Method for producing cyclic peptide crystals

Abstract

The present invention discloses a method for producing cyclic peptide crystals, the method comprising bringing a cyclic peptide into contact with a specific solvent.

Description

Method for producing cyclic peptide crystals

[0001] The present invention relates to a method for producing crystals of cyclic peptides containing N-substituted amino acid residues, and a method for screening for such crystals.

[0002] Until now, compounds used as oral drugs have been considered desirable to have a molecular weight of 500 g / mol or less, as known as Lipinski's rule (Non-Patent Document 1). In recent years, it has become clear that compounds with a molecular weight exceeding 500 g / mol can contribute to inhibiting protein-protein interactions in so-called tough targets, proteins that have been considered difficult to target with conventional low-molecular-weight compounds. These molecules are called medium-molecular-weight compounds (molecular weights of 500-2000 g / mol), which are neither the low-molecular-weight compounds with a molecular weight of 500 g / mol or less that have been primarily used as oral drugs, nor the high-molecular-weight compounds with a molecular weight of over 100,000 g / mol, such as antibody drugs. These molecules have attracted attention as a new modality that could enable drug discovery against tough targets (Non-Patent Document 2).

[0003] Peptides composed of natural amino acids, such as insulin, which is used to treat hyperglycemia, have poor metabolic stability, making it difficult to develop them as oral drugs. However, it has been found that peptide cyclization or the use of unnatural amino acids, such as N-methylamino acids, in peptides can improve the metabolic stability and membrane permeability of peptides (Non-Patent Documents 3 and 4).

[0004] It has become known that cyclic peptides containing unnatural amino acids, particularly those containing N-substituted amino acids, can have metabolic stability and membrane permeability, i.e., drug-like properties (Patent Document 1). It has also been suggested that cyclic peptides containing unnatural amino acids are useful for creating inhibitors of protein-protein interactions (Non-Patent Document 5).

[0005] While cyclic peptides as medium-sized molecules have attracted attention in drug discovery, there have been no reports on the crystallization of many cyclic peptides containing N-substituted amino acids.On the other hand, cyclosporin A, a long-known cyclic peptide, has been reported to have various crystalline forms (Patent Documents 2 and 3, Non-Patent Documents 6, 7, and 8).

[0006] International Publication No. 2013 / 100132 International Publication No. 2012 / 166610 Japanese Patent Application Laid-Open No. 2017-210488

[0007] Adv. Drug Del. Rev. 1997, 23, 3-25.Future Med. Chem., 2009, 1, 1289-1310.Acc. Chem. Res., 2008, 41, 1331-1342.Angew. Chem. Int. Ed., 2013, 52, 254-269.Chem. Rev., 2019, 119, 10360-10391.J. Pharm. Sci., 2018, 107, 3070-3079.J. Inclusion Phenomena & Macrocyclic Chem., 2000, 37, 137-153.Zeitschrift fuer Kristallographie, 1996, 211, 313-318.

[0008] Crystallization of cyclic peptides in pharmaceutical development has traditionally required trial and error searching and discovery of optimal crystallization conditions for each individual cyclic peptide. A general and simple technique for obtaining these cyclic peptides as crystals is needed. The present invention has been made in light of these circumstances, and in one aspect, it is an object of the present invention to provide a method for producing crystals of cyclic peptides containing N-substituted amino acid residues. In one aspect, it is an object of the present invention to provide a method for screening crystals of cyclic peptides containing N-substituted amino acid residues. In another aspect, it is an object of the present invention to provide a method for screening crystallization methods. In yet another aspect, it is an object of the present invention to provide a method for isolating and purifying a target cyclic peptide, or a salt thereof, or a solvate thereof, as crystals, without relying on column chromatography.

[0009] As a result of intensive research aimed at solving the above problems, the present inventors have discovered an efficient crystal screening method for obtaining cyclic peptide crystals by contacting the cyclic peptide with a specific solvent, and have completed the present invention as a crystal production method applicable to various cyclic peptides.

[0010] That is, the present invention provides the following. [A1] A method for producing a crystal of a cyclic peptide, comprising a step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide has the following characteristics (I), (II), and (III): (I) comprising a cyclic portion consisting of a total of 8 to 16 amino acid residues, and the total number of amino acid residues is 8 to 20; (II) comprising at least two N-substituted amino acid residues; (III) having a molecular weight (g / mol) of 1204 or more and 3000 or less. [A1-1] The method according to [A1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarized light when observed with a polarizing microscope. [A1-2] The method according to [A1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [A2] The method according to any one of [A1] to [A1-2], wherein the solvent is any one of the following (1), (2), and (3): (1) (i) a solvent having a molecular weight of 18 to 170 or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 to 170; (2) water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent, based on the total amount of the solvent; (3) (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water. [A3] The method according to any one of [A1] to [A1-2], wherein the solvent is any one of (i) a solvent having a molecular weight of 18 to 170 or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 to 170. [A4] The method according to [A3], wherein the solvent is selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, ketone solvents, aliphatic hydrocarbon solvents, and water. [A5] The method according to [A3], wherein the solvent is selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents.[A6] The method according to [A3], wherein the solvent is selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, and ester solvents. [A7] The method according to [A3], wherein the solvent is selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogenated solvents. [A8] The method according to [A3], wherein the solvent is selected from the group consisting of amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents. [A9] The method according to any one of [A1] to [A1-2], wherein the solvent is a solvent (A) having a molecular weight of 18 to 170, or a mixed solvent of solvent (A) having a molecular weight of 18 to 170 and solvent (B) having a molecular weight of 18 to 170, wherein solvent (A) is one or more solvents selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and solvent (B) is one or more solvents selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water. [A10] The method according to any one of [A1] to [A1-2], wherein the solvent (A) is a solvent having a molecular weight of 18 to 170, or a mixed solvent of a solvent (A) having a molecular weight of 18 to 170 and a solvent (B) having a molecular weight of 18 to 170, wherein the solvent (A) is selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and the solvent (B) is selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water. [A11] The method according to [A9], wherein the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, and ester solvents. [A12] The method according to [A9], wherein the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogenated solvents.[A13] The method according to [A9], wherein the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents. [A14] The method according to [A9] or [A10], wherein the solvent (A) is an amide solvent. [A15] The method according to [A14], wherein the amide solvent is one or more selected from the group consisting of formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone. [A16] The method according to [A14], wherein the amide solvent is formamide. [A17] The method according to [A9] or [A10], wherein the solvent (A) is a sulfoxide solvent. [A18] The method according to [A17], wherein the sulfoxide solvent is one or more selected from the group consisting of dimethyl sulfoxide, phenylmethyl sulfoxide, and diethyl sulfoxide. [A19] The method according to [A17], wherein the sulfoxide solvent is dimethyl sulfoxide. [A20] The method according to [A9] or [A10], wherein the solvent (A) is an aromatic hydrocarbon solvent. [A21] The method according to [A20], wherein the aromatic hydrocarbon solvent is one or more selected from the group consisting of benzene, toluene, xylene, ethylbenzene, tetralin, and cumene. [A22] The method according to [A20], wherein the aromatic hydrocarbon solvent is toluene, tetralin, or cumene. [A23] The method according to [A9] or [A10], wherein the solvent (A) is a halogenated solvent. [A24] The method according to [A23], wherein the halogenated solvent is one or more selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride. [A25] The method according to [A23], wherein the halogenated solvent is dichloromethane or chlorobenzene. [A26] The method according to [A9] or [A10], wherein the solvent (A) is an alcohol-based solvent.[A27] The method according to [A26], wherein the alcoholic solvent is one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and benzyl alcohol. [A28] The method according to [A26], wherein the alcoholic solvent is methanol, ethanol, 1-propanol, isopropanol, or n-butanol. [A29] The method according to [A9] or [A10], wherein the solvent (A) is an ether-based solvent. [A30] The method according to [A29], wherein the ether-based solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, anisole, and t-butyl methyl ether. [A31] The method according to [A29], wherein the ether-based solvent is tetrahydrofuran, 1,4-dioxane, diisopropyl ether, anisole, or t-butyl methyl ether. [A32] The method according to [A9] or [A10], wherein the solvent (A) is an ester-based solvent. [A33] The method according to [A32], wherein the ester-based solvent is one or more selected from the group consisting of ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone. [A34] The method according to [A32], wherein the ester-based solvent is ethyl acetate, isopropyl acetate, or n-butyl acetate. [A35] The method according to [A9] or [A10], wherein the solvent (A) is a nitrile-based solvent. [A36] The method according to [A35], wherein the nitrile-based solvent is one or more selected from the group consisting of acetonitrile, benzonitrile, and propionitrile. [A37] The method according to [A35], wherein the nitrile-based solvent is acetonitrile.[A38] The method according to [A9] or [A10], wherein the solvent (A) is a ketone-based solvent. [A39] The method according to [A38], wherein the ketone-based solvent is one or more selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, cyclohexanone, diethyl ketone, cyclopentanone, and 3-acetylpyridine. [A40] The method according to [A38], wherein the ketone-based solvent is acetone, methyl ethyl ketone, or methyl isobutyl ketone. [A41] The method according to any one of [A9] to [A40], wherein the solvent (B) is one or more solvents selected from the group consisting of an aliphatic hydrocarbon-based solvent, ethylene glycol, and water. [A42] The method according to any one of [A9] to [A40], wherein the solvent (B) is an aliphatic hydrocarbon-based solvent, ethylene glycol, or water. [A43] The method according to any one of [A9] to [A40], wherein the solvent (B) is an aliphatic hydrocarbon-based solvent. [A44] The method according to [A43], wherein the aliphatic hydrocarbon solvent is one or more selected from the group consisting of n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane. [A45] The method according to [A43], wherein the aliphatic hydrocarbon solvent is n-heptane, cyclohexane, or methylcyclohexane. [A46] The method according to any one of [A9] to [A40], wherein the solvent (B) is water. [A46-1] The method according to any one of [A9] to [A40], wherein the solvent (B) is ethylene glycol. [A47] The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:40. [A48] The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:30, 1:0 to 1:20, 1:0 to 1:10, 1:0 to 1:7, or 1:0 to 1:5. [A49] The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:4.[A50] The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 10:1 to 1:40. [A51] The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 5:1 to 1:30, 3:1 to 1:20, 2:1 to 1:10, 1:1 to 1:7, or 1:2 to 1:5. [A52] The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:2 to 1:4. [A52-1] The method according to any one of [A9] to [A52], wherein the solvent (A) has a molecular weight of 18 to 160, 18 to 150, 18 to 140, or 32 to 135. [A52-2] The method according to any one of [A9] to [A52], wherein the solvent (A) has a molecular weight of 32 to 135. [A52-3] The method according to any one of [A9] to [A52-2], wherein the solvent (B) has a molecular weight of 18 to 160, 18 to 135, 18 to 120, or 18 to 105. [A52-4] The method according to any one of [A9] to [A52-2], wherein the solvent (B) has a molecular weight of 18 to 105. [A53] The method according to any one of [A9] to [A52-4], wherein the melting points of the solvent (A) and the solvent (B) are 25° C. or lower. [A54] The method according to any one of [A1] to [A1-2], wherein the solvent is water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent, based on the total amount of solvent. [A55] The method according to [A54], wherein the surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.[A56] The method according to [A54], wherein the surfactant is one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosinate salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkylphosphates, N-alkyl β-aminopropionic acids, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethyleneglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylenesorbitan fatty acid esters. [A57] The method according to [A54], wherein the surfactant is one or more selected from the group consisting of alkyl sulfates, alkylarylpolyoxyethylene ethers, polyoxyethyleneglycerin fatty acid esters, and polyoxyethylenesorbitan fatty acid esters. [A58] The method according to [A54], wherein the surfactant is an alkyl sulfate, an alkylaryl polyoxyethylene ether, a polyoxyethylene glycerin fatty acid ester, or a polyoxyethylene sorbitan fatty acid ester. [A59] The method according to [A54], wherein the surfactant is sodium lauryl sulfate, 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 Hydrogenated Castor Oil, or polyoxyethylene sorbitan monolaurate. [A59-1] The method according to [A54], wherein the surfactant is Polyoxyl 35 Hydrogenated Castor Oil. [A60] The method according to [A54], wherein the surfactant is an ionic surfactant or a nonionic surfactant. [A61] The method according to [A54], wherein the surfactant is an ionic surfactant. [A62] The method according to [A61], wherein the ionic surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, and amphoteric surfactants.[A63] The method according to [A61], wherein the ionic surfactant is one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosinate salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl β-aminopropionic acid, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, and lecithin. [A64] The method according to [A61], wherein the ionic surfactant is an alkyl sulfate. [A65] The method according to [A61], wherein the ionic surfactant is lauryl sulfate. [A66] The method according to [A61], wherein the ionic surfactant is sodium lauryl sulfate. [A67] The method according to [A54], wherein the surfactant is a nonionic surfactant. [A68] The method according to [A67], wherein the nonionic surfactant is one or more selected from the group consisting of alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. [A69] The method according to [A67], wherein the nonionic surfactant is one or more selected from the group consisting of alkylaryl polyoxyethylene ethers, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. [A70] The method according to [A67], wherein the nonionic surfactant is one or more selected from the group consisting of 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 Hydrogenated Castor Oil, and polyoxyethylene sorbitan monolaurate. [A71] The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is an alcohol solvent, an amide solvent, a nitrile solvent, or a sulfoxide solvent.[A72] The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is an alcohol solvent or a sulfoxide solvent. [A73] The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is methanol, ethanol, 1-propanol, 2-propanol, or dimethyl sulfoxide. [A74] The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is ethanol or dimethyl sulfoxide. [A75] The method according to any one of [A54] to [A74], wherein the content of the surfactant is 0.02 to 20 wt / v%, 0.05 to 15 wt / v%, 0.1 to 10 wt / v%, 0.12 to 8 wt / v%, 0.15 to 5 wt / v%, or 0.18 to 3 wt / v%, based on the total amount of solvent, and the content of the water-soluble organic solvent is 5 to 40 v / v%, 5 to 30 v / v%, 5 to 25 v / v%, 8 to 20 v / v%, or 10 to 15 v / v%, based on the total amount of solvent. [A76] The method according to any one of [A54] to [A74], wherein the content of the surfactant is 0.1 to 10 wt / v%, based on the total amount of solvent, and the content of the water-soluble organic solvent is 5 to 25 v / v%, based on the total amount of solvent. [A77] The method according to any one of [A1] to [A1-2], wherein the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water. [A78] The method according to any one of [A1] to [A1-2], wherein the solvent is a PEG-based solvent. [A79] The method according to any one of [A1] to [A1-2], wherein the solvent is a mixed solvent of a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water. [A80] The PEG-based solvent is (i) R. １ (OCHR ３ CH ２ ) n OR ２ where n is a natural number of 1 or more and 10 or less, or (ii) R １ (OCHR ３ CH ２ ) n OR ２wherein the average of n is 3 to 100, １ and R ２ are each independently hydrogen, C １ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ may be substituted with a hydroxyl group; １ ~C １８ C optionally substituted with an alkyl or hydroxyl group １ ~C １８ [A81] The method according to [A78] or [A79], wherein the PEG-based solvent is (i) R １ (OCHR ３ CH ２ ) n OR ２ wherein n is a natural number of 1, 2, 3, or 4, or (ii) R １ (OCHR ３ CH ２ ) n OR ２ wherein the average of n is 3 to 100, １ is hydrogen or C １ ~C ４ alkyl, and R ２ is hydrogen, C １ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ is C １０ ~C １８ [A82] The method according to [A78] or [A79], wherein the PEG-based solvent is (i) R １ (OCHR ３ CH ２ ) n OR ２ wherein n is a natural number of 1, 2, 3, or 4; or (ii) R １ (OCHR ３ CH ２) n OR ２ wherein the average of n is 3 to 100, １ is hydrogen or methyl, and R ２ is hydrogen, methyl or —C(═O)R ４ and R ３ is hydrogen or methyl, and R ４ is C １１ ~C １７The method according to [A78] or [A79], wherein the PEG-based solvent is diglyme, triglyme, tetraglyme, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or a polyethylene glycol mono-fatty acid ester. [A84] The method according to [A78] or [A79], wherein the PEG-based solvent is polyethylene glycol. [A84-2] The method according to [A84], wherein the number-average molecular weight of the polyethylene glycol is 150 to 5000. [A84-3] The method according to [A84], wherein the number-average molecular weight of the polyethylene glycol is 360 to 440, 540 to 660, 900 to 1100, or 1800 to 2200. [A85] The method according to [A84], wherein the polyethylene glycol is PEG400, PEG600, PEG1000, or PEG2000. [A86] The method according to [A78] or [A79], wherein the PEG-based solvent is a polyethylene glycol mono-fatty acid ester. [A87] The method according to [A86], wherein the polyethylene glycol mono-fatty acid ester is polyethylene glycol monostearate or polyethylene glycol monolaurate. [A88] The method according to any one of [A77] and [A79] to [A87], wherein the one or more solvents selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more solvents selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water.[A89] The method according to any one of [A77] or [A79] to [A87], wherein the one or more solvents selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more solvents selected from the group consisting of 2-propanol, n-heptane, and water. [B1] A method for producing a crystal of a cyclic peptide, comprising a step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide has the following characteristics (I) and (II): (I) comprising a cyclic portion consisting of a total of 8 to 16 amino acid residues and a total number of amino acid residues of 8 to 20; (II) comprising at least two N-substituted amino acid residues; and the solvent is solvent (A) or a mixed solvent comprising solvent (A) and solvent (B), wherein solvent (A) is one or more solvents selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, and ester solvents, and solvent (B) is one or more solvents selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water. [B1-1] The method according to [B1], wherein the crystal exhibits one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or exhibits polarized light when observed with a polarizing microscope. [B1-2] The method according to [B1], wherein the crystals have one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [B2] The method according to any one of [B1] to [B1-2], wherein the solvent (A) is one or more solvents selected from the group consisting of amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents. [B3] The method according to any one of [B1] to [B1-2], wherein the solvent (A) is an amide solvent. [B4] The method according to [B3], wherein the amide solvent is one or more solvents selected from the group consisting of formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone. [B5] The method according to [B3], wherein the amide solvent is formamide. [B6] The method according to any one of [B1] to [B1-2], wherein the solvent (A) is a sulfoxide solvent.[B7] The method according to [B6], wherein the sulfoxide solvent is one or more selected from the group consisting of dimethyl sulfoxide, phenylmethyl sulfoxide, and diethyl sulfoxide. [B8] The method according to [B6], wherein the sulfoxide solvent is dimethyl sulfoxide. [B9] The method according to any one of [B1] to [B1-2], wherein the solvent (A) is an aromatic hydrocarbon solvent. [B10] The method according to [B9], wherein the aromatic hydrocarbon solvent is one or more selected from the group consisting of benzene, toluene, xylene, ethylbenzene, tetralin, and cumene. [B11] The method according to [B9], wherein the aromatic hydrocarbon solvent is toluene, tetralin, or cumene. [B12] The method according to any one of [B1] to [B1-2], wherein the solvent (A) is a halogenated solvent. [B13] The method according to [B12], wherein the halogen-based solvent is one or more selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride. [B14] The method according to [B12], wherein the halogen-based solvent is dichloromethane or chlorobenzene. [B15] The method according to any one of [B1] to [B1-2], wherein the solvent (A) is an ester-based solvent. [B16] The method according to [B15], wherein the ester-based solvent is one or more selected from the group consisting of ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone. [B17] The method according to [B15], wherein the ester-based solvent is ethyl acetate, isopropyl acetate, or n-butyl acetate. [B18] The method according to any one of [B1] to [B17], wherein the solvent (B) is an aliphatic hydrocarbon-based solvent. [B19] The method according to [B18], wherein the aliphatic hydrocarbon solvent is one or more selected from the group consisting of n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane.[B20] The method according to [B18], wherein the aliphatic hydrocarbon solvent is n-heptane, cyclohexane, or methylcyclohexane. [B21] The method according to any one of [B1] to [B17], wherein the solvent (B) is water. [B21-1] The method according to any one of [B1] to [B17], wherein the solvent (B) is ethylene glycol. [B22] The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:40. [B23] The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:30, 1:0 to 1:20, 1:0 to 1:10, 1:0 to 1:7, or 1:0 to 1:5. [B24] The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:4. [B25] The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 10:1 to 1:40. [B26] The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 5:1 to 1:30, 3:1 to 1:20, 2:1 to 1:10, 1:1 to 1:7, or 1:2 to 1:5. [B27] The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:2 to 1:4. [B28] The method according to any one of [B1] to [B27], wherein the melting points of the solvent (A) and the solvent (B) are 25° C. or lower. [B29] A method for producing crystals of a cyclic peptide, comprising a step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide has the following characteristics (I) and (II): (I) comprising a cyclic portion consisting of a total of 8 to 16 amino acid residues, and the total number of amino acid residues is 8 to 20; (II) comprising at least two N-substituted amino acid residues; and the solvent is water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent, based on the total amount of the solvent.[B29-1] The method according to [B29], wherein the crystals have one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or have polarized light when observed with a polarizing microscope. [B29-2] The method according to [B29], wherein the crystals have one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [B30] The method according to any one of [B29] to [B29-2], wherein the surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants. [B31] The method according to any one of [B29] to [B29-2], wherein the surfactant is one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosinate salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkylphosphates, N-alkyl β-aminopropionic acids, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethyleneglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylenesorbitan fatty acid esters. [B32] The method according to any one of [B29] to [B29-2], wherein the surfactant is one or more selected from the group consisting of alkyl sulfates, alkylarylpolyoxyethylene ethers, polyoxyethyleneglycerin fatty acid esters, and polyoxyethylenesorbitan fatty acid esters. [B33] The method according to any one of [B29] to [B29-2], wherein the surfactant is an alkyl sulfate, an alkylaryl polyoxyethylene ether, a polyoxyethylene glycerin fatty acid ester, or a polyoxyethylene sorbitan fatty acid ester.[B34] The method according to any one of [B29] to [B29-2], wherein the surfactant is sodium lauryl sulfate, 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 Hydrogenated Castor Oil, or polyoxyethylene sorbitan monolaurate. [B35] The method according to any one of [B29] to [B29-2], wherein the surfactant is an ionic surfactant or a nonionic surfactant. [B36] The method according to any one of [B29] to [B29-2], wherein the surfactant is an ionic surfactant. [B37] The method according to [B36], wherein the ionic surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, and amphoteric surfactants. [B38] The method according to [B36], wherein the ionic surfactant is one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosinate salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl β-aminopropionic acid, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, and lecithin. [B39] The method according to [B36], wherein the ionic surfactant is an alkyl sulfate. [B40] The method according to [B36], wherein the ionic surfactant is lauryl sulfate. [B41] The method according to [B36], wherein the ionic surfactant is sodium lauryl sulfate. [B42] The method according to any one of [B29] to [B29-2], wherein the surfactant is a nonionic surfactant. [B43] The method described in [B42], wherein the nonionic surfactant is one or more selected from the group consisting of alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.[B44] The method according to [B42], wherein the nonionic surfactant is one or more selected from the group consisting of alkylaryl polyoxyethylene ether, polyoxyethylene glycerin fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. [B45] The method according to [B42], wherein the nonionic surfactant is one or more selected from the group consisting of 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 Hydrogenated Castor Oil, and polyoxyethylene sorbitan monolaurate. [B46] The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is an alcohol solvent, an amide solvent, a nitrile solvent, or a sulfoxide solvent. [B47] The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is an alcohol solvent or a sulfoxide solvent. [B48] The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is methanol, ethanol, 1-propanol, 2-propanol, or dimethyl sulfoxide. [B49] The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is ethanol or dimethyl sulfoxide. [B50] The method according to any one of [B29] to [B49], wherein the content of the surfactant is 0.02 to 20 wt / v%, 0.05 to 15 wt / v%, 0.1 to 10 wt / v%, 0.12 to 8 wt / v%, 0.15 to 5 wt / v%, or 0.18 to 3 wt / v%, based on the total amount of solvent, and the content of the water-soluble organic solvent is 5 to 40 v / v%, 5 to 30 v / v%, 5 to 25 v / v%, 8 to 20 v / v%, or 10 to 15 v / v%, based on the total amount of solvent. [B51] The method according to any one of [B29] to [B49], wherein the content of the surfactant is 0.1 to 10 wt / v% based on the total amount of the solvent, and the content of the water-soluble organic solvent is 5 to 25 v / v% based on the total amount of the solvent.[B52] A method for producing a crystal of a cyclic peptide, comprising a step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide has the following characteristics (I) and (II): (I) comprising a cyclic portion consisting of a total of 8 to 16 amino acid residues, and the total number of amino acid residues is 8 to 20; (II) comprising at least two N-substituted amino acid residues; and the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water. [B52-1] The method according to [B52], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or exhibits polarized light when observed with a polarizing microscope. [B52-2] The method according to [B52], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [B53] The method according to any one of [B52] to [B52-2], wherein the solvent is a PEG-based solvent. [B54] The method according to any one of [B52] to [B52-2], wherein the solvent is a mixed solvent of a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water. [B55] The method according to any one of [B52] to [B52-2], wherein the PEG-based solvent is (i) R. １ (OCHR ３ CH ２ ) n OR ２ where n is a natural number of 1 or more and 10 or less, or (ii) R １ (OCHR ３ CH ２ ) n OR ２ wherein the average of n is 3 to 100, １ and R ２ are each independently hydrogen, C １ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ may be substituted with a hydroxyl group; １ ~C １８C optionally substituted with an alkyl or hydroxyl group １ ~C １８ [B56] The method according to [B53] or [B54], wherein the PEG-based solvent is (i) R １ (OCHR ３ CH ２ ) n OR ２ wherein n is a natural number of 1, 2, 3, or 4; or (ii) R １ (OCHR ３ CH ２ ) n OR ２ wherein the average of n is 3 to 100, １ is hydrogen or C １ ~C ４ alkyl, and R ２ is hydrogen, C １ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ is C １０ ~C １８ [B57] The method according to [B53] or [B54], wherein the PEG-based solvent is (i) R １ (OCHR ３ CH ２ ) n OR ２ wherein n is a natural number of 1, 2, 3, or 4; or (ii) R １ (OCHR ３ CH ２ ) n OR ２ wherein the average of n is 3 to 100, １ is hydrogen or methyl, and R ２ is hydrogen, methyl or —C(═O)R ４ and R ３ is hydrogen or methyl, and R ４ is C １１ ~C １７[B58] The method according to [B53] or [B54], wherein the PEG-based solvent is diglyme, triglyme, tetraglyme, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or a polyethylene glycol mono-fatty acid ester. [B59] The method according to [B53] or [B54], wherein the PEG-based solvent is polyethylene glycol. [B59-2] The method according to [B59], wherein the number-average molecular weight of the polyethylene glycol is 150 to 5000. [B59-3] The method according to [B59], wherein the number-average molecular weight of the polyethylene glycol is 360 to 440, 540 to 660, 900 to 1100, or 1800 to 2200. [B60] The method according to [B59], wherein the polyethylene glycol is PEG400, PEG600, PEG1000, or PEG2000. [B61] The method according to [B53] or [B54], wherein the PEG-based solvent is a polyethylene glycol mono-fatty acid ester. [B62] The method according to [B61], wherein the polyethylene glycol mono-fatty acid ester is polyethylene glycol monostearate or polyethylene glycol monolaurate. [B63] The method according to any one of [B52] to [B52-2] or [B54] to [B62], wherein the one or more solvents selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more solvents selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water.[B64] The method according to any one of [B52] to [B52-2] or [B54] to [B62], wherein the one or more selected from the group consisting of alcoholic solvents, aliphatic hydrocarbon solvents, and water are one or more selected from the group consisting of 2-propanol, n-heptane, and water. [C1] The method according to any one of [A1] to [A89] or [B1] to [B64], wherein the concentration of the cyclic peptide in the step of contacting the cyclic peptide with a solvent is 1 mg to 2000 mg / mL. [C2] The method according to any one of [A1] to [A89] or [B1] to [B64], wherein the concentration of the cyclic peptide in the step of contacting the cyclic peptide with a solvent is 5 mg to 1500 mg / mL, 10 mg to 1000 mg / mL, 10 mg to 500 mg / mL, 10 mg to 100 mg / mL, 10 mg to 50 mg / mL, 100 mg to 400 mg / mL, 100 mg to 200 mg / mL, or 500 mg to 1000 mg / mL. [C3] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C2], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is a lyophilized product. [C4] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C2], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is a product lyophilized from a dimethyl sulfoxide solution. [C5] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C4], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is 0.5 mg to 200 kg. [C6] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C4], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is 1 mg to 1 g. [C7] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C4], wherein the amount of the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is 0 g to 200 kg, 100 g to 100 kg, 0.5 mg to 10 g, 1 mg to 1 g, 1 mg to 100 mg, 1 mg to 10 mg, or 1 mg to 5 mg.[C8] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C7], wherein the step of contacting the cyclic peptide with a solvent does not include the addition of seed crystals. [C9] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C7], wherein the step of contacting the cyclic peptide with a solvent includes the addition of seed crystals. [C10] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C9], wherein the step of contacting the cyclic peptide with a solvent further includes a filtration step. [C11] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C10], wherein the step of contacting the cyclic peptide with a solvent is carried out at a temperature of -10°C to 120°C for 30 minutes to 12 weeks. [C12] The method according to any one of [A1] to [A89], [B1] to [B64], and [C1] to [C10], wherein the step of contacting the cyclic peptide with a solvent is carried out at a constant temperature of 0°C to 110°C, 10°C to 100°C, 15°C to 90°C, or 20°C to 80°C, or wherein heating and cooling is repeated 10 or more, 20 or more, or 30 or more times, and 1000 or less, 500 or less, or 100 or less times, between a lower limit temperature of 10°C, 20°C, 30°C, 40°C, 45°C, 50°C, or 55°C and an upper limit temperature of 100°C, 90°C, 85°C, 80°C, 75°C, 70°C, or 60°C, and the heating and cooling is carried out for 1 hour to 6 weeks, 2 hours to 4 weeks, 4 hours to 2 weeks, or 6 hours to 7 days. [C13] The method according to any one of [A1] to [A89], [B1] to [B64], and [C1] to [C10], wherein the step of contacting the cyclic peptide with a solvent is carried out for 12 hours to 7 days at a constant temperature of 20° C. to 90° C. [C14] The method according to any one of [A1] to [A89], [B1] to [B64], and [C1] to [C10], wherein the step of contacting the cyclic peptide with a solvent is carried out for 12 hours to 7 days by repeatedly heating and cooling the cyclic peptide 30 times or more and 100 times or less between a lower limit temperature of 50° C. and an upper limit temperature of 90° C.[D1] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C14], wherein the cyclic peptide comprises a cyclic portion consisting of a total of 7 to 15, 8 to 14, 9 to 13, 10 to 13, 11 to 13, 11 to 12, or 11 amino acid residues, and the total number of amino acids is 9 to 18, 10 to 16, 10 to 14, 11 to 14, 11 to 13, 11 to 12, or 11. [D2] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C14], wherein the cyclic peptide comprises a cyclic portion consisting of a total of 11 to 13 amino acid residues, and the total number of amino acids is 11 to 14. [D2-1] The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C14], wherein the cyclic peptide comprises a cyclic portion consisting of a total of 11 amino acid residues, and the total number of amino acids is 11. [D3] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D2], wherein the cyclic peptide comprises at least 3, 4, or 5 N-substituted amino acid residues. [D3-1] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D3], wherein the cyclic peptide comprises at least 1, 2, or 3 N-unsubstituted amino acid residues. [D4] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D2], wherein the cyclic peptide comprises at least five N-substituted amino acid residues. [D4-1] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4], wherein the cyclic peptide comprises at least three N-unsubstituted amino acid residues. [D4-2] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-1], wherein the N-substituted amino acid is an N-alkyl amino acid.[D4-3] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-1], wherein the N-substituted amino acid is an N-methyl amino acid or an N-ethyl amino acid. [D4-4] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-1], wherein the N-substituted amino acid is an N-methyl amino acid. [D5] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-4], wherein the cyclic peptide comprises at least one β-amino acid backbone. [D6] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-4], wherein the cyclic peptide contains at least one β-amino acid backbone in the cyclic portion. [D7] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D6], wherein the cyclic peptide contains a cyclic portion consisting of a 28-55, 28-49, 31-46, 34-43, 34-40, 34-37, or 34-membered ring. [D8] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D6], wherein the cyclic peptide contains a cyclic portion consisting of a 34-40-membered ring. [D8-1] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D6], wherein the cyclic peptide includes a cyclic portion consisting of a 34-membered ring. [D8-2] The method according to [D8-1], wherein the cyclic portion consisting of a 34-membered ring is a cyclic peptide consisting of 11 amino acid residues in total, including 10 α-amino acid residues and 1 amino acid residue having a β-amino acid backbone, and has the following cyclic structure: [D8-3] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D6], wherein the cyclic peptide has the following structure: [Here, P １ , P ３ , P ５ , P ６ , P １０ and P １１ is C１ ~C ６ alkyl, and P ４ is C １ ~C ６ alkyl or P ４ Is, P ４ is bonded to the nitrogen atom, R4, and the carbon atom to which R4 is bonded together to form a 4- to 7-membered saturated heterocyclic ring, ８ is C １ ~C ６ alkyl or P ８ Is, P ８ a nitrogen atom to which R is bonded; ８ , and R ８ together with the carbon atom to which it is attached to form a 4- to 7-membered saturated heterocyclic ring, and the 4- to 7-membered saturated heterocyclic ring is C １ ~C ６ may be substituted by alkoxy, R １ , R ２ , R ３ , R ５ , R ７ and R １０ is a hydrogen atom, C １ ~C ６ Alkyl, C ３ ~C ６ is a cycloalkyl or an aralkyl which may have a substituent, and R ４ and P ４ Except when R forms a 4- to 7-membered saturated heterocyclic ring, ４ is a hydrogen atom or C １ ~C ６ alkyl, and R ８ and P ８ Except when R forms a 4- to 7-membered saturated heterocyclic ring, ８ is a hydrogen atom or C １ ~C ６ alkyl, and R ９ Is, Q ９ and R ９ and Q ９ together with the carbon atom to which R is attached to form a 3- to 7-membered saturated carbocyclic ring, １１ is a hydrogen atom, C １ ~C ６ Alkyl, diC １ ~C ６alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl.] [D8-4] The P １ , P ３ , P ５ , P ６ , P １０ and P １１ [D8-5] The method according to [D8-3], wherein P is methyl or ethyl. ４ is methyl, or P ４ is bonded to the nitrogen atom, R4, and the carbon atom to which R4 is bonded form a 4-membered saturated heterocycle. [D8-6] The method according to [D8-3] or [D8-4]. ８ Is, P ８ a nitrogen atom to which R is bonded; ８ , and R ８ together with the carbon atom to which it is attached to form a 5-membered saturated heterocyclic ring, and the 5-membered saturated heterocyclic ring is C １ ~C ６ [D8-7] The method according to any one of [D8-3] to [D8-5], wherein the R １ and R ２ is C １ ~C ６ alkyl, and the R ３ is a hydrogen atom or C １ ~C ６ alkyl, and the R ４ is R ４ and P ４ is a hydrogen atom except when R forms a 4- to 7-membered saturated heterocyclic ring, ５ is C ３ ~C ６ cycloalkyl or benzyl which may have a substituent, ７ is an optionally substituted phenylethyl, and the R ９ Is, Q ９ and R ９ and Q ９ forms a five-membered saturated carbocyclic ring together with the carbon atom to which R is attached, １０ is C １ ~C ６ Alkyl or C ３ ~C ６ is cycloalkyl, and R１１ is methyl, diC １ ~C ６[D9] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D8-7], wherein the cyclic peptide has a molecular weight (g / mol) of 1205 or more, 1206 or more, 1207 or more, 1208 or more, 1210 or more, 1220 or more, 1230 or more, 1250 or more, or 1300 or more, and 2800 or less, 2500 or less, 2000 or less, 1900 or less, 1800 or less, 1700 or less, or 1600 or less. [D10] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D8-7], wherein the molecular weight (g / mol) of the cyclic peptide is 1300 or more and 1600 or less. [D11] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D10], wherein the ClogP of the cyclic peptide is 4 or more and 25 or less. [D12] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D10], wherein the ClogP of the cyclic peptide is 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more, and 24 or less, 23 or less, 22 or less, 21 or less, 20 or less, 19 or less, or 18 or less. [D13] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D10], wherein the Clog P of the cyclic peptide is 9 to 18. [D14] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D10], wherein the Clog P of the cyclic peptide is larger than the Clog P of cyclosporin A. [D14-1] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14], wherein the Clog P / number of amino acid residues of the cyclic peptide is 0.3 to 2.3, 0.5 to 1.9, 0.7 to 1.8, or 0.8 to 1.6.[D14-2] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the ClogP / number of amino acid residues of the cyclic peptide is 0.8 to 1.6. [D14-3] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 1200 mg / mL or less, 800 mg / mL or less, 600 mg / mL or less, 300 mg / mL or less, 200 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, 25 mg / mL or less, 10 mg / mL or less, 5.0 mg / mL or less, or 2.6 mg / mL or less. [D14-4] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 0.8 mg / mL or more. [D14-5] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 0.9 mg / mL or more, 1.0 mg / mL or more, or 1.1 mg / mL or more. [D14-6] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the cyclic peptide has a solubility of 1.1 mg / mL or more in 50 mM phosphate buffer (pH 6.5). [D14-7] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the cyclic peptide has two or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [D14-8] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-2], wherein the cyclic peptide has three or more diffraction peaks in powder X-ray diffraction using CuKα radiation.[D15] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D14-4], wherein the cyclic peptide is a cyclic peptide other than cyclosporin A. [D16] The cyclic peptide is (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0]. １２，１５[E1] A method for screening crystals of a cyclic peptide, the method comprising the following steps (a) and (b): (a) producing a crystal of a cyclic peptide by the method of any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16]; (b) analyzing the crystal by powder X-ray crystal diffraction. [E2] The method of [E1], wherein the crystal to be screened includes a crystal produced using a solvent containing formamide. [E3] The method of [E1], wherein the crystal to be screened includes a crystal produced using a solvent containing formamide and a solvent containing dimethyl sulfoxide. [E4] The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane. [E5] The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil. [E6] The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester. [E7] The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing polyethylene glycol. [E8] The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil, a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol.[E9] The method described in [E1], wherein the crystals to be screened include crystals produced using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil, crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester, and crystals produced using a solvent containing formamide. [F1] A method for screening crystallization methods for a cyclic peptide, comprising the following steps (a) and (b): (a) producing crystals of a cyclic peptide by a method described in any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16]; (b) analyzing the crystals by powder X-ray crystal diffraction. [F2] The method described in [F1], wherein the crystallization methods to be screened include a crystallization method using a solvent containing formamide. [F3] The method described in [F1], wherein the crystallization methods to be screened include a crystallization method using a solvent containing formamide and a solvent containing dimethyl sulfoxide. [F4] The method described in [F1], wherein the crystallization methods to be screened include crystallization methods using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane. [F5] The method described in [F1], wherein the crystallization methods to be screened include a crystallization method using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil. [F6] The method described in [F1], wherein the crystallization methods to be screened include a crystallization method using a solvent containing polyethylene glycol mono-fatty acid ester. [F7] The method described in [F1], wherein the crystallization methods to be screened include a crystallization method using a solvent containing polyethylene glycol. [F8] The method described in [F1], wherein the crystallization methods to be screened include crystallization methods using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil, a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol.[F9] The method according to [F1], wherein the crystallization methods to be screened include crystallization methods using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil, a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing formamide. [F10] The method according to any one of [E1] to [E9] or [F1] to [F9], wherein in the step of contacting the cyclic peptide with a solvent, 0.5 mg to 10 mg of cyclic peptide is used per condition. [F11] The method according to any one of [E1] to [E9] or [F1] to [F10], wherein two or more, five or more, ten or more, fifteen or more, or twenty or more types of crystals or crystallization methods to be screened are used. [F12] The method according to any one of [E1] to [E9] or [F1] to [F11], wherein the step of contacting the cyclic peptide with a solvent does not include adding seed crystals. [G1] A method for increasing the probability of producing cyclic peptide crystals, comprising a step of producing cyclic peptide crystals by the method described in any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16]. [H1] Use of a solvent selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, polyoxyethylene glycerin fatty acid esters, and polyethylene glycol mono-fatty acid esters in producing cyclic peptide crystals. [H2] Use of an amide solvent in producing cyclic peptide crystals. [H3] Use of formamide in producing cyclic peptide crystals. [H4] Use of a sulfoxide solvent in producing cyclic peptide crystals. [H5] Use of dimethyl sulfoxide in producing cyclic peptide crystals. [H6] Use of an aromatic hydrocarbon solvent in producing cyclic peptide crystals. [H7] Use of toluene, tetralin, or cumene in producing cyclic peptide crystals. [H8] Use of Polyoxyl 35 Hydrogenated Castor Oil in the production of cyclic peptide crystals. [H9] Use of polyethylene glycol mono-fatty acid ester in the production of cyclic peptide crystals. [H10] Use of polyethylene glycol in the production of cyclic peptide crystals.[H11] The use according to any one of [H1] to [H10], wherein the cyclic peptide crystals are produced by the method according to any one of [D1] to [D16]. [I1] A method for purifying a cyclic peptide, comprising the steps of producing cyclic peptide crystals by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16], and collecting the crystals by solid-liquid separation. [J1] A screening kit for producing cyclic peptide crystals, wherein the cyclic peptide crystals are produced by the use according to any one of [H1] to [H11]. [K1] A method for producing a cyclic peptide, comprising the step of producing a cyclic peptide crystal containing formamide. [K2] A method for producing a cyclic peptide, comprising the step of producing a cyclic peptide crystal containing dimethyl sulfoxide. [K3] A method for producing a cyclic peptide, comprising the step of producing a cyclic peptide crystal containing an aromatic hydrocarbon solvent. [K4] A method for producing a cyclic peptide, comprising the step of producing a cyclic peptide crystal containing toluene, tetralin, or cumene. [K5] A method for producing a cyclic peptide, comprising a step of producing a crystal of a cyclic peptide containing Polyoxyl 35 Hydrogenated Castor Oil. [K6] A method for producing a cyclic peptide, comprising a step of producing a crystal of a cyclic peptide containing a polyethylene glycol monofatty acid ester. [K7] A method for producing a cyclic peptide, comprising a step of producing a crystal of a cyclic peptide containing polyethylene glycol. [K8] The method according to any one of [K1] to [K7], wherein a crystal of a cyclic peptide is produced by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16].[L1] (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0] １２，１５ 3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl 3-[2-[ ... -N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0 １２，１５A method for producing a crystal of ]nonatriacontane-33,1'-cyclopentane-27-carboxamide, wherein the solvent is solvent (A) or a mixed solvent containing solvent (A) and solvent (B), wherein solvent (A) is one or more selected from the group consisting of amide-based solvents, sulfoxide-based solvents, aromatic hydrocarbon-based solvents, halogen-based solvents, and ester-based solvents, and solvent (B) is one or more selected from the group consisting of aliphatic hydrocarbon-based solvents, ethylene glycol, and water. [L2] The method according to [L1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or exhibits polarized light when observed with a polarizing microscope. [L3] The method according to [L1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [L4] The method according to any one of [L1] to [L3], wherein the solvent is toluene. [L5] The method according to any one of [L1] to [L3], wherein the solvent is dimethyl sulfoxide. [L6] The method according to any one of [L1] to [L3], wherein the solvent is a mixed solvent of ethanol and water. [L7] The method according to any one of [L1] to [L3], wherein the solvent is a mixed solvent of acetonitrile and water. [L8] The method according to any one of [L1] to [L3], wherein the solvent is cumene. [L9] The method according to any one of [L1] to [L3], wherein the solvent is tetralin. [L10] The method according to any one of [L1] to [L3], wherein the solvent is formamide. [L11] The method according to any one of [L1] to [L3], wherein the solvent is diisopropyl ether. [L12] The method according to any one of [L1] to [L3], wherein the solvent is a mixed solvent of 3-acetylpyridine and ethylene glycol.[L13] (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0] １２，１５ 3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl 3-[2-[ ... -N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0 １２，１５[L14] A method for producing a crystal of ]nonatriacontane-33,1'-cyclopentane]-27-carboxamide, wherein the solvent is water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent, based on the total amount of the solvent. [L14] The method according to [L13], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or exhibits polarized light when observed with a polarizing microscope. [L15] The method according to [L13], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [L16] The method according to any one of [L13] to [L15], wherein the surfactant is one or more surfactants selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants. [L17] The method according to any one of [L13] to [L15], wherein the surfactant is 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol and the water-soluble organic solvent is ethanol. [L18] The method according to any one of [L13] to [L15], wherein the surfactant is 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol and the water-soluble organic solvent is dimethyl sulfoxide. [L19] The method according to any one of [L13] to [L15], wherein the surfactant is Polyoxyl 35 Hydrogenated Castor Oil and the water-soluble organic solvent is ethanol. [L20] The method according to any one of [L13] to [L15], wherein the surfactant is Polyoxyl 35 Hydrogenated Castor Oil and the water-soluble organic solvent is dimethyl sulfoxide. [L21] The method according to any one of [L13] to [L15], wherein the surfactant is polyoxyethylene sorbitan monolaurate (Tween 80) and the water-soluble organic solvent is ethanol. [L22] The method according to any one of [L13] to [L15], wherein the surfactant is polyoxyethylene sorbitan monolaurate and the water-soluble organic solvent is dimethyl sulfoxide. [L23] The method according to any one of [L13] to [L15], wherein the surfactant is sodium lauryl sulfate and the water-soluble organic solvent is ethanol.[L24] The method according to any one of [L13] to [L15], wherein the surfactant is sodium lauryl sulfate and the water-soluble organic solvent is dimethyl sulfoxide. [L25] (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0] １２，１５ 3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl 3-[2-[ ... -N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0 １２，１５A method for producing a crystal of ]nonatriacontane-33,1'-cyclopentane]-27-carboxamide, wherein the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water. [L26] The method according to [L25], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarized light when observed with a polarizing microscope. [L27] The method according to [L25], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. [L28] The method according to any one of [L13] to [L15], wherein the solvent is tetraethylene glycol. [L29] The method according to any one of [L13] to [L15], wherein the solvent is polyethylene glycol. [L30] The method according to any one of [L13] to [L15], wherein the solvent is triglyme. [L31] The method according to any one of [L13] to [L15], wherein the solvent is ethylene glycol. [L32] The method according to any one of [L13] to [L15], wherein the solvent is PEG400. [M1] A crystal produced by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], [D1] to [D16], [K1] to [K7], or [L32] to [L32]. [M2] A pharmaceutical composition comprising a crystal produced by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], [D1] to [D16], [K1] to [K7], or [L32] to [L32].

[0011] The present invention provides a method for producing crystals of cyclic peptides containing N-substituted amino acid residues. The present invention also provides a method for screening crystals of cyclic peptides containing N-substituted amino acid residues. The present invention also provides a method for screening crystallization methods. The present invention also provides a method for isolating and purifying a target cyclic peptide, or a salt thereof, or a solvate thereof, as crystals, without relying on column chromatography.

[0012] (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-1-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-3-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-4-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-4-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-3. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-5-5. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-5-6. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-5-7. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-5-8. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). Powder X-ray diffraction measurement results for the crystals obtained in Example 2-5-9. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-6-1.The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-3. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-8. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-7-9. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-7-10. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-7-12. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-7-14. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-7-15. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-7-16. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-17. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-18. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-19. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-20. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-21. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).(C) Powder X-ray diffraction results for the crystals obtained in Example 2-7-22. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction results for the crystals obtained in Example 2-7-23. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction results for the crystals obtained in Example 2-7-24. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction results for the crystals obtained in Example 2-7-25. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction results for the crystals obtained in Example 2-7-26. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction results for the crystals obtained in Example 2-7-29. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-31. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-32. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-33. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-7-34. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-3. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-5. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-6. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-10. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-13. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).(D) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-14. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-15. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-16. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-17. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-19. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-20. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-21 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-22 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-23 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-24 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-25 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-26 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-28 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-30 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-31 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-32 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).(E) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-33. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-34. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-35. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-36. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-37. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 2-8-38. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-39. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-40. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-41. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-42. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-43. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-44 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-8-45 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-1-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-4-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).(D) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-3. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-5. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-6. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-7. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-8. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-9. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-10. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-11. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-12. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-13 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-14 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-15 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-16 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-17 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).(E) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-18. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-19. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-20. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-21. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-22. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) Powder X-ray diffraction measurement results for the crystals obtained in Example 3-5-23. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-24. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-25. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-26. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-27. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-28. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-29 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-5-30 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-7-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-8-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-8-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).(A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-8-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-8-4 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-8-5 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 3-8-6 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-1-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-3-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-3. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-5. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-6 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). In addition to the 19.2° and 24.4° peaks attributable to PEG2000, several other diffraction peaks are observed. These are the diffraction peaks of the CP04 crystals. (D) The results of powder X-ray diffraction measurement of PEG2000 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). Characteristic peaks are observed at 19.2° and 24.4°. (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-7 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).In addition to the diffraction peaks at 21.7° and 24.1° attributable to polyethylene glycol monostearate (n = approximately 4) (palmitate and stearate mixture), several other diffraction peaks are observed. These are the diffraction peaks of the CP04 crystals. (B) The results of powder X-ray diffraction measurement of polyethylene glycol monostearate (n = approximately 4) (palmitate and stearate mixture) are shown. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Characteristic peaks are observed at 21.7° and 24.1°. (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-8 are shown. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-9 are shown. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). (E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-4-10 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-5-1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-5-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-5-3. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-5-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (E) This shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 4-5-5. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-5-6 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-7-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-7-2 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-7-3 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-7-4 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).(E) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-8-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-8-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (B) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-8-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (C) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-8-4 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (D) The results of powder X-ray diffraction measurement of the crystals obtained in Example 4-8-5 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). (A) The crystal structure of the crystals of compound CP01 obtained in Example 2-1-1, as determined by single crystal X-ray structural analysis.

[0013] As used herein, "room temperature" means a temperature of about 20°C to about 25°C.

[0014] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0015] In this specification, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range that is equal to or greater than A and equal to or less than B.

[0016] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0017] In the present invention, the meaning of the term "and / or" includes any combination of "and" and "or" appropriately combined. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

[0018] In this specification, "v / v %" represents volume % and "wt / v %" represents weight / volume %.

[0019] As used herein, the term "peptide" refers to two or more amino acids linked together via amide bonds. Peptides having an ester bond in part of the main chain, such as depsipeptides, are also included in the term "peptide" as used herein.

[0020] As used herein, a "cyclic peptide" refers to a peptide having a cyclic structure composed of four or more amino acid residues. The cyclization of a cyclic peptide may be any form, such as cyclization via a carbon-nitrogen bond such as an amide bond, cyclization via a carbon-oxygen bond such as an ester bond or an ether bond, cyclization via a carbon-sulfur bond such as a thioether bond, cyclization via a carbon-carbon bond, or cyclization via a heterocyclic ring structure. Among these, cyclization via a covalent bond such as an amide bond, a carbon-sulfur bond, or a carbon-carbon bond is preferred. Cyclization via an amide bond is more preferred, and the position of the carboxyl group or amino group used for cyclization may be on either the main chain or the side chain. Most preferred is cyclization via an amide bond between a carboxyl group in the side chain and an amino group in the main chain at the N-terminus.

[0021] As used herein, the term "heterocycle" refers to a non-aromatic heterocycle containing preferably 1 to 5, more preferably 1 to 3, heteroatoms among the atoms constituting the ring. The heterocycle may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl. The heterocycle may be a monocyclic, fused ring, or spiro ring. The number of atoms constituting the ring of the heterocycle is preferably 3 to 12 (3- to 12-membered heterocycle), more preferably 4 to 10 (4- to 10-membered heterocycle). Specific examples of the heterocyclic ring include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a diphenyl ring, a ... Examples thereof include an oxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, a 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, an azocane ring, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, an azepane ring, a dioxepane ring, a 5,9-dioxaspiro[3.5]nonane ring, and rings in which one or more single bonds in these saturated heterocycles are replaced with double bonds or triple bonds.

[0022] "Cyclization" of a peptide refers to the formation of a cyclic portion containing four or more amino acid residues. The number of amino acids contained in the cyclic portion of a cyclic peptide herein is not particularly limited as long as it is four or more, but examples include 4 to 20 residues, 5 to 15 residues, 6 to 13 residues, 9 to 13 residues, and 11 residues, preferably 5 to 15 residues, more preferably 9 to 13 residues, and most preferably 11 residues. A linear peptide can be converted into a cyclic peptide by carrying out an intramolecular bond formation reaction using a method such as those described in "Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition" (by R.C. Larock) or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition" (by M.B. Smith and J. March). After the bond formation reaction, a functional group transformation reaction can also be carried out. Examples of bonds at the cyclization site of cyclic peptides include a C(O)-N bond formed between a carboxylic acid and an amine, a C-O-C bond mediated by an oxygen atom, a C(O)-O bond, a C(S)-O bond, a C(O)-S bond mediated by a sulfur atom, a C(S)-S bond, a C-S-C bond, a C-S-C bond, a C-S-C bond, a C-S-C bond, a C-S-C bond, a C-N-C bond, a C=N-C bond, an N-C(O)-N bond, an N-C(S)-N bond, and a C(S)-N bond mediated by a nitrogen atom. Further examples include C-C bonds formed by transition metal-catalyzed coupling reactions such as the Suzuki reaction, the Heck reaction, and the Sonogashira reaction. Examples of functional group conversion reactions that can be performed after the bond formation reaction include oxidation and reduction reactions. Specifically, a reaction that oxidizes a sulfur atom to convert it to a sulfoxide or sulfone group is exemplified. Another example is a reduction reaction that reduces a triple or double carbon-carbon bond to convert it to a double or single bond. Two amino acids may be linked at the backbone of the amino acids to form a closed ring structure by a peptide bond, or a covalent bond between the two amino acids may be formed by bonding the side chains of the two amino acids together, or between the side chain and the backbone, etc.

[0023] As used herein, the "cyclic portion" of a cyclic peptide refers to a cyclic portion formed by linking four or more amino acid residues.

[0024] In this specification, the term "crystal of a cyclic peptide" is understood to mean (i) a crystal of a free cyclic peptide, (ii) a crystal of a solvate of a cyclic peptide, and (iii) a mixture thereof, and may be any of them.

[0025] As used herein, the term "solvate" refers to a compound that forms a single molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is acceptable for ingestion accompanying pharmaceutical administration. Examples of solvates include solvates with a single solvent such as hydrates, alcoholates (ethanol solvates, methanol solvates, 1-propanol solvates, 2-propanol solvates, etc.), formamide, and dimethyl sulfoxide, as well as solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. As described in Crystal Growth & Design 2012, 12, 2147-2152, solvates are distinguished from cocrystals. A cocrystal is defined herein as a crystal composed of a compound and a component that is solid at 25°C. As used herein, the term "crystal of a cyclic peptide" includes (i) a crystal of a free cyclic peptide, (ii) a crystal of a solvate of a cyclic peptide, and (iii) a mixture thereof, but does not include a co-crystal containing a cyclic peptide or a mixture of a co-crystal containing a cyclic peptide with any of the crystals (i) to (iii) above.

[0026] As used herein, "amino acid" includes natural amino acids and unnatural amino acids. Furthermore, as used herein, "amino acid" may refer to amino acid residues. As used herein, "natural amino acids" refer to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Examples of unnatural amino acids include, but are not limited to, β-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains different from those of natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids may have any stereoconfiguration. The side chain of an amino acid is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, heteroarylalkyl groups, cycloalkyl groups, and spiro-linked cycloalkyl groups. Each of these may have a substituent, and the substituents are not limited. For example, one or more may be independently selected from any substituents including a halogen atom, an O atom, a S atom, a N atom, a B atom, a Si atom, or a P atom. Examples include optionally substituted alkyl groups, alkoxy groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, cycloalkyl groups, etc., as well as oxo, aminocarbonyl, and halogen atoms. In a non-limiting embodiment, the amino acid herein may be a compound having a carboxyl group and an amino group in the same molecule. Even in this case, compounds in which the nitrogen atom of the amino group and any atom in the side chain are joined together to form a ring (e.g., proline, hydroxyproline, azetidine-2-carboxylic acid, etc.) are also included in the amino acid herein.

[0027] In this specification, "optionally substituted" means that a group may be substituted with any substituent.Furthermore, each of these may be given a substituent, and the substituents are not limited, and for example, one or more may be independently selected from any substituent containing a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom.Examples of the substituent include alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, halogen, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, formyl, etc.

[0028] As used herein, "halogen" is exemplified by F, Cl, Br, or I.

[0029] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Alkyl preferably has 1 to 20 carbon atoms (C １ -C ２０ , hereinafter referred to as “C ｐ -C ｑ " means that the number of carbon atoms is p to q), and preferably C １ -C １０ Alkyl, more preferably C １ -C ６Specific examples of the alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0030] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. C ２ -C １０ Alkynyl, more preferably C ２ -C ６ Specific examples include alkynyl, ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0031] As used herein, "alkenyl" refers to a monovalent group having at least one double bond (two adjacent SP2 carbon atoms). Depending on the configuration of the double bond and substituents (if any), the geometry of the double bond can be entgegen (E) or zusammen (Z), cis or trans. Alkenyl includes not only straight chain but also branched chain. C is preferred as alkenyl. ２ -C １０ alkenyl, more preferably C ２ -C６ Specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0032] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring or aromatic hydrocarbon ring group. Preferred examples of aryl include C ６ -C １０ Specific examples of the aryl include phenyl and naphthyl (for example, 1-naphthyl and 2-naphthyl).

[0033] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group or aromatic heterocyclic group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a monocyclic ring or a condensed ring with another ring, and may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl.

[0034] As used herein, "aralkyl (arylalkyl)" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with an "aryl" as defined above. ７-C １４ Aralkyl is preferred, C ７ -C １０ Aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0035] As used herein, "heteroarylalkyl" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with a "heteroaryl" as defined above. Heteroarylalkyl includes 5- to 10-membered heteroaryl C １ -C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ -C ２ Specific examples of heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0036] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. ３ -C ８ Specific examples include cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0037] As used herein, "alkoxy" refers to an oxy group to which the above-defined "alkyl" is bonded. １ -C ６Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[0038] As used herein, "alkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "alkoxy" as defined above. １ -C ６ Alkoxy C １ -C ６ Alkyl is preferred, C １ -C ６ Alkoxy C １ -C ２ Alkyl is more preferred. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0039] In the present specification, "amino" means, in a narrow sense, -NH ２ and broadly, -NRR', where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a ring. ２ , Mono C １ -C ６ Alkylamino, DiC １ -C ６ Examples thereof include alkylamino and 4- to 8-membered cyclic amino.

[0040] As used herein, "monoalkylamino" refers to a group in which R is hydrogen and R' is an "alkyl" as defined above, among the "amino" groups defined above. Preferred examples of monoalkylamino include mono C1-C6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0041] As used herein, "dialkylamino" refers to a group in which R and R' are independently "alkyl" as defined above, among the "amino" groups defined above. As dialkylamino, diC １ -C ６ Specific examples of dialkylamino include dimethylamino and diethylamino.

[0042] As used herein, "alkylsulfonylamino" refers to a group in which a sulfonyl group is bonded to the "amino" defined above. １ -C ６ Alkylsulfonyl-NH-, (C １ -C ６ Alkylsulfonyl-) ２ Specific examples of the aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino, and the like.

[0043] As used herein, "aminocarbonyl" refers to a carbonyl group to which the above-defined "amino" is bonded. As the aminocarbonyl, -CONH is preferable. ２ , Mono C １ -C ６ Alkylaminocarbonyl, diC １ -C ６ Examples of the aminocarbonyl include alkylaminocarbonyl and 4- to 8-membered cyclic aminocarbonyl. ２, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, and the like.

[0044] In this specification, the "amino acid residues" that constitute a peptide may be simply referred to as "amino acids".

[0045] As used herein, the term "side chain of an amino acid" refers to, in the case of an α-amino acid, an atomic group other than the amino group and the carboxyl group that is bonded to the carbon (α-carbon) to which the amino group and the carboxyl group are bonded. For example, the methyl group of Ala is the side chain of an amino acid. In the case of a β-amino acid, an atomic group bonded to the α-carbon and / or the β-carbon, other than the amino group bonded to the β-carbon and the carboxyl group bonded to the α-carbon, can serve as the side chain of an amino acid. In the case of a γ-amino acid, an atomic group bonded to the α-carbon, the β-carbon, and / or the γ-carbon, other than the amino group bonded to the γ-carbon and the carboxyl group bonded to the α-carbon, can serve as the side chain of an amino acid.

[0046] As used herein, the term "amino acid main chain" refers to the chain portion composed of an amino group, an α-carbon, and a carboxyl group in the case of an α-amino acid; the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group in the case of a β-amino acid; and the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group in the case of a γ-amino acid. Furthermore, the term "α-amino acid backbone" refers to the chain portion composed of an amino group, an α-carbon, and a carboxyl group; the term "β-amino acid backbone" refers to the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group; and the term "γ-amino acid backbone" refers to the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group. As used herein, amino acids having a "β-amino acid backbone" as an entire or partial structure may be referred to as "amino acids having a β-amino acid backbone." For example, aspartic acid has a chain portion (β-amino acid skeleton) composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group, and therefore falls under the category of "amino acids having a β-amino acid skeleton."

[0047] As used herein, the term "main chain of a peptide" refers to a structure in which multiple amino acids are linked via amide bonds. As used herein, the terms "main chain of a cyclic peptide" and "main chain of a cyclic portion" refer to a structure in which multiple amino acids contained in the cyclic portion of a cyclic peptide are linked via amide bonds. The "main chain of a peptide," "main chain of a cyclic peptide," and "main chain of a cyclic portion" may partially contain other bonds, such as ester bonds, instead of amide bonds. Furthermore, the "main chain of a cyclic peptide" and the "main chain of a cyclic portion" may contain bonds exemplified herein as bonds at the cyclization site of a cyclic peptide, or bonds formed by a cyclization reaction of the peptide.

[0048] As used herein, the term "N-substituted amino acid" refers to an amino acid in which the amino group contained therein is substituted, i.e., -NHR (R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl which may have a substituent, and one or two non-adjacent methylene groups in these groups are replaced with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO ２ -), or, as in proline, the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring. The "N-substituted amino acid" herein may be an N-alkyl amino acid, and preferably an N-C １ ~C ６ The alkylamino acid is more preferably N-C １ ~C ４ Alkylamino acids are most preferably N-ethylamino acids or N-methylamino acids, but are not limited thereto. Preferred examples of "N-substituted amino acids" herein include N-substituted amino acids in which the amino group contained in the "amino acid main chain" is substituted.

[0049] As used herein, an "N-unsubstituted amino acid" refers to an amino acid in which the amino group contained therein is not substituted, i.e., -NH ２ As used herein, the "N-unsubstituted amino acid" is preferably an N-unsubstituted amino acid in which the amino group contained in the "amino acid main chain" is not substituted.

[0050] In the present specification, when the amino acid constituting a cyclic peptide is aspartic acid, an amino acid in which one or more of the hydrogens on the α-carbon and the β-carbon of aspartic acid have been substituted, or an amino acid in which the amino group in the "main chain of amino acid" of such an amino acid has been substituted, the carboxy group bonded to the α-carbon in the "main chain of amino acid" may be included in the "main chain of cyclic peptide." On the other hand, the carboxy group bonded to the β-carbon in the "side chain of amino acid" may be included in the "main chain of cyclic peptide," in which case the "β-amino acid backbone" is included in the "main chain of cyclic peptide."

[0051] As used herein, the terms "number of amino acids" and "number of amino acid residues" refer to the number of amino acid residues (amino acid units) constituting a peptide, and refer to the number of amino acid units generated upon cleavage of the amide bonds, ester bonds, and cyclized bond linking the amino acids. For example, the number of amino acids and amino acid residues in a cyclic peptide consisting of 10 amino acid residues in the cyclic portion and 1 amino acid residue in the linear portion is 11.

[0052] As used herein, the phrase "containing an amino acid in the cyclic portion of a cyclic peptide" means that the main chain of the cyclic portion of the cyclic peptide contains an amino acid as a partial structure.

[0053] As used herein, the term "saturated heterocycle" refers to a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and containing no double and / or triple bonds within the ring. The saturated heterocycle may be a monocycle or may form a condensed ring with another ring, for example, an aromatic ring such as a benzene ring. Preferred examples of the saturated heterocycle include 4- to 10-membered saturated heterocycles. Specific examples of the saturated heterocycle include an azetidine ring, an oxoazetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, an indoline ring, an azepane ring, a dioxepane ring, and a 5,9-dioxaspiro[3.5]nonane ring.

[0054] In this specification, the molecular weight of a cyclic peptide or a solvent is expressed in g / mol unless otherwise specified. Furthermore, whether the cyclic peptide crystal is a crystal of a free form of the cyclic peptide, a crystal of a solvate of the cyclic peptide, or a mixture thereof, the "molecular weight of the cyclic peptide" is based on the molecular weight of the free form of the cyclic peptide.

[0055] The molecular weight (g / mol) of the cyclic peptide according to one embodiment of the present invention may be 1205 or more, 1206 or more, 1207 or more, 1208 or more, 1210 or more, 1220 or more, 1230 or more, 1250 or more, or 1300 or more, and may be 2800 or less, 2500 or less, 2000 or less, 1900 or less, 1800 or less, 1700 or less, or 1600 or less. The molecular weight (g / mol) of the cyclic peptide of the present invention is preferably 1204 or more and 3000 or less, more preferably 1300 or more and 1600 or less, and most preferably 1400 or more and 1500 or less.

[0056] A cyclic peptide according to one embodiment of the present invention may comprise a cyclic portion consisting of a total of 8 to 16 amino acid residues and may comprise a total of 8 to 20 amino acid residues. Alternatively, a cyclic peptide according to one embodiment of the present invention may comprise a cyclic portion consisting of a total of 7 to 15, 8 to 14, 9 to 13, 10 to 13, 11 to 13, 11 to 12, or 11 amino acid residues, and may comprise a total of 9 to 18, 10 to 16, 10 to 14, 11 to 14, 11 to 13, 11 to 12, or 11 amino acid residues. The cyclic peptides of the present invention preferably comprise a cyclic portion consisting of 8 to 16 residues and a total of 8 to 20 amino acid residues, more preferably a cyclic portion consisting of 11 to 13 residues and a total of 11 to 14 amino acid residues, and most preferably a cyclic portion consisting of a total of 11 amino acid residues and a total of 11 amino acid residues.

[0057] A cyclic peptide according to one embodiment of the present invention may contain at least 3, 4, or 5 N-substituted amino acid residues, and in another embodiment, at least 5 N-substituted amino acid residues. A cyclic peptide according to one embodiment of the present invention may contain at least 1, 2, or 3 N-unsubstituted amino acid residues, and in another embodiment, at least 3 N-unsubstituted amino acid residues. The cyclic peptide of the present invention preferably contains at least 3 N-substituted amino acid residues, more preferably contains at least 5 N-substituted amino acid residues, and most preferably contains at least 7 N-substituted amino acid residues.

[0058] The N-substituted amino acid contained in the cyclic peptide according to one embodiment of the present invention may be an N-alkyl amino acid, and in another embodiment, may be an N-methyl amino acid or an N-ethyl amino acid. The N-substituted amino acid contained in the cyclic peptide of the present invention is preferably an N-alkyl amino acid, more preferably an N-methyl amino acid or an N-ethyl amino acid, and most preferably an N-methyl amino acid.

[0059] A cyclic peptide according to one embodiment of the present invention may be a cyclic peptide having the following characteristics (I), (II), and (III): (I) comprising a cyclic portion consisting of a total of 8 to 16 amino acid residues, and the total number of amino acid residues is 8 to 20; (II) comprising at least two N-substituted amino acid residues; and (III) having a molecular weight (g / mol) of 1204 or more and 3000 or less.

[0060] A cyclic peptide according to one embodiment of the present invention may be a cyclic peptide having the following characteristics (I) and (II): (I) comprising a cyclic portion consisting of a total of 8 to 16 amino acid residues, and the total number of amino acid residues is 8 to 20; (II) comprising at least two N-substituted amino acid residues.

[0061] A cyclic peptide according to one embodiment of the present invention may include at least one β-amino acid backbone. Also, a cyclic peptide according to one embodiment of the present invention may include at least one β-amino acid backbone in the cyclic portion.

[0062] A cyclic peptide according to one embodiment of the present invention may comprise a cyclic portion consisting of a 28-55, 28-49, 31-46, 34-43, 34-40, 34-37, or 34-membered ring. A cyclic peptide according to one embodiment of the present invention may comprise a cyclic portion consisting of a 34- to 40-membered ring, and a cyclic peptide according to another embodiment may comprise a cyclic portion consisting of a 34-membered ring.

[0063] When a cyclic peptide according to one embodiment of the present invention includes a cyclic portion consisting of a 34-membered ring, the cyclic portion consisting of the 34-membered ring may be a cyclic peptide consisting of a total of 11 amino acid residues, including 10 α-amino acid residues and 1 amino acid residue having a β-amino acid backbone.

[0064] A cyclic peptide according to one embodiment of the present invention may have the following structure: [Here, P １ , P ３ , P ５ , P ６ , P １０ and P １１ is C １ ~C ６ alkyl, and P ４ is C １ ~C ６ alkyl or P ４ Is, P ４ is bonded to the nitrogen atom, R4, and the carbon atom to which R4 is bonded together to form a 4- to 7-membered saturated heterocyclic ring, ８ is C １ ~C ６ alkyl or P ８ Is, P ８ a nitrogen atom to which R is bonded; ８ , and R ８ together with the carbon atom to which it is attached to form a 4- to 7-membered saturated heterocyclic ring, and the 4- to 7-membered saturated heterocyclic ring is C １ ~C ６ may be substituted by alkoxy, R １ , R ２ , R ３ , R ５ , R ７ and R １０ is a hydrogen atom, C １ ~C ６ Alkyl, C ３ ~C ６ is a cycloalkyl or an aralkyl which may have a substituent, and R ４ and P ４ Except when R forms a 4- to 7-membered saturated heterocyclic ring, ４ is a hydrogen atom or C １ ~C ６ alkyl, and R ８ and P８ Except when R forms a 4- to 7-membered saturated heterocyclic ring, ８ is a hydrogen atom or C １ ~C ６ alkyl, and R ９ Is, Q ９ and R ９ and Q ９ together with the carbon atom to which R is attached to form a 3- to 7-membered saturated carbocyclic ring, １１ is a hydrogen atom, C １ ~C ６ Alkyl, diC １ ~C ６ alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl.

[0065] In one embodiment, the P １ , P ３ , P ５ , P ６ , P １０ and P １１ may be methyl or ethyl. ４ is methyl, or P ４ may be bonded to the nitrogen atom, R, and the carbon atom to which R is bonded to form a 4-membered saturated heterocyclic ring. ８ Is, P ８ a nitrogen atom to which R is bonded; ８ , and R ８ may be taken together with the carbon atom to which it is attached to form a 5-membered saturated heterocyclic ring, and the 5-membered saturated heterocyclic ring is C １ ~C ６ It may be substituted by alkoxy.

[0066] In one embodiment, the R １ and R ２ is C １ ~C ６ alkyl, and the R ３ is a hydrogen atom or C １ ~C ６ alkyl, and the R ４ is R ４ and P ４ is a hydrogen atom except when R forms a 4- to 7-membered saturated heterocyclic ring.５ is C ３ ~C ６ cycloalkyl or benzyl which may have a substituent, ７ is an optionally substituted phenylethyl, and the R ９ Is, Q ９ and R ９ and Q ９ forms a five-membered saturated carbocyclic ring together with the carbon atom to which R １０ is C １ ~C ６ Alkyl or C ３ ~C ６ cycloalkyl, and the R １１ is methyl, diC １ ~C ６ It may be an alkylaminocarbonyl or a 6-membered cyclic aminocarbonyl.

[0067] The ClogP of a cyclic peptide according to one embodiment of the present invention can be calculated in accordance with the principles described in "CLOGP Reference Manual Daylight Version 4.9 (Release Date: August 1, 2011, https: / / www.daylight.com / dayhtml / doc / clogp / )." As an example of a method for calculating ClogP, the ClogP may be calculated using the ClogP calculation method published by Daylight Chemical Information Systems, Inc. One example is calculation using Daylight Version 4.95 (release date: August 1, 2011, ClogP algorithm version 5.4, database version 28, https: / / www.daylight.com / dayhtml / doc / release_notes / index.html) by Yahoo! Japan.

[0068] The ClogP of a cyclic peptide according to one embodiment of the present invention may be 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more, and may be 24 or less, 23 or less, 22 or less, 21 or less, 20 or less, 19 or less, or 18 or less. Examples of the ClogP range of a cyclic peptide according to one embodiment of the present invention include 5 or more and 23 or less, 6 or more and 21 or less, 7 or more and 20 or less, 8 or more and 19 or less, 9 or more and 18 or less, 10 or more and 17 or less, 11 or more and 16.5 or less, and 11.2 or more and 16.1 or less. Furthermore, the ClogP of a cyclic peptide according to one embodiment of the present invention may be 4 or more and 25 or less, and the ClogP of a cyclic peptide according to another embodiment may be 9 or more and 18 or less. Furthermore, the ClogP of a cyclic peptide according to one embodiment of the present invention may be greater than the ClogP of cyclosporin A (ClogP: 14.36). The ClogP of the cyclic peptide of the present invention is preferably 5 or more and 23 or less, more preferably 9 or more and 18 or less, and most preferably 11.2 or more and 16.1 or less.

[0069] The cyclic peptide according to one embodiment of the present invention preferably has a ClogP / amino acid residue ratio of 1.0 or more. The ClogP / amino acid residue ratio is a value calculated by dividing the ClogP of a cyclic peptide by the number of amino acid residues contained in the cyclic peptide. For example, when the ClogP of a cyclic peptide is 14.0 and the number of amino acid residues contained in the cyclic peptide is 7, the ClogP / amino acid residue ratio of the cyclic peptide is calculated to be 2.0.

[0070] The ClogP / number of amino acid residues of a cyclic peptide according to one embodiment of the present invention is preferably 0.3 or more, more preferably 0.5 or more, and most preferably 0.8 or more. The upper limit of the ClogP / number of amino acid residues of a cyclic peptide according to one embodiment of the present invention is preferably 2.3 or less, more preferably 1.9 or less, and most preferably 1.6 or less. Examples of ranges of the ClogP / number of amino acid residues of a cyclic peptide according to one embodiment of the present invention include 0.3 to 2.3, 0.4 to 2.3, 0.5 to 1.9, 0.7 to 1.8, and 0.8 to 1.6. The ClogP / number of amino acid residues of a cyclic peptide according to one embodiment may be 0.8 to 1.6.

[0071] The solubility of a cyclic peptide according to one embodiment of the present invention in 50 mM phosphate buffer (pH 6.5) can be measured by a common method. For example, 50 mM phosphate buffer (PPB, pH 6.5) is added to a lyophilized compound powder, followed by shaking (1800 rpm, 22 to 24 hours), filtration, and the compound concentration of the filtrate is measured by LC / MS / MS. The solubility (μg / mL) can be calculated from the measured compound concentration. Note that "solubility" refers to the solubility under conditions of 25°C and 1 atmosphere. The solubility of the cyclic peptide according to one embodiment of the present invention in 50 mM phosphate buffer (pH 6.5) may be 1200 mg / mL or less, 800 mg / mL or less, 600 mg / mL or less, 300 mg / mL or less, 200 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, 25 mg / mL or less, 10 mg / mL or less, 5.0 mg / mL or less, or 2.6 mg / mL or less, and may be 0.8 mg / mL or more, 0.9 mg / mL or more, 1.0 mg / mL or more, or 1.1 mg / mL or more. The solubility of the cyclic peptide according to one embodiment in 50 mM phosphate buffer (pH 6.5) may be 0.8 mg / mL or more, and in another embodiment, 1.1 mg / mL or more.

[0072] A specific example of a cyclic peptide having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) according to one embodiment of the present invention is cyclosporin A.

[0073] A crystal of a cyclic peptide according to one embodiment of the present invention may have one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. A crystal of a cyclic peptide according to another embodiment of the present invention may have two or more diffraction peaks in powder X-ray diffraction using CuKα radiation. A crystal of a cyclic peptide according to another embodiment of the present invention may have three or more diffraction peaks in powder X-ray diffraction using CuKα radiation. Powder X-ray diffraction using CuKα radiation can be measured, for example, under the following conditions. Specific examples include a powder X-ray diffractometer such as a D8 Discover or a 2D VÅNTEC-500 solid state detector (manufactured by Bruker) using CuKα as the radiation source, with a tube voltage / current of 40 kV / 40 mA or 50 kV / 1000 μA, a measurement range of 5 to 31°, and an exposure time of 40 to 600 seconds.

[0074] The crystal of the cyclic peptide according to one embodiment of the present invention may be a crystal having one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or having polarized light when observed using a polarizing microscope.

[0075] The cyclic peptide according to one embodiment of the present invention may be a cyclic peptide other than cyclosporin A, and another embodiment of the cyclic peptide is (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0]１２，１５ ]nonatriacontane-33,1′-cyclopentane]-27-carboxamide, and another embodiment of the cyclic peptide is cyclosporin A and (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl] -10-Ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0 １２，１５ ]nonatriacontane-33,1'-cyclopentane]-27-carboxamide. Another embodiment of the cyclic peptide of the present invention is (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.0.0.0] １２，１５ ]nonatriacontane-33,1'-cyclopentane]-27-carboxamide.

[0076] As used herein, "amide solvent" refers to a solvent containing an amide bond in the molecule. Examples of "amide solvents" or "amide solvents having a molecular weight of 18 to 170" include formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone. In one embodiment of the present invention, the "amide solvent" or "amide solvents having a molecular weight of 18 to 170" may be one or more solvents selected from the group consisting of formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone, and is preferably formamide, N-methylformamide, N,N-dimethylformamide, 2-pyrrolidone, or N-methylpyrrolidone, more preferably formamide or N,N-dimethylformamide, and most preferably formamide.

[0077] As used herein, "sulfoxide solvent" refers to a solvent that falls under the category of sulfoxide. Examples of "sulfoxide solvent" or "sulfoxide solvent having a molecular weight of 18 to 170" as used herein include dimethyl sulfoxide, phenylmethyl sulfoxide, and diethyl sulfoxide. In one embodiment of the present invention, the "sulfoxide solvent" or "sulfoxide solvent having a molecular weight of 18 to 170" may be one or more solvents selected from the group consisting of dimethyl sulfoxide and diethyl sulfoxide, and is preferably dimethyl sulfoxide, phenylmethyl sulfoxide, or diethyl sulfoxide, more preferably dimethyl sulfoxide or diethyl sulfoxide, and most preferably dimethyl sulfoxide.

[0078] As used herein, the term "hydrocarbon solvent" refers to a solvent consisting only of carbon and hydrogen atoms.

[0079] As used herein, "aromatic hydrocarbon solvent" refers to a hydrocarbon solvent having one or more aromatic rings in the molecule. As used herein, "aromatic hydrocarbon solvent" is preferably a solvent having one or more benzene rings in the molecule, more preferably a solvent having one benzene ring in the molecule. As used herein, "aromatic hydrocarbon solvent" or "aromatic hydrocarbon solvent having a molecular weight of 18 or more and 170 or less" includes, for example, benzene, toluene, xylene, ethylbenzene, tetralin, and cumene. In one embodiment of the present invention, the "aromatic hydrocarbon solvent" or "aromatic hydrocarbon solvent having a molecular weight of 170 or less" may be one or more selected from the group consisting of benzene, toluene, xylene, ethylbenzene, tetralin, and cumene, preferably one or more selected from the group consisting of toluene, xylene, ethylbenzene, tetralin, and cumene, more preferably toluene, xylene, tetralin, or cumene, and most preferably toluene, tetralin, or cumene.

[0080] As used herein, a "halogenated solvent" refers to a solvent having one or more halogen atoms in the molecule. A "halogenated solvent" as used herein is preferably a solvent having one or more chlorine atoms and / or bromine atoms in the molecule, and more preferably a solvent having one or more chlorine atoms in the molecule. Examples of a "halogenated solvent" or a "halogenated solvent having a molecular weight of 18 or more and 170 or less" as used herein include dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride. In one embodiment of the present invention, the "halogenated solvent" or "halogenated solvent having a molecular weight of 170 or less" may be one or more selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride, preferably one or more selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, more preferably dichloromethane, chloroform, 1,2-dichloroethane, or chlorobenzene, and most preferably dichloromethane or chlorobenzene.

[0081] As used herein, "alcohol-based solvent" refers to a solvent having one or more hydroxyl groups bonded to a carbon atom in the molecule. Examples of "alcohol-based solvents" or "alcohol-based solvents having a molecular weight of 18 to 170" include methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and benzyl alcohol. In one embodiment of the present invention, the "alcohol-based solvent" or "alcohol-based solvent having a molecular weight of 18 or more and 170 or less" may be one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and benzyl alcohol, preferably one or more selected from the group consisting of methanol, ethanol, 1-propanol, isopropanol, and n-butanol, more preferably methanol, ethanol, 1-propanol, isopropanol, or n-butanol, and most preferably ethanol.

[0082] As used herein, the term "ether solvent" refers to a solvent having one or more ether bonds in the molecule. Examples of the "ether solvent" or "ether solvent having a molecular weight of 18 to 170" include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, anisole, and t-butyl methyl ether. In one embodiment of the present invention, the "ether-based solvent" or "ether-based solvent having a molecular weight of 18 or more and 170 or less" may be one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, anisole, and t-butyl methyl ether, preferably one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane, diisopropyl ether, anisole, and t-butyl methyl ether, more preferably tetrahydrofuran, 1,4-dioxane, diisopropyl ether, anisole, or t-butyl methyl ether, and most preferably 1,4-dioxane, anisole, or t-butyl methyl ether.

[0083] As used herein, "ester solvent" refers to a solvent having one or more ester bonds in the molecule. Examples of "ester solvents" or "ester solvents having a molecular weight of 18 to 170" as used herein include ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone. In one embodiment of the present invention, the "ester solvent" or "ester solvents having a molecular weight of 18 to 170" may be one or more solvents selected from the group consisting of ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone, preferably one or more solvents selected from the group consisting of ethyl acetate, isopropyl acetate, and n-butyl acetate, more preferably ethyl acetate, isopropyl acetate, or n-butyl acetate, and most preferably ethyl acetate or n-butyl acetate.

[0084] As used herein, "nitrile solvent" refers to a solvent having one or more cyano groups bonded to a carbon atom in the molecule. Examples of "nitrile solvent" or "nitrile solvent having a molecular weight of 18 to 170" as used herein include acetonitrile, benzonitrile, and propionitrile. In one embodiment of the present invention, the "nitrile solvent" or "nitrile solvent having a molecular weight of 18 to 170" may be one or more solvents selected from the group consisting of acetonitrile and propionitrile, preferably one or more solvents selected from the group consisting of acetonitrile, benzonitrile, and propionitrile, more preferably acetonitrile, benzonitrile, or propionitrile, and most preferably acetonitrile.

[0085] The term "ketone solvent" as used herein refers to a ketone solvent represented by R １ -C(=O)-R ２ A solvent represented by R １ and R ２ are each independently an alkyl group, an aryl group, or a heteroaryl group, or R １ and R２ means a solvent in which the groups taken together form an alkylene group. Examples of "ketone solvents" or "ketone solvents having a molecular weight of 18 or more and 170 or less" in this specification include acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, cyclohexanone, diethyl ketone, cyclopentanone, and 3-acetylpyridine. In one embodiment of the present invention, the "ketone solvent" or "ketone solvents having a molecular weight of 18 or more and 170 or less" may be one or more solvents selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, cyclohexanone, diethyl ketone, cyclopentanone, and 3-acetylpyridine, preferably one or more solvents selected from the group consisting of acetone, methyl ethyl ketone, cyclohexanone, methyl isobutyl ketone, and 3-acetylpyridine, more preferably acetone, methyl ethyl ketone, cyclohexanone, or methyl isobutyl ketone, and most preferably acetone or methyl ethyl ketone.

[0086] As used herein, "aliphatic hydrocarbon solvent" refers to a hydrocarbon solvent that does not have an aromatic ring in the molecule. Examples of "aliphatic hydrocarbon solvents" or "aliphatic hydrocarbon solvents having a molecular weight of 18 to 170" as used herein include n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane. In one embodiment of the present invention, the "aliphatic hydrocarbon solvent" or "aliphatic hydrocarbon solvents having a molecular weight of 18 to 170" may be one or more solvents selected from the group consisting of n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane, preferably one or more solvents selected from the group consisting of n-heptane, cyclohexane, and methylcyclohexane, more preferably n-heptane, cyclohexane, or methylcyclohexane, and most preferably n-heptane or cyclohexane.

[0087] As used herein, the term "water-soluble organic solvent" refers to an organic solvent that is miscible with water in any proportion. Examples of the "water-soluble organic solvent" as used herein include alcohol solvents, amide solvents, nitrile solvents, and sulfoxide solvents. The "water-soluble organic solvent" in one embodiment of the present invention may be an alcohol solvent, an amide solvent, a nitrile solvent, or a sulfoxide solvent, preferably an alcohol solvent or a sulfoxide solvent, more preferably methanol, ethanol, 1-propanol, 2-propanol, or dimethyl sulfoxide, and most preferably ethanol or dimethyl sulfoxide.

[0088] The term "PEG-based solvent" as used herein refers to a solvent selected from the group consisting of R １ (OCHR ３ CH ２ ) n OR ２ n is a natural number of 1 or more, and R １ and R ２ are each independently hydrogen, C １ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ may be substituted with a hydroxyl group; １ ~C １８ C optionally substituted with an alkyl or hydroxyl group １ ~C １８ In one embodiment of the present invention, the "PEG-based solvent" is (i) R １ (OCHR ３ CH ２ ) n OR ２ where n is a natural number of 1 or more and 10 or less, or (ii) R １ (OCHR ３ CH ２ ) n OR ２ and n is an average of 3 to 100, wherein R １ and R ２ are each independently hydrogen, C１ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ may be substituted with a hydroxyl group; １ ~C １８ C optionally substituted with an alkyl or hydroxyl group １ ~C １８ In a preferred embodiment of the present invention, the "PEG-based solvent" is (i) R １ (OCHR ３ CH ２ ) n OR ２ wherein n is a natural number of 1, 2, 3, or 4, or (ii) R １ (OCHR ３ CH ２ ) n OR ２ and n is an average of 3 to 100, wherein R １ is hydrogen or C １ ~C ４ alkyl, and R ２ is hydrogen, C １ ~C ４ Alkyl or —C(═O)R ４ and R ３ is hydrogen or C １ ~C ４ alkyl, and R ４ is C １０ ~C １８ In a more preferred embodiment of the present invention, the "PEG-based solvent" is (i) R １ (OCHR ３ CH ２ ) n OR ２ wherein n is a natural number of 1, 2, 3, or 4; or (ii) R １ (OCHR ３ CH ２ ) n OR ２ and n is an average of 3 to 100, wherein R １ is hydrogen or methyl, and R２ is hydrogen, methyl or —C(═O)R ４ and R ３ is hydrogen or methyl, and R ４ is C １１ ~C １７ In a further preferred embodiment of the present invention, the "PEG-based solvent" may be diglyme, triglyme, tetraglyme, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or a polyethylene glycol mono-fatty acid ester. In an even more preferred embodiment of the present invention, the "PEG-based solvent" may be polyethylene glycol, in which case the number-average molecular weight of the polyethylene glycol may be 150 to 5000, preferably 360 to 440, 540 to 660, 900 to 1100, or 1800 to 2200, and the polyethylene glycol may be PEG400, PEG600, PEG1000, or PEG2000. In another even more preferred embodiment of the present invention, the "PEG-based solvent" may be a polyethylene glycol mono-fatty acid ester, in which case the polyethylene glycol mono-fatty acid ester may be polyethylene glycol monostearate or polyethylene glycol monolaurate. The "PEG-based solvent" in the present invention is preferably diglyme, triglyme, tetraglyme, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or a polyethylene glycol mono-fatty acid ester, more preferably polyethylene glycol or a polyethylene glycol mono-fatty acid ester, and most preferably a polyethylene glycol mono-fatty acid ester.

[0089] One aspect of the present disclosure is a method for producing a crystal of a cyclic peptide, comprising contacting the cyclic peptide with a solvent.

[0090] The solvent in the production method according to one aspect of the present disclosure may be any solvent selected from the group consisting of (1), (2), and (3) below: (1) (i) a solvent having a molecular weight of 18 to 170 or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 to 170; (2) water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent based on the total amount of solvent; (3) (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water;

[0091] The solvent in the production method according to one aspect of the present disclosure may be (i) a solvent having a molecular weight of 18 or more and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or more and 170 or less.

[0092] In the production method according to one aspect of the present disclosure, when the solvent is (i) a solvent having a molecular weight of 18 to 170 or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 to 170, the solvent may be selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogen-based solvent, an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, a ketone solvent, an aliphatic hydrocarbon solvent, ethylene glycol, and water, or may be selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogen-based solvent, an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, and a ketone solvent, preferably a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogen-based solvent, and an ester solvent, more preferably a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, and a halogen-based solvent, and most preferably a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, and an aromatic hydrocarbon solvent.

[0093] In one embodiment, the solvent in the production method according to one aspect of the present disclosure may be solvent (A) having a molecular weight of 18 to 170, or a mixed solvent of solvent (A) having a molecular weight of 18 to 170 and solvent (B) having a molecular weight of 18 to 170, or in another embodiment, solvent (A) or a mixed solvent containing solvent (A) and solvent (B). In these cases, the solvent (A) may be one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and the solvent (B) may be one or more selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water. In these cases, the solvent (A) may be selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and the solvent (B) may be selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water.

[0094] The solvent (A) may be, for example, one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, and ester solvents, or may be one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogenated solvents, or may be one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogenated solvents, or may be an amide solvent, sulfoxide solvent, aromatic hydrocarbon solvent, halogenated solvent, alcohol solvent, ether solvent, ester solvent, nitrile solvent, or ketone solvent. The solvent (A) is preferably one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, and ester solvents, more preferably an amide solvent, sulfoxide solvent, aromatic hydrocarbon solvent, or halogenated solvent, and most preferably an amide solvent, sulfoxide solvent, or aromatic hydrocarbon solvent.

[0095] The solvent (B) may be, for example, one or more solvents selected from the group consisting of an aliphatic hydrocarbon solvent, ethylene glycol, and water, or may be an aliphatic hydrocarbon solvent, ethylene glycol, or water. The solvent (B) is preferably one or more solvents selected from the group consisting of an aliphatic hydrocarbon solvent, ethylene glycol, and water, more preferably an aliphatic hydrocarbon solvent, ethylene glycol, or water, and most preferably n-heptane, cyclohexane, or water.

[0096] The volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent according to the production method of one aspect of the present disclosure may be 1:0 to 1:40, 1:0 to 1:30, 1:0 to 1:20, 1:0 to 1:10, 1:0 to 1:7, or 1:0 to 1:5, or 1:0 to 1:4, or 10:1 to 1:40, 5:1 to 1:30, 3:1 to 1:20, 2:1 to 1:10, 1:1 to 1:7, or 1:2 to 1:5, or 1:2 to 1:4. The volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is preferably 1:0 to 1:4, more preferably 1:1 to 1:4, and most preferably 1:2 to 1:4.

[0097] The solvent (A) in the solvent according to the production method of one aspect of the present disclosure may be a solvent having a molecular weight of 18 to 170, and may be a solvent having a molecular weight of 18 to 160, 18 to 150, 18 to 140, or 32 to 135. The solvent (A) preferably has a molecular weight of 18 to 150, more preferably 18 to 140, and most preferably 32 to 135.

[0098] The solvent (B) in the solvent according to the production method of one aspect of the present disclosure may be a solvent having a molecular weight of 18 to 170, and may be a solvent having a molecular weight of 18 to 160, 18 to 135, 18 to 120, or 18 to 105. The solvent (B) preferably has a molecular weight of 18 to 135, more preferably 18 to 120, and most preferably 18 to 105.

[0099] The melting points of the solvent (A) and the solvent (B) in the solvent according to the production method of one aspect of the present disclosure may be 25° C. or lower.

[0100] The solvent in the production method according to one aspect of the present disclosure may be water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent, based on the total amount of the solvent.

[0101] When the solvent in the production method of one aspect of the present disclosure is water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent based on the total amount of the solvent, in one embodiment, the surfactant may be one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants, and in another embodiment, may be one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosinate salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkylphosphates, N-alkyl β-aminopropionic acids, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, The fatty acid ester may be one or more selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. In yet another embodiment, the fatty acid ester may be one or more selected from the group consisting of alkyl sulfates, alkylaryl polyoxyethylene ethers, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. Preferably, the fatty acid ester is an alkyl sulfate, alkylaryl polyoxyethylene ether, polyoxyethylene glycerin fatty acid ester, or polyoxyethylene sorbitan fatty acid ester. More preferably, the fatty acid ester is sodium lauryl sulfate, 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol (Triton X-100 (registered trademark), Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), or polyoxyethylene sorbitan monolaurate (Tween (registered trademark)), and most preferably Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)).

[0102] When the solvent in the production method of one aspect of the present disclosure is water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent based on the total amount of the solvent, the surfactant may be an ionic surfactant or a nonionic surfactant in one embodiment, an ionic surfactant in another embodiment, or a nonionic surfactant in yet another embodiment.

[0103] The ionic surfactant in one embodiment of the present invention may be one or more selected from the group consisting of cationic surfactants, anionic surfactants, and amphoteric surfactants. In another embodiment, the ionic surfactant may be one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosinate salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl β-aminopropionic acids, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, and lecithins. Preferably, the ionic surfactant is an alkyl sulfate, more preferably lauryl sulfate, and most preferably sodium lauryl sulfate.

[0104] In one embodiment of the present invention, the nonionic surfactant may be one or more selected from the group consisting of alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters, preferably one or more selected from the group consisting of alkylaryl polyoxyethylene ethers, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters, more preferably one or more selected from the group consisting of 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol (Triton X-100 (registered trademark)), Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), and polyoxyethylene sorbitan monolaurate (Tween (registered trademark)), and most preferably Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL®).

[0105] In one embodiment, when the solvent in the production method of one aspect of the present disclosure is water containing 0.01 to 30 wt / v % of a surfactant and 5 to 50 v / v % of a water-soluble organic solvent based on the total amount of the solvent, the content of the surfactant is 0.02 to 20 wt / v %, 0.05 to 15 wt / v %, 0.1 to 10 wt / v %, 0.12 to 8 wt / v %, 0.15 to 5 wt / v %, or 0.18 to 3 wt / v %, based on the total amount of the solvent, and the content of the water-soluble organic solvent is 5 to 40 v / v %, 5 to 30 v / v %, 5 to 25 v / v %, 8 to 20 v / v %, or 10 to 15 v / v %, based on the total amount of the solvent. / v%, preferably, the content of the surfactant is 0.01 to 30 wt / v% based on the total amount of solvent, and the content of the water-soluble organic solvent is 5 to 40 v / v% based on the total amount of solvent; more preferably, the content of the surfactant is 0.05 to 15 wt / v% based on the total amount of solvent, and the content of the water-soluble organic solvent is 5 to 30 v / v% based on the total amount of solvent; and most preferably, the content of the surfactant is 0.1 to 10 wt / v% based on the total amount of solvent, and the content of the water-soluble organic solvent is 5 to 25 v / v% based on the total amount of solvent.

[0106] The solvent in the production method according to one aspect of the present disclosure may be (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water.

[0107] The solvent in the manufacturing method of one aspect of the present disclosure may be a PEG-based solvent.

[0108] The solvent in the production method according to one aspect of the present disclosure may be a mixed solvent of a PEG-based solvent and one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water.

[0109] In one embodiment of the present invention, the "one or more selected from the group consisting of alcoholic solvents, aliphatic hydrocarbon solvents, and water" may be, for example, one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water, and preferably methanol. The alcohol is preferably one or more selected from the group consisting of ethanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water, more preferably one or more selected from the group consisting of 2-propanol, n-heptane, and water, and most preferably 2-propanol, n-heptane, or water.

[0110] The production method according to one aspect of the present disclosure can be carried out, for example, by the following method: Crystals of the cyclic peptide can be produced by dissolving the cyclic peptide in a solvent and contacting the solvent with shaking and stirring under a predetermined temperature condition for a predetermined time.

[0111] In the step of contacting a cyclic peptide with a solvent included in the manufacturing method of one aspect of the present disclosure, the concentration of the cyclic peptide may be 1 mg to 2000 mg / mL, or may be 5 mg to 1500 mg / mL, 10 mg to 1000 mg / mL, 10 mg to 500 mg / mL, 10 mg to 100 mg / mL, 10 mg to 50 mg / mL, 100 mg to 400 mg / mL, 100 mg to 200 mg / mL, or 500 mg to 1000 mg / mL.

[0112] The cyclic peptide used in the step of contacting the cyclic peptide with a solvent included in the manufacturing method of one aspect of the present disclosure may be a freeze-dried product, for example, a product freeze-dried from a dimethyl sulfoxide solution.

[0113] The amount of cyclic peptide used in the step of contacting the cyclic peptide with a solvent included in the production method of one aspect of the present disclosure may be 0.5 mg to 200 kg in one embodiment, 1 mg to 1 g in another embodiment, or 0 g to 200 kg, 100 g to 100 kg, 0.5 mg to 10 g, 1 mg to 1 g, 1 mg to 100 mg, 1 mg to 10 mg, or 1 mg to 5 mg in yet another embodiment.

[0114] In one embodiment of the production method of this aspect of the disclosure, the step of contacting the cyclic peptide with a solvent does not include adding a seed crystal. In another embodiment, the step of contacting the cyclic peptide with a solvent includes adding a seed crystal. The seed crystal may be a crystal of a cyclic peptide produced by the production method of this aspect of the disclosure, or may be a crystal of a cyclic peptide produced by another method.

[0115] In one embodiment of the manufacturing method of one aspect of the present disclosure, a filtration step is further included after the step of contacting the cyclic peptide with a solvent. The filtration step is a step of filtering the solvent containing the cyclic peptide crystals and collecting the crystals by solid-liquid separation. The filtration step can be carried out, for example, by filtering the solvent containing the cyclic peptide crystals through filter paper or the like and collecting the cyclic peptide crystals by filtration.

[0116] In one embodiment, the step of contacting the cyclic peptide with a solvent according to the production method of one aspect of the present disclosure may be carried out at a temperature of -10°C to 120°C for 30 minutes to 12 weeks, and in a preferred embodiment, at a constant temperature of 20°C to 90°C for 12 hours to 7 days. In one embodiment, the step of contacting the cyclic peptide with a solvent according to the production method of one aspect of the present disclosure is carried out at a constant temperature of 0°C to 110°C, 10°C to 100°C, 15°C to 90°C, or 20°C to 80°C, or may be carried out by repeatedly heating and cooling 10 or more, 20 or more, or 30 or more, and 1000 or less, 500 or less, or 100 or less times between a lower limit temperature of 10°C, 20°C, 30°C, 40°C, 45°C, 50°C, or 55°C and an upper limit temperature of 100°C, 90°C, 85°C, 80°C, 75°C, 70°C, or 60°C, for 1 hour to 6 weeks, 2 hours to 4 weeks, 4 hours to 2 weeks, or 6 hours to 7 days; in a preferred embodiment, the step of repeatedly heating and cooling 30 or more, and 100 or less times between a lower limit temperature of 50°C and an upper limit temperature of 90°C, for 12 hours to 7 days.

[0117] The fact that cyclic peptide crystals have been produced by the production method of one aspect of the present disclosure can be confirmed, for example, by the presence of a diffraction peak in powder X-ray diffraction using CuKα radiation and by observing the polarized light and external shape using a polarizing microscope.

[0118] Another aspect of the present disclosure is a method for screening cyclic peptide crystals, comprising the following steps (a) and (b): (a) producing cyclic peptide crystals by the method for producing cyclic peptide crystals according to one aspect of the present disclosure; and (b) analyzing the crystals by powder X-ray crystal diffraction. In this case, the crystals to be screened may, in one embodiment, include crystals produced using a solvent containing formamide, in a preferred embodiment, include crystals produced using a solvent containing formamide and a solvent containing dimethyl sulfoxide, and in a more preferred embodiment, include crystals produced using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane. In this case, the crystals to be screened may, in one embodiment, include crystals produced using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), in another embodiment, include crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester, and in yet another embodiment, include crystals produced using a solvent containing polyethylene glycol. In a preferred embodiment, they may include crystals produced using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol. In another preferred embodiment, they may include crystals produced using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol. EL (registered trademark), crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester, and crystals produced using a solvent containing formamide.

[0119] Another aspect of the present disclosure is a method for screening methods for crystallizing a cyclic peptide, comprising the following steps (a) and (b): (a) producing cyclic peptide crystals by the method for producing cyclic peptide crystals according to one aspect of the present disclosure; and (b) analyzing the crystals by powder X-ray crystal diffraction. In this case, the crystallization methods to be screened may, in one embodiment, include a crystallization method using a solvent containing formamide, in a preferred embodiment, a crystallization method using a solvent containing formamide and a solvent containing dimethyl sulfoxide, and in a more preferred embodiment, a crystallization method using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane. In this case, the crystallization method to be screened may, in one embodiment, include a crystallization method using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), in another embodiment, include a crystallization method using a solvent containing polyethylene glycol mono-fatty acid ester, and in yet another embodiment, include a crystallization method using a solvent containing polyethylene glycol, and in one preferred embodiment, include a crystallization method using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol, and in another preferred embodiment, include a crystallization method using a solvent containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing formamide.

[0120] In the step of contacting a cyclic peptide with a solvent included in the method for screening a crystallization method for a cyclic peptide, the amount of cyclic peptide used per condition may be 0.5 mg to 10 mg.

[0121] The number of crystals or crystallization methods to be screened in the above-mentioned method for screening crystallization methods for cyclic peptides may be 2 or more, 5 or more, 10 or more, 15 or more, or 20 or more.

[0122] In one embodiment, the step of contacting a cyclic peptide with a solvent, which is included in the method for screening a crystallization method for a cyclic peptide, may not include adding seed crystals.

[0123] Another aspect of the present disclosure is a method for increasing the probability of producing cyclic peptide crystals, the method comprising a step of producing cyclic peptide crystals using a method for producing cyclic peptide crystals according to one aspect of the present disclosure.

[0124] Another aspect of the present disclosure is the use of a solvent in producing crystals of a cyclic peptide. In one embodiment, the solvent may be selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogenated solvents, polyoxyethylene glycerin fatty acid esters, and polyethylene glycol mono-fatty acid esters. In another embodiment, the solvent may be an amide solvent, and in a preferred embodiment, the solvent may be formamide. In another embodiment, the solvent may be a sulfoxide solvent, and in a preferred embodiment, the solvent may be dimethyl sulfoxide. In another embodiment, the solvent may be an aromatic hydrocarbon solvent, and in a preferred embodiment, the solvent may be toluene, tetralin, or cumene. In another preferred embodiment, the solvent may be Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL®), and in yet another preferred embodiment, the solvent may be polyethylene glycol mono-fatty acid esters, and in yet another preferred embodiment, the solvent may be polyethylene glycol.

[0125] Another aspect of the present disclosure is a screening kit for producing cyclic peptide crystals, which produces cyclic peptide crystals by using a solvent for producing cyclic peptide crystals according to one aspect of the present disclosure.

[0126] Another aspect of the present disclosure is a method for purifying a cyclic peptide, the method comprising the steps of producing crystals of a cyclic peptide by a method for producing crystals of a cyclic peptide according to one aspect of the present disclosure, and collecting the crystals by solid-liquid separation. The step of collecting the crystals by solid-liquid separation may be, for example, a filtration step.

[0127] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of the cyclic peptide containing formamide. In one embodiment, the production method may be a method for producing a crystal of the cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of the cyclic peptide according to one aspect of the present disclosure may be a crystal of a formamide solvate of the cyclic peptide.

[0128] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of the cyclic peptide containing dimethyl sulfoxide. In one embodiment, the production method may be a method for producing a crystal of the cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of the cyclic peptide according to one aspect of the present disclosure may be a crystal of a dimethyl sulfoxide solvate of the cyclic peptide.

[0129] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of the cyclic peptide containing an aromatic hydrocarbon solvent. In one embodiment, the production method may be a method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure may be a crystal of an aromatic hydrocarbon solvate of the cyclic peptide.

[0130] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of a cyclic peptide containing toluene, tetralin, or cumene. In one embodiment, the production method may be a method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure may be a crystal of a toluene solvate, tetralin solvate, or cumene solvate of the cyclic peptide.

[0131] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of a cyclic peptide containing Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)). In one embodiment, the production method may be a method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure may be a hydrate of the cyclic peptide, or may be a crystal of a Polyoxyl 35 Hydrogenated Castor Oil (Cremophor EL (registered trademark)) solvate of the cyclic peptide.

[0132] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of a cyclic peptide containing a polyethylene glycol mono-fatty acid ester. In one embodiment, the production method may be a method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of a cyclic peptide according to one aspect of the present disclosure may be a hydrate of the cyclic peptide, or a crystal of a polyethylene glycol mono-fatty acid ester solvate of the cyclic peptide.

[0133] Another aspect of the present disclosure is a method for producing a cyclic peptide, comprising the step of producing a crystal of the cyclic peptide containing polyethylene glycol. In one embodiment, the production method may be a method for producing a crystal of the cyclic peptide according to one aspect of the present disclosure. That is, the crystal produced by the method for producing a crystal of the cyclic peptide according to one aspect of the present disclosure may be a hydrate of the cyclic peptide, or a crystal of a polyethylene glycol solvate of the cyclic peptide.

[0134] The present invention is further illustrated, but not limited, by the following examples. Unless otherwise noted, starting materials, starting materials, solvents, and reagents were obtained from commercial suppliers or synthesized using known methods.

[0135] [Example 1] Synthesis of cyclic peptides The cyclic peptides CP01 to CP08 shown in Table 1 (also simply referred to as compounds CP01 to CP08) were synthesized by a method similar to that described in WO 2013 / 100132, WO 2018 / 225864, or WO 2021 / 90855, and the final product was obtained as a dried product. Specifically, compound 2118 in WO 2021 / 90855 corresponds to compound CP01, compound 1787 corresponds to compound CP02, compound 926 corresponds to compound CP03, compound 1147 corresponds to compound CP04, compound 1217 corresponds to compound CP05, compound 1201 corresponds to compound CP06, compound 301 corresponds to compound CP07, and compound 640 corresponds to compound CP08. Table 1 shows the structural formulas of compounds CP01 to CP08.

[0136]

[0137] The molecular weights of compounds CP01 to CP08 are as follows: Compound CP01: 1443.8 Compound CP02: 1454.2 Compound CP03: 1456.2 Compound CP04: 1478.2 Compound CP05: 1437.7 Compound CP06: 1459.7 Compound CP07: 1451.1 Compound CP08: 1463.1

[0138] The IUPAC names of compounds CP01 to CP08 are as follows: Compound CP01: (3S,9S,18S,21S,25S,28S,34S,36R)-9-(cyclohexylmethyl)-36-ethoxy-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1'-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecaone Compound CP02: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-23-isobutyl-7,10,17,18,24,28,31-heptamethyl-20-[(1S)-1-methylpropyl]-27-(piperidine-1-carbonyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecaone Compound CP03: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-23-isobutyl-7,10,17,18,24,28,31-heptamethyl-20-[(1S)-1-methylpropyl]-27-(morpholine-4-carbonyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[3.0].Compound CP01: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-30-cyclopentyl-10-ethyl-23-isobutyl-7,17,18,24,28,31-hexamethyl-20-[(1S)-1-methylpropyl]- 27-(morpholine-4-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecaone Compound CP05: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1S)-1-methyl [p-tolylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-27-carboxamide Compound CP06: (3S,9S,12S,17S,20S,23S,27S,30S,36S,38R)-9-(cyclohexylmethyl)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-38-ethoxy-23-isobutyl-N,N,7,10,17,18,24,28,31-nonamethyl-20-[(1S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[3.0].012,15]nonatriacontane-33,1'-cyclopentane]-27-carboxamide Compound CP07: (3S,9S,12S,17S,20S,23S,27R,30S,36S,38R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-38-ethoxy-23-isobutyl-7,10,17,18,24,27,28,31-octamethyl-20,30-bis[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecaone Compound CP08: (3S,9S,12S,17S,20S,23S,27R,30S,36S,38R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-30-cyclopentyl-38-ethoxy-23-isobutyl-7,10,17,18,24,27,28,31-octamethyl-20-[(1S)-1-methyl [[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecaone.

[0139] Example 2: Production of cyclic peptide crystals using a solvent with a molecular weight of 18 to 170, or a mixed solvent of two or more thereof. Crystals of a cyclic peptide were produced by a method including a step of contacting with (i) a solvent with a molecular weight of 18 to 170, or (ii) a mixed solvent containing two or more solvents with a molecular weight of 18 to 170. Note that no seed crystals were used in the step of contacting with the solvent in the following production. In the following examples, % (percent) represents % by volume (v / v%).

[0140] (Example 2-1-1) Compound CP01 (136.7 mg) was dissolved in dimethyl sulfoxide (0.684 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A water / isopropanol mixture (water ratio 75%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 5 days to obtain crystals of compound CP01.

[0141] (Example 2-1-2) Compound CP01 (72.5 mg) was dissolved in dimethyl sulfoxide (0.363 mL), and this solution (0.015 mL) was freeze-dried for 3 days at −20° C. A dichloromethane / n-heptane mixture (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP01.

[0142] (Example 2-2-1) Compound CP02 (149.2 mg) was dissolved in dimethyl sulfoxide (0.746 mL), and this solution (0.015 mL) was freeze-dried for 3 days at −20° C. Formamide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP02.

[0143] (Example 2-2-2) Compound CP02 (72.4 mg) was dissolved in dimethyl sulfoxide (0.362 mL), and this solution (0.015 mL) was freeze-dried for 3 days at −20° C. A formamide / n-heptane mixture (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP02.

[0144] (Example 2-2-3) Compound CP02 (72.4 mg) was dissolved in dimethyl sulfoxide (0.362 mL), and this solution (0.015 mL) was freeze-dried for 3 days at −20° C. A dimethyl sulfoxide / t-butyl methyl ether mixture (t-butyl methyl ether ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP02.

[0145] (Example 2-3-1) Compound CP03 (147.4 mg) was dissolved in dimethyl sulfoxide (0.737 mL), and this solution (0.015 mL) was freeze-dried for 3 days at −20° C. Formamide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP03.

[0146] (Example 2-4-1) Compound CP04 (120.2 mg) was dissolved in dimethyl sulfoxide (0.601 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. To the resulting freeze-dried product, t-butyl methyl ether (0.015 mL) was added, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP04.

[0147] (Example 2-4-2) Compound CP04 (120.2 mg) was dissolved in dimethyl sulfoxide (0.601 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Toluene (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain a solid of compound CP04. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0148] (Example 2-4-3) Compound CP04 (120.2 mg) was dissolved in dimethyl sulfoxide (0.601 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. n-Butyl acetate (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days, after which n-heptane (0.015 mL) was added. The mixture was shaken and stirred at room temperature for 4 days to obtain a solid of compound CP04. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0149] (Example 2-4-4) Compound CP04 (120.2 mg) was dissolved in dimethyl sulfoxide (0.601 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Cumene (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain a solid of compound CP04. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0150] (Example 2-4-5) Compound CP04 (50.3 mg) was dissolved in dimethyl sulfoxide (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. An ethyl acetate / cyclohexane mixture (80% cyclohexane, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP04. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0151] (Example 2-4-6) Compound CP04 (50.3 mg) was dissolved in dimethyl sulfoxide (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. A mixed solution of n-butyl acetate / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP04. The resulting solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0152] (Example 2-5-1) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Toluene (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0153] (Example 2-5-2) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Dimethyl sulfoxide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0154] (Example 2-5-3) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. An ethanol / water mixture (75% water ratio, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0155] (Example 2-5-4) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of acetonitrile / water (water ratio 75%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0156] (Example 2-5-5) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Cumene (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0157] (Example 2-5-6) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Tetralin (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0158] (Example 2-5-7) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Formamide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP05.

[0159] (Example 2-5-8) Compound CP05 (122.3 mg) was dissolved in dimethyl sulfoxide (0.612 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Diisopropyl ether (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP05.

[0160] (Example 2-5-9) Compound CP05 (148.8 mg) was dissolved in dimethyl sulfoxide (0.744 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 3 days. A 3-acetylpyridine / ethylene glycol mixture (3-acetylpyridine ratio 50% by volume, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was stirred with shaking at room temperature for 11 days. Approximately 10 zirconia beads with a diameter of 1 mm were then added, and the mixture was stirred with shaking for 2 days. The mixture was allowed to stand for 5 days, and then shaken for an additional 3 days to obtain crystals of compound CP05.

[0161] (Example 2-6-1) Compound CP06 (122.1 mg) was dissolved in dimethyl sulfoxide (0.611 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Formamide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 3 days to obtain crystals of compound CP06.

[0162] (Example 2-7-1) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Acetonitrile (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP07.

[0163] (Example 2-7-2) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Ethyl acetate (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP07. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0164] (Example 2-7-3) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Acetone (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP07.

[0165] (Example 2-7-4) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Propyl acetate (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP07.

[0166] (Example 2-7-5) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. n-Butyl acetate (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP07. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0167] (Example 2-7-6) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Methyl ethyl ketone (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP07. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0168] (Example 2-7-7) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Methyl isobutyl ketone (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP07. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0169] (Example 2-7-8) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. To the resulting freeze-dried product, t-butyl methyl ether (0.015 mL) was added, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP07.

[0170] (Example 2-7-9) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Dimethyl sulfoxide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP07.

[0171] (Example 2-7-10) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A water / acetonitrile mixture (water ratio 75%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP07.

[0172] (Example 2-7-11) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Tetrahydrofuran (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days, after which n-heptane (0.015 mL) was added. The mixture was shaken and stirred at room temperature for 14 days to obtain crystals of compound CP07. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0173] (Example 2-7-12) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at −20° C. for 2 days. 1,4-dioxane (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days, after which n-heptane (0.015 mL) was added. The mixture was shaken and stirred at room temperature for 14 days to obtain crystals of compound CP07.

[0174] (Example 2-7-13) Compound CP07 (75.3 mg) was dissolved in 1,4-dioxane (0.377 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Toluene (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days, after which n-heptane (0.015 mL) was added. The mixture was shaken and stirred at room temperature for 14 days to obtain a solid of compound CP07. The obtained solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0175] (Example 2-7-14) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. An ethanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0176] (Example 2-7-15) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. A 2-propanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0177] (Example 2-7-16) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio: 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. Acetonitrile / t-butyl methyl ether mixed solution (t-butyl methyl ether ratio: 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0178] (Example 2-7-17) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. A n-butanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0179] (Example 2-7-18) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. An anisole / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0180] (Example 2-7-19) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio: 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. A dimethyl sulfoxide / t-butyl methyl ether mixed solution (t-butyl methyl ether ratio: 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0181] (Example 2-7-20) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70° C., and this solution (0.06 mL) was freeze-dried for 3 days at −20° C. Acetonitrile / water mixed solution (water ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP07.

[0182] (Example 2-7-21) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of isopropanol / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0183] (Example 2-7-22) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. A 1,4-dioxane / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP07. The obtained solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0184] (Example 2-7-23) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of ethyl acetate / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0185] (Example 2-7-24) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of acetone / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0186] (Example 2-7-25) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A tetrahydrofuran / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0187] (Example 2-7-26) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A dichloromethane / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0188] (Example 2-7-27) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. An anisole / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0189] (Example 2-7-28) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. An n-butanol / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0190] (Example 2-7-29) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. A toluene / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed to be a needle-shaped crystal with polarized light using a polarizing microscope.

[0191] (Example 2-7-30) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. A propyl acetate / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0192] (Example 2-7-31) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of n-butyl acetate / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0193] (Example 2-7-32) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A methyl ethyl ketone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0194] (Example 2-7-33) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. A methyl isobutyl ketone / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed to be needle-shaped crystals that were polarized using a polarizing microscope.

[0195] (Example 2-7-34) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A chlorobenzene / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP07.

[0196] (Example 2-8-1) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Acetonitrile (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP08.

[0197] (Example 2-8-2) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Ethyl acetate (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0198] (Example 2-8-3) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Acetone (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP08.

[0199] (Example 2-8-4) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Propyl acetate (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0200] (Example 2-8-5) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. n-Butyl acetate (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0201] (Example 2-8-6) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Methyl ethyl ketone (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP08.

[0202] (Example 2-8-7) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Methyl isobutyl ketone (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0203] (Example 2-8-8) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. t-Butyl methyl ether (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized needle-like crystals using a polarizing microscope.

[0204] (Example 2-8-9) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. Toluene (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain a solid of compound CP08. The obtained solid was confirmed to be a plate-like crystal with polarized light using a polarizing microscope.

[0205] (Example 2-8-10) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. Dimethyl sulfoxide (0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days to obtain crystals of compound CP08.

[0206] (Example 2-8-11) Compound CP08 (75.3 mg) was dissolved in 1,4-dioxane (0.376 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. 1,4-dioxane (0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 6 days, after which n-heptane (0.015 mL) was added. The mixture was shaken and stirred at room temperature for 14 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized needle-shaped crystals using a polarizing microscope.

[0207] (Example 2-8-12) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixture (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried at −20° C. for 3 days. An ethanol / n-heptane mixture (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain a solid of compound CP08. The obtained solid was confirmed to be a plate-like crystal with polarized light using a polarizing microscope.

[0208] (Example 2-8-13) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A mixed solution of isopropanol / n-heptane (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0209] (Example 2-8-14) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A mixed solution of ethyl acetate / n-heptane (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0210] (Example 2-8-15) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A mixture of acetone / n-heptane (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0211] (Example 2-8-16) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A tetrahydrofuran / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0212] (Example 2-8-17) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A dichloromethane / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0213] (Example 2-8-18) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixture (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried at −20° C. for 3 days. A formamide / water mixture (water ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain a solid of compound CP08. The obtained solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0214] (Example 2-8-19) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A n-butanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0215] (Example 2-8-20) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A propyl acetate / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0216] (Example 2-8-21) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A n-butyl acetate / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0217] (Example 2-8-22) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A methyl ethyl ketone / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0218] (Example 2-8-23) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A methyl isobutyl ketone / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0219] (Example 2-8-24) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A formamide / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0220] (Example 2-8-25) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A mixed solution of anisole / n-heptane (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0221] (Example 2-8-26) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A 1,4-dioxane / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0222] (Example 2-8-27) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixture (1,4-dioxane ratio: 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried at −20° C. for 3 days. A dimethyl sulfoxide / t-butyl methyl ether mixture (t-butyl methyl ether ratio: 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain a solid of compound CP08. The resulting solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0223] (Example 2-8-28) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. An ethanol / water mixed solution (water ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0224] (Example 2-8-29) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixture (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried at −20° C. for 3 days. An acetonitrile / water mixture (water ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain a solid of compound CP08. The obtained solid was confirmed to be polarized microcrystals using a polarizing microscope.

[0225] (Example 2-8-30) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A chlorobenzene / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0226] (Example 2-8-31) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and this solution (0.03 mL) was freeze-dried for 3 days at −20° C. A mixture of acetone / water (water ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 8 days to obtain crystals of compound CP08.

[0227] (Example 2-8-32) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. An isopropanol / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0228] (Example 2-8-33) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A 1,4-dioxane / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0229] (Example 2-8-34) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of ethyl acetate / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0230] (Example 2-8-35) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of acetone / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0231] (Example 2-8-36) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A tetrahydrofuran / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0232] (Example 2-8-37) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A dichloromethane / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0233] (Example 2-8-38) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. An anisole / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0234] (Example 2-8-39) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A butanol / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0235] (Example 2-8-40) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A toluene / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0236] (Example 2-8-41) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A propyl acetate / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0237] (Example 2-8-42) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A mixed solution of n-butyl acetate / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0238] (Example 2-8-43) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A methyl ethyl ketone / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0239] (Example 2-8-44) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A methyl isobutyl ketone / cyclohexane mixture (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0240] (Example 2-8-45) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and this solution (0.015 mL) was freeze-dried for 2 days at −20° C. A chlorobenzene / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound CP08.

[0241] From the above results, crystals of all eight types of cyclic peptides were obtained under any condition using a solvent with a molecular weight of 18 to 170, or a mixture of two or more of these solvents. Specifically, under conditions using a solvent containing formamide as the solvent, crystals of five types of eight types of cyclic peptides were obtained (Examples). Under conditions using a solvent containing dimethyl sulfoxide as the solvent, crystals of four types of eight types of cyclic peptides were obtained (Examples). Under conditions using a solvent containing aromatic hydrocarbon solvents such as toluene, cumene, or tetralin as the solvent, crystals of four types of eight types of cyclic peptides were obtained (Examples). Under conditions using a solvent containing halogenated solvents such as dichloromethane or chlorobenzene as the solvent, crystals of three types of eight types of cyclic peptides were obtained (Examples). Under conditions using a solvent containing an alcohol-based solvent, crystals of four types of eight types of cyclic peptides were obtained (Examples). Under conditions using a solvent containing an ether-based solvent, crystals of four types of eight types of cyclic peptides were obtained (Examples). Under conditions using a solvent containing an ester-based solvent, crystals of three types of eight types of cyclic peptides were obtained (Examples). Under conditions where a solvent containing a nitrile solvent was used as the solvent, crystals of three types of eight cyclic peptides were obtained (Examples). Under conditions where a solvent containing a ketone solvent was used as the solvent, crystals of two types of eight cyclic peptides were obtained (Examples). As a solvent for crystallizing various cyclic peptides, one or more solvents selected from the group consisting of formamide, dimethyl sulfoxide, aromatic hydrocarbon solvents, and halogenated solvents are preferred, and by using at least one of these solvents, all eight types of cyclic peptides could be crystallized. Solvents containing formamide or dimethyl sulfoxide were more preferred, and solvents containing formamide were the most preferred.

[0242] Example 3: Preparation of cyclic peptide crystals using an aqueous solution containing a surfactant and a water-soluble organic solvent. Crystals of a cyclic peptide were prepared by a method including a step of contacting the crystals with water containing 0.01 to 30 wt / v % of a liquid surfactant and 5 to 50 v / v % of a water-soluble organic solvent, based on the total amount of the solvent. Note that no seed crystals were used in the step of contacting the crystals with the solvent in the following preparation.

[0243] (Example 3-1-1) Compound CP01 (19.7 mg) was dissolved in ethanol (0.197 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range of 50°C to 90°C, to obtain crystals of compound CP01.

[0244] (Example 3-4-1) Compound CP04 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP04.

[0245] (Example 3-5-1) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0246] (Example 3-5-2) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0247] (Example 3-5-3) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0248] (Example 3-5-4) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0249] (Example 3-5-5) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0250] (Example 3-5-6) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0251] (Example 3-5-7) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0252] (Example 3-5-8) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0253] (Example 3-5-9) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range of 50°C to 90°C, to obtain crystals of compound CP05.

[0254] (Example 3-5-10) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range of 50°C to 90°C, to obtain crystals of compound CP05.

[0255] (Example 3-5-11) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0256] (Example 3-5-12) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range of 50°C to 90°C, to obtain crystals of compound CP05.

[0257] (Example 3-5-13) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). A sodium lauryl sulfate / water mixture (sodium lauryl sulfate ratio 1 wt / v%, 0.090 mL) was added to this solution (0.010 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range of 50°C to 90°C, to obtain crystals of compound CP05.

[0258] (Example 3-5-14) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). A sodium lauryl sulfate / water mixture (sodium lauryl sulfate ratio 0.2 wt / v%, 0.090 mL) was added to this solution (0.010 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0259] (Example 3-5-15) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). A sodium lauryl sulfate / water mixture (sodium lauryl sulfate ratio 1 wt / v%, 0.090 mL) was added to this solution (0.010 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP05.

[0260] (Example 3-5-16) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0261] (Example 3-5-17) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0262] (Example 3-5-18) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0263] (Example 3-5-19) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred at 25° C. for 10 hours to obtain crystals of compound CP05.

[0264] (Example 3-5-20) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL), a Tween 80 / water mixture (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) was added, and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0265] (Example 3-5-21) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0266] (Example 3-5-22) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0267] (Example 3-5-23) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0268] (Example 3-5-24) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0269] (Example 3-5-25) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0270] (Example 3-5-26) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0271] (Example 3-5-27) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0272] (Example 3-5-28) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). A sodium lauryl sulfate / water mixture (sodium lauryl sulfate ratio 1 wt / v%, 0.090 mL) was added to this solution (0.010 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0273] (Example 3-5-29) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a sodium lauryl sulfate / water mixture (sodium lauryl sulfate ratio 0.2 wt / v%, 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0274] (Example 3-5-30) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this solution (0.010 mL) was added a sodium lauryl sulfate / water mixture (sodium lauryl sulfate ratio 1 wt / v%, 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP05.

[0275] (Example 3-7-1) Compound CP07 (19.3 mg) was dissolved in dimethyl sulfoxide (0.193 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP07.

[0276] (Example 3-8-1) Compound CP08 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range from 50°C to 90°C, to obtain crystals of compound CP08.

[0277] (Example 3-8-2) Compound CP08 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL). The mixture was stirred for 10 hours while raising and lowering the temperature 36 times within the range of 50°C to 90°C, to obtain crystals of compound CP08.

[0278] (Example 3-8-3) Compound CP08 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Cremophor EL / water mixture (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL), and the mixture was stirred at 25° C. for 10 hours to obtain crystals of compound CP08.

[0279] (Example 3-8-4) Compound CP08 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP08.

[0280] (Example 3-8-5) Compound CP08 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Tween 80 / water mixture (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP08.

[0281] (Example 3-8-6) Compound CP08 (19.5 mg) was dissolved in ethanol (0.195 mL). To this solution (0.010 mL) was added a Triton X-100 / water mixture (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours to obtain crystals of compound CP08.

[0282] From the above results, under conditions using an aqueous solution containing a surfactant and a water-soluble organic solvent, five types of crystals were obtained out of eight types of cyclic peptides. When Cremophor EL was used as the surfactant, four types of crystals were obtained out of eight types of cyclic peptides (Example). When Triton X-100 was used as the surfactant, three types of crystals were obtained out of eight types of cyclic peptides (Example). Conditions for crystallizing various cyclic peptides were preferably those using Cremophor EL, Tween 80, or Triton X-100 as the surfactant, with temperature fluctuating between 50°C and 90°C, and with ethanol as the water-soluble organic solvent. More preferably, Cremophor EL was used as the surfactant. Furthermore, the most preferable results were obtained under conditions using Cremophor EL as the surfactant, temperature fluctuating between 50°C and 90°C, and ethanol as the water-soluble organic solvent.

[0283] Example 4: Preparation of cyclic peptide crystals using a PEG-based solvent or a mixed solvent containing a PEG-based solvent. A cyclic peptide crystal was prepared by a method including a step of contacting (i) a PEG-based solvent, or (ii) one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water with a mixed solvent containing a PEG-based solvent. Note that no seed crystals were used in the solvent contact step in the following preparation. In the following examples, % (percent) represents volume % (v / v%).

[0284] (Example 4-1-1) To compound CP01 (4.8 mg), PEG400 (0.015 mL), isopropanol (0.005 mL), and water (0.005 mL) were added, and the mixture was stirred at 80° C. to dissolve. The next day, the temperature was lowered to room temperature, and the mixture was stirred for another 3 days, whereupon crystals of compound CP01 were precipitated.

[0285] (Example 4-3-1) Polyethylene glycol monolaurate (n = approximately 10) (0.015 mL) was added to compound CP03 (5.8 mg) and dissolved by stirring at 80° C. When this solution was further stirred at 80° C. for one day, crystals of compound CP03 were precipitated.

[0286] (Example 4-4-1) Tetraethylene glycol (0.030 mL) was added to compound CP04 (6.3 mg), and the mixture was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature and further stirred for 1 day to obtain crystals of compound CP04.

[0287] (Example 4-4-2) PEG400 (0.030 mL) was added to compound CP04 (5.5 mg), and the mixture was stirred at 80°C for 40 minutes to obtain crystals of compound CP04.

[0288] (Example 4-4-3) PEG400 (0.020 mL) was added to compound CP04 (5.6 mg) and stirred at 80°C for 30 minutes to obtain crystals of compound CP04.

[0289] (Example 4-4-4) Polyethylene glycol monolaurate (n=approximately 10) (0.020 mL) was added to compound CP04 (5.4 mg), and the mixture was stirred at 80°C for 40 minutes to obtain crystals of compound CP04.

[0290] (Example 4-4-5) Compound CP04 (5.6 mg) was heated to 60°C and melted, and PEG600 (0.020 mL) was added thereto, followed by stirring at 60°C for 10 minutes. The mixture was further stirred at 80°C for 16 hours, and then stirred at room temperature for an additional 3 hours to obtain crystals of compound CP04.

[0291] (Example 4-4-6) Compound CP04 (5.7 mg) was heated to 60°C and melted, and PEG2000 (0.020 mL) was added, followed by stirring at 60°C for 30 minutes. The mixture was heated to 80°C, and PEG2000 (0.080 mL) was added, followed by stirring for 15 hours. After cooling to room temperature, a mixture of compound CP04 crystals and PEG2000 crystals was obtained. Figure 26(D) shows the X-ray diffraction peaks of PEG2000, which have characteristic peaks at 19.2° and 24.4°. Figure 26(C) shows the X-ray diffraction peaks of the resulting mixture, and several diffraction peaks are observed in addition to those at 19.2° and 24.4°. These are the diffraction peaks of CP04 crystals.

[0292] (Example 4-4-7) Compound CP04 (6.1 mg) was heated to 60°C and melted, and polyethylene glycol monostearate (n = approximately 4) (palmitate and stearate mixture) (0.030 mL) was added. The mixture was then stirred at 80°C for 16 hours. Stirring was continued for an additional 3 hours at room temperature to obtain a mixture of crystals of compound CP04 and crystals of polyethylene glycol monostearate (n = approximately 4) (palmitate and stearate mixture). Figure 27(B) shows the X-ray diffraction peaks of polyethylene glycol monostearate (n = approximately 4) (palmitate and stearate mixture), which have characteristic peaks at 21.7° and 24.1°. Figure 27(A) shows the X-ray diffraction peaks of the resulting mixture, and several diffraction peaks are observed in addition to those at 21.7° and 24.1°. These are the diffraction peaks of CP04 crystals.

[0293] (Example 4-4-8) To compound CP04 (5.0 mg), polyethylene glycol monostearate (n = approximately 10) (palmitate and stearate mixture) (0.020 mL) melted by heating to 60°C was added, and the mixture was stirred at 80°C for 16 hours. The mixture was further stirred at room temperature for 3 hours to obtain crystals of compound CP04.

[0294] (Example 4-4-9) Diglyme (0.015 mL) was added to compound CP04 (6.1 mg), and n-heptane (0.015 mL) was further added thereto, followed by stirring at room temperature for 5 days to obtain crystals of compound CP04.

[0295] (Example 4-4-10) Triglyme (0.005 mL) was added to compound CP04 (5.0 mg) and dissolved by stirring at 80° C. When this solution was further stirred at 80° C. for 18 hours, crystals of compound CP04 were precipitated.

[0296] (Example 4-5-1) Compound CP05 (approximately 5 mg) was dissolved in tetraethylene glycol (0.020 mL) with stirring. The solution was heated to 80° C. and stirred for 1 hour, whereupon crystals of compound CP05 were precipitated.

[0297] (Example 4-5-2) PEG400 (0.020 mL) was added to compound CP05 (approximately 5 mg) and dissolved with stirring. This solution was heated to 80°C and stirred for 1 hour, whereupon crystals of compound CP05 were precipitated.

[0298] (Example 4-5-3) Compound CP05 (approximately 5 mg) was dissolved in polypropylene glycol (average molecular weight: 425) (0.020 mL) with stirring. The solution was heated to 80°C and stirred for 1 hour, resulting in the precipitation of crystals of compound CP05.

[0299] (Example 4-5-4) Compound CP05 (approximately 5 mg) was dissolved in polyethylene glycol monolaurate (n = approximately 10) (0.020 mL) by stirring. The solution was heated to 80°C and stirred for 1 hour, whereupon crystals of compound CP05 were precipitated.

[0300] (Example 4-5-5) Triglyme (0.020 mL) was added to compound CP05 (approximately 5 mg) and dissolved with stirring. This solution was heated to 80° C. and stirred for 1 hour, whereupon crystals of compound CP05 were precipitated.

[0301] (Example 4-5-6) Compound CP05 (5.3 mg) was dissolved in a water / ethylene glycol mixed solution (ethylene glycol ratio 80% by volume, 0.015 mL) by stirring at 100° C. This solution was cooled to room temperature and stirred for 3 days, whereupon crystals of compound CP05 were precipitated.

[0302] (Example 4-7-1) Triglyme (0.010 mL) was added to compound CP07 (4.8 mg) and dissolved by stirring at room temperature. When this solution was further stirred at room temperature for 35 minutes, crystals of compound CP07 were precipitated.

[0303] (Example 4-7-2) Compound CP07 (4.6 mg) was dissolved in polyethylene glycol monolaurate (n = approximately 10) (0.015 mL) by stirring at 80° C. This solution was stirred at 80° C. for an additional 18 hours, whereupon crystals of compound CP07 were precipitated.

[0304] (Example 4-7-3) Triglyme (0.010 mL) was added to compound CP07 (4.8 mg), and the mixture was stirred at room temperature for 15 hours, whereupon crystals of compound CP07 were precipitated.

[0305] (Example 4-7-4) PEG400 (0.020 mL) was added to compound CP07 (10.0 mg) and dissolved by stirring at 80° C. When this solution was further stirred at 80° C. for 18 hours, crystals of compound CP07 were precipitated.

[0306] (Example 4-8-1) Triglyme (0.010 mL) was added to compound CP08 (5.0 mg) and stirred at room temperature for 20 minutes, whereupon crystals of compound CP08 were precipitated.

[0307] (Example 4-8-2) PEG400 (0.015 mL) was added to compound CP08 (5.1 mg) and dissolved at 80° C. After stirring at 80° C. for 18 hours, the mixture was returned to room temperature and stirred for another day, whereupon crystals of compound CP08 were precipitated.

[0308] (Example 4-8-3) Polyethylene glycol monolaurate (n = approximately 10) (0.015 mL) was added to compound CP08 (5.3 mg) and dissolved by stirring at 80° C. When this solution was stirred at 80° C. for an additional 10 minutes, crystals of compound CP08 were precipitated.

[0309] (Example 4-8-4) Triglyme (0.010 mL) was added to compound CP08 (5.1 mg) and dissolved by stirring at room temperature. When this solution was further stirred at room temperature for 15 hours, crystals of compound CP08 were precipitated.

[0310] (Example 4-8-5) PEG400 (0.020 mL) was added to compound CP08 (10.1 mg) and dissolved by stirring at 80° C. When this solution was further stirred at 80° C. for 5 hours, crystals of compound CP08 were precipitated.

[0311] From the above results, under the conditions using a PEG-based solvent or a mixed solvent containing a PEG-based solvent, six types of crystals were obtained out of eight types of cyclic peptides. When polyethylene glycol mono-fatty acid ester was used as the PEG-based solvent, five types of crystals were obtained out of eight types of cyclic peptides (Examples). When a solvent containing polyethylene glycol (PEG400, PEG600, PEG2000) was used as the PEG-based solvent, five types of crystals were obtained out of eight types of cyclic peptides (Examples). As conditions for crystallizing various cyclic peptides, conditions using polyethylene glycol mono-fatty acid ester or polyethylene glycol as the PEG-based solvent were preferred. More preferably, polyethylene glycol monolaurate or PEG400 was used as the PEG-based solvent, and the temperature was in the range of room temperature to 80°C. The most preferred results were obtained when polyethylene glycol monolaurate was used as the PEG-based solvent and the temperature was 80°C.

[0312] [Example 5] X-ray diffraction measurement of cyclic peptide crystals (Example 5-1) The crystals obtained in Examples 2, 3, and 4 were each subjected to powder X-ray diffraction measurement using the following measurement method. The results are shown in Figures 1A to 30D. Measurement equipment: D8 Discover, 2D VÅNTEC-500 solid state detector (manufactured by Bruker) Radiation source: CuKα Tube voltage / current: 40 kV / 40 mA or 50 kV / 1000 μA Measurement range: 5 to 31° Exposure time: 40 to 600 seconds

[0313] (Example 5-2) Single crystal X-ray structural analysis was performed on the crystal obtained in Example 2-1-1 using the following measurement method: Measurement device: Rigaku R-AXIS RAPID-II with a VariMax Cu diffractometer (manufactured by Rigaku Corporation) Radiation source: CuKα Tube voltage / current: 40 kV / 30 mA Temperature: -180°C Measurement: Measurement was performed using a strategy and exposure time that was thought to be able to obtain diffraction spots sufficient for structural analysis. Structural analysis: Initial structure determination was performed using a direct method (SHELXD97, CrystalStructure 4.2.2, Rigaku), and structure refinement was performed using the full-matrix least-squares method (SHELXL97, CrystalStructure 4.2.2, Rigaku). All temperature factors were refined as isotropic. The results are shown in Figure 31A.

Claims

1. A method for producing crystals of a cyclic peptide, comprising the step of contacting the cyclic peptide with a solvent, wherein the cyclic peptide has the following characteristics: (I), (II), and (III): (I) Characterized by containing a cyclic region consisting of a total of 8 to 16 amino acid residues, and having a total of 8 to 20 amino acid residues; (II) Characterized by containing at least two N-substituted amino acid residues; (III) The characteristic of having a molecular weight (g / mol) of 1204 or more and 3000 or less; A method for a cyclic peptide having the properties of a cyclic peptide.

2. The method according to claim 1, wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα emission, or has polarization in observation using a polarizing microscope.

3. The method according to claim 1, wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα emission.

4. The solvent is as follows: (1), (2), and (3): (1) (i) a solvent with a molecular weight of 18 to 170 or (ii) a mixed solvent containing two or more solvents with a molecular weight of 18 to 170; (2) Water containing 0.01 to 30 wt / v% surfactant and 5 to 50 v / v% water-soluble organic solvent based on the total amount of solvent; (3) (i) a PEG-based solvent, or (ii) a mixed solvent containing one or more solvents selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents, and water, and a PEG-based solvent; The method according to any one of claims 1 to 3, wherein the solvent is selected from the group consisting of the following.

5. The method according to any one of claims 1 to 3, wherein the solvent is a solvent (A) with a molecular weight of 18 to 170, or a mixed solvent of solvent (A) with a molecular weight of 18 to 170 and solvent (B) with a molecular weight of 18 to 170, wherein solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents and ketone solvents, and solvent (B) is one or more selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol and water.

6. The method according to claim 5, wherein the solvent (A) is formamide.

7. The method according to claim 5, wherein the solvent (B) is one or more solvents selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water.

8. The method according to claim 5, wherein the volume ratio (v / v) of solvent (A) to solvent (B) in the solvent is 1:0 to 1:

40.

9. The method according to claim 5, wherein the melting points of solvent (A) and solvent (B) are 25°C or lower.

10. The method according to any one of claims 1 to 3, wherein the solvent is water containing 0.01 to 30 wt / v% of a surfactant and 5 to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent, and the surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants and nonionic surfactants.

11. The method according to any one of claims 1 to 3, wherein the solvent is water containing 0.01 to 30 wt / v% of a surfactant and 5 to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent, and the surfactant is one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamine, fatty acid salts, rosinates, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkylβ-aminopropionic acid, N-alkyl sulfobetaine, N-alkylhydroxysulfobetaine, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

12. The solvent is (i) a PEG-based solvent, or (ii) a mixed solvent comprising one or more selected from the group consisting of alcohol-based solvents, aliphatic hydrocarbon-based solvents and water, and a PEG-based solvent, wherein the PEG-based solvent is (i) R １ (OCHR ３ CH ２ )nOR ２ a solvent represented by the formula, wherein n is a natural number of 1 to 10, or (ii) R １ (OCHR ３ CH ２ )nOR ２ a mixture of solvents represented by the formula, wherein the average of n is 3 to 100, wherein R １ and R ２ are each independently hydrogen, C １ to C ４ alkyl or -C(=O)R ４ and R ３ is hydrogen or C １ to C ４ alkyl, R ４ is C １ to C １８ alkyl which may be substituted with a hydroxyl group, or C １ to C １８ alkenyl which may be substituted with a hydroxyl group, the method according to any one of claims 1 to 3.

13. The method according to any one of claims 1 to 3, wherein the solvent is a mixed solvent comprising (i) a PEG-based solvent, or (ii) one or more selected from the group consisting of an alcohol-based solvent, an aliphatic hydrocarbon-based solvent, and water, and the PEG-based solvent is diglyme, triglyceride, tetraglyceride, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or polyethylene glycol monofatty acid ester.

14. A method for producing crystals of a cyclic peptide, comprising the step of contacting the cyclic peptide with a solvent, wherein the cyclic peptide has the following characteristics (I) and (II): (I) Characterized by containing a cyclic region consisting of a total of 8 to 16 amino acid residues, and having a total of 8 to 20 amino acid residues; (II) Characterized by containing at least two N-substituted amino acid residues; A method comprising a cyclic peptide having a solvent, wherein the solvent is solvent (A) or a mixed solvent containing solvent (A) and solvent (B), wherein solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents and ester solvents, and solvent (B) is one or more selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol and water.

15. The method according to any one of claims 1 to 3 and 14, wherein in the step of contacting the cyclic peptide with a solvent, the concentration of the cyclic peptide is 1 mg to 2000 mg / mL.

16. The method according to any one of claims 1 to 3 and 14, wherein the step of contacting the cyclic peptide with a solvent is carried out at a temperature of -10°C to 120°C for 30 minutes to 12 weeks.

17. A method for screening crystallization methods of cyclic peptides, comprising the following steps (a) and (b): (a) A step of producing crystals of a cyclic peptide by the method described in any one of claims 1 to 3 and 14; (b) A step of analyzing the crystal by powder X-ray diffraction; Methods that include...