CN115124514A - Eutectic crystal of KD-025 and preparation method thereof - Google Patents
Eutectic crystal of KD-025 and preparation method thereof Download PDFInfo
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- CN115124514A CN115124514A CN202210269048.7A CN202210269048A CN115124514A CN 115124514 A CN115124514 A CN 115124514A CN 202210269048 A CN202210269048 A CN 202210269048A CN 115124514 A CN115124514 A CN 115124514A
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- GKHIVNAUVKXIIY-UHFFFAOYSA-N 2-[3-[4-(1h-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)COC1=CC=CC(C=2N=C3C=CC=CC3=C(NC=3C=C4C=NNC4=CC=3)N=2)=C1 GKHIVNAUVKXIIY-UHFFFAOYSA-N 0.000 title claims abstract description 179
- 239000013078 crystal Substances 0.000 title claims abstract description 156
- 230000005496 eutectics Effects 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title abstract description 24
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 110
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 106
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 76
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 55
- 229940116298 l- malic acid Drugs 0.000 claims description 55
- 235000011090 malic acid Nutrition 0.000 claims description 55
- 239000001530 fumaric acid Substances 0.000 claims description 53
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 12
- 238000001757 thermogravimetry curve Methods 0.000 claims description 12
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- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 77
- 239000001384 succinic acid Substances 0.000 description 35
- 238000000113 differential scanning calorimetry Methods 0.000 description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 238000001228 spectrum Methods 0.000 description 17
- 238000002411 thermogravimetry Methods 0.000 description 17
- 238000012360 testing method Methods 0.000 description 16
- 239000003960 organic solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 230000008859 change Effects 0.000 description 8
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
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- 229940079593 drug Drugs 0.000 description 5
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- 201000001320 Atherosclerosis Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
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- 201000006417 multiple sclerosis Diseases 0.000 description 4
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
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- 150000003839 salts Chemical class 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 2
- -1 KD-025 compound Chemical class 0.000 description 2
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 2
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- 150000001875 compounds Chemical class 0.000 description 2
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- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 1
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- 101710088493 Rho-associated protein kinase 2 Proteins 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000000048 melt cooling Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
The invention relates to a KD-025 eutectic crystal and a preparation method thereof, belonging to the technical field of pharmaceutical chemicals. The eutectic of KD-025 provided by the invention has the advantages of good stability, difficulty in being influenced by solvents and the like; the preparation method is simple, convenient to operate, mild in condition and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and relates to a KD-025 eutectic and a preparation method thereof.
Background
KD-025 is a selective ROCK2(Rho-associated protein kinase 2) inhibitor, and has multiple clinical indications such as treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, nonalcoholic fatty liver disease and the like in development and experiments.
The KD-025 structure is shown as the following formula (1):
drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same medicament may have obvious difference in physicochemical properties such as appearance, fluidity, solubility, storage stability, bioavailability and the like, may have great difference, and may have different influences on storage transfer, application, stability, curative effect and the like of the medicament; in order to obtain a crystal form which is effective for production or for pharmaceutical preparations, the crystallization behavior of the drug needs to be comprehensively investigated in order to obtain a crystal form which meets production requirements. The pharmaceutically active substances used for the preparation of the pharmaceutical compositions should be as pure as possible and must ensure long-term storage stability under various environmental conditions. Therefore, the chemical stability, solid state stability, "shelf life" and material handling properties of the pharmaceutically active substance are very important factors.
According to the invention, through carrying out a large number of experimental researches on the KD-025 compound, L-malic acid eutectic, succinic acid eutectic and fumaric acid eutectic of the compound are obtained, and the novel eutectic crystal form has the advantages of good stability in water, stability under illumination, high temperature and high humidity conditions, simple preparation process, easiness in operation and the like, and has superiority in industrial production. The research on the new KD-025 eutectic provides opportunities for improving the overall performance (such as easy synthesis or processing, improved dissolution rate or improved stability and shelf life) of the medicinal product, and simultaneously enlarges the variety of materials available for formulation scientists to design the medicament, and is of great importance to the research and development of medicaments.
Summary of The Invention
The invention provides co-crystals of KD-025. The eutectic of KD-025 provided by the invention is selected from eutectic of KD-025 and succinic acid, eutectic of KD-025 and L-malic acid and eutectic of KD-025 and fumaric acid.
The research on the novel eutectic crystal form disclosed by the invention finds that the novel eutectic crystal form is not easily influenced by solvents and has good stability in water, and the influence factor test proves that the novel eutectic crystal form has good performance and can be used for preparing pharmaceutical preparation production.
The eutectic of KD-025 and succinic acid provided by the invention has the advantages of good stability, stability under the condition of influencing factors and the like.
The eutectic crystal of KD-025 and succinic acid comprises diffraction peaks with 2theta angles of 6.68, 7.73, 25.66 and 25.89 degrees in an X-ray powder diffraction pattern.
In some embodiments, the co-crystal of KD-025 and succinic acid of the present invention has an X-ray powder diffraction pattern comprising diffraction peaks at 2 θ angles of 6.68,6.93, 7.73, 19.46, 20.17, 25.66, and 25.89 degrees. In some embodiments, the co-crystal of KD-025 and succinic acid has an X-ray powder diffraction pattern comprising diffraction peaks at 2 θ angles of 6.68,6.93, 7.73, 9.67, 18.04, 19.46, 20.17, 25.66, and 25.89 degrees. In some embodiments, the X-ray powder diffraction pattern of the co-crystal of KD-025 and succinic acid comprises diffraction peaks at 2 θ angles of 5.81, 6.07, 6.68,6.93, 7.73, 9.67, 12.13, 12.58, 13.81, 15.01, 15.79, 16.69, 17.72, 18.04, 18.52, 19.46, 20.17, 20.81, 22.68, 25.25, 25.66, 25.89, 27.01, and 28.54 degrees.
In some embodiments, the co-crystal of KD-025 and succinic acid has an X-ray powder diffraction pattern substantially as shown in fig. 1.
The differential scanning calorimetry curve of the eutectic of KD-025 and succinic acid has an endothermic peak at 187 ℃ -196 ℃. In some embodiments, the differential scanning calorimetry curve of the co-crystal of KD-025 and succinic acid of the present invention has an endothermic peak at 191 ℃. In some embodiments, the differential scanning calorimetry curve of the co-crystal of KD-025 and succinic acid according to the present invention is substantially as shown in fig. 2.
The thermogravimetric analysis curve of the eutectic of KD-025 and succinic acid shows that the weight loss of the eutectic of KD-025 and succinic acid is less than 1.0 percent in the temperature range of 175-200 ℃. In some embodiments, the co-crystal of KD-025 and succinic acid, wherein the thermogravimetric analysis curve shows that the co-crystal loses 0.1% weight over a temperature range of 30 ℃ to 150 ℃. In some embodiments, the co-crystal of KD-025 and succinic acid has a thermogravimetric analysis curve substantially as shown in fig. 3. The weight loss of the eutectic of KD-025 and succinic acid is less than 1.0%, and the eutectic of KD-025 and succinic acid can be considered to be an anhydrous crystal form.
In some embodiments, the aforementioned co-crystal of KD-025 and succinic acid has a molar ratio of KD-025 to succinic acid of 1:1.
The eutectic crystal of KD-025 and L-malic acid provided by the invention has the advantages of good stability, difficulty in being influenced by a solvent and the like.
The eutectic crystal of KD-025 and L-malic acid contains diffraction peaks with 2theta angles of 6.46, 16.35, 19.79 and 25.31 degrees in an X-ray powder diffraction pattern.
In some embodiments, the co-crystals of KD-025 and L-malic acid described herein have an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.46, 12.97, 15.26, 16.35, 19.79, and 25.31 degrees. In some embodiments, the co-crystal of KD-025 and L-malic acid has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.46, 12.48, 12.97, 15.26, 16.35, 19.79, 25.31, and 26.40 degrees. In some embodiments, the X-ray powder diffraction pattern of the co-crystal of KD-025 and L-malic acid comprises diffraction peaks at 2 Θ angles of 6.46, 7.60, 10.64, 12.48, 12.97, 15.26, 16.35, 18.41, 19.79, 21.26, 22.46, 22.90, 24.50, 25.31, 26.40, 29.68, and 32.40 degrees.
In some embodiments, the co-crystal of KD-025 and L-malic acid has an X-ray powder diffraction pattern substantially as shown in fig. 4.
The differential scanning calorimetry curve of the eutectic of KD-025 and L-malic acid has endothermic peaks at 82-92 ℃ and 205-215 ℃. In some embodiments, the differential scanning calorimetry curve of a co-crystal of KD-025 and L-malic acid described herein has endothermic peaks at 87 ℃ and 210 ℃. In some embodiments, the differential scanning calorimetry curve of the co-crystals of KD-025 and L-malic acid of the present invention is substantially as shown in fig. 5.
The thermogravimetric analysis curve of the eutectic of KD-025 and L-malic acid shows that the weight loss of the eutectic is less than 5.0 percent in the temperature range of 30-150 ℃. In some embodiments, the co-crystal of KD-025 and L-malic acid, whose thermogravimetric analysis curve shows a weight loss of 1.5% over the temperature range of 30 ℃ to 150 ℃, is considered to be a hemihydrate. In some embodiments, the thermogravimetric analysis curve of the co-crystal of KD-025 and L-malic acid is substantially as shown in fig. 6.
In some embodiments of the aforementioned co-crystal of KD-025 and L-malic acid, the molar ratio of KD-025 to L-malic acid is 1:1.
The eutectic crystal of KD-025 and fumaric acid provided by the invention has the advantages of good stability, difficulty in influence of solvents and the like.
The eutectic crystal of KD-025 and fumaric acid comprises diffraction peaks with 2theta angles of 6.38 degrees, 12.76 degrees, 17.03 degrees, 19.18 degrees and 25.67 degrees in an X-ray powder diffraction pattern.
In some embodiments, the co-crystal of KD-025 and fumaric acid of the present invention has an X-ray powder diffraction pattern comprising diffraction peaks at 2 θ angles of 6.38, 9.77, 12.76, 17.03, 19.18, 20.39, 20.75, 25.67, and 26.62 degrees. In some embodiments, the co-crystal of KD-025 and fumaric acid has an X-ray powder diffraction pattern comprising diffraction peaks at 2 θ angles of 6.38, 9.77, 12.76, 13.19, 17.03, 19.18, 19.80, 20.39, 20.75, 23.88, 24.95, 25.67, and 26.62 degrees. In some embodiments, the X-ray powder diffraction pattern of the co-crystal of KD-025 and fumaric acid comprises diffraction peaks at 2 θ angles of 6.38, 9.77, 12.76, 13.19, 15.16, 15.66, 17.03, 18.30, 19.18, 19.80, 20.39, 20.75, 21.74, 22.06, 23.88, 24.95, 25.67, 26.62, 27.35, 27.88, 28.54, and 30.54 degrees.
In some embodiments, the co-crystal of KD-025 and fumaric acid has an X-ray powder diffraction pattern substantially as shown in fig. 7.
The differential scanning calorimetry curve of the eutectic of KD-025 and fumaric acid has endothermic peaks at 118-128 ℃ and 234-244 ℃. In some embodiments, the differential scanning calorimetry curve of a co-crystal of KD-025 and fumaric acid according to the present invention has endothermic peaks at 123 ℃ and 239 ℃. In some embodiments, the differential scanning calorimetry curve of the co-crystals of KD-025 and fumaric acid according to the present invention is substantially as shown in fig. 8.
The thermogravimetric analysis curve of the eutectic of KD-025 and fumaric acid shows that the weight loss of the eutectic of KD-025 and fumaric acid is less than 5.0 percent in the temperature range of 175-200 ℃. In some embodiments, the thermogravimetric analysis curve of the co-crystal of KD-025 and fumaric acid shows that the co-crystal of KD-025 and fumaric acid loses 3.1% of weight in the temperature range of 30 ℃ to 150 ℃, and the co-crystal of KD-025 and fumaric acid can be considered as a monohydrate. In some embodiments, the co-crystal of KD-025 and fumaric acid has a thermogravimetric analysis curve substantially as shown in fig. 9.
In some embodiments, the aforementioned co-crystal of KD-025 and fumaric acid has a molar ratio of KD-025 to fumaric acid of 1:1.
It is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned co-crystals and a pharmaceutically acceptable adjuvant or excipient. The pharmaceutical composition or formulation is typically prepared by mixing or contacting a therapeutically effective amount of the co-crystals with one or more pharmaceutical excipients in a manner well known in the pharmaceutical art. The pharmaceutical composition or formulation may be used for the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver disease, and the like.
The invention provides a pharmaceutical composition which can contain at least 0.1-10% of the eutectic crystal based on the total weight of the composition. The invention provides a pharmaceutical composition which may contain at least 0.1% to 5% by weight of the total composition of the co-crystal. The invention provides a pharmaceutical composition which may contain at least 0.1% to 1% by weight of the total composition of the co-crystal. In some embodiments, the present invention provides a pharmaceutical composition comprising at least 0.1% to 0.5% of the co-crystal by total weight of the composition.
The pharmaceutical composition provided by the invention contains the eutectic crystal, wherein at least 80% of KD-025 is the eutectic crystal according to the mass ratio. In some embodiments, a pharmaceutical composition comprises the aforementioned co-crystal, wherein at least 90% of KD-025 by mass is the co-crystal. In some embodiments, a pharmaceutical composition comprises the aforementioned co-crystal, wherein at least 95% of KD-025 by mass is the co-crystal. In some embodiments, a pharmaceutical composition comprises the aforementioned co-crystal, wherein at least 99% of KD-025 by mass is the co-crystal.
The pharmaceutical composition containing the co-crystal can be used for preparing pharmaceutical preparations for treating multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, nonalcoholic fatty liver and the like. The pharmaceutical composition provided by the invention can be used in a method for treating diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis and non-alcoholic fatty liver disease.
In some embodiments, the pharmaceutical composition comprises a co-crystal of KD-025 and L-malic acid, or a co-crystal of KD-025 and fumaric acid, or a mixture thereof.
The eutectic provided by the invention has good stability and solubility, is not easy to deliquesce under a high-humidity condition, is convenient for long-term storage and placement of the drug, and can well avoid crystal transformation in the drug storage and development processes, thereby avoiding the change of bioavailability and drug effect and having strong economic value.
In a second aspect of the invention, a method for preparing a co-crystal of KD-025 is provided. The preparation method is simple, convenient to operate, mild in condition and suitable for industrial production.
The invention provides a preparation method of the eutectic of KD-025 and succinic acid.
The preparation method of the eutectic of KD-025 and succinic acid is simple, convenient to operate, mild in condition and suitable for industrial production.
A method of making a co-crystal of KD-025 and succinic acid comprising: and (2) placing the KD-025 in an organic solvent 1, adding succinic acid, suspending and pulping for a period of time at room temperature, filtering, and drying to obtain the eutectic of the KD-025 and the succinic acid.
The feeding molar ratio of KD-025 to succinic acid can be 1: 1-1: 3. In some embodiments, the KD-025 to succinic acid feed molar ratio is 1: 1.2.
The organic solvent 1 is an ether. In some embodiments, the organic solvent 1 is methyl tert-butyl ether.
The mass-to-volume ratio of KD-025 to an ether solvent such as methyl tert-butyl ether may be 10mg/mL to 50 mg/mL. In some embodiments, the ratio of KD-025 to methyl tert-butyl ether by mass to volume is 20 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to methyl tert-butyl ether is 30 mg/mL. In some embodiments, the ratio of KD-025 to methyl tert-butyl ether by mass to volume is 40 mg/mL.
The pulping time can be 18-30 h. In some embodiments, the break time is 22 hours. In some embodiments, the pulping time is 24 hours. In some embodiments, the break up time is 26 hours.
The invention provides a preparation method of the eutectic of KD-025 and L-malic acid.
The preparation method of the eutectic of KD-025 and L-malic acid is simple, convenient to operate, mild in condition and suitable for industrial production.
A method of preparing a co-crystal of KD-025 and L-malic acid comprising: putting KD-025 into an organic solvent 2, adding L-malic acid, suspending and pulping for a period of time at room temperature, filtering, and drying to obtain the KD-025 and L-malic acid eutectic.
The feeding molar ratio of the KD-025 to the L-malic acid can be 1: 1-1: 3. In some embodiments, the KD-025 to L-malic acid feed molar ratio is 1: 1.2.
The organic solvent 2 is an ester. In some embodiments, the organic solvent 2 is ethyl acetate.
The mass-volume ratio of the KD-025 to the ester solvent such as ethyl acetate can be 10 mg/mL-80 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to ethyl acetate is 30 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to ethyl acetate is 50 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to ethyl acetate is 70 mg/mL.
The pulping time can be 18-30 h. In some embodiments, the break time is 22 hours. In some embodiments, the pulping time is 24 hours. In some embodiments, the break up time is 26 hours.
The invention provides a preparation method of the eutectic of KD-025 and fumaric acid.
The preparation method of the eutectic of KD-025 and fumaric acid is simple, convenient to operate, mild in condition and suitable for industrial production.
A method of preparing a co-crystal of KD-025 and fumaric acid comprising: and (3) putting KD-025 into an organic solvent 3, adding fumaric acid, suspending and pulping for a period of time at room temperature, filtering, and drying to obtain the eutectic of KD-025 and fumaric acid.
The feeding molar ratio of KD-025 to fumaric acid can be 1: 1-1: 3. In some embodiments, the KD-025 to fumaric acid feed molar ratio is 1: 1.2.
The organic solvent 3 is selected from ethers or esters. In some embodiments, the organic solvent is methyl tert-butyl ether. In some embodiments, the organic solvent is ethyl acetate.
The mass-volume ratio of the KD-025 to the organic solvent 3 can be 10 mg/mL-50 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to organic solvent 3 is 16 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to organic solvent 3 is 30 mg/mL. In some embodiments, the mass to volume ratio of KD-025 to organic solvent 3 is 40 mg/mL.
The pulping time can be 18-30 h. In some embodiments, the break time is 22 hours. In some embodiments, the pulping time is 24 hours. In some embodiments, the break up time is 26 hours.
The preparation method can obtain the crystal form, and has convenient operation and mild conditions.
Definition of terms
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
Crystalline forms or amorphous forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures herein. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program 2 O 3 ) The energy difference therebetween varies with temperature. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The melting peak has a tolerance of + -3 deg.C depending on the condition of the instrument used in the test.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.
The term "substantially as shown in the figure" means that substantially pure certain "crystalline form" has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in its X-ray powder diffraction pattern that appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in a sample is gradually reduced, diffraction peaks in an X-ray powder diffraction pattern of the crystal form, which are attributed to the crystal form, may be reduced due to the detection sensitivity of an instrument.
In the context of the present invention, the diffraction angle 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (. degree.).
The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may differ by 1%, 2%, or 5%. When used to approximate the 2theta (also known as 2theta or diffraction peak) value used to describe the X-ray powder diffraction peak, approximately means that there may be a +/-0.2 unit or +/-0.1 unit or +/-0.05 unit difference in the 2theta value.
The term "room temperature" means a temperature of about 20 ℃ to 35 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.
In the present invention, mg/mL means mg/mL, h means hour, g means g, mL means mL, DEG C means centigrade, mL/min means mL/min, and RH means relative humidity.
Drawings
FIG. 1 shows an XRPD spectrum of the co-crystal of KD-025 and succinic acid, with the abscissa representing 2 θ degrees, in degrees (°), and the ordinate representing relative intensity counts (intensity (counts));
FIG. 2 shows a DSC spectrum of the co-crystal of KD-025 and succinic acid, with the abscissa representing temperature, in degrees C, and the ordinate representing Heat Flow (Heat Flow), in watts/gram (W/g);
FIG. 3 shows a TGA spectrum of a co-crystal of KD-025 and succinic acid with temperature on the abscissa and Weight loss in degrees C on the ordinate (Weight,%);
FIG. 4 shows an XRPD spectrum of a co-crystal of KD-025 and L-malic acid, with the abscissa representing 2 θ angle, in units of degrees (°), and the ordinate representing relative intensity counts (intensity (counts));
FIG. 5 shows a DSC spectrum of a co-crystal of KD-025 and L-malic acid with the abscissa representing temperature in degrees C and the ordinate representing Heat Flow in watts/gram (W/g);
FIG. 6 shows a TGA spectrum of a co-crystal of KD-025 and L-malic acid with temperature on the abscissa and Weight loss in units C on the ordinate (Weight,%);
FIG. 7 shows an XRPD spectrum of a co-crystal of KD-025 and fumaric acid, with 2 θ degrees in degrees (. degree.) on the abscissa and relative intensity counts (intensity (counts)) on the ordinate;
FIG. 8 shows a DSC spectrum of the co-crystal of KD-025 and fumaric acid, with the abscissa representing temperature, in degrees C, and the ordinate representing Heat Flow (Heat Flow), in watts/gram (W/g);
FIG. 9 shows a TGA spectrum of a co-crystal of KD-025 and fumaric acid, with temperature on the abscissa and Weight loss in degrees Celsius on the ordinate (Weight,%);
FIG. 10 shows a DVS spectrum of a co-crystal of KD-025 and succinic acid;
FIG. 11 shows a DVS spectrum of a co-crystal of KD-025 and L-malic acid;
FIG. 12 shows a DVS spectrum of a co-crystal of KD-025 and fumaric acid;
FIG. 13 shows the results of a 15-day effect experiment of the co-crystal of KD-025 and succinic acid, with the abscissa representing 2 θ angle (2Theta), units degrees (°), and the ordinate representing relative intensity counts (intensity (counts));
FIG. 14 shows the results of a 15-day influencing factor experiment of co-crystals of KD-025 and L-malic acid, with the abscissa representing 2 θ angle (2Theta), units degrees (. degree.), and the ordinate representing relative intensity counts (intensity (counts));
FIG. 15 shows the results of a 15-day effect factor experiment for co-crystals of KD-025 and fumaric acid, plotted on the abscissa for 2 θ angle (2Theta), in units of degrees (. degree.), and on the ordinate for relative intensity counts (intensity (counts));
FIG. 16 shows an XRPD spectrum of eutectic solvent stability of KD-025 and L-malic acid, with the abscissa representing 2 θ angle, in degrees (°), and the ordinate representing relative intensity counts (intensity (counts));
FIG. 17 shows an XRPD spectrum of the eutectic solvent stability of KD-025 and fumaric acid, with 2 θ degrees in degrees (. degree.) on the abscissa and relative intensity counts (intensities) (counts) on the ordinate;
FIG. 18 shows an XRPD spectrum of the stability in water of a co-crystal of KD-025 and L-malic acid, with the abscissa representing 2 θ angle, in units of degrees (°), and the ordinate representing relative intensity counts (intensity (counts));
FIG. 19 shows an XRPD spectrum of the stability in water of a co-crystal of KD-025 and fumaric acid, with 2 θ degrees in degrees (. degree.) on the abscissa and relative intensity counts (intensity (counts)) on the ordinate;
FIG. 20 shows an XRPD spectrum of the stability in water of a co-crystal of KD-025 and succinic acid, with the abscissa representing 2 θ angle in degrees (. degree.) and the ordinate representing relative intensity counts (intensity (counts)).
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention is further described in detail by further disclosing some non-limiting examples.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
Example 1: preparation of Co-crystals of KD-025 and succinic acid
Weighing 45mg of KD-025 and 14mg of succinic acid solid, mixing, placing in 1.5mL of methyl tert-butyl ether at room temperature, suspending and stirring for 22h, filtering, and drying to obtain the eutectic of KD-025 and succinic acid: 38.4 mg. The XRPD, DSC, TGA patterns were determined to be substantially in accordance with figures 1, 2 and 3, respectively.
Example 2: preparation of Co-crystals of KD-025 and succinic acid
Weighing 225mg of KD-025 and 60mg of succinic acid solid, mixing, placing in 8mL of methyl tert-butyl ether at room temperature, suspending and stirring for 22h, filtering, and drying to obtain the eutectic of KD-025 and succinic acid: 193.8 mg. The XRPD, DSC, TGA patterns were determined to be substantially in accordance with figures 1, 2 and 3, respectively.
Example 3: preparation of co-crystals of KD-025 and L-malic acid
Weighing 45mg of KD-025 and 16mg of L-malic acid solid, mixing, placing in 1.0mL of ethyl acetate at room temperature, suspending and stirring for 22h, filtering, and drying to obtain the eutectic of KD-025 and L-malic acid: 42.7 mg. The XRPD, DSC, TGA patterns were determined to be substantially in accordance with figures 7, 8 and 9, respectively.
Example 4: preparation of co-crystals of KD-025 and L-malic acid
Weighing 225mg KD-025 and 80mg L-malic acid solid, mixing, placing in 8.0mL ethyl acetate at room temperature, suspending and stirring for 22h, filtering, and drying to obtain eutectic of KD-025 and L-malic acid: 210.5 mg. The XRPD, DSC, TGA patterns were determined to be substantially in accordance with fig. 7, 8, and 9, respectively.
Example 5: preparation of Co-crystals of KD-025 and fumaric acid
Weighing 45mg of KD-025 and 14mg of fumaric acid solid, mixing, placing in 1.5mL of methyl tert-butyl ether at room temperature, suspending and stirring for 22h, filtering, and drying to obtain the eutectic of KD-025 and fumaric acid: 44.3 mg. The XRPD, DSC, TGA patterns were determined to be substantially in accordance with fig. 7, 8, and 9, respectively.
Example 6: preparation of Co-crystals of KD-025 and fumaric acid
Weighing 225mg of KD-025 and 60mg of fumaric acid solid, mixing, placing in 8.0mL of ethyl acetate at room temperature, suspending and stirring for 22h, filtering, and drying to obtain the eutectic of KD-025 and fumaric acid: 216.6 mg. The XRPD, DSC, TGA patterns were determined to be substantially in accordance with fig. 7, 8, and 9, respectively.
Example 7: examination of hygroscopicity
A certain amount of each eutectic sample was taken and changed with relative humidity (0% -95.0% -0%) at 25.0 ℃ by a DVS instrument from 0% relative humidity to 95% relative humidity in 5% relative humidity steps and then to 0% relative humidity in 5% relative humidity steps. When the absolute value of the change dm/dt in the weight of the sample per unit time under a certain relative humidity condition is less than 0.1%, the sample is considered to reach the equilibrium, and then the next relative humidity is entered. And detecting the change of the hygroscopicity of the sample under the relative humidity cycling condition of (0% -95.0% -0%). The experimental results are shown in fig. 10, 11 and 12.
The results show that: the eutectic of KD-025 and succinic acid and the eutectic of KD-025 and fumaric acid have stable properties and are not influenced by the environmental humidity; the eutectic crystal of KD-025 and L-malic acid has certain hygroscopicity.
Example 8: test for influencing factor
According to the guiding principle of the stability test of the pharmaceutical preparation, the influence factor test is carried out on each eutectic crystal, including a high temperature test, a high humidity test and a strong light irradiation test, the stability conditions influencing the crystal form are investigated, the results are shown in the following tables 1, 2 and 3 and fig. 13, 14 and 15, and the attached drawings are as follows from bottom to top: x-ray powder diffraction (XRPD) pattern of 0 day, 5 days at high temperature, 5 days at high humidity, 5 days at illumination, 10 days at high temperature, 10 days at high humidity, 10 days at illumination, 15 days at high temperature, 15 days at high humidity, and 15 days at illumination.
High-temperature test: taking a proper amount of each eutectic sample, flatly spreading the eutectic sample in a weighing bottle, placing the eutectic sample in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5%, then taking about 100mg of the eutectic sample in 0, 5 and 15 days respectively, and testing the crystal form condition of the eutectic sample by powder X-ray powder diffraction (XRPD).
High humidity test: taking a proper amount of each eutectic sample, flatly spreading the eutectic sample in a weighing bottle, placing the eutectic sample in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5 percent, then taking about 100mg of the eutectic sample respectively in 0, 5 and 15 days, and testing the crystal form condition of the eutectic sample by powder X-ray powder diffraction (XRPD).
And (3) illumination test: an appropriate amount of each eutectic sample is taken, spread into a weighing bottle, placed in a constant temperature and humidity box (25 ℃, RH 60% +/-5%) with visible light 4500Lux +/-500 Lux (VIS) and ultraviolet light 1.7W X h/m2(UV), then taken about 100mg of the sample at 0, 5 and 15 days respectively, and the crystal form condition of the sample is tested by powder X-ray powder diffraction (XRPD).
Table 1: stability test conditions of Co-crystals of KD-025 and succinic acid investigation results
Table 2: stability test condition investigation result of eutectic of KD-025 and L-malic acid
Table 3: stability test conditions of Co-crystals of KD-025 and fumaric acid
The results show that: the powder X-ray diffraction (XRPD) pattern results of each eutectic sample under the test conditions of three influencing factors of high temperature, high humidity and illumination show that crystal transformation does not occur under each influencing factor, and the eutectic crystal has good stability.
Example 9: investigation of solvent stability
The eutectic of KD-025 and L-malic acid is respectively placed in n-heptane and dioxane solvents for suspension for 12h, and then the crystal form condition of the eutectic is tested by powder X-ray powder diffraction (XRPD).
Table 4: solvent stability test results of co-crystals of KD-025 and L-malic acid
Experiments show that the eutectic of KD-025 and L-malic acid is stable in both n-heptane and dioxane solvents, and the results are shown in FIG. 16, which are from bottom to top: no solvent, n-heptane, dioxane.
The eutectic crystal of KD-025 and fumaric acid is respectively placed in acetone, ethylene glycol dimethyl ether, n-heptane and dioxane solvents for suspension for 12h, and then the crystal form condition of the eutectic crystal is tested by powder X-ray powder diffraction (XRPD).
Table 5: solvent stability test results of cocrystal of KD-025 and fumaric acid
Experiments show that the eutectic of KD-025 and fumaric acid is stable in acetone, ethylene glycol dimethyl ether, n-heptane and dioxane solvents, and the results are shown in FIG. 16, which sequentially comprises the following steps from bottom to top: no solvent, acetone, ethylene glycol dimethyl ether, n-heptane and dioxane.
The results show that: the eutectic crystal of KD-025 and L-malic acid and the eutectic crystal sample of KD-025 and fumaric acid have good solvent stability.
Example 10: investigation of stability in Water
The co-crystal of 50mg KD-025 and L-malic acid was placed in 1mL of purified water, warmed to 37 ℃ and suspended for 12h, and then its crystal form was tested by powder X-ray powder diffraction (XRPD), and the results are shown in FIG. 18.
The co-crystal of 50mg kd-025 and fumaric acid was placed in 1mL of purified water, warmed to 37 ℃ and suspended for 12 hours, and then its crystal form was tested using powder X-ray powder diffraction (XRPD), and the results are shown in fig. 19.
50mg of the co-crystal of KD-025 and succinic acid was placed in 1mL of purified water, warmed to 37 ℃ and suspended for 12h, and then the crystal form was tested by powder X-ray powder diffraction (XRPD), and the results are shown in FIG. 20.
The results show that: the eutectic of KD-025 and succinic acid is transformed. The eutectic of KD-025 and L-malic acid and the eutectic of KD-025 and fumaric acid samples do not generate crystal transformation in water, and have good stability.
Instrument parameters, test conditions and characterization results
Instrument information:
1) x-ray powder diffraction analyzer (XRPD) -PANalytical;
2) differential Scanning Calorimeter (DSC) -TA Q2000;
3) thermogravimetric analyzer (TGA) - -TA Q500;
the test method comprises the following steps:
1) XRPD method
2) DSC method
The DSC method parameters were as follows:
30-300℃，10℃/min；N 2 (50mL/min)；
3) TGA process
The TGA process parameters are as follows:
30-350℃，10℃/min；N 2 (60mL/min)。
while the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A co-crystal of KD-025 and L-malic acid, characterized in that the X-ray powder diffraction pattern of the co-crystal comprises diffraction peaks at 2 Θ angles of 6.46, 16.35, 19.79 and 25.31 degrees.
2. A co-crystal of KD-025 and L-malic acid according to claim 1, characterised in that the co-crystal comprises diffraction peaks at 2 Θ angles of 6.46, 12.97, 15.26, 16.35, 19.79 and 25.31 degrees in its X-ray powder diffraction pattern; or the X-ray powder diffraction pattern of the co-crystal comprises diffraction peaks with 2theta angles of 6.46, 12.48, 12.97, 15.26, 16.35, 19.79, 25.31 and 26.40 degrees; or the X-ray powder diffraction pattern of the co-crystal comprises diffraction peaks with 2theta angles of 6.46, 7.60, 10.64, 12.48, 12.97, 15.26, 16.35, 18.41, 19.79, 21.26, 22.46, 22.90, 24.50, 25.31, 26.40, 29.68 and 32.40 degrees; or the X-ray powder diffraction pattern of the co-crystal is substantially as shown in figure 4.
3. A co-crystal of KD-025 and L-malic acid according to any one of claims 1 to 2, characterised in that the differential scanning calorimetry curve of the co-crystal has endothermic peaks at 82 ℃ -92 ℃ and 205 ℃ -215 ℃, and/or the thermogravimetric analysis curve of the co-crystal shows a 1.5% weight loss of the co-crystal over the temperature range 30 ℃ -150 ℃.
4. A method of preparing a co-crystal of KD-025 and L-malic acid according to any one of claims 1 to 3, comprising: putting KD-025 into ethyl acetate, adding L-malic acid, suspending and pulping for 18-30 h at room temperature, filtering, and drying to obtain eutectic of KD-025 and L-malic acid; the mass-volume ratio of the KD-025 to the ethyl acetate is 10 mg/mL-80 mg/mL, and the feeding molar ratio of the KD-025 to the L-malic acid is 1: 1-1: 3.
5. A pharmaceutical composition comprising: a co-crystal of KD-025 and L-malic acid as described in any one of claims 1 to 4, and a pharmaceutically acceptable adjuvant or excipient; wherein the eutectic of KD-025 and L-malic acid accounts for at least 0.1% -10% of the total weight of the composition, or at least 80% of KD-025 accounts for the eutectic of KD-025 and L-malic acid according to the mass ratio of KD-025.
6. A co-crystal of KD-025 and fumaric acid, characterized in that it comprises diffraction peaks at 2theta angles of 6.38, 12.76, 17.03, 19.18 and 25.67 degrees in its X-ray powder diffraction pattern.
7. The co-crystal of claim 6, wherein the co-crystal comprises diffraction peaks at 2 Θ angles of 6.38, 9.77, 12.76, 17.03, 19.18, 20.39, 20.75, 25.67, and 26.62 degrees in an X-ray powder diffraction pattern; or the X-ray powder diffraction pattern of the co-crystal comprises diffraction peaks with 2theta angles of 6.38, 9.77, 12.76, 13.19, 17.03, 19.18, 19.80, 20.39, 20.75, 23.88, 24.95, 25.67 and 26.62 degrees; or the X-ray powder diffraction pattern of the co-crystal comprises diffraction peaks at 2theta angles of 6.38, 9.77, 12.76, 13.19, 15.16, 15.66, 17.03, 18.30, 19.18, 19.80, 20.39, 20.75, 21.74, 22.06, 23.88, 24.95, 25.67, 26.62, 27.35, 27.88, 28.54 and 30.54 degrees; or the X-ray powder diffraction pattern of the co-crystal is substantially as shown in figure 7.
8. The co-crystal according to any one of claims 6 to 7, characterized in that the differential scanning calorimetry curve of the co-crystal has endothermic peaks at 118 ℃ -128 ℃ and 234 ℃ -244 ℃, and/or the thermogravimetric analysis curve of the co-crystal shows a 3.1% weight loss of the co-crystal in the temperature range of 30 ℃ -150 ℃.
9. A method of preparing the co-crystal of any one of claims 6 to 8, comprising: placing KD-025 in methyl tert-butyl ether or ethyl acetate, adding fumaric acid, suspending and pulping at room temperature for 18-30 h, filtering, and drying to obtain KD-025 fumaric acid eutectic; the mass-volume ratio of KD-025 to methyl tert-butyl ether or ethyl acetate is 10 mg/mL-50 mg/mL, and the feeding molar ratio of KD-025 to fumaric acid is 1: 1-1: 3.
10. A pharmaceutical composition comprising: a co-crystal as claimed in any one of claims 6 to 9 and a pharmaceutically acceptable adjuvant or excipient; wherein the eutectic is at least 0.1-10% of the total weight of the composition, or at least 80% of KD-025 is the eutectic of KD-025 and fumaric acid according to the mass ratio of KD-025.
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