WO2018103726A1 - 一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途 - Google Patents

一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途 Download PDF

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WO2018103726A1
WO2018103726A1 PCT/CN2017/115143 CN2017115143W WO2018103726A1 WO 2018103726 A1 WO2018103726 A1 WO 2018103726A1 CN 2017115143 W CN2017115143 W CN 2017115143W WO 2018103726 A1 WO2018103726 A1 WO 2018103726A1
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crystal form
apabetalone
crystalline form
ray powder
powder diffraction
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PCT/CN2017/115143
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English (en)
French (fr)
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陈敏华
张炎锋
翟晓婷
鄢楷强
张晓宇
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苏州科睿思制药有限公司
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Priority to EP17878872.5A priority Critical patent/EP3553058A1/en
Priority to JP2019531044A priority patent/JP6849804B2/ja
Priority to AU2017373239A priority patent/AU2017373239B2/en
Priority to US16/467,774 priority patent/US10752595B2/en
Priority to CN201780075689.6A priority patent/CN110049981A/zh
Publication of WO2018103726A1 publication Critical patent/WO2018103726A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystal of 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one
  • the type, its preparation method and use belong to the field of medicine.
  • Apabetalone 2-[4-(2-Hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one, also known as Apabetalone, is a A bromodomain (BET) protein inhibitor, developed by Resverlogix, Canada, is a drug for the treatment of cardiovascular, cholesterol or lipid-related disorders, especially for the treatment of atherosclerosis, acute crowns. Pulse syndrome and pre-diabetes have significant effects.
  • BET bromodomain
  • Cardiovascular disease also known as circulatory disease, can be subdivided into acute and chronic diseases, usually associated with arteriosclerosis. Cardiovascular disease is one of the most serious diseases threatening human life in the world today, and its morbidity and mortality have surpassed that of neoplastic diseases. There are only about 290 million cardiovascular patients in China, and the number of patients is increasing year by year. However, drugs for treating cardiovascular diseases have not yet met people's needs, and new drugs need to be developed continuously. Studies have shown that Apabetalone can inhibit the BRD4 region in the BET family, thereby regulating the expression of apolipoprotein A-1 (ApoA-1) and the synthesis of high-density lipoprotein cholesterol, and achieving cardiovascular-related diseases. No patents or literature reports on Apabetalone have been found by domestic and foreign patents and literature searches.
  • AdoA-1 apolipoprotein A-1
  • the inventors of the present application have conducted a large number of experimental studies and found that Apabetalone's crystalline form CS2, crystalline form CS8, crystalline form CS13, crystalline form CS20, crystalline form CS1, crystalline form CS7, crystalline form CS9, crystalline form CS11 and crystalline form CS4
  • the above crystal form has good stability and can be stably placed for at least 2 weeks at 25 ° C / 60% RH and / or 40 ° C / 75% RH, further stable for at least 4 weeks, and further stable for at least 6 weeks.
  • the crystal form is simple in preparation, good in repeatability, high in crystal purity, good in solubility and low in moisture repellency, meets medicinal requirements, and is suitable for production and application. .
  • the main object of the present invention is to provide a crystal form of Apabetalone, a preparation method and use thereof.
  • the present invention provides a crystal form CS2 of Apabetalone (hereinafter referred to as "crystal form CS2").
  • the crystal form CS2 is a hydrate.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 11.5° ⁇ 0.2°, 6.6° ⁇ 0.2°, and 8.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 5.1° ⁇ 0.2° and 15.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks in the diffraction angle 2 ⁇ values of 5.1° ⁇ 0.2° and 15.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ of 11.5° ⁇ 0.2°, 6.6° ⁇ 0.2°, 8.8° ⁇ 0.2°, 5.1° ⁇ 0.2°, 15.3°. Characteristic peaks are found at ⁇ 0.2°, 13.3° ⁇ 0.2°, 20.2° ⁇ 0.2°, 23.1° ⁇ 0.2°, and 25.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is shown in Figure 1A.
  • the present invention also provides a method for preparing a crystalline form CS2 of Apabetalone, which comprises adding a raw material of Apabetalone to a mixed solvent of an alcohol, an alcohol and an ether, a mixed solvent of an alcohol and a ketone, an alcohol and a fragrance.
  • a mixed solvent of an alcohol, an alcohol and an ether a mixed solvent of an alcohol and a ketone
  • an alcohol and a fragrance a mixed solvent of an alcohol and a ketone
  • the mixed solvents of hydrocarbons it is dissolved by heating, filtered, and the solid is precipitated by cooling to obtain a crystal form CS2 of Apabetalone.
  • the alcohol comprises methanol
  • the ether comprises 2-methyltetrahydrofuran
  • the aromatic hydrocarbon comprises toluene
  • the ketone comprises methyl isobutyl ketone
  • the heating temperature is 50 to 100 ° C
  • the crystal temperature is -20 to 5 °C.
  • the crystalline form CS2 of the present invention has good solubility in SGF (simulated human gastric juice) and FeSSIF (artificial intestinal juice in fed state), especially in SGF, the solubility of crystalline form CS2 is as high as 0.61 mg in 24 hours. mL.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug, which is of great significance for drug research.
  • the present invention also provides a crystal form CS8 of Apabetalone (hereinafter referred to as "crystal form CS8").
  • crystal form CS8 is an anhydride.
  • the X-ray powder diffraction of the crystalline form CS8 has a diffraction angle 2 ⁇ of 23.9° ⁇ 0.2°, 13.5° ⁇ 0.2°, 7.8° ⁇ 0.2°, 22.5° ⁇ 0.2°, 11.4° ⁇ 0.2. There are characteristic peaks at °.
  • the X-ray powder diffraction of the crystal form CS8 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 25.9° ⁇ 0.2° and 13.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS8 has characteristic peaks in the diffraction angle 2 ⁇ values of 25.9° ⁇ 0.2° and 13.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS8 has a characteristic peak at a diffraction angle 2 ⁇ value of 28.1 ⁇ 0.2°, 20.2° ⁇ 0.2° or at two places.
  • the X-ray powder diffraction of the crystalline form CS8 has characteristic peaks in the diffraction angle 2 ⁇ values of 28.1° ⁇ 0.2° and 20.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS8 has a diffraction angle 2 ⁇ of 23.9° ⁇ 0.2°, 13.5° ⁇ 0.2°, 7.8° ⁇ 0.2°, 22.5° ⁇ 0.2°, 11.4°. Characteristic peaks are found at ⁇ 0.2°, 25.9° ⁇ 0.2°, 13.1° ⁇ 0.2°, 28.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, and 9.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS8 is as shown in Figure 2A.
  • the present invention further provides a method for preparing Apabetalone crystal form CS8, which comprises adding Apabetalone raw material to a halogenated hydrocarbon or a mixed solvent of a halogenated hydrocarbon and an alcohol, heating and dissolving, filtering, and cooling to precipitate a solid to obtain Apabetalone.
  • Crystal form CS8 comprises adding Apabetalone raw material to a halogenated hydrocarbon or a mixed solvent of a halogenated hydrocarbon and an alcohol, heating and dissolving, filtering, and cooling to precipitate a solid to obtain Apabetalone.
  • the halogenated hydrocarbon comprises dichloromethane
  • the alcohol comprises isopropanol
  • the volume ratio of the halogenated hydrocarbon to the alcohol is 4:1
  • the heating temperature is 40 to 60 ° C, preferably 50 °C
  • the crystallization temperature is -20 to 5 °C.
  • the crystalline form CS8 of the invention has good long-term stability and can be stably placed for at least 2 weeks in the environment of 25 ° C / 60% RH, which is convenient for long-term storage, and the crystal form CS8 maintains good stability, and can ensure the preparation of the medicine.
  • the phenomenon of crystal transformation does not occur and affects the quality of the drug. It is of great significance to ensure the efficacy and safety of the drug and prevent the occurrence of adverse drug reactions.
  • the crystal form CS8 of the invention has low wettability, and the weight gain is 0.34% under 80% relative humidity, which is slightly wetted, and does not need to control the environmental humidity during the preparation process, and has no special requirements for packaging and storage conditions, and saves cost. Easy to industrialize production and long-term storage of pharmaceuticals. Because the storage conditions are not demanding, the material storage and quality control costs will be greatly reduced, and it has strong economic value and is more suitable for medicinal use.
  • the present invention also provides a crystal form CS13 of Apabetalone (hereinafter referred to as "crystal form CS13").
  • crystal form CS13 is a hydrate.
  • the X-ray powder diffraction of the crystal form CS13 has characteristic peaks at diffraction angle 2 ⁇ values of 5.1° ⁇ 0.2°, 12.5° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS13 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS13 has characteristic peaks in the diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS13 has a characteristic peak at a diffraction angle 2 ⁇ value of 7.8° ⁇ 0.2°, 16.0° ⁇ 0.2° or at two places.
  • the X-ray powder diffraction of the crystal form CS13 has characteristic peaks in the diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2° and 16.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS13 has a diffraction angle 2 ⁇ of 5.1° ⁇ 0.2°, 12.5° ⁇ 0.2°, 17.1° ⁇ 0.2°, 6.4° ⁇ 0.2°, 8.5°. Characteristic peaks are found at ⁇ 0.2°, 25.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, and 16.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS13 is shown in Figure 3A.
  • the present invention also provides a method for preparing Apabetalone crystal form CS13, which is prepared by adding Apabetalone raw material to a mixed solvent of ether and water or a mixed solvent of ketone and water, dissolving and filtering, and then volatilizing at room temperature to precipitate. Solid, the crystal form CS13 of Apabetalone was obtained.
  • the ether comprises tetrahydrofuran
  • the ketone comprises acetone; preferably, the volume ratio of the ether to water is 4:1; and the volume ratio of the ketone to water is 9:1.
  • the crystalline form CS13 of the present invention has good solubility in both SGF and FeSSIF.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug.
  • the present invention also provides a crystal form CS20 of Apabetalone (hereinafter referred to as "crystal form CS20").
  • the crystalline form CS20 is an acetic acid solvate.
  • the X-ray powder diffraction of the crystalline form CS20 has characteristic peaks at diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 13.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS20 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 11.3° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 5.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS20 has characteristic peaks in the diffraction angle 2 ⁇ values of 11.3° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 5.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS20 has a characteristic peak at a diffraction angle 2 ⁇ value of 26.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS20 has characteristic peaks in the diffraction angle 2 ⁇ values of 26.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS20 has a characteristic peak at a diffraction angle 2 ⁇ value of 14.5° ⁇ 0.2°, 16.9 ⁇ °°, 22.8° ⁇ 0.2°, or two or three places.
  • the X-ray powder diffraction of the crystalline form CS20 has characteristic peaks in the diffraction angle 2 ⁇ values of 14.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS20 has a diffraction angle 2 ⁇ of 8.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 13.5° ⁇ 0.2°, 11.3° ⁇ 0.2°, 9.4°. ⁇ 0.2°, 5.6° ⁇ 0.2°, 26.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 24.4° ⁇ 0.2°, 14.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 22.8° ⁇ 0.2 There are characteristic peaks at °.
  • the X-ray powder diffraction pattern of Form CS20 is shown in Figure 4A.
  • the present invention also provides a process for the preparation of crystalline form CS20 of Apabetalone, which comprises adding Apabetalone to a mixed solvent of a nitrile and acetic acid or a mixed solvent of an ester and acetic acid, filtering and placing at room temperature. The mixture was volatilized, and a solid was precipitated to obtain a crystal form CS20 of Apabetalone.
  • the nitrile comprises acetonitrile
  • the ester comprises ethyl acetate
  • the volume ratio of the nitrile to acetic acid is 9:1
  • the volume ratio of the ester to acetic acid is 4:1.
  • the crystalline form CS20 of the present invention has good long-term stability and can be stably placed for at least 2 weeks in an environment of 25 ° C / 60% RH and 40 ° C / 75% RH. Crystalline CS20 has good stability, can ensure that the drug does not undergo crystal transformation during the preparation, transportation, storage and preservation process, which affects the quality of the drug, guarantees the efficacy and safety of the drug, and prevents the occurrence of adverse drug reactions. Significance.
  • the crystalline form CS20 of the present invention has good solubility in both SGF and FeSSIF.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug.
  • the present invention also provides a crystal form CS1 of Apabetalone (hereinafter referred to as "crystal form CS1").
  • crystal form CS1 is an anhydride.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 6.1 ° ⁇ 0.2 °, 12.3 ° ⁇ 0.2 °, 26.1 ° ⁇ 0.2 °, and 26.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 16.4° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 23.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has characteristic peaks in the diffraction angle 2 ⁇ values of 16.4° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 23.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has one or more of the diffraction angle 2 ⁇ values of 13.0° ⁇ 0.2°, 14.1° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 24.5° ⁇ 0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystalline form CS1 has characteristic peaks in the diffraction angle 2 ⁇ values of 13.0° ⁇ 0.2°, 14.1° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ values of 6.1 ° ⁇ 0.2 °, 12.3 ° ⁇ 0.2 °, 26.1 ° ⁇ 0.2 °, 26.8 ° ⁇ 0.2 °, 16.4 °. Characteristic peaks at ⁇ 0.2°, 18.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.1° ⁇ 0.2°, 17.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 20.5° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of Form CS1 is as shown in Figure 5A.
  • the present invention also provides a method for preparing the crystalline form CS1 of Apabetalone, comprising the following methods:
  • Dissolution step dissolving the Apabetalone raw material with a positive solvent to obtain a solution
  • a precipitation step adding the solution to an anti-solvent or adding an anti-solvent to the solution, and precipitating the solid to obtain a crystal form CS1 of Apabetalone;
  • the positive solvent includes one or a combination of two or more of tetrahydrofuran, chloroform, dimethyl sulfoxide, and dimethylacetamide; and the anti-solvent includes: n-heptane, methyl tert-butyl ether, toluene One of water, acetonitrile or a combination of two or more.
  • Method 2 Dissolution step: dissolving the Apabetalone starting material in a solvent at 40 to 60 ° C to obtain a solution;
  • a precipitation step the temperature of the solution is lowered to -20 to 5 ° C, and a solid is precipitated to obtain a crystal form CS1 of Apabetalone;
  • the solvent includes a mixed solvent of tetrahydrofuran, acetone, tetrahydrofuran and methyl tert-butyl ether, a mixed solvent of ethyl acetate and acetone, and a mixed solvent of acetonitrile and N,N-dimethylformamide.
  • the volume ratio of the tetrahydrofuran to the methyl tert-butyl ether is 2:1
  • the volume ratio of the ethyl acetate to the acetone is 1:1
  • the acetonitrile and N,N-dimethylformamide are The volume ratio is 9:1.
  • the crystalline form CS1 of the present invention has good long-term stability and mechanical stability, and can be stably placed for at least 10 months under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH, and the stability of the crystal form is on the drug.
  • the development of the crystal is critical.
  • the crystal form CS1 has good stability and can ensure that the drug does not undergo crystal transformation during preparation, transportation, storage and preservation, which affects the quality of the drug and ensures the efficacy and safety of the drug. To prevent the occurrence of adverse drug reactions is of great significance.
  • the crystal form CS1 has not changed after manual grinding, indicating that the crystal form CS1 has good mechanical stability, and the grinding and pulverization of the raw material medicine is often required in the preparation process, and the high grinding stability can reduce the preparation process. There is a risk of crystallinity change and crystal transformation of the drug substance.
  • the crystal form CS1 of the present invention has almost no hygroscopicity, and the weight gain at 80% relative humidity is only 0.13%, and the crystal form before and after the wettability The type has not changed.
  • the almost non-hygroscopic crystal form does not need to control the environmental humidity during the preparation process, and has no special requirements for packaging and storage conditions, cost saving, easy industrial production and long-term storage of medicines. Because the storage conditions are not demanding, the material storage and quality control costs will be greatly reduced, and it has strong economic value and is more suitable for medicinal use.
  • the crystalline form CS1 of the invention has a good dissolution rate.
  • the rapid release rate of the crystalline form CS1 can accelerate the rapid dissolution in the body after the administration of the drug, and the drug can be controlled to be quickly exerted in a specific part by adjusting the auxiliary material. The role of increasing the rate of action of the drug.
  • the present invention also provides a crystal form CS7 of Apabetalone (hereinafter referred to as "crystal form CS7").
  • crystal form CS7 is an anhydride.
  • the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks at diffraction angle 2 ⁇ values of 5.9 ° ⁇ 0.2 °, 6.7 ° ⁇ 0.2 °, 10.7 ° ⁇ 0.2 °, and 12.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS7 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 16.9° ⁇ 0.2, and 13.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks in the diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 16.9° ⁇ 0.2, and 13.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has one or more of the diffraction angle 2 ⁇ values of 16.0° ⁇ 0.2°, 25.1° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 21.8° ⁇ 0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks in the diffraction angle 2 ⁇ values of 16.0° ⁇ 0.2°, 25.1° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 21.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has a diffraction angle 2 ⁇ values of 5.9° ⁇ 0.2°, 6.7° ⁇ 0.2°, 10.7° ⁇ 0.2°, 12.5° ⁇ 0.2°, 8.4°. Characteristic peaks are found at ⁇ 0.2°, 16.9° ⁇ 0.2, 13.3° ⁇ 0.2°, 16.0° ⁇ 0.2°, 25.1° ⁇ 0.2°, 15.0° ⁇ 0.2°, 21.8° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS7 is as shown in Figure 6A.
  • the present invention also provides a method for preparing a crystalline form CS7 of Apabetalone, comprising the following steps:
  • Dissolving step dissolving the Apabetalone raw material using a halogenated hydrocarbon solvent to obtain a solution
  • Precipitation step separating solids by gas-liquid diffusion to obtain crystal form CS7 of Apabetalone;
  • the precipitating step comprises: placing the solution in the dissolving step in the first reactor, placing the first reactor in a second reactor containing a ketone solvent, and depositing a solid to obtain a crystal form of Apabetalone CS7 ;
  • the halogenated hydrocarbon comprises chloroform
  • the ketone comprises methyl isobutyl ketone
  • the crystalline form CS7 of the present invention has good stability and can be stably placed for at least 4 weeks in an environment of 25 ° C / 60% RH and 40 ° C / 75% RH.
  • the stability of the crystal form is crucial for the development of the drug.
  • the crystalline form CS7 has good stability and can ensure that the drug does not undergo crystal transformation during the preparation, transportation, storage and preservation, which affects the quality of the drug. It is of great significance to ensure the efficacy and safety of drugs and prevent the occurrence of adverse drug reactions.
  • the present invention also provides a crystal form CS9 of Apabetalone (hereinafter referred to as "crystal form CS9").
  • crystal form CS9 is an anhydride.
  • the X-ray powder diffraction of the crystal form CS9 has a characteristic peak at a diffraction angle 2 ⁇ of 7.3 ° ⁇ 0.2 °, 9.9 ° ⁇ 0.2 °, and 17.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS9 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 13.4° ⁇ 0.2°, 3.9° ⁇ 0.2°, and 12.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks in the diffraction angle 2 ⁇ values of 13.4° ⁇ 0.2°, 3.9° ⁇ 0.2°, and 12.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has one or more of the diffraction angle 2 ⁇ values of 12.1° ⁇ 0.2°, 24.9° ⁇ 0.2°, 22.5° ⁇ 0.2°, and 24.2° ⁇ 0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks in the diffraction angle 2 ⁇ values of 12.1 ⁇ 0.2°, 24.9° ⁇ 0.2°, 22.5° ⁇ 0.2°, and 24.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a diffraction angle 2 ⁇ of 7.3 ° ⁇ 0.2 °, 9.9 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 13.4 ° ⁇ 0.2 °, 3.9 °. Characteristic peaks are found at ⁇ 0.2°, 12.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 24.9° ⁇ 0.2°, 22.5° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 6.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS9 is as shown in Figure 7A.
  • the present invention also provides a method for preparing a crystalline form CS9 of Apabetalone, comprising the following steps:
  • Dissolving step dissolving the Apabetalone raw material by using a mixed solvent of an ether and an alcohol or a mixed solvent of a halogenated hydrocarbon and an alcohol to obtain a solution;
  • a precipitation step volatilizing the solution at room temperature until a solid precipitates to obtain a crystalline form CS9 of Apabetalone;
  • the ether comprises tetrahydrofuran; the alcohol comprises isopropanol; the halogenated hydrocarbon comprises dichloromethane and chloroform; and the volume ratio of the ether to the alcohol is 1:1; The volume ratio of halogenated hydrocarbon to alcohol is 4:1.
  • the crystalline form CS9 of the present invention has good stability and can be stably placed for at least 10 months in an environment of 25 ° C / 60% RH and 40 ° C / 75% RH.
  • the stability of the crystal form is crucial for the development of the drug.
  • the crystal form CS9 maintains good stability and can ensure that the drug does not undergo crystal transformation during the preparation, transportation, storage and preservation, which affects the quality of the drug. It is of great significance to ensure the efficacy and safety of drugs and prevent the occurrence of adverse drug reactions.
  • the crystalline form CS9 of the present invention has almost no hygroscopicity, and the weight gain is only 0.18% in an environment of 80% relative humidity, and the crystal form does not change before and after the wettability test.
  • the almost non-hygroscopic crystal form does not need to control the environmental humidity during the preparation process, and has no special requirements for packaging and storage conditions, cost saving, easy industrial production and long-term storage of medicines. Because the storage conditions are not demanding, the material storage and quality control costs will be greatly reduced, and it has strong economic value and is more suitable for medicinal use.
  • the present invention also provides a crystal form CS11 of Apabetalone (hereinafter referred to as "crystal form CS11").
  • crystal form CS11 is a hydrate.
  • the X-ray powder diffraction of the crystal form CS11 has characteristic peaks at diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, 9.7° ⁇ 0.2°, and 13.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS11 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 4.4° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS11 has characteristic peaks in the diffraction angle 2 ⁇ values of 4.4° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS11 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 13.0° ⁇ 0.2° and 15.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS11 is at a diffraction angle 2 ⁇ value. There are characteristic peaks in 13.0 ° ⁇ 0.2 ° and 15.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS11 has a diffraction angle 2 ⁇ of 7.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, 9.7° ⁇ 0.2°, 13.6° ⁇ 0.2°, 4.4°. Characteristic peaks at ⁇ 0.2°, 16.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.3° ⁇ 0.2°, 22.7° ⁇ 0.2°, 7.6° ⁇ 0.2°, 17.6° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of Form CS11 is shown in Figure 8A.
  • the present invention also provides a process for the preparation of crystalline form CS11 of Apabetalone, comprising the following methods:
  • Dissolution step dissolving the Apabetalone raw material using an alcohol solvent to obtain a solution
  • a precipitation step adding the solution to water or adding water to the solution, and precipitating the solid to obtain a crystal form CS11 of Apabetalone.
  • Method 2 Dissolving step: dissolving the Apabetalone raw material using a mixed solvent of a halogenated hydrocarbon, an alcohol and a ketone, a mixed solvent of an alcohol and an aromatic hydrocarbon to obtain a solution;
  • a precipitation step volatilizing the solution at room temperature until a solid precipitates to obtain Apabetalone crystal form CS11;
  • the alcohol in the method 1 comprises methanol; the alcohol in the method 2 comprises methanol; the ketone comprises acetone and methyl isobutyl ketone; and the volume ratio of the alcohol to the ketone is 1: 1 to 2:1; the volume ratio of the alcohol to the aromatic hydrocarbon is 4:1.
  • the crystalline form CS11 of the present invention has good stability and can be stably placed for at least 6 weeks in an environment of 25 ° C / 60% RH and 40 ° C / 75% RH.
  • the crystalline form CS11 has good stability and can ensure that the drug does not undergo crystal transformation during the preparation, transportation, storage and preservation process, which affects the quality of the drug, ensures the efficacy and safety of the drug, and prevents the occurrence of adverse drug reactions. Significance.
  • the crystalline form CS11 of the present invention has excellent solubility, especially in SGF, the solubility of the crystalline form CS11 is as high as 0.71 mg/mL in 1 hour, and the real-time solubility in the FeSSIF is higher than 0.26 at 1 hour, 4 hours, and 24 hours. Mg/mL.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug.
  • the present invention also provides a crystal form CS4 of Apabetalone (hereinafter referred to as "crystal form CS4").
  • crystal form CS4 is an anhydride.
  • the X-ray powder diffraction of the crystalline form CS4 has characteristic peaks at diffraction angle 2 ⁇ values of 9.1 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 23.5 ° ⁇ 0.2 °, and 24.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS4 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 10.3° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS4 has characteristic peaks in the diffraction angle 2 ⁇ values of 10.3° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS4 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, and 19.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS4 has characteristic peaks in the diffraction angle 2 ⁇ values of 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, and 19.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS4 has a diffraction angle 2 ⁇ of 9.1° ⁇ 0.2°, 14.5° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.2° ⁇ 0.2°, 10.3°. Characteristic peaks are found at ⁇ 0.2°, 25.0° ⁇ 0.2°, 26.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, and 19.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS4 is as shown in Figure 9A.
  • the present invention also provides a process for the preparation of crystalline form CS4 of Apabetalone comprising the steps of heating a crystalline form CS11 of Apabetalone to 200-220 ° C to obtain crystalline form CS4 of Apabetalone.
  • the crystalline form CS4 of the present invention has good long-term stability and mechanical stability, and can be stably placed for at least 10 months under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH, and the stability of the crystal form is on the drug.
  • the development of the crystal is critical.
  • the crystal form CS4 maintains good stability and can ensure that the drug does not undergo crystal transformation during preparation, transportation, storage and preservation, which affects the quality of the drug and ensures the efficacy and safety of the drug. To prevent the occurrence of adverse drug reactions is of great significance.
  • the crystal form of CS4 has not changed after manual grinding, which indicates that the crystal form CS4 has good mechanical stability.
  • the grinding and pulverization of the raw material medicine is often required in the preparation process, and the high grinding stability can reduce the preparation process. There is a risk of crystallinity change and crystal transformation of the drug substance.
  • the crystal form CS4 of the present invention has almost no hygroscopicity, and the weight gain is only 0.12% in an environment of 80% relative humidity, and the crystal form does not change before and after the wettability.
  • the almost non-hygroscopic crystal form does not need to control the environmental humidity during the preparation process, and has no special requirements for packaging and storage conditions, cost saving, easy industrial production and long-term storage of medicines. Because the storage conditions are not demanding, the material storage and quality control costs will be greatly reduced, and it has strong economic value and is more suitable for medicinal use.
  • the crystalline form CS8 In the preparation method of the crystalline form CS2, the crystalline form CS8, the crystalline form CS13, the crystalline form CS20, the crystalline form CS1, the crystalline form CS7, the crystalline form CS9, the crystalline form CS11 and the crystalline form CS4 of the present invention:
  • room temperature is not an accurate temperature value, and refers to a temperature range of 10 to 30 ° C;
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and to stand for volatilization;
  • the rapid volatilization is to place the container open and volatilize;
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm;
  • cooling is accomplished using conventional methods in the art, such as “slow cooling” and “rapid cooling”, “slow cooling” is typically performed at 0.1 °C / minute, and “rapid cooling” generally refers to samples at elevated temperatures for 10 seconds. Transfer quickly to a low temperature environment.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall deviation of the peak angle is caused, usually Make a certain offset.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CS2, crystalline form CS8, crystalline form CS13, crystalline form CS20, crystalline form CS1, crystalline form CS7, crystalline form CS9, crystalline form CS11, and crystalline form CS4 of the present invention are pure, single. Basically, no other crystal forms are mixed.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the invention also provides a mixed crystal form of Apabetalone, which comprises the crystal form CS2, the crystal form CS8, the crystal form CS13, the form form CS20, the form form CS1, the form form CS7, the form form CS9, the form form CS11 of the invention. And a combination of two or more of the crystal forms CS4.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the crystalline form CS2 of the Apabetalone of the present invention, the crystalline form CS8, the crystalline form CS13, the crystalline form CS20, the crystalline form CS1, and the crystal Form CS7, Form CS9, Form CS11 and Form CS4, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides Apabetalone's crystalline form CS2, crystalline form CS8, crystalline form CS13, crystalline form CS20, crystalline form CS1, crystalline form CS7, crystalline form CS9, crystalline form CS11 and crystalline form CS4 in the treatment of cardiovascular, cholesterol or Use in lipid related disorders.
  • the present invention provides Apabetalone's crystalline form CS2, crystalline form CS8, crystalline form CS13, crystalline form CS20, crystalline form CS1, crystalline form CS7, crystalline form CS9, crystalline form CS11 and crystalline form CS4 in preparation for prevention and treatment.
  • Example 1A is an XRPD pattern of a crystal form CS2 obtained according to Example 1 of the present invention.
  • Example 1B is a DSC chart of a crystalline form CS2 obtained according to Example 1 of the present invention.
  • 1C is a TGA diagram of a crystalline form CS2 obtained according to Example 1 of the present invention.
  • Example 2A is an XRPD of a crystalline form CS8 obtained according to Example 2 of the present invention.
  • Example 2B is a DSC chart of the crystal form CS8 obtained according to Example 2 of the present invention.
  • 2C is a TGA diagram of a crystalline form CS8 obtained in accordance with Example 2 of the present invention.
  • Figure 2D is an XRPD overlay of the crystalline CS8 placed at 25 °C / 60% RH for 2 weeks (from top to bottom, XRPD before placement, XRPD placed at 25 °C / 60% RH for 2 weeks) Figure).
  • 2E is a DVS diagram of a crystalline form CS8 obtained according to Example 2 of the present invention.
  • 2F is an XRPD overlay of the crystal form CS8 obtained according to Example 2 of the present invention before and after the DVS test.
  • Figure 3A is an XRPD pattern of a crystalline form CS13 obtained in accordance with Example 3 of the present invention.
  • Figure 3B is a DSC chart of the crystalline form CS13 obtained in accordance with Example 3 of the present invention.
  • Figure 3C is a TGA diagram of a crystalline form CS13 obtained in accordance with Example 3 of the present invention.
  • 4A is an XRPD pattern of a crystalline form CS20 obtained according to Example 4 of the present invention.
  • 4B is a DSC chart of a crystalline form CS20 obtained according to Example 4 of the present invention.
  • 4C is a TGA diagram of a crystalline form CS20 obtained in accordance with Example 4 of the present invention.
  • 4D is a 1 H NMR chart of the crystalline form CS20 obtained according to Example 4 of the present invention.
  • Figure 4E is an XRPD overlay of the crystalline CS20 placed at 25 °C / 60% RH and 40 °C / 75% RH for 2 weeks (from top to bottom, the XRPD pattern before placement, placed at 25 ° C / 60% The XRPD pattern for 2 weeks under RH conditions was placed in an XRPD pattern for 2 weeks at 40 ° C / 75% RH).
  • Figure 5C is a TGA diagram of the crystalline form CS1 obtained in Process 1 of Example 5 of the present invention.
  • Figure 5D is an XRPD pattern of the crystalline form CS1 obtained in Process 2 of Example 5 of the present invention.
  • Figure 5E is an XRPD overlay of the crystalline CS1 placed at 25 °C / 60% RH and 40 °C / 75% RH for 10 months (from top to bottom, the XRPD pattern before placement, placed at 25 ° C / 60 The 10-month XRPD pattern under %RH conditions was placed in a 10 month XRPD pattern at 40 °C / 75% RH).
  • Figure 5F is a DVS diagram of a crystalline form CS1 obtained in accordance with Example 5 of the present invention.
  • 5G is an XRPD overlay of the crystal form CS1 obtained according to Example 5 of the present invention before and after the DVS test.
  • Fig. 5H is an XRPD overlay of the crystal form CS1 obtained according to Example 5 of the present invention before and after polishing.
  • Figure 6A is an XRPD pattern of a crystalline form CS7 obtained in accordance with Example 6 of the present invention.
  • Figure 6B is a DSC chart of the crystalline form CS7 obtained in accordance with Example 6 of the present invention.
  • Figure 6D is an XRPD overlay of the crystalline CS7 placed at 25 °C / 60% RH and 40 °C / 75% RH for 4 weeks and 80 °C for 1 day (from top to bottom before the crystal form CS7 is placed) XRPD pattern, XRPD pattern placed at 25 ° C / 60% RH for 4 weeks, XRPD pattern placed at 40 ° C / 75% RH for 4 weeks and XRPD pattern placed at 80 ° C for 1 day).
  • 6E is an XRPD overlay of the crystal form CS7 obtained in Example 6 according to the present invention before and after the DVS test.
  • Figure 7A is an XRPD pattern of a crystalline form CS9 obtained in accordance with Example 7 of the present invention.
  • Figure 7B is a DSC chart of the crystalline form CS9 obtained according to Example 7 of the present invention.
  • Figure 7C is a TGA diagram of a crystalline form CS9 obtained in accordance with Example 7 of the present invention.
  • Figure 7D is an XRPD overlay of the crystalline CS9 placed at 25 °C / 60% RH and 40 °C / 75% RH for 10 months (from top to bottom, the XRPD pattern before placement, placed at 25 ° C / 60 The 10-month XRPD pattern under %RH conditions was placed in a 10 month XRPD pattern at 40 °C / 75% RH).
  • Figure 7E is a DVS diagram of a crystalline form CS9 obtained in accordance with Example 7 of the present invention.
  • Example 7F is an XRPD overlay of the crystal form CS9 obtained according to Example 7 of the present invention before and after the DVS test.
  • Fig. 8A is an XRPD pattern of the crystal form CS11 obtained in the production method 1 of Example 8 according to the present invention.
  • Figure 8B is a DSC chart of the crystalline form CS11 obtained in Process 1 of Preparation Example 8 according to the present invention.
  • Figure 8C is a TGA diagram of the crystalline form CS11 obtained in Process 1 of Preparation Example 8 according to the present invention.
  • Figure 8D is an XRPD pattern of the crystalline form CS11 obtained in Process 2 of Example 8 according to the present invention.
  • Figure 8E is an XRPD overlay of the crystalline form CS11 placed at 25 ° C / 60% RH and 40 ° C / 75% RH for 6 weeks (from top to bottom, the XRPD pattern before placement, placed at 25 ° C / 60% The XRPD pattern for 6 weeks under RH conditions was placed in an XRPD pattern of 6 weeks at 40 ° C / 75% RH).
  • Figure 9A is an XRPD pattern of a crystalline form CS4 obtained in accordance with Example 9 of the present invention.
  • Figure 9B is a DSC chart of the crystalline form CS4 obtained in accordance with Example 9 of the present invention.
  • Figure 9C is a TGA diagram of a crystalline form CS4 obtained in accordance with Example 9 of the present invention.
  • Figure 9D is an XRPD overlay of the crystalline CS4 placed at 25 °C / 60% RH and 40 °C / 75% RH for 10 months (from top to bottom, the XRPD pattern before placement, placed at 25 ° C / 60 10-month XRPD pattern under %RH conditions, placed in XRPD for 10 months at 40 °C / 75% RH)
  • Figure 9F is an XRPD overlay of the pattern CS4 obtained prior to DVS testing according to Example 9 of the present invention.
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis.
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1 to 5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2 to 10 mg/mL.
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software
  • the analysis software is DVS-Intrinsic Analysis software.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • the dissolution data in the present invention was determined from the Agilent 708-DS.
  • Samples 1-a to 1-i were all crystalline form CS2 by XRPD.
  • Sample 1-i was selected for test characterization, and its XRPD is shown in Figure 1A and Table 1.2. Its DSC is shown in Figure 1B.
  • the first endothermic peak begins to appear when heated to 60 °C.
  • the second endothermic peak begins to appear when heated to 113 °C.
  • the first exothermic peak begins to heat up to 126 °C and is heated to 232.
  • a third endothermic peak begins to appear at °C. Its TGA, as shown in Figure 1C, had a mass loss gradient of about 3.4% when heated to 100 °C.
  • the Apabetalone crystal form CS2 provided by the present invention has good solubility in both SGF and FeSSIF, especially in SGF solution, and its solubility in 24 hours can reach 0.61 mg/mL.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug, which is of great significance for drug research.
  • a certain amount of Apabetalone raw material was weighed and dissolved in a certain volume of solvent in Table 2.1 at T 1 temperature. After filtration, it was slowly or rapidly cooled to T 2 . After solid precipitation, the solid was collected by centrifugation and dried to obtain a sample.
  • a sample of Apabetalone crystal form CS8 was placed in a 25 ° C / 60% RH constant temperature and humidity chamber for 2 weeks, and then XRPD and purity were sampled. The results are shown in Fig. 2D (from top to bottom, the pre-XRPD pattern of the crystal form CS8 was placed, and the XRPD pattern was placed for 2 weeks under the condition of 25 ° C / 60% RH).
  • Apabetalone crystal form CS8 was placed at 25 ° C / 60% RH for 2 weeks, and the crystal form and purity did not change significantly. The above test results show that Apabetalone crystal form CS8 has good stability.
  • the Apabetalone crystal form CS8 provided by the present invention has better solubility in SGF and FeSSIF.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug, which is of great significance for drug research.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the Apabetalone crystal form CS8 of the present invention has a weight gain of 0.34% after being equilibrated at 80% humidity, and is slightly hygroscopic according to the definition standard of the wet weight gain.
  • the XRPD pattern of the crystalline form CS8 after the wettability test was as shown in Fig. 2F. It was found that the crystal form did not change before and after the test, indicating that the crystalline form CS8 has good humidity stability.
  • a certain amount of Apabetalone raw material was weighed, dissolved in a certain volume of solvent in Table 3.1, filtered, and slowly volatilized at room temperature without adding a high polymer or adding a polymer until a solid precipitated to obtain a sample.
  • the "polymer” is polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose.
  • the mixture has a mass ratio of 1:1:1:1:1.
  • Samples 3-a to 3-d were all crystalline form CS13 by XRPD.
  • Sample 3-d was selected for test characterization, and its XRPD is shown in Figure 3A and Table 3.2.
  • the DSC starts to appear at the first endothermic peak when heated to 70 °C, and a second endothermic peak appears when heated to 86 °C.
  • a third endothermic peak begins to appear, and heating starts at 205 °C.
  • a fourth endothermic peak appeared, heating to 207 ° C showed the first exothermic peak, heating to 230 ° C began to appear the fifth endothermic peak.
  • the TGA as shown in Figure 3C, had a mass loss gradient of about 11.9% when heated to 100 °C.
  • the prepared Apabetalone crystal form CS13 sample was separately prepared into a saturated solution by SGF, FeSSIF of pH 5.0, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 1 hour, 4 hours and 24 hours.
  • the solubility data of the Apabetalone crystal form CS13 of the present invention is shown in Table 3.3.
  • Samples 4-a to 4-b were all Apabetalone crystal form CS20 by XRPD.
  • Sample 4-a was selected for test characterization, and its XRPD is shown in Figure 4A and Table 4.2. Its DSC is as shown in Fig. 4B.
  • DSC is as shown in Fig. 4B.
  • the first endothermic peak begins to appear.
  • a second endothermic peak appears.
  • a third endothermic peak begins to appear and is heated to 207.
  • the fourth endothermic peak begins to appear at °C, and a fifth endothermic peak begins to appear near 230 °C.
  • the Apabetalone crystal form CS20 sample was placed in a constant temperature and humidity chamber at 25 ° C / 60% RH and 40 ° C / 75% RH for 2 weeks, and then XRPD and purity were sampled.
  • the result is shown in Figure 4E (from top to bottom, before the crystal form CS20 is placed) XRPD pattern, placed at 25 ° C / 60% RH for 2 weeks, placed at 40 ° C / 75% RH for 2 weeks XRPD), Apabetalone crystal form CS20 at 25 ° C / 60% RH and 40 ° C / 75% After 2 weeks at RH, the crystal form remained unchanged and the purity was not significantly reduced.
  • the above test results show that Apabetalone crystal form CS20 has good stability.
  • the prepared Apabetalone crystal form CS20 sample was prepared into a saturated solution by SGF, FeSSIF of pH 5.0, respectively, and the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content.
  • the solubility data of the Apabetalone crystal form CS20 of the present invention is shown in Table 4.3.
  • the Apabetalone crystal form CS20 provided by the present invention has better solubility in SGF and FeSSIF.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug, which is of great significance for drug research.
  • the preparation method of Apabetalone crystal form CS1 includes the following steps:
  • Dissolution step about 10 mg of Apabetalone raw material was dissolved using a positive solvent in Table 5.1 below, and filtered to obtain a solution;
  • a precipitation step adding the solution dropwise to the anti-solvent in Table 5.1 or adding the anti-solvent dropwise to the solution, stirring to a large amount of solid precipitation, collecting the solid by centrifugation, and drying to obtain Apabetalone crystal form CS1;
  • Samples 5-a to 5-i were all Apabetalone crystal form CS1 by XRPD.
  • Sample 5-a was selected for test characterization, and its XRPD is shown in Figure 5A and Table 5.2.
  • the DSC starts to appear at the first endothermic peak when heated to 207 ° C, and the first exothermic peak appears when heated to 211 ° C.
  • the second endothermic peak begins to appear when heated to 231 ° C.
  • Its TGA, as shown in Figure 5C had a mass loss gradient of about 0.7% when heated to 200 °C.
  • the preparation method of Apabetalone crystal form CS1 includes the following steps:
  • Precipitation step rapid cooling or slow cooling to -20 ⁇ 5 ° C, precipitated solid, centrifuged to collect solids, dried to obtain Apabetalone crystal form CS1;
  • Apabetalone crystal form CS1 was allowed to stand at 25 ° C / 60% RH, 40 ° C / 75% RH for 10 months, the crystal form remained unchanged, and the purity did not change significantly.
  • the above test results show that the Apabetalone crystal form CS1 has excellent stability and high crystal purity.
  • the prepared Apabetalone crystal form CS1 sample was prepared into a saturated solution by SGF, FeSSIF of pH 5.0, respectively, and the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content.
  • the solubility data of the Apabetalone crystal form CS1 of the present invention is shown in Table 5.6.
  • the crystal form CS1 of the invention has low wettability, and can well resist the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unprocessability of the preparation caused by external factors such as environmental moisture, and is advantageous for preparation of the preparation. Accurate quantification and later transport and storage.
  • the results show that under the action of certain mechanical stress, the Apabetalone crystal form CS1 of the present invention does not change, and the crystallinity does not change significantly, and the stable physical and chemical properties can be maintained, which is suitable for medicine and storage.
  • the grinding and pulverization of the raw material medicine is often required in the preparation process, and the high grinding stability can reduce the risk of crystallinity change and crystal transformation of the raw material medicine during the processing of the preparation.
  • microcrystalline cellulose, croscarmellose sodium and 2 mg of magnesium stearate were weighed and mixed for 2 minutes. It was pressed into a piece by a manual tableting machine, and a circular die having a diameter of 20 mm was pressed at a pressure of 5 kN. Manually passed through a 20 mesh screen, 2 mg of magnesium stearate was added and mixed for 1 minute. The above mixture was filled into a 1# capsule shell. Packed in 35cc HDPE (high density polyethylene) bottles (one per bottle), each bottle contains 1g desiccant and sealed with a sealing machine. The composition of the preparation (per 200 mg) is shown in Table 5.8 below, and it was detected that the crystalline form CS1 was stably present in the preparation.
  • the obtained capsules were tested for dissolution and the test conditions were as follows:
  • Dissolution method slurry method
  • the dissolution rate of the crystalline form CS1 is shown in Fig. 5I.
  • the results show that the dissolution rate of the crystalline form CS1 is fast, and the elution amount at 20 min can reach more than 90%.
  • the rapid dissolution rate of the drug can accelerate the rapid dissolution in the body after the administration of the drug, and the drug can be controlled to act at a specific site to improve the onset rate of the drug by adjusting the auxiliary material.
  • the preparation method of Apabetalone crystal form CS7 includes the following steps:
  • Dissolution step 5.3 mg of Apabetalone raw material was dissolved in 1 mL of chloroform and filtered to obtain a solution;
  • Precipitation step the solution was placed in a 3 mL glass bottle, and the glass bottle containing the solution was placed in a 20 mL glass bottle containing 5 mL of methyl isobutyl ketone, and sealed at room temperature for a period of time until solid. The precipitate was collected by centrifugation and dried to obtain Apabetalone crystal form CS7.
  • the XRPD of Form CS7 is shown in Figure 6A and Table 6.1.
  • the prepared Apabetalone crystal form CS7 sample was prepared into a saturated solution by SGF, FeSSIF of pH 5.0, respectively, and the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content.
  • the solubility data of the Apabetalone crystal form CS7 of the present invention is shown in Table 6.2.
  • the Apabetalone crystal form CS7 provided by the present invention has better solubility in SGF and FeSSIF.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug, which is of great significance for drug research.
  • the Apabetalone crystal form CS7 of the present invention has a weight gain of 0.79% after being equilibrated at 80% humidity, and is slightly hygroscopic according to the definition of the wettability weight gain.
  • the XRPD pattern of the crystalline form CS7 after the wettability test was as shown in Fig. 6E, and it was found that the crystal form did not change before and after the test, indicating that the crystalline form CS7 has good humidity stability.
  • the preparation method of Apabetalone crystal form CS9 comprises the following steps:
  • Dissolution step about 10 mg of Apabetalone material was dissolved using the solvent in Table 7.1 below, and filtered to obtain a solution;
  • Sample 7-b was selected for test characterization, and its XRPD is shown in Figure 7A, Table 7.2. Its DSC, as shown in Fig. 7B, began to appear at the first endothermic peak when heated to 203 °C. Its TGA, as shown in Figure 7C, had a mass loss gradient of about 0.9% when heated to 200 °C.
  • Apabetalone crystal form CS9 was allowed to stand at 25 ° C / 60% RH, 40 ° C / 75% RH for 10 months, the crystal form remained unchanged, and the purity did not change significantly.
  • the above test results show that Apabetalone crystal form CS9 has good stability.
  • the prepared Apabetalone crystal form CS9 sample was made into a saturated solution by SGF, FeSSIF of pH 5.0, respectively, and the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content.
  • the solubility data of the Apabetalone crystal form CS9 of the present invention is shown in Table 7.3.
  • Approximately 10 mg of the Apabetalone crystal form CS9 of the present invention was tested for its wettability by a dynamic moisture adsorption (DVS) instrument.
  • the experimental results are shown in Table 7.4.
  • the DVS pattern of the wettability test of Apabetalone crystal form CS9 is shown in Fig. 7E.
  • the XRPD pattern of the crystalline form CS9 after the wettability test was as shown in Fig. 7F, and it was found that the crystal form did not change before and after the test, indicating that the crystalline form CS9 has good humidity stability.
  • the Apabetalone crystal form CS9 of the present invention has a weight gain of 0.18% after being equilibrated at 80% humidity, and is almost non-wettable according to the definition of the wettability weight gain.
  • the use of the crystalline form CS9 of the present invention can well resist the problem of crystal instability in the process of pharmaceutical preparation and/or storage, and the unworkability of the preparation caused by external factors such as environmental moisture, and is advantageous for accurate quantification in preparation of the preparation. And later transportation and storage.
  • the preparation method of Apabetalone crystal form CS11 comprises the following steps:
  • Dissolution step about 10 mg of Apabetalone raw material is dissolved using 1.7 mL of methanol, and filtered to obtain a solution;
  • Precipitation step The solution was added to 3 mL of water or 3 mL of water was added to the solution, stirred until a large amount of solid precipitated, and the solid was collected by centrifugation, and dried to obtain Apabetalone crystal form CS11.
  • Sample 8-b was selected for test characterization, and its XRPD data is shown in Figure 8A, Table 8.2. Its DSC is as shown in Fig. 8B. When it is heated to 49 °C, the first endothermic peak begins to appear. When heated to 206 °C, a second endothermic peak appears. When heated to 208 °C, the first exothermic peak appears and is heated to 230 °C. A third endothermic peak begins to appear. Its TGA, as shown in Figure 8C, had a mass loss gradient of about 3.0% when heated to 100 °C.
  • the preparation method of Apabetalone crystal form CS11 comprises the following steps:
  • Dissolution step about 10 mg of Apabetalone material was dissolved using the solvent in Table 8.3 below, and filtered to obtain a solution;
  • Precipitation step The solution was slowly volatilized at room temperature until solids were precipitated to obtain Apabetalone crystal form CS11.
  • Apabetalone crystal form CS11 was placed at 25 ° C / 60% RH, 40 ° C / 75% RH for 6 weeks, the crystal form remained unchanged, and the purity did not change significantly.
  • the above test results show that Apabetalone crystal form CS11 has good stability.
  • the prepared sample of Apabetalone crystal form CS11 was prepared into a saturated solution by SGF, FeSSIF of pH 5.0, respectively, and the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content.
  • the solubility data of the Apabetalone crystal form CS11 of the present invention is shown in Table 8.5.
  • the Apabetalone crystal form CS11 provided by the present invention has excellent solubility in both SGF and FeSSIF.
  • the high solubility crystal form is beneficial to increase the blood concentration of the drug in the human body and improve the bioavailability of the drug, which is of great significance for drug research.
  • the Apabetalone crystal form CS11 was heated to 220 ° C to obtain Apabetalone crystal form CS4.
  • Apabetalone crystal form CS4 was allowed to stand at 25 ° C / 60% RH, 40 ° C / 75% RH for 10 months, the crystal form remained unchanged, and the purity did not change significantly.
  • the above test results show that Apabetalone crystal form CS4 has excellent stability.
  • the XRPD pattern of the crystalline form CS4 after the wettability test was as shown in Fig. 9F, and it was found that the crystal form did not change before and after the test, indicating that the crystalline form CS4 has good humidity stability.
  • the crystal form CS4 of the invention has low wettability, and can well resist the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unprocessability of the preparation caused by external factors such as environmental moisture, and is advantageous for preparation of the preparation. Accurate quantification and later transport and storage.
  • the Apabetalone Form CS4 sample of the present invention was placed in a mortar and manually ground for 5 minutes to test the solid XRPD. The result is shown in Fig. 9G.
  • the results show that under the action of certain mechanical stress, the Apabetalone crystal form CS4 of the present invention does not change, and the crystallinity does not change significantly, and the stable physical and chemical properties can be maintained, which is suitable for medicine and storage.
  • the grinding and pulverization of the raw material medicine is often required in the preparation process, and the high grinding stability can reduce the risk of crystallinity change and crystal transformation of the raw material medicine during the processing of the preparation.

Abstract

一种式I所示的溴结构域蛋白抑制剂2-[4-(2-羟基乙氧基)-3,5-二甲基苯基]-5,7-二甲氧基喹唑啉-4(3H)-酮的晶型及其制备方法和用途，属于医药领域。所述晶型为晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11及晶型CS4，可用于制备治疗心血管、胆固醇或脂质相关紊乱疾病的药物。

Description

一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途 技术领域
本发明涉及一种2-[4-(2-羟基乙氧基)-3,5-二甲基苯基]-5,7-二甲氧基喹唑啉-4(3H)-酮的晶型及其制备方法和用途，属于医药领域。
背景技术
2-[4-(2-羟基乙氧基)-3,5-二甲基苯基]-5,7-二甲氧基喹唑啉-4(3H)-酮，又名Apabetalone，是一种溴结构域(BET)蛋白抑制剂，由加拿大雷斯韦洛吉克斯公司(Resverlogix)研发，属于治疗心血管、胆固醇或脂质相关紊乱疾病的药物，尤其是治疗动脉粥样硬化、急性冠脉综合症和前驱糖尿病具有显著疗效。所述Apabetalone的结构式为：
Figure PCTCN2017115143-appb-000001
心血管疾病，又称为循环系统疾病，可以细分为急性疾病和慢性疾病，一般都是与动脉硬化有关。心血管疾病是当今世界上威胁人类生命的最严重的疾病之一，其发病率和死亡率已超过肿瘤性疾病而跃居第一。仅中国约有2.9亿心血管病患者，并且患病人数在逐年的增加，然而治疗心血管疾病类的药物尚未满足人们的需求，需要不断开发新的药物。研究表明，Apabetalone能够对BET家族中的BRD4区域有抑制作用，从而调节载脂蛋白A-1(ApoA-1)的表达和高密度脂蛋白胆固醇的合成，实现心血管相关疾病的治疗。经国内外专利与文献检索，未发现有关Apabetalone的晶型专利或文献报道。
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。本申请发明人经过了大量的实验研究，发现了Apabetalone的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4，为含Apabetalone的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
发明内容
本申请发明人经过了大量的实验研究，发现了Apabetalone的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4，上述晶型稳定性好，在25℃/60％RH和/或40℃/75％RH条件至少可稳定放置2周，进一步的至少可稳定放置4周，进一步的至少可稳定放置6周，进一步的至少可稳定放置10个月；本申请发明人发现的晶型制备方法简单，重复性好，晶型纯度高，且具有良好的溶解性和低引湿性，符合药用要求，适合生产应用。
本发明的主要目的是提供Apabetalone的晶型及其制备方法和用途。
根据本发明的目的，本发明提供Apabetalone的晶型CS2(以下称作“晶型CS2”)。所述晶型CS2为水合物。
使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为11.5°±0.2°、6.6°±0.2°、8.8°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为5.1°±0.2°、15.3°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为5.1°±0.2°、15.3°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS2的X射线粉末衍射在衍射角2θ值为11.5°±0.2°、6.6°±0.2°、8.8°±0.2°、5.1°±0.2°、15.3°±0.2°、13.3°±0.2°、20.2°±0.2°、23.1°±0.2°、25.3°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS2的X射线粉末衍射谱图如图1A所示。
根据本发明的目的，本发明还提供了Apabetalone的晶型CS2的制备方法，将Apabetalone原料加入到醇类、醇类和醚类的混合溶剂、醇类和酮类的混合溶剂、醇类和芳香烃的混合溶剂中的一种中，加热溶解后过滤，降温析出固体，得到Apabetalone的晶型CS2。
其中：所述醇类包含甲醇；所述醚类包含2-甲基四氢呋喃；所述芳香烃包含甲苯；所述酮类包含甲基异丁基酮；所述加热温度为50～100℃；所述析晶温度为-20～5℃。
本发明的晶型CS2的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS2。
2)本发明的晶型CS2，在SGF(模拟人胃液)，FeSSIF(进食状态下人工肠液)中均具有良好的溶解性，尤其在SGF中，晶型CS2在24小时的溶解度高达0.61mg/mL。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度，对药物研究具有重要意义。
根据本发明的目的，本发明还提供Apabetalone的晶型CS8(以下称作“晶型CS8”)。所述晶型CS8为无水物。
使用Cu-Kα辐射，所述晶型CS8的X射线粉末衍射在衍射角2θ值为23.9°±0.2°、13.5°±0.2°、7.8°±0.2°、22.5°±0.2°、11.4°±0.2°处有特征峰。
进一步的，所述晶型CS8的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、13.1°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS8的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、13.1°±0.2°中均有特征峰。
进一步的，所述晶型CS8的X射线粉末衍射在衍射角2θ值为28.1°±0.2°、20.2°±0.2°一处或两处有特征峰。优选的，所述晶型CS8的X射线粉末衍射在衍射角2θ值为28.1°±0.2°、20.2°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS8的X射线粉末衍射在衍射角2θ值为23.9°±0.2°、13.5°±0.2°、7.8°±0.2°、22.5°±0.2°、11.4°±0.2°、25.9°±0.2°、13.1°±0.2°、28.1°±0.2°、20.2°±0.2°、9.7°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS8的X射线粉末衍射谱图如图2A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS8的制备方法，将Apabetalone原料加入到卤代烃或者卤代烃和醇类的混合溶剂中，加热溶解后过滤，降温析出固体，得到Apabetalone的晶型CS8。
其中：所述卤代烃包含二氯甲烷；所述醇类包含异丙醇；所述卤代烃和醇类的体积比为4:1；所述加热温度为40～60℃，优选为50℃；所述析晶温度为-20～5℃。
本发明的晶型CS8的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS8。
2)本发明的晶型CS8具有良好的长期稳定性，在25℃/60％RH环境下至少可稳定放置2周，便于长期存储，晶型CS8保持较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
3)本发明的晶型CS8引湿性低，80％相对湿度下增重0.34％，属于略有引湿性，制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，更适合药用。
根据本发明的目的，本发明还提供Apabetalone的晶型CS13(以下称作“晶型CS13”)。所述晶型CS13为水合物。
使用Cu-Kα辐射，所述晶型CS13的X射线粉末衍射在衍射角2θ值为5.1°±0.2°、12.5°±0.2°、17.1°±0.2°处有特征峰。
进一步的，所述晶型CS13的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、8.5°±0.2°、25.7°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS13的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、8.5°±0.2°、25.7°±0.2°中均有特征峰。
进一步的，所述晶型CS13的X射线粉末衍射在衍射角2θ值为7.8°±0.2°、16.0°±0.2°一处或两处有特征峰。优选的，所述晶型CS13的X射线粉末衍射在衍射角2θ值为7.8°±0.2°、16.0°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS13的X射线粉末衍射在衍射角2θ值为5.1°±0.2°、12.5°±0.2°、17.1°±0.2°、6.4°±0.2°、8.5°±0.2°、25.7°±0.2°、7.8°±0.2°、16.0°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS13的X射线粉末衍射谱图如图3A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS13的制备方法，将Apabetalone原料加入醚类和水的混合溶剂或者酮类和水的混合溶剂中，溶解过滤后放置在室温下挥发，析出固体，得到Apabetalone的晶型CS13。
其中：所述醚类包含四氢呋喃；所述酮类包含丙酮；优选的，所述醚类和水的体积比为4:1；所述酮类和水的体积比是9:1。
本发明的晶型CS13的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS13。
2)本发明的晶型CS13，在SGF，FeSSIF中均具有良好的溶解性。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度。
根据本发明的目的，本发明还提供Apabetalone的晶型CS20(以下称作“晶型CS20”)。所述晶型CS20为乙酸溶剂合物。
使用Cu-Kα辐射，所述晶型CS20的X射线粉末衍射在衍射角2θ值为8.4°±0.2°、18.9°±0.2°、13.5°±0.2°处有特征峰。
进一步的，所述晶型CS20的X射线粉末衍射在衍射角2θ值为11.3°±0.2°、9.4°±0.2°、5.6°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS20的X射线粉末衍射在衍射角2θ值为11.3°±0.2°、9.4°±0.2°、5.6°±0.2°中均有特征峰。
进一步的，所述晶型CS20的X射线粉末衍射在衍射角2θ值为26.3°±0.2°、20.1°±0.2°、20.6°±0.2°、24.4°±0.2°一处或多处有特征峰。优选的，所述晶型CS20的X射线粉末衍射在衍射角2θ值为26.3°±0.2°、20.1°±0.2°、20.6°±0.2°、24.4°±0.2°中均有特征峰。
进一步的，所述晶型CS20的X射线粉末衍射在衍射角2θ值为14.5°±0.2°、16.9°±0.2°、22.8°±0.2°一处或两处或三处有特征峰。优选的，所述晶型CS20的X射线粉末衍射在衍射角2θ值为14.5°±0.2°、16.9°±0.2°、22.8°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS20的X射线粉末衍射在衍射角2θ值为8.4°±0.2°、18.9°±0.2°、13.5°±0.2°、11.3°±0.2°、9.4°±0.2°、5.6°±0.2°、26.3°±0.2°、20.1°±0.2°、20.6°±0.2°、24.4°±0.2°、14.5°±0.2°、16.9°±0.2°、22.8°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS20的X射线粉末衍射谱图如图4A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS20的制备方法，所述制备方法包括将Apabetalone加入到腈类和乙酸的混合溶剂或者酯类和乙酸的混合溶剂中，过滤后放置在室温下挥发，析出固体，得到Apabetalone的晶型CS20。
其中：所述腈类包括乙腈；所述酯类包括乙酸乙酯；所述腈类和乙酸的体积比为9：1；所述酯类和乙酸的体积比为4：1。
本发明的晶型CS20的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS20。
2)本发明的晶型CS20具有良好的长期稳定性，在25℃/60％RH和40℃/75％RH环境下至少可稳定放置2周。晶型CS20具有较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
3)本发明的晶型CS20，在SGF，FeSSIF中均具有良好的溶解性。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度。
根据本发明的目的，本发明还提供Apabetalone的晶型CS1(以下称作“晶型CS1”)。 所述晶型CS1为无水物。
使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在衍射角2θ值为6.1°±0.2°、12.3°±0.2°、26.1°±0.2°、26.8°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为16.4°±0.2°、18.5°±0.2°、23.2°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为16.4°±0.2°、18.5°±0.2°、23.2°±0.2°中均有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为13.0°±0.2°、14.1°±0.2°、17.1°±0.2°、24.5°±0.2°中的一处或多处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为13.0°±0.2°、14.1°±0.2°、17.1°±0.2°、24.5°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在衍射角2θ值为6.1°±0.2°、12.3°±0.2°、26.1°±0.2°、26.8°±0.2°、16.4°±0.2°、18.5°±0.2°、23.2°±0.2°、13.0°±0.2°、14.1°±0.2°、17.1°±0.2°、24.5°±0.2°、20.5°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射谱图如图5A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS1的制备方法，包括以下方法：
方法1)溶解步骤：使用正溶剂将Apabetalone原料溶解，得到溶液；
析出步骤：将所述溶液添加至反溶剂中或者将反溶剂添加至所述溶液中，析出固体，得到Apabetalone的晶型CS1；
所述正溶剂包括：四氢呋喃、氯仿、二甲基亚砜、二甲基乙酰胺中的一种或两种以上的组合；所述反溶剂包括：正庚烷、甲基叔丁基醚、甲苯、水、乙腈中的一种或两种以上的组合。
方法2)溶解步骤：在40～60℃下，将Apabetalone原料在溶剂中溶解，得到溶液；
析出步骤：将所述溶液温度降至-20～5℃，析出固体，得到Apabetalone的晶型CS1；
所述溶剂包括四氢呋喃、丙酮、四氢呋喃和甲基叔丁基醚的混合溶剂、乙酸乙酯和丙酮的混合溶剂、乙腈和N,N-二甲基甲酰胺的混合溶剂中的一种。
优选的，所述四氢呋喃和甲基叔丁基醚的体积比为2:1，所述乙酸乙酯和丙酮的体积比为1:1，所述乙腈和N,N-二甲基甲酰胺的体积比为9:1。
本发明的晶型CS1的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS1。
2)本发明的晶型CS1具有良好的长期稳定性和机械稳定性，在25℃/60％RH和40℃/75％RH环境下至少可稳定放置10个月，晶型的稳定性对药物的开发是至关重要的，晶型CS1具有较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。此外，晶型CS1经过手动研磨后晶型未发生变化，说明晶型CS1具有较好的机械稳定性，制剂加工过程中常需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
3)本发明的晶型CS1几乎无引湿性，80％相对湿度下增重仅0.13％，且引湿性前后晶 型未发生改变。几乎无引湿性的晶型在制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，更适合药用。
4)本发明的晶型CS1具有很好的溶出速率，在制剂开发中，晶型CS1具有快速的溶出速率可加快药物服用后在体内快速溶解，可通过调整辅料，控制药物在特定部位快速发挥作用，提高药物的起效速率。
根据本发明的目的，本发明还提供Apabetalone的晶型CS7(以下称作“晶型CS7”)。所述晶型CS7为无水物。
使用Cu-Kα辐射，所述晶型CS7的X射线粉末衍射在衍射角2θ值为5.9°±0.2°、6.7°±0.2°、10.7°±0.2°、12.5°±0.2°处有特征峰。
进一步的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为8.4°±0.2°、16.9°±0.2、13.3°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为8.4°±0.2°、16.9°±0.2、13.3°±0.2°中均有特征峰。
进一步的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为16.0°±0.2°、25.1°±0.2°、15.0°±0.2°、21.8°±0.2°中的一处或多处有特征峰。优选的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为16.0°±0.2°、25.1°±0.2°、15.0°±0.2°、21.8°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS7的X射线粉末衍射在衍射角2θ值为5.9°±0.2°、6.7°±0.2°、10.7°±0.2°、12.5°±0.2°、8.4°±0.2°、16.9°±0.2、13.3°±0.2°、16.0°±0.2°、25.1°±0.2°、15.0°±0.2°、21.8°±0.2°、24.5°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS7的X射线粉末衍射谱图如图6A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS7的制备方法，包括以下步骤：
溶解步骤：使用卤代烃溶剂将Apabetalone原料溶解，得到溶液；
析出步骤：通过气液扩散的方式析出固体，得到Apabetalone的晶型CS7；
所述析出步骤包括：将溶解步骤中溶液置于第一反应器中，将第一反应器敞口放置于含有酮类溶剂的第二反应器中，至有固体析出，得到Apabetalone的晶型CS7；
优选的，所述卤代烃包含氯仿，所述酮类包含甲基异丁基酮。
本发明的晶型CS7的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS7。
2)本发明的晶型CS7具有良好的稳定性，在25℃/60％RH和40℃/75％RH环境下至少可稳定放置4周。晶型的稳定性对药物的开发是至关重要的，晶型CS7具有较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
根据本发明的目的，本发明还提供Apabetalone的晶型CS9(以下称作“晶型CS9”)。所述晶型CS9为无水物。
使用Cu-Kα辐射，所述晶型CS9的X射线粉末衍射在衍射角2θ值为7.3°±0.2°、9.9°±0.2°、17.0°±0.2°处有特征峰。
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为13.4°±0.2°、3.9°±0.2°、12.8°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为13.4°±0.2°、3.9°±0.2°、12.8°±0.2°中均有特征峰。
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为12.1°±0.2°、24.9°±0.2°、22.5°±0.2°、24.2°±0.2°中的一处或多处有特征峰。优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为12.1°±0.2°、24.9°±0.2°、22.5°±0.2°、24.2°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS9的X射线粉末衍射在衍射角2θ值为7.3°±0.2°、9.9°±0.2°、17.0°±0.2°、13.4°±0.2°、3.9°±0.2°、12.8°±0.2°、12.1°±0.2°、24.9°±0.2°、22.5°±0.2°、24.2°±0.2°、6.0°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS9的X射线粉末衍射谱图如图7A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS9的制备方法，包括以下步骤：
溶解步骤：使用醚类和醇类的混合溶剂或卤代烃和醇类的混合溶剂将Apabetalone原料溶解，得到溶液；
析出步骤：将所述溶液于室温下挥发，至有固体析出，得到Apabetalone的晶型CS9；
优选的，所述醚类包含四氢呋喃；所述醇类包含异丙醇；所述卤代烃包含二氯甲烷和三氯甲烷；所述醚类和醇类的体积比为1:1；所述卤代烃和醇类的体积比为4:1。
本发明的晶型CS9的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS9。
2)本发明的晶型CS9具有良好的稳定性，在25℃/60％RH和40℃/75％RH环境下至少可稳定放置10个月。晶型的稳定性对药物的开发是至关重要的，晶型CS9保持较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
3)本发明的晶型CS9几乎无引湿性，80％相对湿度环境下增重仅0.18％，且引湿性测试前后晶型未发生改变。几乎无引湿性的晶型在制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，更适合药用。
根据本发明的目的，本发明还提供Apabetalone的晶型CS11(以下称作“晶型CS11”)。所述晶型CS11为水合物。
使用Cu-Kα辐射，所述晶型CS11的X射线粉末衍射在衍射角2θ值为7.8°±0.2°、8.8°±0.2°、9.7°±0.2°、13.6°±0.2°处有特征峰。
进一步的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为4.4°±0.2°、16.9°±0.2°、21.6°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为4.4°±0.2°、16.9°±0.2°、21.6°±0.2°中均有特征峰。
进一步的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为13.0°±0.2°、15.3°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为 13.0°±0.2°、15.3°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS11的X射线粉末衍射在衍射角2θ值为7.8°±0.2°、8.8°±0.2°、9.7°±0.2°、13.6°±0.2°、4.4°±0.2°、16.9°±0.2°、21.6°±0.2°、13.0°±0.2°、15.3°±0.2°、22.7°±0.2°、7.6°±0.2°、17.6°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS11的X射线粉末衍射谱图如图8A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS11的制备方法，包括以下方法：
方法1)溶解步骤：使用醇类溶剂将Apabetalone原料溶解，得到溶液；
析出步骤：将所述溶液添加至水中或者将水添加至所述溶液中，析出固体，得到Apabetalone的晶型CS11。
方法2)溶解步骤：使用卤代烃、醇类和酮类的混合溶剂、醇类和芳香烃类的混合溶剂中的一种将Apabetalone原料溶解，得到溶液；
析出步骤：将所述溶液在室温下挥发，至有固体析出，得到Apabetalone晶型CS11；
优选的，方法1中所述醇类包含甲醇；方法2中所述醇类包含甲醇；所述酮类包含丙酮和甲基异丁基酮；所述醇类和酮类的体积比为1:1～2:1；所述醇类和芳香烃类的体积比为4:1。
本发明的晶型CS11的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS11。
2)本发明的晶型CS11具有良好的稳定性，在25℃/60％RH和40℃/75％RH环境下至少可稳定放置6周。晶型CS11具有较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
3)本发明的晶型CS11具有优异的溶解性，尤其在SGF中，晶型CS11在1小时的溶解度高达0.71mg/mL，在FeSSIF中1小时、4小时、24小时实时溶解度均高于0.26mg/mL。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度。
根据本发明的目的，本发明还提供Apabetalone的晶型CS4(以下称作“晶型CS4”)。所述晶型CS4为无水物。
使用Cu-Kα辐射，所述晶型CS4的X射线粉末衍射在衍射角2θ值为9.1°±0.2°、14.5°±0.2°、23.5°±0.2°、24.2°±0.2°处有特征峰。
进一步的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为10.3°±0.2°、25.0°±0.2°、26.3°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为10.3°±0.2°、25.0°±0.2°、26.3°±0.2°中均有特征峰。
进一步的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为10.8°±0.2°、11.6°±0.2°、19.5°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为10.8°±0.2°、11.6°±0.2°、19.5°±0.2°中均有特征峰。
在一个优选的实施方案中，所述晶型CS4的X射线粉末衍射在衍射角2θ值为9.1°±0.2°、14.5°±0.2°、23.5°±0.2°、24.2°±0.2°、10.3°±0.2°、25.0°±0.2°、26.3°±0.2°、10.8°±0.2°、11.6°±0.2°、19.5°±0.2°处均有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS4的X射线粉末衍射谱图如图9A所示。
根据本发明的目的，本发明还提供Apabetalone的晶型CS4的制备方法，包括以下步骤：将Apabetalone的晶型CS11加热至200-220℃，得到Apabetalone的晶型CS4。
本发明的晶型CS4的有益效果为：
1)目前尚无专利或文献报导Apabetalone的晶型，本发明的发明人经过大量实验研究，突破了这一难题，找到了一种适合开发的晶型CS4。
2)本发明的晶型CS4具有良好的长期稳定性和机械稳定性，在25℃/60％RH和40℃/75％RH环境下至少可稳定放置10个月，晶型的稳定性对药物的开发是至关重要的，晶型CS4保持较好的稳定性，能够保证药品在制备、运输、贮藏及保存过程中不会发生转晶现象而影响到药品质量，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。此外，晶型CS4经过手动研磨后晶型未发生变化，说明晶型CS4具有较好的机械稳定性，制剂加工过程中常需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
3)本发明的晶型CS4几乎无引湿性，80％相对湿度环境下增重仅0.12％，且引湿性前后晶型未发生改变。几乎无引湿性的晶型在制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，更适合药用。
在本发明的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4的制备方法中：
所述“室温”不是精确的温度值，是指10～30℃温度范围；
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发；
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟；
所述“冷却”，采用本领域的常规方法完成，例如“缓慢冷却”和“快速冷却”，“缓慢冷却”通常以0.1℃/分钟进行，“快速冷却”通常指将高温下的样品10秒内迅速转移至低温环境下。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允 许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明还提供一种Apabetalone的混合晶型，含有任意比例的本发明的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4中的两种以上的组合。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明Apabetalone的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步的，本发明提供Apabetalone的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4在治疗心血管、胆固醇或脂质相关紊乱药物中的用途。
进一步的，本发明提供Apabetalone的晶型CS2、晶型CS8、晶型CS13、晶型CS20、晶型CS1、晶型CS7、晶型CS9、晶型CS11和晶型CS4在制备用于预防和治疗心血管疾病和糖尿病药物中的用途。尤其是动脉粥样硬化和急性冠脉综合症和前驱糖尿病的治疗药物。
附图说明
图1A为根据本发明实施例1所得晶型CS2的XRPD图。
图1B为根据本发明实施例1所得晶型CS2的DSC图。
图1C为根据本发明实施例1所得晶型CS2的TGA图。
图2A为根据本发明实施例2所得晶型CS8的XRPD。
图2B为根据本发明实施例2所得晶型CS8的DSC图。
图2C为根据本发明实施例2所得晶型CS8的TGA图。
图2D为晶型CS8放置在25℃/60％RH条件下2周前后的XRPD叠图(从上至下依次为放置前的XRPD图，放置于25℃/60％RH条件下2周的XRPD图)。
图2E为根据本发明实施例2所得晶型CS8的DVS图。
图2F为根据本发明实施例2所得晶型CS8的DVS测试前后的XRPD叠图。
图3A为根据本发明实施例3所得晶型CS13的XRPD图。
图3B为根据本发明实施例3所得晶型CS13的DSC图。
图3C为根据本发明实施例3所得晶型CS13的TGA图。
图4A为根据本发明实施例4所得晶型CS20的XRPD图。
图4B为根据本发明实施例4所得晶型CS20的DSC图。
图4C为根据本发明实施例4所得晶型CS20的TGA图。
图4D为根据本发明实施例4所得晶型CS20的1H NMR图。
图4E为晶型CS20放置在25℃/60％RH和40℃/75％RH条件下2周前后的XRPD叠图(从上至下依次为放置前的XRPD图，放置于25℃/60％RH条件下2周的XRPD图，放置于40℃/75％RH条件下2周的XRPD图)。
图5A为根据本发明实施例5制备方法1所得晶型CS1的XRPD图。
图5B为根据本发明实施例5制备方法1所得晶型CS1的DSC图。
图5C为根据本发明实施例5制备方法1所得晶型CS1的TGA图。
图5D为根据本发明实施例5制备方法2所得晶型CS1的XRPD图。
图5E为晶型CS1放置在25℃/60％RH和40℃/75％RH条件下10个月前后的XRPD叠图(从上至下依次为放置前的XRPD图，放置于25℃/60％RH条件下10个月的XRPD图，放置于40℃/75％RH条件下10个月的XRPD图)。
图5F为根据本发明实施例5所得晶型CS1的DVS图。
图5G为根据本发明实施例5所得晶型CS1的DVS测试前后的XRPD叠图。
图5H为根据本发明实施例5所得晶型CS1的研磨前后的XRPD叠图。
图5I为根据本发明实施例5所得晶型CS1在制剂中的溶出速率图。
图6A为根据本发明实施例6所得晶型CS7的XRPD图。
图6B为根据本发明实施例6所得晶型CS7的DSC图。
图6C为根据本发明实施例6所得晶型CS7的TGA图。
图6D为晶型CS7放置在25℃/60％RH和40℃/75％RH条件下4周和80℃条件下1天前后的XRPD叠图(从上至下依次为晶型CS7放置前的XRPD图，放置于25℃/60％RH条件下4周的XRPD图，放置于40℃/75％RH条件下4周的XRPD图和放置于80℃条件下1天的XRPD图)。
图6E为根据本发明实施例6所得晶型CS7的DVS测试前后的XRPD叠图。
图7A为根据本发明实施例7所得晶型CS9的XRPD图。
图7B为根据本发明实施例7所得晶型CS9的DSC图。
图7C为根据本发明实施例7所得晶型CS9的TGA图。
图7D为晶型CS9放置在25℃/60％RH和40℃/75％RH条件下10个月前后的XRPD叠图(从上至下依次为放置前的XRPD图，放置于25℃/60％RH条件下10个月的XRPD图，放置于40℃/75％RH条件下10个月的XRPD图)。
图7E为根据本发明实施例7所得晶型CS9的DVS图。
图7F为根据本发明实施例7所得晶型CS9的DVS测试前后的XRPD叠图。
图8A为根据本发明实施例8制备方法1所得晶型CS11的XRPD图。
图8B为根据本发明实施例8制备方法1所得晶型CS11的DSC图。
图8C为根据本发明实施例8制备方法1所得晶型CS11的TGA图。
图8D为根据本发明实施例8制备方法2所得晶型CS11的XRPD图。
图8E为晶型CS11放置在25℃/60％RH和40℃/75％RH条件下6周前后的XRPD叠图(从上至下依次为放置前的XRPD图，放置于25℃/60％RH条件下6周的XRPD图，放置于40℃/75％RH条件下6周的XRPD图)。
图9A为根据本发明实施例9所得晶型CS4的XRPD图。
图9B为根据本发明实施例9所得晶型CS4的DSC图。
图9C为根据本发明实施例9所得晶型CS4的TGA图。
图9D为晶型CS4放置在25℃/60％RH和40℃/75％RH条件下10个月前后的XRPD叠图(从上至下依次为放置前的XRPD图，放置于25℃/60％RH条件下10个月的XRPD图，放置于40℃/75％RH条件下10个月的XRPD图)
图9E为根据本发明实施例9所得晶型CS4的DVS图。
图9F为根据本发明实施例9所得晶型CS4的DVS测试前后的XRPD叠图。
图9G为根据本发明实施例9所得晶型CS4的研磨前后的XRPD叠图。
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的名词解释如下：
XRPD：X射线粉末衍射
HPLC：高效液相色谱
DSC：差示扫描量热
TGA：热重分析
1HNMR：核磁共振氢谱
RH：相对湿度
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Kα1
Figure PCTCN2017115143-appb-000002
1.540598；Kα2
Figure PCTCN2017115143-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
差热分析(DSC)数据采自于TA Instruments Q200 MDSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。
扫描速率：10℃/min
保护气体：氮气
热重分析(TGA)数据采自于TA Instruments Q500 TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。
扫描速率：10℃/min
保护气体：氮气
核磁共振氢谱数据(1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1～5mg样品，用0.5mL氘代二甲亚砜溶解，配成2～10mg/mL的溶液。
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software，分析软件是DVS-Intrinsic Analysis software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。本发明所述的测试纯度的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18 150×4.6mm,5μm
2、流动相：A：0.1％的三氟乙酸水溶液
B：0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
Time(min) ％B
0.0 20
5.0 30
6.0 80
8.0 80
8.1 20
10.0 20
3、流速：1.6mL/min
4、进样量：5μL
5、检测波长：260nm
6、柱温：40℃
7、稀释剂：50％乙腈水溶液
本发明中溶出度数据测定采自于安捷伦708-DS。
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用的Apabetalone原料根据CN101641339B专利中所记载的方法制备。
实施例1
晶型CS2的制备
称取一定质量的Apabetalone原料，在T1温度下溶于表1.1中一定体积的溶剂中，过滤后缓慢或快速冷却至T2，析出固体后，离心收集固体，干燥后得到样品。
表1.1
Figure PCTCN2017115143-appb-000004
经XRPD检测，样品1-a～1-i均为晶型CS2。其中选取样品1-i测试表征，其XRPD如图1A，表1.2所示。其DSC如图1B所示，加热至60℃开始出现第一个吸热峰，加热至113℃开始出现第二个吸热峰，加热至126℃开始出现第一个放热峰，加热至232℃开始出现第三个吸热峰。其TGA如图1C所示，将其加热至100℃时，具有约3.4％的质量损失梯度。
表1.2
衍射角2θ d值 强度％
5.08 17.39 30.31
6.57 13.46 100.00
8.85 10.00 34.56
11.54 7.67 41.68
13.31 6.65 8.72
15.28 5.80 14.13
20.22 4.39 7.21
23.10 3.85 4.08
25.35 3.51 2.44
晶型CS2溶解度研究
将制备得到的Apabetalone晶型CS2样品分别用SGF(模拟人胃液),pH5.0FeSSIF(进食状态下人工肠液)配制成饱和溶液，在1个小时、24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS2的溶解度数据如表1.3所示。
表1.3
Figure PCTCN2017115143-appb-000005
以上结果表明，本发明提供的Apabetalone晶型CS2在SGF和FeSSIF中均具有较好的溶解性,尤其在SGF溶液中，其24小时溶解度可达0.61mg/mL。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度，对药物研究具有重要意义。
实施例2
晶型CS8的制备
称取一定质量的Apabetalone原料，在T1温度下溶于表2.1中一定体积的溶剂中，过滤后缓慢或快速冷却至T2，析出固体后，离心收集固体，干燥后得到样品。
表2.1
Figure PCTCN2017115143-appb-000006
经XRPD检测，样品2-a～2-d均是晶型CS8。其中选取样品2-a测试表征，其XRPD数据如图2A，表2.2所示。DSC如图2B所示，加热至177℃开始出现第一个放热峰，加热至211℃开始出现第一个吸热峰，加热至217℃出现第二个放热峰，加热至230℃开始出现第二个吸热峰。TGA如图2C所示，将其加热至120℃时，具有约0.4％的质量损失梯度。
表2.2
衍射角2θ d值 强度％
4.23 20.89 3.93
7.83 11.30 60.72
9.74 9.08 6.55
10.58 8.36 5.86
11.36 7.79 16.82
13.11 6.75 16.65
13.55 6.54 40.35
18.00 4.93 10.44
19.29 4.60 9.65
20.17 4.40 14.20
22.47 3.96 25.75
23.91 3.72 100.00
24.22 3.67 32.56
24.87 3.58 11.65
25.88 3.44 14.42
26.18 3.40 17.03
28.16 3.17 14.65
31.72 2.82 2.11
晶型CS8稳定性研究
Apabetalone晶型CS8的稳定性试验研究：
取一份Apabetalone晶型CS8样品置于25℃/60％RH恒温恒湿箱中敞口放置2周，然后取样测XRPD和纯度。结果如图2D(从上至下依次为晶型CS8放置前XRPD图，放置于25℃/60％RH条件下2周的XRPD图)。
Apabetalone晶型CS8在25℃/60％RH下放置2周，晶型和纯度未发生明显改变。上述试验结果表明，Apabetalone晶型CS8具有良好的稳定性。
晶型CS8溶解度研究
将制备得到的Apabetalone晶型CS8样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS8的溶解度数据如表2.3所示。
表2.3
Figure PCTCN2017115143-appb-000007
以上结果表明，本发明提供的Apabetalone晶型CS8在SGF和FeSSIF中溶解性较好。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度，对药物研究具有重要意义。
晶型CS8引湿性研究
取本发明的Apabetalone晶型CS8约10mg采用动态水分吸附仪测试其引湿性。实验结果如表2.4所示。Apabetalone晶型CS8的引湿性实验的DVS图如图2E所示。
表2.4
Figure PCTCN2017115143-appb-000008
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的Apabetalone晶型CS8在80％湿度下平衡后增重0.34％，根据引湿性增重的界定标准，属于略有引湿性。引湿性测试后测定晶型CS8的XRPD图如图2F，发现测试前后晶型未发生改变，说明晶型CS8具有很好的湿度稳定性。
本发明晶型CS8的引湿性低，能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存。
实施例3
晶型CS13的制备
称取一定质量的Apabetalone原料，溶于表3.1中一定体积的溶剂中，过滤，在不添加高聚物或添加高聚物的情况下，室温缓慢挥发，直至有固体析出，得到样品。
表3.1
Figure PCTCN2017115143-appb-000009
所述“高聚物”为聚己内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素 的混合物，其质量比为1：1：1：1：1。
经XRPD检测，样品3-a～3-d均是晶型CS13。其中选取样品3-d进行测试表征，其XRPD如图3A，表3.2所示。DSC如图3B所示，加热至70℃开始出现第一个吸热峰，加热至86℃出现第二个吸热峰，加热至170℃开始出现第三个吸热峰，加热至205℃开始出现第四个吸热峰，加热至207℃出现第一个放热峰，加热至230℃开始出现第五个吸热峰。TGA如图3C所示，将其加热至100℃时，具有约11.9％的质量损失梯度。
表3.2
衍射角2θ d值 强度％
5.09 17.35 48.06
6.38 13.85 22.94
7.76 11.39 4.83
8.54 10.35 12.25
10.17 8.70 0.71
11.48 7.71 3.89
12.54 7.06 100.00
13.29 6.66 3.59
15.30 5.79 1.21
15.56 5.69 2.14
16.01 5.54 4.65
17.13 5.18 47.37
19.15 4.64 0.27
20.41 4.35 1.35
20.84 4.26 4.59
22.11 4.02 0.59
23.43 3.80 3.37
25.67 3.47 8.18
26.75 3.33 1.24
27.06 3.29 3.65
28.72 3.11 1.18
29.56 3.02 1.42
30.89 2.90 0.43
32.26 2.77 1.36
34.67 2.59 0.58
37.28 2.41 2.20
38.97 2.31 0.89
晶型CS13的溶解度研究
将制备得到的Apabetalone晶型CS13样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS13的溶解度数据如表3.3所示。
表3.3
Figure PCTCN2017115143-appb-000010
以上结果表明，本发明提供的Apabetalone晶型CS13在SGF和FeSSIF中均具有较好的溶解性。
实施例4
晶型CS20的制备
称取一定质量的Apabetalone原料，溶于表4.1中一定体积的溶剂中，过滤，室温下缓慢挥发，直至有固体析出，得到样品。
表4.1
Figure PCTCN2017115143-appb-000011
经XRPD检测，样品4-a～4-b均为Apabetalone晶型CS20。其中选取样品4-a测试表征，其XRPD如图4A，表4.2所示。其DSC如图4B所示，加热至123℃开始出现第一个吸热峰，加热至185℃开始出现第二个吸热峰，加热至201℃开始出现第三个吸热峰，加热至207℃开始出现第四个吸热峰，加热至230℃附近开始出现第五个吸热峰。其TGA如图4C所示，将其加热至160℃时，具有约14.9％的质量损失梯度。其1H NMR如图4D所示，核磁数据如下：1H NMR(400MHz,DMSO)δ11.83(s,1H),7.89(s,2H),6.74(d,J＝2.3Hz,1H),6.52(d,J＝2.3Hz,1H),4.91(s,1H),3.89(s,3H),3.87-3.81(m,5H),3.72(s,2H),2.31(s,6H),1.90(s,3H)。
表4.2
衍射角2θ d值 强度％
5.59 15.81 21.68
7.20 12.28 4.52
8.39 10.53 100.00
9.37 9.44 22.64
11.26 7.86 25.84
11.67 7.58 8.95
13.52 6.55 83.84
13.88 6.38 7.82
14.48 6.12 11.79
14.92 5.94 3.42
16.92 5.24 11.24
18.88 4.70 30.97
19.57 4.54 1.85
20.15 4.41 12.22
20.56 4.32 12.06
22.30 3.99 5.29
22.76 3.91 10.73
24.10 3.69 2.41
24.38 3.65 4.37
25.26 3.53 1.52
25.93 3.44 3.39
26.33 3.38 13.70
26.78 3.33 3.08
28.11 3.17 2.02
28.81 3.10 3.75
34.30 2.61 1.52
35.68 2.52 2.00
36.85 2.44 2.14
晶型CS20稳定性研究
取Apabetalone晶型CS20样品置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置2周，然后取样测XRPD和纯度。结果如图4E(从上至下依次为晶型CS20放置前的 XRPD图，放置于25℃/60％RH条件下2周，放置于40℃/75％RH条件下2周的XRPD图)，Apabetalone晶型CS20在25℃/60％RH和40℃/75％RH下放置2周，晶型保持不变，且纯度未见明显降低。上述试验结果表明，Apabetalone晶型CS20具有良好的稳定性。
晶型CS20溶解度研究
将制备得到的Apabetalone晶型CS20样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS20的溶解度数据如表4.3所示。
表4.3
Figure PCTCN2017115143-appb-000012
以上结果表明，本发明提供的Apabetalone晶型CS20在SGF和FeSSIF中溶解性较好。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度，对药物研究具有重要意义。
实施例5
晶型CS1的制备方法1
Apabetalone的晶型CS1的制备方法，包括以下步骤：
溶解步骤：使用下表5.1中的正溶剂将约10mg的Apabetalone原料溶解，过滤，得到溶液；
析出步骤：将所述溶液逐滴添加至下表5.1中的反溶剂中或者将反溶剂逐滴添加至所述溶液中，搅拌至大量固体析出，离心收集固体，干燥得到Apabetalone晶型CS1；
其中，所述Apabetalone晶型CS1的制备方法的反应条件、正溶剂和反溶剂的成分及加入量如下表5.1所示。
表5.1
Figure PCTCN2017115143-appb-000013
经XRPD检测，样品5-a～5-i均为Apabetalone晶型CS1。其中选取样品5-a测试表征，其XRPD如图5A，表5.2所示。其DSC如图5B所示，加热至207℃开始出现第一个吸热峰，加热至211℃出现第一个放热峰，加热至231℃开始出现第二个吸热峰。其TGA如图5C所示，将其加热至200℃时，具有约0.7％的质量损失梯度。
表5.2
衍射角2θ d值 强度％
4.38 20.19 1.10
6.11 14.47 100.00
10.19 8.68 2.41
10.70 8.27 1.40
12.11 7.31 21.04
12.27 7.21 62.62
12.99 6.82 5.91
14.12 6.27 3.01
16.37 5.41 4.60
17.09 5.19 3.31
17.63 5.03 1.77
18.18 4.88 1.63
18.48 4.80 7.06
20.12 4.41 2.93
20.49 4.33 4.18
21.55 4.12 1.12
21.93 4.05 2.34
23.16 3.84 5.71
23.45 3.79 4.16
24.45 3.64 2.64
25.02 3.56 1.26
26.11 3.41 8.67
26.84 3.32 7.12
28.00 3.19 0.96
28.60 3.12 0.96
30.04 2.98 0.86
31.04 2.88 1.25
35.60 2.52 0.25
36.80 2.44 0.50
38.30 2.35 0.89
晶型CS1的制备方法2
Apabetalone的晶型CS1的制备方法，包括以下步骤：
溶解步骤：在50℃下，将Apabetalone原料在下表5.3中的溶剂中溶解，得到溶液；
析出步骤：快速冷却或缓慢冷却至-20～5℃，析出固体后，离心收集固体，干燥，得到Apabetalone晶型CS1；
所述Apabetalone晶型CS1的制备方法的反应条件、溶剂的成分及加入量如下表5.3所示。经XRPD检测，样品5-j～5-n均为Apabetalone晶型CS1。其中样品5-j的XRPD如图5D，表5.4所示。
表5.3
Figure PCTCN2017115143-appb-000014
表5.4
衍射角2θ d值 强度％
3.57 24.78 1.09
6.10 14.48 100.00
10.26 8.62 0.50
12.28 7.21 65.97
13.01 6.81 2.85
14.15 6.26 2.43
16.36 5.42 3.05
17.13 5.18 2.82
18.47 4.80 6.67
19.24 4.61 0.64
20.14 4.41 0.92
20.51 4.33 1.86
22.01 4.04 1.19
23.16 3.84 7.43
24.45 3.64 2.81
25.01 3.56 1.21
26.15 3.41 10.57
26.86 3.32 8.29
28.76 3.10 0.82
30.08 2.97 0.92
31.07 2.88 1.86
34.62 2.59 0.49
36.83 2.44 0.62
38.30 2.35 1.75
晶型CS1的长期稳定性研究
取两份Apabetalone晶型CS1样品分别置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置10个月，然后取样测XRPD和纯度。结果如图5E(从上至下依次为Apabetalone晶型CS1参比XRPD图，放置25℃/60％RH和40℃/75％RH条件下10个月的XRPD图)和表5.5所示。
Apabetalone晶型CS1在25℃/60％RH，40℃/75％RH下放置10个月，晶型保持不变，且纯度未见显著变化。上述试验结果表明，Apabetalone晶型CS1具有优异的稳定性，且晶型纯度较高。
表5.5
条件 1周 2周 5周 10个月
25℃/60％RH 99.27 99.23 99.25 99.24
40℃/75％RH 99.20 99.20 99.25 99.21
晶型CS1的溶解度研究
将制备得到的Apabetalone晶型CS1样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS1的溶解度数据如表5.6所示。
表5.6
Figure PCTCN2017115143-appb-000015
以上结果表明，本发明提供的Apabetalone晶型CS1在SGF和FeSSIF中均具有较好的 溶解性。
晶型CS1的引湿性研究
取本发明的Apabetalone晶型CS1约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表5.7所示。Apabetalone晶型CS1的引湿性实验的DVS图如图5F所示。
表5.7
Figure PCTCN2017115143-appb-000016
结果表明，本发明的Apabetalone晶型CS1在80％湿度下平衡后增重0.13％，根据引湿性增重的界定标准，属于几乎无引湿性。引湿性测试后测定晶型CS1的XRPD图如图5G，发现测试前后晶型未发生改变，说明晶型CS1具有很好的湿度稳定性。
本发明晶型CS1的引湿性低，能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存。
晶型CS1的机械稳定性研究
将本发明的Apabetalone晶型CS1样品置于研钵中，手动研磨5分钟，测试固体XRPD。结果如图5H所示。
结果表明，在一定机械应力的作用下，本发明的Apabetalone晶型CS1未发生改变，且结晶度也无明显变化，仍可保持稳定的物理化学性质，适合成药和储存。制剂加工过程中常需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
晶型CS1的制剂研究
称量下表中含量的原料药、微晶纤维素、交联羧甲基纤维素钠和2mg硬脂酸镁，混合2分钟。用手动压片机压制成片，直径20mm圆形冲模，压力5kN。手工过20目筛网，加入2mg硬脂酸镁，混合1分钟。将上述混合物装入1#胶囊壳。用35cc HDPE(高密度聚乙烯)瓶包装(每瓶一粒)，每瓶含有1g干燥剂，用封口机封口。制剂的组成(每200mg)如下表5.8，经检测，晶型CS1在制剂中能够稳定存在。
表5.8
成分 用量(mg/胶囊)
原料药 50
微晶纤维素 136
交联羧甲基纤维素钠 10
硬脂酸镁 4
将获得的胶囊测试溶出情况，测试条件如下：
溶出介质：0.1mol/L的HCl
溶出方法：浆法
介质体积：900mL
转速：75rpm
介质温度：37℃
晶型CS1的溶出速率结果见图5I，结果表明晶型CS1溶出速率快，20min时的溶出量即可达90％以上的。在制剂开发中，药物具有快速的溶出速率可加快药物服用后在体内快速溶解，可通过调整辅料，控制药物在特定部位快速发挥作用，提高药物的起效速率。
实施例6
晶型CS7的制备
Apabetalone晶型CS7的制备方法，包括以下步骤：
溶解步骤：使用1mL氯仿将5.3mg的Apabetalone原料溶解后过滤，得到溶液；
析出步骤：将所述溶液置于3mL玻璃瓶中，将含有所述溶液的玻璃瓶敞口放置于含有5mL的甲基异丁基酮的20mL的玻璃瓶中，室温密闭一段时间，直至有固体析出，离心收集固体，干燥，得到Apabetalone晶型CS7。晶型CS7的XRPD如图6A，表6.1所示。
当进行差示量热分析时，加热至231℃开始出现一个吸热峰，其DSC如图6B所示。当进行热重分析时，加热至160℃时，具有约0.4％的质量损失梯度，其TGA如图6C所示。
表6.1
衍射角2θ d值 强度％
4.27 20.68 3.98
5.87 15.06 55.68
6.69 13.21 100
8.43 10.50 77.7
10.70 8.27 80.13
12.08 7.32 9.24
12.46 7.10 53.68
13.25 6.68 49.94
14.99 5.91 9.73
15.96 5.55 34.89
16.94 5.23 53.34
19.16 4.63 3.48
20.32 4.37 6.07
21.76 4.08 15.6
23.67 3.76 4.6
24.47 3.64 9.66
25.09 3.55 15.93
26.01 3.43 3.31
27.42 3.25 2.99
30.79 2.90 3.25
32.57 2.75 1.7
36.50 2.46 1.75
37.45 2.40 1.96
晶型CS7的稳定性研究
取三份Apabetalone晶型CS7样品分别置于25℃/60％RH,40℃/75％RH的恒温恒湿箱中敞口放置4周和80℃条件下放置1天，然后取样测XRPD和纯度。结果如图6D(从上至下依次为Apabetalone晶型CS7放置前的XRPD图，放置于25℃/60％RH条件下4周的XRPD图，放置于40℃/75％RH条件下4周的XRPD图和放置于80℃条件下1天的XRPD)。
Apabetalone晶型CS7在25℃/60％RH，40℃/75％RH下放置4周和在80℃条件下放置1天，晶型保持不变，且纯度未见显著变化。上述试验结果表明，Apabetalone晶型CS7具有良好的稳定性。
晶型CS7的溶解度研究
将制备得到的Apabetalone晶型CS7样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS7的溶解度数据如表6.2所示。
表6.2
Figure PCTCN2017115143-appb-000017
以上结果表明，本发明提供的Apabetalone晶型CS7在SGF和FeSSIF中溶解性较好。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度，对药物研究具有重要意义。
晶型CS7的引湿性研究
取本发明的Apabetalone晶型CS7约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表6.3所示。
表6.3
Figure PCTCN2017115143-appb-000018
结果表明，本发明的Apabetalone晶型CS7在80％湿度下平衡后增重0.79％，根据引湿性增重的界定标准，属于略有引湿性。引湿性测试后测定晶型CS7的XRPD图如图6E，发现测试前后晶型未发生改变，说明晶型CS7具有很好的湿度稳定性。
本发明晶型CS7的引湿性低，能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存。
实施例7
晶型CS9的制备
Apabetalone晶型CS9的制备方法，包括以下步骤：
溶解步骤：使用下表7.1中的溶剂将约10mg的Apabetalone原料溶解，过滤，得到溶液；
析出步骤：将所述溶液于室温下缓慢挥发，直至有固体析出，得到Apabetalone晶型CS9；
所述Apabetalone晶型CS9的制备方法的反应条件、溶剂的成分及加入量如下表7.1所示，经XRPD检测，样品7-a～7-c均是晶型CS9。
表7.1
Figure PCTCN2017115143-appb-000019
选取样品7-b测试表征，其XRPD如图7A，表7.2所示。其DSC如图7B所示，加热至203℃开始出现第一个吸热峰。其TGA如图7C所示，将其加热至200℃时，具有约0.9％的质量损失梯度。
表7.2
衍射角2θ d值 强度％
3.92 22.55 17.55
5.99 14.75 7.28
7.25 12.19 64.22
7.94 11.13 6.24
9.92 8.91 24.30
12.09 7.32 8.02
12.78 6.93 17.69
13.36 6.63 22.02
13.53 6.54 10.74
14.48 6.12 2.15
16.98 5.22 19.92
20.01 4.44 7.41
20.88 4.26 5.94
21.42 4.15 21.02
21.77 4.08 16.45
22.00 4.04 14.36
22.53 3.95 100.00
23.02 3.86 25.09
23.95 3.72 34.15
24.19 3.68 58.53
24.86 3.58 16.90
25.83 3.45 25.83
26.11 3.41 24.07
26.53 3.36 7.10
27.03 3.30 6.89
27.81 3.21 7.53
28.51 3.13 10.88
30.61 2.92 3.05
31.17 2.87 2.73
32.29 2.77 2.32
32.80 2.73 2.65
33.67 2.66 2.03
36.63 2.45 1.42
37.12 2.42 1.68
晶型CS9的稳定性研究
取两份Apabetalone晶型CS9样品分别置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置10个月，然后取样测XRPD和纯度。结果如图7D(从上至下依次为Apabetalone晶型CS9参比XRPD图，放置于25℃/60％RH和40℃/75％RH条件下10个月的XRPD图)。
Apabetalone晶型CS9在25℃/60％RH，40℃/75％RH下放置10个月，晶型保持不变，且纯度未见显著变化。上述试验结果表明，Apabetalone晶型CS9具有良好的稳定性。
晶型CS9的溶解性研究
将制备得到的Apabetalone晶型CS9样品分别用SGF,pH5.0的FeSSIF制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS9的溶解度数据如表7.3所示。
表7.3
Figure PCTCN2017115143-appb-000020
以上结果表明，本发明提供的Apabetalone晶型CS9在SGF和FeSSIF中具有较好的溶解性。
晶型CS9的引湿性研究
取本发明的Apabetalone晶型CS9约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表7.4所示。Apabetalone晶型CS9的引湿性实验的DVS图如图7E所示。引湿性测试后测定晶型CS9的XRPD图如图7F，发现测试前后晶型未发生改变，说明晶型CS9具有很好的湿度稳定性。
表7.4
Figure PCTCN2017115143-appb-000021
结果表明，本发明的Apabetalone晶型CS9在80％湿度下平衡后增重0.18％，根据引湿性增重的界定标准，属于几乎无引湿性。本发明晶型CS9的使用能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存。
实施例8
晶型CS11的制备方法1
Apabetalone晶型CS11的制备方法，包括以下步骤：
溶解步骤：使用1.7mL的甲醇将约10mg的Apabetalone原料溶解，过滤，得到溶液；
析出步骤：将所述溶液添加至3mL水中或者将3mL水添加至所述溶液中，搅拌至有大量固体析出，离心收集固体，干燥得到Apabetalone晶型CS11。
所述Apabetalone晶型CS11的制备方法的反应条件、甲醇与水的加入量如下表8.1所示。经XRPD检测，样品8-a和8-b均为晶型CS11。
表8.1
Figure PCTCN2017115143-appb-000022
选取样品8-b测试表征，其XRPD数据如图8A，表8.2所示。其DSC如图8B所示，加热至49℃开始出现第一个吸热峰，加热至206℃开始出现第二个吸热峰，加热至208℃出现第一个放热峰，加热至230℃开始出现第三个吸热峰。其TGA如图8C所示，将其加热至100℃时，具有约3.0％的质量损失梯度。
表8.2
衍射角2θ d值 强度％
4.36 20.25 22.75
7.61 11.61 35.17
7.80 11.33 71.58
8.79 10.06 75.43
9.70 9.12 100.00
10.11 8.75 11.17
13.02 6.80 8.06
13.55 6.54 23.03
15.32 5.79 8.84
15.70 5.64 7.37
16.87 5.26 11.53
17.64 5.03 10.29
18.67 4.75 1.01
19.55 4.54 3.26
20.40 4.35 5.32
20.99 4.23 5.64
21.58 4.12 21.02
22.72 3.91 9.87
23.67 3.76 3.85
25.65 3.47 5.77
26.85 3.32 2.83
27.34 3.26 5.29
30.28 2.95 1.82
32.57 2.75 1.07
34.69 2.59 2.33
35.80 2.51 2.02
36.56 2.46 1.51
晶型CS11的制备方法2
Apabetalone晶型CS11的制备方法，包括以下步骤：
溶解步骤：使用下表8.3中的溶剂将约10mg的Apabetalone原料溶解，过滤，得到溶液；
析出步骤：将所述溶液在室温下缓慢挥发，直至有固体析出，得到Apabetalone晶型CS11。
所述Apabetalone晶型CS11的制备方法的反应条件、溶剂的组成及加入量如下表8.3所示。经XRPD检测，样品8-c～8-f均为晶型CS11。其中样品8-d的XRPD如图8D，表8.4所示
表8.3
Figure PCTCN2017115143-appb-000023
表8.4
衍射角2θ d值 强度％
4.36 20.26 9.4
7.60 11.64 29.25
7.79 11.34 74.56
8.78 10.07 28.33
9.68 9.14 100
10.13 8.73 8.22
13.00 6.81 6.84
13.54 6.54 13.96
15.29 5.80 8.47
15.68 5.65 5.67
16.83 5.27 7.76
17.65 5.02 4.52
19.48 4.56 3.39
20.37 4.36 4.97
20.97 4.24 3.31
21.60 4.11 8.44
22.65 3.93 9.42
23.08 3.85 2.33
23.67 3.76 3.29
25.65 3.47 0.78
27.34 3.26 2.23
30.18 2.96 1.12
32.46 2.76 0.27
34.67 2.59 0.62
36.15 2.48 0.32
晶型CS11的稳定性研究
取两份Apabetalone晶型CS11样品分别置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置6周，然后取样测XRPD和纯度。结果如图8E(从上至下依次为Apabetalone晶型CS11放置前的XRPD图，放置于25℃/60％RH和40℃/75％RH条件下6周的XRPD图)。
Apabetalone晶型CS11在25℃/60％RH，40℃/75％RH下放置6周，晶型保持不变，且纯度未见显著变化。上述试验结果表明，Apabetalone晶型CS11具有良好的稳定性。
晶型CS11的溶解性研究
将制备得到的Apabetalone晶型CS11样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS11的溶解度数据如表8.5所示。
表8.5
Figure PCTCN2017115143-appb-000024
以上结果表明，本发明提供的Apabetalone晶型CS11在SGF和FeSSIF中均具有优异的溶解性。高溶解度的晶型有利于增加药物在人体内的血药浓度，提高药物的生物利用度，对药物研究具有重要意义。
实施例9
晶型CS4的制备
将Apabetalone晶型CS11加热至220℃，得到Apabetalone晶型CS4。
其XRPD如图9A，表9.1所示。其DSC如图9B所示，加热至231℃开始出现第一个吸热峰。其TGA如图9C所示，将其加热至220℃时，具有约1.1％的质量损失梯度。
表9.1
衍射角2θ d值 强度％
8.48 10.43 6.12
9.11 9.71 53.67
10.29 8.60 26.02
10.81 8.18 10.09
11.64 7.60 14.92
14.17 6.25 7.64
14.45 6.13 45.98
14.84 5.97 7.80
15.34 5.78 2.53
16.38 5.41 4.37
17.06 5.20 2.02
17.72 5.00 1.91
18.32 4.84 2.30
19.25 4.61 6.41
19.53 4.55 12.06
19.80 4.48 2.96
20.73 4.29 2.28
22.60 3.93 2.69
23.51 3.78 83.35
24.23 3.67 100.00
24.99 3.56 19.67
25.47 3.50 7.99
25.89 3.44 4.39
26.32 3.39 35.61
26.97 3.31 6.81
28.30 3.15 5.10
29.95 2.98 2.52
32.05 2.79 5.67
33.73 2.66 2.67
36.61 2.45 3.15
37.68 2.39 1.06
晶型CS4的长期稳定性研究
取两份Apabetalone晶型CS4样品分别置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置10个月，然后取样测XRPD和纯度。结果如图9D(从上至下依次为Apabetalone晶型CS4放置前的XRPD图，放置于25℃/60％RH和40℃/75％RH条件下10个月的XRPD图)和表9.2所示。
Apabetalone晶型CS4在25℃/60％RH，40℃/75％RH下放置10个月，晶型保持不变，且纯度未见显著变化。上述试验结果表明，Apabetalone晶型CS4具有优异的稳定性。
表9.2
条件 1周 2周 4周 10月
25℃/60％RH 99.10 99.06 99.05 99.04
40℃/75％RH 99.10 98.99 99.04 99.02
晶型CS4的溶解度研究
将制备得到的Apabetalone晶型CS4样品分别用SGF,pH5.0的FeSSIF配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明Apabetalone晶型CS4的溶解度数据如表9.3所示，结果表明晶型CS4具有良好的溶解性。
表9.3
Figure PCTCN2017115143-appb-000025
晶型CS4的引湿性研究
取本发明的Apabetalone晶型CS4约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表9.4所示。Apabetalone晶型CS4的引湿性实验的DVS图如图9E所示。
表9.4
Figure PCTCN2017115143-appb-000026
结果表明，本发明的Apabetalone晶型CS4在80％湿度下平衡后增重0.12％，根据引湿性增重的界定标准，属于几乎无引湿性。引湿性测试后测定晶型CS4的XRPD图如图9F，发现测试前后晶型未发生改变，说明晶型CS4具有很好的湿度稳定性。
本发明晶型CS4的引湿性低，能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存。
晶型CS4的机械稳定性研究
将本发明的Apabetalone晶型CS4样品置于研钵中，手动研磨5分钟，测试固体XRPD。结果如图9G所示。
结果表明，在一定机械应力的作用下，本发明的Apabetalone晶型CS4未发生改变，且结晶度也无明显变化，仍可保持稳定的物理化学性质，适合成药和储存。制剂加工过程中常需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (46)

  1. 一种Apabetalone的晶型CS1，其特征在于，其X射线粉末衍射图在2θ值为6.1°±0.2°、12.3°±0.2°、26.1°±0.2°、26.8°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS1，其特征在于，其X射线粉末衍射图在2θ值为16.4°±0.2°、18.5°±0.2°、23.2°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的晶型CS1，其特征在于，其X射线粉末衍射图在2θ值为13.0°±0.2°、14.1°±0.2°、17.1°±0.2°、24.5°±0.2°中的一处或多处具有特征峰。
  4. 一种权利要求1所述晶型CS1的制备方法，所述制备方法包含方法1)或方法2)，其特征在于：
    方法1)溶解步骤：使用正溶剂将Apabetalone原料溶解，得到溶液；
    析出步骤：将所述溶液添加至反溶剂中或者将反溶剂添加至所述溶液中，析出固体，得到Apabetalone的晶型CS1；
    所述正溶剂包括：四氢呋喃、氯仿、二甲基亚砜、二甲基乙酰胺中的一种或两种以上的组合；所述反溶剂包括：正庚烷、甲基叔丁基醚、甲苯、水、乙腈中的一种或两种以上的组合；
    方法2)溶解步骤：在40～60℃下，将Apabetalone原料在溶剂中溶解，得到溶液；
    析出步骤：将所述溶液温度降至-20～5℃，析出固体，得到Apabetalone的晶型CS1；
    所述溶剂包括四氢呋喃、丙酮、四氢呋喃和甲基叔丁基醚的混合溶剂、乙酸乙酯和丙酮的混合溶剂、乙腈和N,N-二甲基甲酰胺的混合溶剂中的一种。
  5. 根据权利要求4所述的制备方法，其特征在于，方法2)的所述四氢呋喃和甲基叔丁基醚的体积比为2:1；所述乙酸乙酯和丙酮的体积比为1:1；所述乙腈和N,N-二甲基甲酰胺的体积比为9:1。
  6. 一种Apabetalone的晶型CS2，其特征在于，其X射线粉末衍射图在2θ值为11.5°±0.2°、6.6°±0.2°、8.8°±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型CS2，其特征在于，其X射线粉末衍射图在2θ值为5.1°±0.2°、15.3°±0.2°中的一处或两处具有特征峰。
  8. 一种权利要求6中所述晶型CS2的制备方法，其特征在于，所述制备方法包含：将Apabetalone原料加入到醇类、醇类和醚类的混合溶剂、醇类和酮类的混合溶剂、醇类和芳香烃的混合溶剂中的一种中，加热溶解后过滤，降温析出固体，得到Apabetalone的晶型CS2。
  9. 根据权利要求8所述的制备方法，其特征在于，所述醇类包含甲醇；所述醚类包含2-甲基四氢呋喃；所述芳香烃包含甲苯；所述酮类包含甲基异丁基酮；所述加热温度为50～100℃；所述析晶温度为-20～5℃。
  10. 一种Apabetalone的晶型CS8，其特征在于，其X射线粉末衍射图在2θ值为23.9°±0.2°、13.5°±0.2°、7.8°±0.2°、22.5°±0.2°、11.4°±0.2°处具有特征峰。
  11. 根据权利要求10所述的晶型CS8，其特征在于，其X射线粉末衍射图在2θ值为25.9°±0.2°、13.1°±0.2°中的一处或两处具有特征峰。
  12. 根据权利要求10所述的晶型CS8，其特征在于，其X射线粉末衍射图在2θ值为28.1°±0.2°、20.2°±0.2°中的一处或两处具有特征峰。
  13. 一种权利要求10中所述晶型CS8的制备方法，其特征在于，所述制备方法包含：将Apabetalone原料加入到卤代烃或者卤代烃和醇类的混合溶剂中，加热溶解后过滤，降温析出固体，得到Apabetalone的晶型CS8。
  14. 根据权利要求13所述的制备方法，其特征在于，所述卤代烃包含二氯甲烷，所述醇类包含异丙醇；所述卤代烃和醇类的体积比为4:1；所述加热温度为40～60℃；所述析晶温度为-20～5℃。
  15. 一种Apabetalone的晶型CS13，其特征在于，其X射线粉末衍射图在2θ值为5.1°±0.2°、12.5°±0.2°、17.1°±0.2°处具有特征峰。
  16. 根据权利要求15所述的晶型CS13，其特征在于，其X射线粉末衍射图在2θ值为6.4°±0.2°、8.5°±0.2°、25.7°±0.2°中的一处或两处或三处具有特征峰。
  17. 根据权利要求15所述的晶型CS13，其特征在于，其X射线粉末衍射图在2θ值为7.8°±0.2°、16.0°±0.2°中的一处或两处具有特征峰。
  18. 一种权利要求15中所述晶型CS13的制备方法，其特征在于，所述制备方法包含：将Apabetalone原料加入到醚类和水的混合溶剂或者酮类和水的混合溶剂中，溶解过滤后放置在室温挥发，至有固体析出，得到Apabetalone的晶型CS13。
  19. 根据权利要求18所述的制备方法，其特征在于，所述醚类包含四氢呋喃；所述酮类包含丙酮；所述醚类和水的体积比为4:1；所述酮类和水的体积比是9:1。
  20. 一种Apabetalone的晶型CS20，其特征在于，其X射线粉末衍射图在2θ值为8.4°±0.2°、18.9°±0.2°、13.5°±0.2°处具有特征峰。
  21. 根据权利要求20所述的晶型CS20，其特征在于，其X射线粉末衍射图在2θ值为11.3°±0.2°、9.4°±0.2°、5.6°±0.2°中的一处或两处或三处具有特征峰。
  22. 根据权利要求20所述的晶型CS20，其特征在于，其X射线粉末衍射图在2θ值为26.3°±0.2°、20.1°±0.2°、20.6°±0.2°、24.4°±0.2°中的一处或多处具有特征峰。
  23. 一种权利要求20中所述晶型CS20的制备方法，其特征在于，所述制备方法包含：Apabetalone原料加入到腈类和乙酸的混合溶剂或者酯类和乙酸的混合溶剂中，过滤后放置在室温下挥发，至有固体析出，得到Apabetalone的晶型CS20。
  24. 根据权利要求23所述的制备方法，其特征在于，所述腈类包含乙腈；所述酯类包含乙酸乙酯；所述腈类和乙酸的体积比为9:1；所述酯类和乙酸的体积比为4:1。
  25. 一种Apabetalone的晶型CS7，其特征在于，其X射线粉末衍射图在2θ值为5.9°±0.2°、6.7°±0.2°、10.7°±0.2°、12.5°±0.2°处具有特征峰。
  26. 根据权利要求25所述的晶型CS7，其特征还在于，其X射线粉末衍射图在2θ值为8.4°±0.2°、16.9°±0.2、13.3°±0.2°中的一处或两处或三处具有特征峰。
  27. 根据权利要求25所述的晶型CS7，其特征还在于，其X射线粉末衍射图在2θ值为16.0°±0.2°、25.1°±0.2°、15.0°±0.2°、21.8°±0.2°中的一处或多处具有特征峰。
  28. 一种权利要求25中所述晶型CS7的制备方法，其特征在于，所述制备方法包括以下步骤：
    溶解步骤：使用卤代烃将Apabetalone原料溶解，得到溶液；
    析出步骤：通过气液扩散的方式析出固体，得到Apabetalone的晶型CS7；
    所述析出步骤包括：将溶解步骤中所述溶液置于第一反应器中，将第一反应器敞口放置于含酮类溶剂的第二反应器中，至有固体析出，得到Apabetalone的晶型CS7。
  29. 根据权利要求28中所述的制备方法，其特征在于，所述卤代烃包含氯仿；所述酮类包含甲基异丁基酮。
  30. 一种Apabetalone的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为7.3°±0.2°、9.9°±0.2°、17.0°±0.2°处具有特征峰。
  31. 根据权利要求30所述的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为13.4°±0.2°、3.9°±0.2°、12.8°±0.2°中的一处或两处或三处具有特征峰。
  32. 根据权利要求30所述的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为12.1°±0.2°、24.9°±0.2°、22.5°±0.2°、24.2°±0.2°中的一处或多处具有特征峰。
  33. 一种权利要求30中所述晶型CS9的制备方法，其特征在于，所述制备方法包括以下步骤：
    溶解步骤：使用醚类和醇类的混合溶剂或卤代烃和醇类的混合溶剂将Apabetalone原料溶解，得到溶液；
    析出步骤：将所述溶液于室温下挥发，至有固体析出，得到Apabetalone的晶型CS9。
  34. 根据权利要求33所述的制备方法，其特征在于，所述醚类包含四氢呋喃；所述醇类包含异丙醇；所述卤代烃包含二氯甲烷和三氯甲烷；所述醚类和醇类的体积比为1:1；所述卤代烃和醇类的体积比为4:1。
  35. 一种Apabetalone的晶型CS11，其特征在于，其X射线粉末衍射图在2θ值为7.8°±0.2°、8.8°±0.2°、9.7°±0.2°、13.6°±0.2°处具有特征峰。
  36. 根据权利要求35所述的晶型CS11，其特征在于，其X射线粉末衍射图在2θ值为4.4°±0.2°、16.9°±0.2°、21.6°±0.2°中的一处或两处或三处具有特征峰。
  37. 根据权利要求35所述的晶型CS11，其特征在于，其X射线粉末衍射图在2θ值为13.0°±0.2°、15.3°±0.2°中的一处或两处具有特征峰。
  38. 一种权利要求35中所述晶型CS11的制备方法，所述制备方法包含方法1)或方法2)，其特征在于：
    方法1)溶解步骤：使用醇类溶剂将Apabetalone原料溶解，得到溶液；
    析出步骤：将所述溶液添加至水中或者将水添加至所述溶液中，析出固体，得到Apabetalone的晶型CS11；
    方法2)溶解步骤：使用卤代烃、醇类和酮类的混合溶剂、醇类和芳香烃类的混合溶剂中的一种将Apabetalone原料溶解，得到溶液；
    析出步骤：将所述溶液在室温下挥发，至有固体析出，得到Apabetalone的晶型CS11。
  39. 根据权利要求38所述的制备方法，其特征在于，方法1)中所述醇类包含甲醇；方法2中所述醇类包含甲醇；所述酮类包含丙酮和甲基异丁基酮；所述醇类和酮类的体积比为1:1～2:1；所述醇类和芳香烃类的体积比为4:1。
  40. 一种Apabetalone的晶型CS4，其特征在于，其X射线粉末衍射图在2θ值为9.1°±0.2°、14.5°±0.2°、23.5°±0.2°、24.2°±0.2°处具有特征峰。
  41. 根据权利要求40所述的晶型CS4，其特征在于，其X射线粉末衍射图在2θ值为 10.3°±0.2°、25.0°±0.2°、26.3°±0.2°中的一处或两处或三处具有特征峰。
  42. 根据权利要求40所述的晶型CS4，其特征在于，其X射线粉末衍射图在2θ值为10.8°±0.2°、11.6°±0.2°、19.5°±0.2°中的一处或两处或三处具有特征峰。
  43. 一种权利要求40中所述晶型CS4的制备方法，其特征在于，所述制备方法包含：将Apabetalone的晶型CS11加热至200～220℃，得到Apabetalone的晶型CS4。
  44. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型CS1、权利要求6中所述的晶型CS2、权利要求10中所述的晶型CS8、权利要求15中所述的晶型CS13、权利要求20中所述的晶型CS20、权利要求25中所述的晶型CS7、权利要求30中所述的晶型CS9、权利要求35中所述的晶型CS11、权利要求40中所述的晶型CS4中的一种或一种以上的晶型和药学上可接受的载体、稀释剂或赋形剂。
  45. 权利要求1中所述的晶型CS1、权利要求6中所述的晶型CS2、权利要求10中所述的晶型CS8、权利要求15中所述的晶型CS13、权利要求20中所述的晶型CS20、权利要求25中所述的晶型CS7、权利要求30中所述的晶型CS9、权利要求35中所述的晶型CS11、权利要求40中所述的晶型CS4在治疗心血管、胆固醇或脂质相关紊乱药物中的用途。
  46. 权利要求1中所述的晶型CS1、权利要求6中所述的晶型CS2、权利要求10中所述的晶型CS8、权利要求15中所述的晶型CS13、权利要求20中所述的晶型CS20、权利要求25中所述的晶型CS7、权利要求30中所述的晶型CS9、权利要求35中所述的晶型CS11、权利要求40中所述的晶型CS4在制备用于预防和治疗动脉粥样硬化、急性冠脉综合症和前驱糖尿病药物中的用途。
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