, 11.225°±0.2°, 11.990°±0.2°, and 13.867°±0.2° in the powder X-ray diffraction pattern is more preferred; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.207°±0.2°, 9.566°±0.2°, 10.024°±0.2°, 11.225°±0.2°, 11.990°±0.2°, 13.867°±0.2°, and 15.293°±0.2° in its powder X-ray diffraction pattern; and even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.207°±0.2°, 9.566°±0.2°, 10.024°±0.2°, 11.225°±0.2°, 11.990°±0.2°, 13.867°±0.2°, 15.293°±0.2°, 16.460°±0.2°, and 17.339°±0.2° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to succinic acid (amenamevir:succinic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.

[0012] (2) Cocrystal of Amenamevir and Malic Acid (e.g., L-Malic Acid, D-Malic Acid) When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of Amenamevir and L-malic acid is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.658°±0.2°, 10.065°±0.2°, 11.281°±0.2°, and 11.836°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.658°±0.2°, 10.065°±0.2°, 11.281°±0.2°, 11.836°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.658°±0.2°, 10.065°±0.2°, 11.281°±0.2°, 11.836°±0.2°, 13.887°±0.2°, and 15.461°±0.2° in its X-ray powder diffraction pattern; and even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.658°±0.2°, 10.065°±0.2°, 11.281°±0.2°, 11.836°±0.2°, 13.887°±0.2°, 15.461°±0.2°, and 17.514°±0.2° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to L-malic acid (amenamevir:L-malic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.As the cocrystal of amenamevir and D-malic acid, when powder X-ray diffraction measurement is performed under the conditions described in the Examples below, a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.151°±0.2°, 9.650°±0.2°, 10.065°±0.2°, 11.278°±0.2°, and 11.834°±0.2° in the powder X-ray diffraction pattern is preferred; a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.151°±0.2°, 9.650°±0.2°, 10.065°±0.2°, 11.278°±0.2°, 11.834°±0.2°, and 13.880°±0.2° in the powder X-ray diffraction pattern is more ... More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.151°±0.2°, 9.650°±0.2°, 10.065°±0.2°, 11.278°±0.2°, 11.834°±0.2°, 13.880°±0.2°, and 15.455°±0.2° in its powder X-ray diffraction pattern; even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.151°±0.2°, 9.650°±0.2°, 10.065°±0.2°, 11.278°±0.2°, 11.834°±0.2°, 13.880°±0.2°, 15.455°±0.2°, 16.337°±0.2°, and 17.508°±0.2° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to D-malic acid (amenamevir:D-malic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.

[0013] (3) Cocrystal of amenamevir and tartaric acid (e.g., L-tartaric acid, D-tartaric acid) As the cocrystal of amenamevir and L-tartaric acid, when powder X-ray diffraction measurement is performed under the conditions described in the Examples below, a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.093°±0.1°, 8.778°±0.1°, 9.758°±0.1°, and 10.122°±0.1° in the powder X-ray diffraction pattern is preferred; a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.093°±0.1°, 8.778°±0.1°, 9.758°±0.1°, 10.122°±0.1°, 11.363°±0.1°, and 11.759°±0.1° in the powder X-ray diffraction pattern is more preferred; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.093°±0.1°, 8.778°±0.1°, 9.758°±0.1°, 10.122°±0.1°, 11.363°±0.1°, 11.759°±0.1°, 13.532°±0.1°, and 13.881°±0.1° in a powder X-ray diffraction pattern; Even more preferred is a cocrystal having characteristic peaks at 0.1°, 9.758°±0.1°, 10.122°±0.1°, 11.363°±0.1°, 11.759°±0.1°, 13.532°±0.1°, 13.881°±0.1°, 15.563°±0.1°, 16.208°±0.1°, and 17.492°±0.1°. The molar ratio of amenamevir to L-tartaric acid (amenamevir:L-tartaric acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.As the cocrystal of amenamevir and D-tartaric acid, when powder X-ray diffraction measurement is performed under the conditions described in the Examples below, a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.100°±0.1°, 8.761°±0.1°, 9.742°±0.1°, and 10.123°±0.1° in the powder X-ray diffraction pattern is preferred; a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.100°±0.1°, 8.761°±0.1°, 9.742°±0.1°, 10.123°±0.1°, 11.359°±0.1°, and 11.737°±0.1° in the powder X-ray diffraction pattern is more preferred; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.100°±0.1°, 8.761°±0.1°, 9.742°±0.1°, 10.123°±0.1°, 11.359°±0.1°, 11.737°±0.1°, 13.517°±0.1°, and 13.869°±0.1° in a powder X-ray diffraction pattern; Even more preferred is a cocrystal having characteristic peaks at 0.1°, 9.742°±0.1°, 10.123°±0.1°, 11.359°±0.1°, 11.737°±0.1°, 13.517°±0.1°, 13.869°±0.1°, 15.541°±0.1°, 16.230°±0.1°, and 17.477°±0.1°. The molar ratio of amenamevir to D-tartaric acid (amenamevir:D-tartaric acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.

[0014] (4) Cocrystal of Amenamevir and Fumaric Acid When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and fumaric acid is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.618°±0.2°, 10.045°±0.2°, 11.261°±0.2°, and 11.866°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.618°±0.2°, 10.045°±0.2°, 11.261°±0.2°, 11.866°±0.2°, and 13.843°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.618°±0.2°, 10.045°±0.2°, 11.261°±0.2°, 11.866°±0.2°, 13.843°±0.2°, and 15.379°±0.2° in its powder X-ray diffraction pattern; and even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.618°±0.2°, 10.045°±0.2°, 11.261°±0.2°, 11.866°±0.2°, 13.843°±0.2°, 15.379°±0.2°, 16.339°±0.2°, and 17.393°±0.2° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to fumaric acid (amenamevir:fumaric acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.

[0015] (5) Cocrystal of Amenamevir and Maleic Acid When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and maleic acid is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.492°±0.2°, 9.172°±0.2°, 10.709°±0.2°, and 11.131°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.492°±0.2°, 9.172°±0.2°, 10.709°±0.2°, 11.131°±0.2°, and 13.764°±0.2° in the powder X-ray diffraction pattern; More preferred are co-crystals having characteristic peaks at diffraction angles (2θ) of 8.492°±0.2°, 9.172°±0.2°, 10.709°±0.2°, 11.131°±0.2°, 13.764°±0.2°, 14.359°±0.2°, and 15.843°±0.2°; even more preferred are co-crystals having characteristic peaks at diffraction angles (2θ) of 8.492°±0.2°, 9.172°±0.2°, 10.709°±0.2°, 11.131°±0.2°, 13.764°±0.2°, 14.359°±0.2°, 15.843°±0.2°, and 17.114°±0.2° in their powder X-ray diffraction patterns. The molar ratio of amenamevir to maleic acid (amenamevir:maleic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0016] (6) Cocrystal of Amenamevir and Phenol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and phenol preferably has characteristic peaks at diffraction angles (2θ) of 8.610°±0.2°, 10.680°±0.2°, and 13.688°±0.2° in the powder X-ray diffraction pattern; more preferably has characteristic peaks at diffraction angles (2θ) of 8.610°±0.2°, 10.680°±0.2°, 13.688°±0.2°, and 14.935°±0.2° in the powder X-ray diffraction pattern; and a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.610°±0.2°, 10.680°±0.2°, 13.688°±0.2°, 14.935°±0.2°, and 16.205°±0.2° in its powder X-ray diffraction pattern is even more preferred. The molar ratio of amenamevir to phenol (amenamevir:phenol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0017] (7) Cocrystal of Amenamevir and Salicylic Acid When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and salicylic acid is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.403°±0.1°, 8.557°±0.1°, 8.871°±0.1°, and 10.781°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.403°±0.1°, 8.557°±0.1°, 8.871°±0.1°, 10.781°±0.1°, and 12.805°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 6.403°±0.1°, 8.557°±0.1°, 8.871°±0.1°, 10.781°±0.1°, 12.805°±0.1°, and 13.923°±0.1° in its X-ray powder diffraction pattern; even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 6.403°±0.1°, 8.557°±0.1°, 8.871°±0.1°, 10.781°±0.1°, 12.805°±0.1°, 13.923°±0.1°, 16.260°±0.1°, and 20.981°±0.1° in its X-ray powder diffraction pattern. The molar ratio of amenamevir to salicylic acid (amenamevir:salicylic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0018] (8) Cocrystal of Amenamevir and D-Camphor When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and D-camphor is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 7.341°±0.2°, 8.087°±0.2°, 11.747°±0.2°, and 13.602°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 7.341°±0.2°, 8.087°±0.2°, 11.747°±0.2°, 13.602°±0.2°, and 15.053°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks in its X-ray powder diffraction pattern at diffraction angles (2θ) of 7.341°±0.2°, 8.087°±0.2°, 11.747°±0.2°, 13.602°±0.2°, 15.053°±0.2°, and 16.147°±0.2°; even more preferred is a co-crystal having characteristic peaks in its X-ray powder diffraction pattern at diffraction angles (2θ) of 7.341°±0.2°, 8.087°±0.2°, 11.747°±0.2°, 13.602°±0.2°, 15.053°±0.2°, 16.147°±0.2°, and 20.436°±0.2°. The molar ratio of amenamevir to D-camphor (amenamevir:D-camphor) in the cocrystal showing such a powder X-ray diffraction pattern is 2:1.

[0019] (9) Cocrystal of Amenamevir and 1-Naphthol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and 1-naphthol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.118°±0.1°, 8.820°±0.1°, 9.166°±0.1°, 10.821°±0.1°, and 12.494°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.118°±0.1°, 8.820°±0.1°, 9.166°±0.1°, 10.821°±0.1°, 12.494°±0.1°, and 14.918°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.118°±0.1°, 8.820°±0.1°, 9.166°±0.1°, 10.821°±0.1°, 12.494°±0.1°, 14.203°±0.1°, and 14.918°±0.1° in its X-ray powder diffraction pattern; and even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.118°±0.1°, 8.820°±0.1°, 9.166°±0.1°, 10.821°±0.1°, 12.494°±0.1°, 14.203°±0.1°, 14.918°±0.1°, and 15.320°±0.1° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to 1-naphthol (amenamevir:1-naphthol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0020] (10) Cocrystal of Amenamevir and 2-Naphthol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and 2-naphthol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, and 11.260°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, 11.260°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, 11.260°±0.2°, and 14.798°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles of 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, 11.260°±0.2°, 13.296°±0.2°, 13.841°±0.2°, and 14.798°±0.2° in a powder X-ray diffraction pattern. Even more preferred is a cocrystal having characteristic peaks at (2θ) 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, 11.260°±0.2°, 13.296°±0.2°, 13.841°±0.2°, 14.798°±0.2°, and 19.562°±0.2°. The molar ratio of amenamevir to 2-naphthol (amenamevir:2-naphthol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:3.

[0021] (11) Cocrystal of Amenamevir and Benzotriazole When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and benzotriazole is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.284°±0.1°, 9.228°±0.1°, 9.585°±0.1°, 12.277°±0.1°, and 12.871°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.284°±0.1°, 9.228°±0.1°, 9.585°±0.1°, 12.277°±0.1°, 12.871°±0.1°, and 15.392°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.284°±0.1°, 9.228°±0.1°, 9.585°±0.1°, 12.277°±0.1°, 12.871°±0.1°, 13.900°±0.1°, 14.718°±0.1°, and 15.392°±0.1° in a powder X-ray diffraction pattern. Even more preferred is a cocrystal having characteristic peaks at 9.228°±0.1°, 9.585°±0.1°, 12.277°±0.1°, 12.871°±0.1°, 13.900°±0.1°, 14.718°±0.1°, 15.392°±0.1°, 15.647°±0.1°, and 15.860°±0.1°. The molar ratio of amenamevir to benzotriazole (amenamevir:benzotriazole) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0022] (12) Cocrystal of Amenamevir and Vanillin When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and vanillin is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.406°±0.05°, 10.643°±0.05°, 10.832°±0.05°, and 13.067°±0.05° in the powder X-ray diffraction pattern; Cocrystals having characteristic peaks at angles (2θ) of 8.406°±0.05°, 10.643°±0.05°, 10.832°±0.05°, 13.067°±0.05°, and 16.043°±0.05° are more preferred; cocrystals having characteristic peaks at angles (2θ) of 8.406°±0.05°, 9.548°±0.05°, 9.786°±0.05°, 10. More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) in a powder X-ray diffraction pattern of 8.406°±0.05°, 9.548°±0.05°, 9.786°±0.05°, 10.643°±0.05°, 10.832°±0.05°, 13.067°±0.05°, and 16.043°±0.05°; Even more preferred is a cocrystal having characteristic peaks at 0.05°, 13.067°±0.05°, 13.405°±0.05°, 13.645°±0.05°, 13.842°±0.05°, 14.496°±0.05°, 15.048°±0.05°, 15.216°±0.05°, 15.927°±0.05°, and 16.043°±0.05°. The molar ratio of amenamevir to vanillin (amenamevir:vanillin) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 3:4.

[0023] (13) Cocrystal of Amenamevir and Anthranilic Acid When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and anthranilic acid is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.345°±0.1°, 9.297°±0.1°, 11.865°±0.1°, 14.516°±0.1°, and 15.092°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.345°±0.1°, 9.297°±0.1°, 11.865°±0.1°, 12.335°±0.1°, 13.037°±0.1°, 13.783°±0.1°, 14.516°±0.1°, and 15.092°±0.1° in a powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.023°±0.1°, 8.345°±0.1°, 9.297°±0.1°, 11.865°±0.1°, 12.335°±0.1°, 13.037°±0.1°, 13.783°±0.1°, 14.516°±0.1°, and 15.092°±0.1° in a powder X-ray diffraction pattern. Even more preferred is a cocrystal having characteristic peaks at 45°±0.1°, 9.297°±0.1°, 10.239°±0.1°, 10.806°±0.1°, 11.045°±0.1°, 11.865°±0.1°, 12.335°±0.1°, 13.037°±0.1°, 13.783°±0.1°, 14.516°±0.1°, and 15.092°±0.1°. The molar ratio of amenamevir to anthranilic acid (amenamevir:anthranilic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0024] (14) Cocrystal of Amenamevir and Thiomalic Acid When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and thiomalic acid is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.137°±0.2°, 9.536°±0.2°, 10.102°±0.2°, 11.321°±0.2°, and 11.815°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.137°±0.2°, 9.536°±0.2°, 10.102°±0.2°, 11.321°±0.2°, 11.815°±0.2°, 13.674°±0.2°, and 15.262°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.137°±0.2°, 9.536°±0.2°, 10.102°±0.2°, 11.321°±0.2°, 11.815°±0.2°, 13.674°±0.2°, 15.262°±0.2°, and 17.274°±0.2° in the powder X-ray diffraction pattern. Even more preferred is a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.137°±0.2°, 9.536°±0.2°, 10.102°±0.2°, 11.321°±0.2°, 11.815°±0.2°, 13.674°±0.2°, 15.262°±0.2°, 16.324°±0.2°, and 17.274°±0.2°. The molar ratio of amenamevir to thiomalic acid (amenamevir:thiomalic acid) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.

[0025] (15) Cocrystal of amenamevir and pyrogallol As the cocrystal of amenamevir and pyrogallol, when powder X-ray diffraction measurement is performed under the conditions described in the Examples below, a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.174°±0.05°, 8.521°±0.05°, 8.707°±0.05°, 10.613°±0.05°, and 13.511°±0.05° in the powder X-ray diffraction pattern is preferred; a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.174°±0.05°, 8.521°±0.05°, 8.707°±0.05°, 10.613°±0.05°, 11.029°±0.05°, and 13.511°±0.05° in the powder X-ray diffraction pattern is more ... More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.174°±0.05°, 8.521°±0.05°, 8.707°±0.05°, 10.613°±0.05°, 11.029°±0.05°, 13.511°±0.05°, and 16.102°±0.05° in a powder X-ray diffraction pattern. Even more preferred is a cocrystal having characteristic peaks at 1:5°, 8.707°±0.05°, 10.613°±0.05°, 11.029°±0.05°, 13.511°±0.05°, 14.964°±0.05°, 15.068°±0.05°, 15.547°±0.05°, 15.812°±0.05°, and 16.102°±0.05°. The molar ratio of amenamevir to pyrogallol (amenamevir:pyrogallol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0026] (16) Cocrystal of Amenamevir and Hydroquinone When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and hydroquinone is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.645°±0.1°, 10.655°±0.1°, 13.723°±0.1°, and 14.898°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.645°±0.1°, 10.655°±0.1°, 13.723°±0.1°, 14.898°±0.1°, and 16.253°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.645°±0.1°, 10.655°±0.1°, 13.723°±0.1°, 14.898°±0.1°, and 16.253°±0.1° in the powder X-ray diffraction pattern; More preferred are co-crystals having characteristic peaks at diffraction angles (2θ) of 8.645°±0.1°, 9.501°±0.1°, 10.655°±0.1°, 11.051°±0.1°, 13.212°±0.1°, 13.723°±0.1°, 14.898°±0.1°, 15.237°±0.1°, 16.253°±0.1°, and 22.205°±0.1° in their powder X-ray diffraction patterns. The molar ratio of amenamevir to hydroquinone (amenamevir:hydroquinone) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0027] (17) Cocrystal of Amenamevir and Lidocaine When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and lidocaine preferably has characteristic peaks at diffraction angles (2θ) of 6.921°±0.05°, 7.071°±0.05°, 12.917°±0.05°, and 13.648°±0.05 in the powder X-ray diffraction pattern; more preferably has characteristic peaks at diffraction angles (2θ) of 6.921°±0.05°, 7.071°±0.05°, 9.043°±0.05°, 12.917°±0.05°, and 13.648°±0.05 in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks in its pattern at diffraction angles (2θ) of 6.921°±0.05°, 7.071°±0.05°, 9.043°±0.05°, 12.107°±0.05°, 12.917°±0.05°, and 13.648°±0.05°; even more preferred is a co-crystal having characteristic peaks in its pattern at diffraction angles (2θ) of 6.921°±0.05°, 7.071°±0.05°, 9.043°±0.05°, 12.107°±0.05°, 12.917°±0.05°, 13.648°±0.05°, and 14.519°±0.05°. The molar ratio of amenamevir to lidocaine (amenamevir:lidocaine) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:1.

[0028] (18) Cocrystal of Amenamevir and Chlorocresol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and chlorocresol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.267°±0.2°, 8.730°±0.2°, 10.384°±0.2°, 12.879°±0.2°, and 15.580°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.267°±0.2°, 8.730°±0.2°, 10.384°±0.2°, 12.879°±0.2°, 15.580°±0.2°, and 21.800°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.267°±0.2°, 8.730°±0.2°, 10.384°±0.2°, 12.879°±0.2°, 14.779°±0.2°, 15.580°±0.2°, and 21.800°±0.2° in an X-ray diffraction pattern; even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.267°±0.2°, 8.730°±0.2°, 10.384°±0.2°, 10.848°±0.2°, 12.879°±0.2°, 14.779°±0.2°, 15.580°±0.2°, and 21.800°±0.2° in an X-ray powder diffraction pattern. The molar ratio of amenamevir to chlorocresol (amenamevir:chlorocresol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0029] (19) Cocrystal of Amenamevir and Chlorobutanol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and chlorobutanol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.082°±0.1°, 8.571°±0.1°, 11.391°±0.1°, 13.649°±0.1°, and 15.216°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.082°±0.1°, 8.571°±0.1°, 10.181°±0.1°, 11.391°±0.1°, 13.649°±0.1°, and 15.216°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.082°±0.1°, 8.571°±0.1°, 10.181°±0.1°, 11.391°±0.1°, 13.649°±0.1°, 15.216°±0.1°, and 17.091°±0.1° in a powder X-ray diffraction pattern; and even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.082°±0.1°, 8.571°±0.1°, 10.181°±0.1°, 11.391°±0.1°, 13.649°±0.1°, 15.216°±0.1°, 16.231°±0.1°, 16.838°±0.1°, and 17.091°±0.1° in a powder X-ray diffraction pattern. The molar ratio of amenamevir to chlorobutanol (amenamevir:chlorobutanol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0030] (20) Cocrystal of Amenamevir and Catechol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and catechol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.481°±0.1°, 8.729°±0.1°, 10.917°±0.1°, 11.079°±0.1°, and 15.154°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.481°±0.1°, 8.729°±0.1°, 10.917°±0.1°, 11.079°±0.1°, 15.154°±0.1°, and 16.59 ... More preferred is a co-crystal having characteristic peaks at diffraction angles of 8.272°±0.1°, 8.481°±0.1°, 8.729°±0.1°, 10.917°±0.1°, 11.079°±0.1°, 14.241°±0.1°, 15.154°±0.1°, and 16.599°±0.1° in a powder X-ray diffraction pattern. Even more preferred is a cocrystal having characteristic peaks at (2θ) 8.272°±0.1°, 8.481°±0.1°, 8.729°±0.1°, 10.917°±0.1°, 11.079°±0.1°, 14.241°±0.1°, 15.154°±0.1°, 16.599°±0.1°, and 20.325°±0.1°. The molar ratio of amenamevir to catechol (amenamevir:catechol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0031] (21) Cocrystal of Amenamevir and Resorcinol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and resorcinol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.518°±0.05°, 8.649°±0.05°, 10.652°±0.05°, 13.535°±0.05°, and 16.091°±0.05° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.518°±0.05°, 8.649°±0.05°, 10.652°±0.05°, 13.535°±0.05°, 14.981°±0.05°, and 16.091°±0.05° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.518°±0.05°, 8.649°±0.05°, 10.652°±0.05°, 10.987°±0.05°, 13.535°±0.05°, 14.981°±0.05°, and 16.091°±0.05°; Even more preferred is a cocrystal having characteristic peaks at 518°±0.05°, 8.649°±0.05°, 10.652°±0.05°, 10.987°±0.05°, 13.535°±0.05°, 14.981°±0.05°, 16.091°±0.05°, 16.621°±0.05°, and 22.093°±0.05°. The molar ratio of amenamevir to resorcinol (amenamevir:resorcinol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:2.

[0032] (22) Cocrystal of Amenamevir and o-Cresol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and o-cresol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.538°±0.1°, 10.629°±0.1°, 11.015°±0.1°, 13.686°±0.1°, and 16.203°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.538°±0.1°, 10.629°±0.1°, 11.015°±0.1°, 13.686°±0.1°, 14.973°±0.1°, and 16.203°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 8.538°±0.1°, 10.629°±0.1°, 11.015°±0.1°, 13.686°±0.1°, 14.973°±0.1°, 15.223°±0.1°, and 16.203°±0.1° in a powder X-ray diffraction pattern; Even more preferred is a cocrystal having characteristic peaks at 8.538°±0.1°, 10.629°±0.1°, 11.015°±0.1°, 13.686°±0.1°, 14.973°±0.1°, 15.223°±0.1°, 15.937°±0.1°, 16.203°±0.1°, and 22.134°±0.1°. The molar ratio of amenamevir to o-cresol (amenamevir:o-cresol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:3.

[0033] (23) Cocrystal of Amenamevir and m-Cresol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and m-cresol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 7.306°±0.2°, 8.827°±0.2°, 10.686°±0.2°, 12.736°±0.2°, and 14.640°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 7.306°±0.2°, 8.279°±0.2°, 8.827°±0.2°, 10.686°±0.2°, 12.736°±0.2°, and 14.640°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 7.306°±0.2°, 8.279°±0.2°, 8.827°±0.2°, 10.686°±0.2°, 12.035°±0.2°, 12.736°±0.2°, and 14.640°±0.2° in a powder X-ray diffraction pattern; even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 7.306°±0.2°, 8.279°±0.2°, 8.827°±0.2°, 10.686°±0.2°, 12.035°±0.2°, 12.736°±0.2°, 13.879°±0.2°, 14.640°±0.2°, and 16.307°±0.2° in a powder X-ray diffraction pattern. The molar ratio of amenamevir to m-cresol (amenamevir:m-cresol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 4:9.

[0034] (24) Cocrystal of p-cresol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and p-cresol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 7.300°±0.2°, 8.159°±0.2°, 8.607°±0.2°, 10.966°±0.2°, and 14.540°±0.2° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 7.300°±0.2°, 8.159°±0.2°, 8.607°±0.2°, 9.419°±0.2°, 10.966°±0.2°, and 14.540°±0.2° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 7.300°±0.2°, 8.159°±0.2°, 8.607°±0.2°, 9.419°±0.2°, 10.966°±0.2°, 13.841°±0.2°, and 14.540°±0.2°; even more preferred is a co-crystal having characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 7.300°±0.2°, 8.159°±0.2°, 8.607°±0.2°, 9.419°±0.2°, 10.966°±0.2°, 13.841°±0.2°, 14.540°±0.2°, 16.432°±0.2°, and 16.740°±0.2°. The molar ratio of amenamevir to p-cresol (amenamevir:p-cresol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:5.

[0035] (25) Cocrystal of amenamevir and 1,2,4-trihydroxybenzene As the cocrystal of amenamevir and 1,2,4-trihydroxybenzene, when powder X-ray diffraction measurement is performed under the conditions described in the Examples below, a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.663°±0.05°, 10.593°±0.05°, 13.432°±0.05°, 14.919°±0.05°, and 16.029°±0.05° in the powder X-ray diffraction pattern is preferred; a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.484°±0.05°, 8.663°±0.05°, 10.593°±0.05°, 13.432°±0.05°, 14.919°±0.05°, and 16.029°±0.05° in the powder X-ray diffraction pattern is more preferred. More preferred is a cocrystal having characteristic peaks at diffraction angles (2θ) of 8.484°±0.05°, 8.663°±0.05°, 10.593°±0.05°, 13.432°±0.05°, 14.919°±0.05°, 16.029°±0.05°, and 17.006°±0.05° in a powder X-ray diffraction pattern; Even more preferred is a cocrystal having characteristic peaks at diffraction angles (2θ) on the turn of 8.484°±0.05°, 8.663°±0.05°, 10.593°±0.05°, 13.432°±0.05°, 14.919°±0.05°, 16.029°±0.05°, 17.006°±0.05°, and 22.042°±0.05°. The molar ratio of amenamevir to 1,2,4-trihydroxybenzene (amenamevir:1,2,4-trihydroxybenzene) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:1.

[0036] (26) Cocrystal of Amenamevir and 1,3,5-Trihydroxybenzene When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and 1,3,5-trihydroxybenzene is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.174°±0.1°, 9.804°±0.1°, 12.006°±0.1°, 12.203°±0.1°, and 15.247°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.174°±0.1°, 9.804°±0.1°, 12.006°±0.1°, 12.203°±0.1°, 15.247°±0.1°, and 18.706°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 6.174°±0.1°, 8.990°±0.1°, 9.804°±0.1°, 12.006°±0.1°, 12.203°±0.1°, 15.247°±0.1°, and 18.706°±0.1° in its X-ray powder diffraction pattern; and even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 6.174°±0.1°, 8.990°±0.1°, 9.804°±0.1°, 12.006°±0.1°, 12.203°±0.1°, 12.551°±0.1°, 15.247°±0.1°, 17.420°±0.1°, and 18.706°±0.1° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to 1,3,5-trihydroxybenzene (amenamevir:1,3,5-trihydroxybenzene) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 2:3.

[0037] (27) Cocrystal of Amenamevir and 4-Methylcatechol When powder X-ray diffraction measurement is performed under the conditions described in the Examples below, the cocrystal of amenamevir and 4-methylcatechol is preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.823°±0.1°, 7.162°±0.1°, 9.311°±0.1°, 14.377°±0.1°, and 14.685°±0.1° in the powder X-ray diffraction pattern; more preferably a cocrystal having characteristic peaks at diffraction angles (2θ) of 6.823°±0.1°, 7.162°±0.1°, 9.311°±0.1°, 13.428°±0.1°, 14.377°±0.1°, and 14.685°±0.1° in the powder X-ray diffraction pattern; More preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 6.823°±0.1°, 7.162°±0.1°, 9.311°±0.1°, 13.428°±0.1°, 13.904°±0.1°, 14.377°±0.1°, and 14.685°±0.1° in its powder X-ray diffraction pattern; even more preferred is a co-crystal having characteristic peaks at diffraction angles (2θ) of 6.823°±0.1°, 7.162°±0.1°, 9.311°±0.1°, 13.428°±0.1°, 13.904°±0.1°, 14.377°±0.1°, 14.685°±0.1°, 16.180°±0.1°, and 18.130°±0.1° in its powder X-ray diffraction pattern. The molar ratio of amenamevir to 4-methylcatechol (amenamevir:4-methylcatechol) in the cocrystal exhibiting such a powder X-ray diffraction pattern is 1:3.

[0038] The cocrystal of the present invention has excellent solubility, which can be confirmed by the dissolution test method described in the test examples below or a method similar thereto.

[0039] In the present invention, the cocrystal can be produced by, for example, the solvent evaporation technique, the anti-solvent method, the solvent drop grinding method, the slurry technique, the solid state grinding method, etc. (Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74).

[0040] The cocrystals of the present invention can be formulated by known methods with carriers, such as excipients and diluents, commonly used in the field of pharmaceutical formulations and administered orally or parenterally. The formulation is intended to encompass a pharmaceutically effective amount of the cocrystals of the present invention containing amenamevir and a pharmaceutically acceptable carrier (excipient, diluent, etc.). As used herein, the term "pharmaceutical composition" includes pharmaceutical compositions such as tablets, powders, pills, liquids, suspensions, emulsions, granules, capsules, suppositories, or injectable formulations. The cocrystals of the present invention have the advantage of being highly soluble, allowing for greater flexibility in formulation than conventional methods. These pharmaceutical compositions can also be prepared using additives commonly used as pharmaceutical additives according to known methods, such as those described in the General Provisions of the Japanese Pharmacopoeia (18th Edition), the United States Pharmacopoeia, or the European Pharmacopoeia.

[0041] The cocrystal of the present invention can be used for known uses of amenamevir (e.g., antiviral (treatment of shingles)), but is not limited to these uses.

[0042] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples and test examples.

[0043] In the following examples and experimental examples, powder X-ray diffraction patterns were obtained using a Bruker D8 Advance equipped with a Cu Kα radiation source (λ=1.54 Å), a 90-position sample holder, and a LYNXEYE ultrafast detector. Samples were analyzed at ambient temperature by transmission. Those skilled in the art will recognize that °2θ values ​​and relative intensity values ​​are generated by performing a peak search on the measured data, and d-spacing values ​​are calculated by the instrument from the °2θ values ​​using Bragg's equation. Those skilled in the art will further recognize that the relative intensities for the measured peaks may vary due to, for example, sample preparation, orientation, and the instrument used.

[0044] In the following examples and test examples, the following reagents were used as solvents: Acetonitrile (for high performance liquid chromatography, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) Acetone (special reagent grade, manufactured by Nacalai Tesque, Ltd.) Ethanol (special reagent grade, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) Isopropanol (for high performance liquid chromatography, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) Chloroform (special reagent grade, manufactured by Nacalai Tesque, Ltd.) Diethyl ether (special reagent grade, manufactured by Nacalai Tesque, Ltd.)

[0045] Example 1 Synthesis of a Cocrystal of Amenamevir and Succinic Acid (Amenamevir: Succinic Acid = 2:1 (Molar Ratio)) Succinic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (0.9 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and succinic acid. The crystals were collected by filtration to obtain 0.4 g of the cocrystal. The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and succinic acid showed characteristic peaks at diffraction angles (2θ) of 8.207°, 9.566°, 10.024°, 11.225°, 11.990°, 13.867°, 15.293°, 16.460°, and 17.339°. The powder X-ray diffraction pattern is shown in Figure 1.

[0046] Example 2 Synthesis of a Cocrystal of Amenamevir and L-Malic Acid (Amenamevir:L-Malic Acid = 2:1 (Molar Ratio)) L-Malic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (0.6 g) was added to this saturated solution (20 mL) and stirred, and a cocrystal of amenamevir and L-malic acid spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (0.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and L-malic acid showed characteristic peaks at diffraction angles (2θ) of 8.152°, 9.658°, 10.065°, 11.281°, 11.836°, 13.887°, 15.461°, and 17.514°. The powder X-ray diffraction pattern is shown in Figure 2.

[0047] Example 3 Synthesis of a Cocrystal of Amenamevir and D-Malic Acid (Amenamevir:D-Malic Acid = 2:1 (Molar Ratio)) D-Malic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.2 g) was added to this saturated solution (20 mL) and stirred, and a cocrystal of amenamevir and D-malic acid spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (1.1 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and D-malic acid showed characteristic peaks at diffraction angles (2θ) of 8.151°, 9.650°, 10.065°, 11.278°, 11.834°, 13.880°, 15.455°, 16.337°, and 17.508°. The powder X-ray diffraction pattern is shown in Figure 3.

[0048] Example 4 Synthesis of a Cocrystal of Amenamevir and L-Tartaric Acid (Amenamevir:L-Tartaric Acid = 2:1 (Molar Ratio)) L-Tartaric acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (0.8 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and L-tartaric acid. The crystals were collected by filtration to obtain the cocrystal (0.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and L-tartaric acid showed characteristic peaks at diffraction angles (2θ) of 8.093°, 8.778°, 9.758°, 10.122°, 11.363°, 11.759°, 13.532°, 13.881°, 15.563°, 16.208°, and 17.492°. The powder X-ray diffraction pattern is shown in FIG.

[0049] Example 5 Synthesis of a Cocrystal of Amenamevir and D-Tartaric Acid (Amenamevir:D-Tartaric Acid = 2:1 (Molar Ratio)) D-Tartaric acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.4 g) was added to this saturated solution (20 mL) and stirred, and a cocrystal of amenamevir and D-tartaric acid spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (1.3 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and D-tartaric acid showed characteristic peaks at diffraction angles (2θ) of 8.100°, 8.761°, 9.742°, 10.123°, 11.359°, 11.737°, 13.517°, 13.869°, 15.541°, 16.230°, and 17.477°. The powder X-ray diffraction pattern is shown in FIG.

[0050] Example 6 Synthesis of a Cocrystal of Amenamevir and Fumaric Acid (Amenamevir:Fumaric Acid = 2:1 (Molar Ratio)) Fumaric acid was added to acetone at room temperature to prepare a saturated solution. Amenamevir (1.2 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and fumaric acid. The crystals were collected by filtration to obtain the cocrystal (0.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and fumaric acid showed characteristic peaks at diffraction angles (2θ) of 8.152°, 9.618°, 10.045°, 11.261°, 11.866°, 13.843°, 15.379°, 16.339°, and 17.393°. The powder X-ray diffraction pattern is shown in Figure 6.

[0051] Example 7 Synthesis of a Cocrystal of Amenamevir and Maleic Acid (Amenamevir:Maleic Acid = 1:1 (Molar Ratio)) Maleic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.0 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and maleic acid. The crystals were collected by filtration to obtain the cocrystal (0.7 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and maleic acid showed characteristic peaks at diffraction angles (2θ) of 8.492°, 9.172°, 10.709°, 11.131°, 13.764°, 14.359°, 15.843°, and 17.114°. The powder X-ray diffraction pattern is shown in Figure 7.

[0052] Example 8 Synthesis of Cocrystal of Amenamevir and Phenol (Amenamevir:Phenol = 1:1 (Molar Ratio)) Phenol was added to acetone at room temperature to prepare a saturated solution. Amenamevir (6.4 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and phenol. The crystals were collected by filtration and washed with chloroform to obtain the cocrystal (1.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and phenol showed characteristic peaks at diffraction angles (2θ) of 8.610°, 10.680°, 13.688°, 14.935°, 16.205°, 20.029°, and 22.151°. The powder X-ray diffraction pattern is shown in Figure 8.

[0053] Example 9 Synthesis of a Cocrystal of Amenamevir and Salicylic Acid (Amenamevir: Salicylic Acid = 1:1 (Molar Ratio)) Salicylic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.5 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and salicylic acid. The crystals were collected by filtration to obtain the cocrystal (0.9 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and salicylic acid showed characteristic peaks at diffraction angles (2θ) of 6.403°, 8.557°, 8.871°, 10.781°, 12.805°, 13.923°, 16.260°, and 20.981°. The powder X-ray diffraction pattern is shown in Figure 9.

[0054] Example 10 Synthesis of Cocrystal of Amenamevir and D-Camphor (Amenamevir:D-Camphor = 2:1 (Molar Ratio)) D-Camphor was added to acetone at room temperature to prepare a saturated solution. Amenamevir (0.9 g) was added to this saturated solution (20 mL) and stirred, and a cocrystal of amenamevir and D-camphor spontaneously formed. The crystals were collected by filtration and washed with ethanol to obtain the cocrystal (0.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and D-camphor showed characteristic peaks at diffraction angles (2θ) of 7.341°, 8.087°, 11.747°, 13.602°, 15.053°, 16.147°, and 20.436°. The powder X-ray diffraction pattern is shown in FIG. 10.

[0055] Example 11 Synthesis of a Cocrystal of Amenamevir and 2-Naphthol (Amenamevir:2-Naphthol = 1:3 (Molar Ratio)) 2-Naphthol was added to acetone at room temperature to prepare a saturated solution. Amenamevir (2.0 g) was added to this saturated solution (20 mL) and stirred, and a cocrystal of amenamevir and 2-naphthol spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (2.8 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and 2-naphthol showed characteristic peaks at diffraction angles (2θ) of 6.903°, 8.658°, 9.445°, 10.710°, 11.260°, 13.296°, 13.841°, 14.798°, and 19.562°. The powder X-ray diffraction pattern is shown in Figure 11.

[0056] Example 12 Synthesis of a Cocrystal of Amenamevir and Benzotriazole (Amenamevir: Benzotriazole = 1:1 (Molar Ratio)) Benzotriazole was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (2.5 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and benzotriazole. The crystals were collected by filtration to obtain the cocrystal (2.2 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and benzotriazole showed characteristic peaks at diffraction angles (2θ) of 8.284°, 9.228°, 9.585°, 12.277°, 12.871°, 13.900°, 14.718°, 15.392°, 15.647°, and 15.860°. The powder X-ray diffraction pattern is shown in Figure 12.

[0057] Example 13 Synthesis of a cocrystal of amenamevir and vanillin (amenamevir:vanillin = 3:4 (molar ratio)) Vanillin was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (3.5 g) was added to this saturated solution (20 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and vanillin. The crystals were collected by filtration to obtain the cocrystal (3.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and vanillin showed characteristic peaks at diffraction angles (2θ) of 8.406°, 9.548°, 9.786°, 10.643°, 10.832°, 13.067°, 13.405°, 13.645°, 13.842°, 14.496°, 15.048°, 15.216°, 15.927°, and 16.043°. The powder X-ray diffraction pattern is shown in Figure 13.

[0058] Example 14 Synthesis of a co-crystal of amenamevir and anthranilic acid (o-aminobenzoic acid) (amenamevir:anthranilic acid = 1:1 (molar ratio)) Anthranilic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.5 g) was added to this saturated solution (20 mL) and stirred, and a co-crystal of amenamevir and anthranilic acid was spontaneously formed. The crystals were collected by filtration to obtain the co-crystal (1.0 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and anthranilic acid showed characteristic peaks at diffraction angles (2θ) of 8.023°, 8.345°, 9.297°, 10.239°, 10.806°, 11.045°, 11.865°, 12.335°, 13.037°, 13.783°, 14.516°, and 15.092°. The powder X-ray diffraction pattern is shown in Figure 14.

[0059] Example 15 Synthesis of Cocrystal of Amenamevir and Thiomalic Acid (Amenamevir:Thiomalic Acid = 2:1 (Molar Ratio)) Thiomalic acid was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (0.5 g) was added to this saturated solution (20 mL) and stirred, and a cocrystal of amenamevir and thiomalic acid spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (0.2 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and thiomalic acid showed characteristic peaks at diffraction angles (2θ) of 8.137°, 9.536°, 10.102°, 11.321°, 11.815°, 13.674°, 15.262°, 16.324°, and 17.274°. The powder X-ray diffraction pattern is shown in Figure 15.

[0060] Example 16 Synthesis of a cocrystal of amenamevir and pyrogallol (amenamevir:pyrogallol = 1:1 (molar ratio)) Pyrogallol was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (3.4 g) was added to this saturated solution (10 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and pyrogallol. The crystals were collected by filtration and washed with diethyl ether to obtain the cocrystal (3.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and pyrogallol showed characteristic peaks at diffraction angles (2θ) of 8.174°, 8.521°, 8.707°, 10.613°, 11.029°, 13.511°, 14.964°, 15.068°, 15.547°, 15.812°, and 16.102°. The powder X-ray diffraction pattern is shown in Figure 16.

[0061] Example 17 Synthesis of Amenamevir and Hydroquinone Cocrystal (Amenamevir:Hydroquinone = 1:1 Molar Ratio) Hydroquinone was added to acetone at room temperature to prepare a saturated solution. Amenamevir (0.7 g) was added to this saturated solution (10 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and hydroquinone. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (0.6 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and hydroquinone showed characteristic peaks at diffraction angles (2θ) of 8.645°, 9.501°, 10.655°, 11.051°, 13.212°, 13.723°, 14.898°, 15.237°, 16.253°, and 22.205°. The powder X-ray diffraction pattern is attached in FIG.

[0062] Example 18 Synthesis of a Cocrystal of Amenamevir and 1-Naphthol (Amenamevir:1-Naphthol = 1:1 (Molar Ratio)) 1-Naphthol was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.1 g) was added to this saturated solution (5 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and 1-naphthol. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (1.0 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and 1-naphthol showed characteristic peaks at diffraction angles (2θ) of 8.118°, 8.820°, 9.166°, 10.821°, 12.494°, 14.203°, 14.918°, and 15.320°. The powder X-ray diffraction pattern is shown in Figure 18.

[0063] Example 19 Synthesis of a Cocrystal of Amenamevir and Lidocaine (Amenamevir: Lidocaine = 2:1 (Molar Ratio)) Lidocaine was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (0.9 g) was added to this saturated solution (8 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and lidocaine. The crystals were collected by filtration and washed with ethanol to obtain the cocrystal (0.6 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and lidocaine showed characteristic peaks at diffraction angles (2θ) of 6.921°, 7.071°, 9.043°, 12.107°, 12.917°, 13.648°, and 14.519°. The powder X-ray diffraction pattern is shown in Figure 19.

[0064] Example 20 Synthesis of a Cocrystal of Amenamevir and Chlorocresol (4-chloro-3-methylphenol) (Amenamevir:Chlorocresol = 1:1 (Molar Ratio)) Chlorocresol was added to ethanol at room temperature to prepare a saturated solution. Amenamevir (1.7 g) was added to this saturated solution (10 mL) and stirred, and a cocrystal of amenamevir and chlorocresol spontaneously formed. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (2.0 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and chlorocresol showed characteristic peaks at diffraction angles (2θ) of 8.267°, 8.730°, 10.384°, 10.848°, 12.879°, 14.779°, 15.580°, and 21.800°. The powder X-ray diffraction pattern is shown in FIG.

[0065] Example 21 Synthesis of a Cocrystal of Amenamevir and Chlorobutanol (Amenamevir:Chlorobutanol = 1:1 (Molar Ratio)) Chlorobutanol was added to acetone at room temperature to prepare a saturated solution. Amenamevir (1.0 g) was added to this saturated solution (10 mL) and stirred, and a cocrystal of amenamevir and chlorobutanol spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (0.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and chlorobutanol showed characteristic peaks at diffraction angles (2θ) of 8.082°, 8.571°, 10.181°, 11.391°, 13.649°, 15.216°, 16.231°, 16.838°, and 17.091°. The powder X-ray diffraction pattern is shown in Figure 21.

[0066] Example 22 Synthesis of a Cocrystal of Amenamevir and Catechol (Amenamevir:Catechol = 1:1 (Molar Ratio)) Catechol was added to ethanol at room temperature to prepare a saturated solution. Amenamevir (1.9 g) was added to this saturated solution (7 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and catechol. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (1.7 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and catechol showed characteristic peaks at diffraction angles (2θ) of 8.272°, 8.481°, 8.729°, 10.917°, 11.079°, 14.241°, 15.154°, 16.599°, and 20.325°. The powder X-ray diffraction pattern is shown in Figure 22.

[0067] Example 23 Synthesis of Amenamevir and Resorcinol Cocrystal (Amenamevir:Resorcinol = 1:2 (Molar Ratio)) Resorcinol was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.8 g) was added to this saturated solution (10 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and resorcinol. The crystals were collected by filtration to obtain the cocrystal (1.8 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and resorcinol showed characteristic peaks at diffraction angles (2θ) of 8.518°, 8.649°, 10.652°, 10.987°, 13.535°, 14.981°, 16.091°, 16.621°, and 22.093°. The powder X-ray diffraction pattern is shown in Figure 23.

[0068] Example 24 Synthesis of a cocrystal of amenamevir and o-cresol (amenamevir:o-cresol = 1:3 (molar ratio)) Amenamevir (1.2 g) was added to o-cresol (2.5 mL) and stirred, and a cocrystal of amenamevir and o-cresol spontaneously formed. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (1.0 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and o-cresol showed characteristic peaks at diffraction angles (2θ) of 8.538°, 10.629°, 11.015°, 13.686°, 14.973°, 15.223°, 15.937°, 16.203°, and 22.134°. The powder X-ray diffraction pattern is shown in Figure 24.

[0069] Example 25 Synthesis of a Cocrystal of Amenamevir and m-Cresol (Amenamevir:m-Cresol = 4:9 (Molar Ratio)) Amenamevir (1.2 g) was added to m-cresol (2.5 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and m-cresol. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (1.4 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and m-cresol showed characteristic peaks at diffraction angles (2θ) of 7.306°, 8.279°, 8.827°, 10.686°, 12.035°, 12.736°, 13.879°, 14.640°, and 16.307°. The powder X-ray diffraction pattern is shown in Figure 25.

[0070] Example 26 Synthesis of a Cocrystal of Amenamevir and p-Cresol (Amenamevir:p-Cresol = 2:5 (Molar Ratio)) Amenamevir (1.4 g) was added to p-cresol (2.5 mL) and stirred, resulting in the spontaneous formation of a cocrystal of amenamevir and p-cresol. The crystals were collected by filtration and washed with isopropanol to obtain the cocrystal (1.4 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and p-cresol showed characteristic peaks at diffraction angles (2θ) of 7.300°, 8.159°, 8.607°, 9.419°, 10.966°, 13.841°, 14.540°, 16.432°, and 16.740°. The powder X-ray diffraction pattern is shown in Figure 26.

[0071] Example 27 Synthesis of a cocrystal of amenamevir and 1,2,4-trihydroxybenzene (amenamevir:1,2,4-trihydroxybenzene=1:1 (molar ratio)) 1,2,4-Trihydroxybenzene was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.0 g) was added to this saturated solution (4 mL) and stirred, and a cocrystal of amenamevir and 1,2,4-trihydroxybenzene spontaneously formed. The crystals were collected by filtration and washed with diethyl ether to obtain the cocrystal (0.8 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and 1,2,4-trihydroxybenzene showed characteristic peaks at diffraction angles (2θ) of 8.484°, 8.663°, 10.593°, 13.432°, 14.919°, 16.029°, 17.006°, and 22.042°. The powder X-ray diffraction pattern is shown in FIG.

[0072] Example 28 Synthesis of a cocrystal of amenamevir and 1,3,5-trihydroxybenzene (amenamevir:1,3,5-trihydroxybenzene=2:3 (molar ratio)) 1,3,5-Trihydroxybenzene was added to acetone at room temperature to prepare a saturated solution. Amenamevir (0.5 g) was added to this saturated solution (4 mL) and stirred, and a cocrystal of amenamevir and 1,3,5-trihydroxybenzene spontaneously formed. The crystals were collected by filtration and washed with diethyl ether to obtain the cocrystal (0.5 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and 1,3,5-trihydroxybenzene showed characteristic peaks at diffraction angles (2θ) of 6.174°, 8.990°, 9.804°, 12.006°, 12.203°, 12.551°, 15.247°, 17.420°, and 18.706°. The powder X-ray diffraction pattern is shown in FIG.

[0073] Example 29 Synthesis of a Cocrystal of Amenamevir and 4-Methylcatechol (Amenamevir:4-methylcatechol = 1:3 (Molar Ratio)) 4-Methylcatechol was added to acetonitrile at room temperature to prepare a saturated solution. Amenamevir (1.8 g) was added to this saturated solution (4 mL) and stirred, and a cocrystal of amenamevir and 4-methylcatechol spontaneously formed. The crystals were collected by filtration to obtain the cocrystal (1.3 g). The powder X-ray diffraction pattern of the obtained cocrystal of amenamevir and 4-methylcatechol showed characteristic peaks at diffraction angles (2θ) of 6.823°, 7.162°, 9.311°, 13.428°, 13.904°, 14.377°, 14.685°, 16.180°, and 18.130°. The powder X-ray diffraction pattern is shown in FIG.

[0074] Test Example 1: The cocrystals of amenamevir and each coformer obtained in Examples 1 to 17 (equivalent to 20 mg of amenamevir) and 20 mg of amenamevir were used as samples. The samples were crushed in a mortar and placed in a glass vial, and 100 mL of a 0.1% hypromellose solution preheated to 37°C was added. The resulting mixture was stirred at 37°C and 150 rpm, and samples were collected at predetermined sampling times (15 minutes, 90 minutes, and 180 minutes) to prepare test solutions. The resulting test solutions were filtered through a 0.45 μm filter, and the amenamevir concentration in the filtrate was measured by ultraviolet-visible absorbance spectrometry. The test results at the predetermined sampling times are shown in Table 1. The results in Table 1 indicate that the comparative example (amenamevir) was poorly soluble in the test solution (0.1% hypromellose solution), while the cocrystals of Examples 1 to 17 exhibited significantly higher dissolution rates than the comparative examples.

[0075]

[0076] Test Example 2 The cocrystals of amenamevir and each coformer obtained in Examples 18 to 29 (equivalent to 20 mg of amenamevir) were used as samples. The samples were crushed in a mortar and placed in a glass vial, and 100 mL of a 0.1% hypromellose solution preheated to 37°C was added. The resulting mixture was stirred at 37°C and 150 rpm, and samples were collected at predetermined sampling times (15 minutes, 90 minutes, and 180 minutes) to prepare test solutions. The resulting test solutions were filtered through a 0.45 μm filter, and the amenamevir concentration in the filtrate was measured by ultraviolet-visible absorbance spectrometry. The test results at the predetermined sampling times are shown in Table 2. The results in Table 2 show that the cocrystals of Examples 18 to 29 exhibited significantly higher dissolution rates than the comparative example (amenamevir) in Test Example 1.

[0077]

[0078] According to the present invention, a novel cocrystal of amenamevir having excellent solubility can be provided.

[0079] This application is based on patent application No. 2024-089693 filed in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. A cocrystal consisting of amenamevir and a coformer, wherein the coformer is one or more selected from the group consisting of succinic acid, L-malic acid, D-malic acid, L-tartaric acid, D-tartaric acid, fumaric acid, maleic acid, phenol, salicylic acid, D-camphor, 1-naphthol, 2-naphthol, benzotriazole, vanillin, anthranilic acid, thiomalic acid, pyrogallol, hydroquinone, lidocaine, chlorocresol, chlorobutanol, catechol, resorcinol, o-cresol, m-cresol, p-cresol, 1,2,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, and 4-methylcatechol.

2. The cocrystal according to claim 1, which consists of amenamevir and succinic acid and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.207°±0.2°, 9.566°±0.2°, 10.024°±0.2°, 11.225°±0.2°, and 11.990°±0.2°.

3. The cocrystal according to claim 1, which consists of amenamevir and L-malic acid and has characteristic peaks at diffraction angles (2θ) of 8.152°±0.2°, 9.658°±0.2°, 10.065°±0.2°, 11.281°±0.2°, and 11.836°±0.2° in its powder X-ray diffraction pattern.

4. The cocrystal according to claim 1, which consists of amenamevir and D-malic acid and has characteristic peaks at diffraction angles (2θ) of 8.151°±0.2°, 9.650°±0.2°, 10.065°±0.2°, 11.278°±0.2°, and 11.834°±0.2° in its powder X-ray diffraction pattern.

5. The cocrystal according to claim 1, which consists of amenamevir and L-tartaric acid and has characteristic peaks at diffraction angles (2θ) of 8.093°±0.1°, 8.778°±0.1°, 9.758°±0.1°, and 10.122°±0.1° in its powder X-ray diffraction pattern.

6. The cocrystal according to claim 1, which consists of amenamevir and D-tartaric acid and has characteristic peaks at diffraction angles (2θ) of 8.100°±0.1°, 8.761°±0.1°, 9.742°±0.1°, and 10.123°±0.1° in a powder X-ray diffraction pattern.

7. The cocrystal of claim 1, which consists of amenamevir and fumaric acid and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.152°±0.2°, 9.618°±0.2°, 10.045°±0.2°, 11.261°±0.2°, and 11.866°±0.2°.

8. The cocrystal of claim 1, which consists of amenamevir and maleic acid and has characteristic peaks at diffraction angles (2θ) of 8.492°±0.2°, 9.172°±0.2°, 10.709°±0.2°, and 11.131°±0.2° in its powder X-ray diffraction pattern.

9. The cocrystal of claim 1, which consists of amenamevir and phenol and has characteristic peaks at diffraction angles (2θ) of 8.610°±0.2°, 10.680°±0.2°, and 13.688°±0.2° in its powder X-ray diffraction pattern.

10. The cocrystal of claim 1, which consists of amenamevir and salicylic acid and has characteristic peaks at diffraction angles (2θ) of 6.403°±0.1°, 8.557°±0.1°, 8.871°±0.1°, and 10.781°±0.1° in its powder X-ray diffraction pattern.

11. The cocrystal according to claim 1, which consists of amenamevir and D-camphor and has characteristic peaks at diffraction angles (2θ) of 7.341°±0.2°, 8.087°±0.2°, 11.747°±0.2°, and 13.602°±0.2° in its powder X-ray diffraction pattern.

12. The cocrystal according to claim 1, which consists of amenamevir and 1-naphthol and has characteristic peaks at diffraction angles (2θ) of 8.118°±0.1°, 8.820°±0.1°, 9.166°±0.1°, 10.821°±0.1°, and 12.494°±0.1° in its powder X-ray diffraction pattern.

13. The cocrystal according to claim 1, which consists of amenamevir and 2-naphthol and has characteristic peaks at diffraction angles (2θ) of 6.903°±0.2°, 8.658°±0.2°, 9.445°±0.2°, 10.710°±0.2°, and 11.260°±0.2° in its powder X-ray diffraction pattern.

14. The cocrystal of claim 1, which consists of amenamevir and benzotriazole and has characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 8.284°±0.1°, 9.228°±0.1°, 9.585°±0.1°, 12.277°±0.1°, and 12.871°±0.1°.

15. The cocrystal of claim 1, which consists of amenamevir and vanillin and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.406°±0.05°, 10.643°±0.05°, 10.832°±0.05°, and 13.067°±0.05°.

16. The cocrystal of claim 1, which consists of amenamevir and anthranilic acid and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.345°±0.1°, 9.297°±0.1°, 11.865°±0.1°, 14.516°±0.1°, and 15.092°±0.1°.

17. The cocrystal of claim 1, which consists of amenamevir and thiomalic acid and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.137°±0.2°, 9.536°±0.2°, 10.102°±0.2°, 11.321°±0.2°, and 11.815°±0.2°.

18. The cocrystal of claim 1, which consists of amenamevir and pyrogallol and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.174°±0.05°, 8.521°±0.05°, 8.707°±0.05°, 10.613°±0.05°, and 13.511°±0.05°.

19. The cocrystal of claim 1, which consists of amenamevir and hydroquinone and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.645°±0.1°, 10.655°±0.1°, 13.723°±0.1°, and 14.898°±0.1°.

20. The cocrystal of claim 1, which consists of amenamevir and lidocaine and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 6.921°±0.05°, 7.071°±0.05°, 12.917°±0.05°, and 13.648°±0.05°.

21. The cocrystal of claim 1, which consists of amenamevir and chlorocresol and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.267°±0.2°, 8.730°±0.2°, 10.384°±0.2°, 12.879°±0.2°, and 15.580°±0.2°.

22. The cocrystal of claim 1, which consists of amenamevir and chlorobutanol and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.082°±0.1°, 8.571°±0.1°, 11.391°±0.1°, 13.649°±0.1°, and 15.216°±0.1°.

23. The cocrystal of claim 1, which consists of amenamevir and catechol and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.481°±0.1°, 8.729°±0.1°, 10.917°±0.1°, 11.079°±0.1°, and 15.154°±0.1°.

24. The cocrystal of claim 1, which consists of amenamevir and resorcinol and has characteristic peaks in its powder X-ray diffraction pattern at diffraction angles (2θ) of 8.518°±0.05°, 8.649°±0.05°, 10.652°±0.05°, 13.535°±0.05°, and 16.091°±0.05°.

25. The cocrystal according to claim 1, which consists of amenamevir and o-cresol and has characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 8.538°±0.1°, 10.629°±0.1°, 11.015°±0.1°, 13.686°±0.1°, and 16.203°±0.2°.

26. The cocrystal of claim 1, which consists of amenamevir and m-cresol and has characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 7.306°±0.2°, 8.827°±0.2°, 10.686°±0.2°, 12.736°±0.2°, and 14.640°±0.2°.

27. The cocrystal of claim 1, which consists of amenamevir and p-cresol and has characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 7.300°±0.2°, 8.159°±0.2°, 8.607°±0.2°, 10.966°±0.2°, and 14.540°±0.2°.

28. The cocrystal of claim 1, which consists of amenamevir and 1,2,4-trihydroxybenzene and has characteristic peaks in a powder X-ray diffraction pattern at diffraction angles (2θ) of 8.663°±0.05°, 10.593°±0.05°, 13.432°±0.05°, 14.919°±0.05°, and 16.029°±0.05°.

29. The cocrystal of claim 1, which consists of amenamevir and 1,3,5-trihydroxybenzene and has characteristic peaks at diffraction angles (2θ) of 6.174°±0.1°, 9.804°±0.1°, 12.006°±0.1°, 12.203°±0.1°, and 15.247°±0.1° in its powder X-ray diffraction pattern.

30. The cocrystal according to claim 1, which consists of amenamevir and 4-methylcatechol and has characteristic peaks at diffraction angles (2θ) of 6.823°±0.1°, 7.162°±0.1°, 9.311°±0.1°, 14.377°±0.1°, and 14.685°±0.1° in its powder X-ray diffraction pattern.

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