CN104812752B - Crystal formation of Azilsartan and preparation method thereof - Google Patents

Crystal formation of Azilsartan and preparation method thereof Download PDF

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CN104812752B
CN104812752B CN201380059509.7A CN201380059509A CN104812752B CN 104812752 B CN104812752 B CN 104812752B CN 201380059509 A CN201380059509 A CN 201380059509A CN 104812752 B CN104812752 B CN 104812752B
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azilsartan
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CN104812752A (en
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沈涛
盛晓霞
盛晓红
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Hangzhou Ling Ye Pharmaceutical Technology Co Ltd
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    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

Crystal formation that the present invention relates to Azilsartan and preparation method thereof.Specifically, the present invention relates to compound 1 [[2 ' (2,5 dihydro 5 oxos 1,2,4 diazole 3 bases) [1,1 ' biphenyl] 4 bases] methyl] the multiple novel crystal forms and preparation method thereof of 2 ethyoxyl 1H benzimidazole 7 carboxylic acids (5 methyl 2 oxos 1,3 two luxuriant 4 bases) methyl ester.In novel crystal forms water of the present invention, dissolubility is high compared with prior art and has relatively low fusing point, therefore relative to existing crystal formation, has more preferable dissolution and bioavailability and is more conducive to use hot-melt extruded method to obtain pharmaceutical preparation.

Description

Crystal formation of Azilsartan and preparation method thereof
Technical field
The present invention relates to medicine crystal technical field.Crystal formation in particular to Azilsartan and preparation method thereof.
Background technology
Azilsartan is a kind of novel hypertension element II receptor resistance of military field (Takeda) drugmaker of Japan exploitation Stagnant dose, obtain U.S. FDA approval listing, trade name Edabi in February, 2011.This medicine is also novel hypertension element II receptor The prodrug of blocker Azilsartan, for hypertension and the treatment of related complication.This medicine is oral medication, both can be alone, also The treatment for hypertension and related complication can be combined with other depressor.At 20 once a day～80mg Azilsartan In the III phase clinical experiment that ester is administered, confirm its safety and effectiveness, and in the comparison with Losartan and olmesartan medoxomil In experiment, there is higher hypotensive activity.The chemical name of Azilsartan is: 1-[[2 '-(2,5-dihydro-5-oxo-1, 2,4-diazole-3-bases) [1,1 '-biphenyl]-4-base] methyl]-2-ethyoxyl-1H-benzimidazole-7-carboxylic acid (5-methyl-2- Oxo-1,3-bis-cyclopentadienyl-4-base) methyl ester；English name: Azilsartan Medoxomil, has another name called TAK-491, and chemical formula is: C30H24N4O8；Molecular weight is: 568.53；Chemical structural formula is as follows:
Patent documentation US2005/018726 discloses the confirmation of Azilsartan, preparation and purposes.Specifically, implementing Example 1～2 discloses confirmation and the preparation of Azilsartan, and points out that product is crystalline state, but crystal formation data are not provided, in order to Convenient, below the crystal formation in embodiment 1～2 is referred to as " known crystal formation I "；Azilsartan is disclosed in example of formulations 1～6 The pharmaceutical composition of ester；The purposes of Azilsartan is disclosed in test example 1～2.
Patent documentation WO2012/090043A1 discloses the confirmation of Azilsartan, preparation and purposes, specifically, Embodiment 1～15 discloses many kinds of crystal habits of J2, J3, J4, J5, J6, J7, J8, J9 and amorphous Azilsartan and Preparation method.Wherein, disclose a kind of crystal formation and preparation method thereof in embodiment 1, and disclose this crystal formation XRPD figure, DSC figure, TGA spectrogram and IR spectrogram.For convenience, below the crystal formation in embodiment 1 is referred to as " known crystal formation J2 ".In embodiment 3, disclose another kind of crystal formation and preparation method thereof in 4 and 5, and disclose the XRPD figure of this crystal formation, DSC figure, TGA spectrogram and IR Spectrogram.For convenience, below the crystal formation in embodiment 3,4 and 5 is referred to as " known crystal formation J4 ".Additionally, this patent documentation is the most public Open Azilsartan and there is the therapeutical effect to hypertension and complication thereof.
Patent documentation WO2013/042066A1 discloses other three kinds of crystal formations of Azilsartan, specifically, is implementing Example 3～5 crystalline state disclosing two kinds of Azilsartans and preparation method thereof.
Experiment and research discovery, the known crystal formation disclosed in patent documentation WO2012/090043A1 is repeated through the present inventor J2 is anhydride, and is better than other crystal formation, it is known that crystal formation J4 is then dihydrate, and is better than other hydrate.
Polymorphic is the character of some molecules and molecular composition.Identical molecule may because of different spread patterns shape Become different crystal.Described polymorphic has different crystal structures and physical property, as dissolubility, stability, thermal property, Engineering properties, purification capacity, X-ray diffractogram, INFRARED ABSORPTION figure, Raman spectrum and solid-state nmr etc..One or more are analyzed Detection mode can be used for distinguishing the different crystal forms of same compound.
Find that the crystal formation (including anhydride, hydrate, solvate) that active constituents of medicine is new can be provided with adding of advantage The material of work character, finds that new anhydrous crystal forms and solvate can provide the material with more preferable physicochemical property, the most more Good bioavailability, stable storing, easy processed, it is easily purified or as promoting that the intermediate being converted into other crystal formations is brilliant Type.The novel crystal forms of the compound of pharmaceutically useful can also help improve the performance of medicine.It expand formulation science man in order to Optimize preparation performance and the kenel of available raw material, such as, improve dissolution, improve shelf life, be easier to processing etc..
The known crystal formation J2 mentioned in patent documentation WO2012/090043A1 dissolubility in water is relatively low, affects medicine Dissolution, and then affect bioavailability, and fusing point be too high, be not suitable for hot-melt extruded method and obtain preparation, and this crystal formation Grain is less, is unfavorable for the compressibility of tablet；The known crystal formation J4 mentioned is hydrate, and its dehydration temperaturre is relatively low, poor heat stability.
Therefore, it is still necessary to the crystal formation that Azilsartan is new, this crystal formation to possess good purity, and it should have relatively low simultaneously Fusing point, is suitable to the features such as formulation application；Or at room temperature there is the hydrate of more preferable stability.
Summary of the invention
For the deficiencies in the prior art, the main object of the present invention is to provide the novel crystal forms of Azilsartan as follows And preparation method thereof.Described novel crystal forms be that dissolubility is higher, fusing point is lower and the anhydride of ambient-temp-stable or room temperature more stable Hydrate, further relates to the preparation method of these novel crystal forms, and its pharmaceutical composition and purposes.
According to the purpose of the present invention, the present invention provides the crystal formation 3 (hereinafter referred to as " crystal formation 3 ") of Azilsartan.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 3 represents with 2 θ angles has in following position Characteristic peak: 5.1 ± 0.2 °, 10.2 ± 0.2 °, 11.5 ± 0.2 °, 11.7 ± 0.2 °, 12.5 ± 0.2 ° and 17.2 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 3 represents with 2 θ angles has a characteristic peak in following position: 5.1±0.2°、8.6±0.2°、10.2±0.2°、11.5°±0.2°、11.7±0.2°、12.5±0.2°、13.6±0.2°、 14.7 ± 0.2 °, 15.7 ± 0.2 °, 17.2 ± 0.2 °, 19.7 ± 0.2 ° and 24.2 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 3 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 3 has X-ray powder diagram as shown in Figure 1.
Thermogravimetric analysis (TGA) the collection of illustrative plates display sample of described crystal formation 3 is anhydride；Decomposition temperature is 234 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 3 shows that its fusing point is 151 DEG C, and occurs to turn in melting process Crystalline substance, transfers the known crystal formation J2 that fusing point is about 170 DEG C to.
Described crystal formation 3 uses following method to prepare: under room temperature, the suspension formed in dichloromethane by known crystal formation J2 Stirring and crystallizing, then separates the crystal separated out, obtains crystal formation 6, then be warming up to slough completely solvent by crystal formation 6, then cool down To room temperature, i.e. obtain described crystal formation 3.
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in dichloromethane of room temperature, preferably It is 1.5～10 times, more preferably 2～5 times；Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Preferably, described intensification be the ramp with 10 DEG C/min to 140 DEG C, the rate of temperature fall of described cooling is 10 ℃/min。
Described crystal formation 3 has the advantages that
Under the most described crystal formation 3 room temperature, in water, dissolubility is 4.0 μ g/g, and more known crystal formation J2 (0.5 μ g/g) is high；
The most described crystal formation 3, under room temperature (40%～75%RH), is placed 4 months, and crystal formation and fusing point are constant, has preferably Stability；
The most described crystal formation 3 fusing point is relatively low, relative to known crystal formation J2, is particularly suited for the preparation of hot-melt extruded method.According to The purpose of the present invention, the present invention provides the crystal formation 4 (hereinafter referred to as " crystal formation 4 ") of Azilsartan.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 4 represents with 2 θ angles has in following position Characteristic peak: 4.5 ± 0.2 °, 7.8 ± 0.2 °, 8.4 ± 0.2 °, 9.6 ± 0.2 °, 10.8 ± 0.2 ° and 18.3 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 4 represents with 2 θ angles has a characteristic peak in following position: 4.5±0.2°、7.8±0.2°、8.4±0.2°、9.0±0.2°、9.6±0.2°、10.8±0.2°、11.0±0.2°、12.8 ± 0.2 °, 16.7 ± 0.2 °, 18.3 ± 0.2 °, 22.6 ± 0.2 ° and 23.4 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 4 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 4 has X-ray powder diagram as shown in Figure 6.
Thermogravimetric analysis (TGA) the collection of illustrative plates display sample of described crystal formation 4 is anhydride；Decomposition temperature is 231 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 4 shows that its fusing point is 154 DEG C, turns crystalline substance in 160 DEG C, forms fusing point It is about the known crystal formation J2 of 170 DEG C.
Described crystal formation 4 use in following method any one prepare:
(1) in room temperature, the suspension stirring and crystallizing that Azilsartan amorphous substance is formed in organic solvent, then will The crystal separated out separates, is dried, and obtains described crystal formation 4；
Described organic solvent is preferably acetonitrile, ethanol, normal propyl alcohol, butanol, diisopropyl ether, methyl tertiary butyl ether(MTBE), heptane, methyl Hexamethylene, more preferably acetonitrile；
In described suspension, the amount of amorphous substance is under room temperature, 1～20 times of its dissolubility in organic solvent, preferably It is 2～10 times, more preferably 2～5 times；Crystallize mixing time is 0.5～3 day, preferably 0.5～1 day.
(2) known crystal formation J2 is dissolved in solution cooling stirring and crystallizing, the crystal that then will separate out that organic solvent is formed Separate, be dried, obtain described crystal formation 4；
Described organic solvent is preferably acetonitrile, acetone, 2-butanone and oxolane, more preferably acetonitrile；
In the organic solvent solution of described crystal formation J2, it is known that the amount of crystal formation J2 is that it is in acetonitrile the 0.1～1 of dissolubility Times, preferably 0.5～1 times, more preferably 0.8～1 times；The time of described crystallize is 0.5～2 day.
It is 40～80 DEG C that described solution forms temperature, preferably 70～80 DEG C；Temperature after cooling is 0～30 DEG C, preferably It it is 0 DEG C.
Described crystal formation 4 has the advantages that
Under the most described crystal formation 4 room temperature, in water, dissolubility is 6.0 μ g/g, and more known crystal formation J2 (0.5 μ g/g) is high；
The most described crystal formation 4 has relatively low fusing point, and more known crystal formation J2 is particularly suited for the preparation of hot-melt extruded method；
The most described crystal formation 4 granule is relatively big, has preferable tablet compressibility；
The most described crystal formation 4 is placed 4 months under room temperature (40%～75%RH), and crystal formation and fusing point are constant, has preferably Stability.
According to the purpose of the present invention, the present invention provides the crystal formation 14 (hereinafter referred to as " crystal formation 14 ") of Azilsartan.
Described crystal formation 14 is hydrate, and every mole of crystal formation 14 is containing about 0.5 mole of water.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 14 represents with 2 θ angles has in following position There is a characteristic peak: 6.2 ± 0.2 °, 8.7 ± 0.2 °, 9.0 ± 0.2 °, 13.5 ± 0.2 °, 16.2 ± 0.2 ° and 26.7 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 14 represents with 2 θ angles has feature in following position Peak: 6.2 ± 0.2 °, 8.7 ± 0.2 °, 9.0 ± 0.2 °, 9.9 ± 0.2 °, 11.8 ± 0.2 °, 13.5 ± 0.2 °, 16.2 ± 0.2 °, 20.5 ± 0.2 °, 23.5 ± 0.2 °, 24.3 ± 0.2 °, 26.7 ± 0.2 ° and 27.9 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 14 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 14 has X-ray powder diagram as shown in figure 29.
Described crystal formation 14 thermogravimetric analysis (TGA) collection of illustrative plates display sample 125 DEG C begin with 2.2% weightlessness, be roughly equal to 0.5 Individual hydrone, for semihydrate, its dehydration temperaturre relatively J4 (95 DEG C) is high, and decomposition temperature is 221 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 14 shows it to lose after solvent to be formed that fusing point is about 170 DEG C anhydrous Known crystal formation J2.
Described crystal formation 14 uses following method to prepare: at room temperature, and known crystal formation J2 is dissolved in the mixed of organic solvent and water Closing in solution, form solution, add polymethyl methacrylate, volatilization crystallize, obtains described crystal formation 14 the most naturally；
Described organic solvent is preferably acetone, 2-butanone and oxolane, more preferably acetone；
In the mixed solvent of described organic solvent and water, the volume fraction of water is 1～5%；
The usage amount of described polymethyl methacrylate (PMMA) is less than or equal to the 5% of known crystal formation J2 weight, the least In equal to 4%, more preferably less than 3%.
In the solution of described crystal formation J2, it is known that the amount of crystal formation J2 is under room temperature, and it is in organic solvent and water mixed solution 0.2～1 times of dissolubility, preferably 0.5～1 times, more preferably 0.8～1 times.
Described crystal formation 14 has the advantages that
The most described crystal formation 14 is more stable, places 4 months crystal formations and fusing point is constant under room temperature (40%～75%RH) environment；
The most described crystal formation 14 more known crystal formation J4 has higher dehydration temperaturre, better heat stability；
The most described crystal formation 14 granule is relatively big, has preferable tablet compressibility.Additionally, according to the purpose of the present invention, this The crystal formation 6 (hereinafter referred to as " crystal formation 6 ") of bright offer Azilsartan.
Described crystal formation 6 is dichloromethane compound, and every mole of crystal formation 6 is containing the dichloromethane of 1 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 6 represents with 2 θ angles has in following position Characteristic peak: 10.8 ± 0.2 °, 12.7 ± 0.2 °, 16.8 ± 0.2 °, 18.3 ± 0.2 °, 23.0 ± 0.2 ° and 23.2 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 6 represents with 2 θ angles has a characteristic peak in following position: 8.3±0.2°、9.5±0.2°、10.8±0.2°、11.1±0.2°、12.7±0.2°、13.8±0.2°、16.8±0.2°、 17.9 ± 0.2 °, 18.3 ± 0.2 °, 18.9 ± 0.2 °, 23.0 ± 0.2 ° and 23.2 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 6 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 6 has X-ray powder diagram as shown in fig. 13 that.
There is the weightlessness of 4.8% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 6, be roughly equal to 1 two Chloromethanes molecule, for dichloromethane compound；Decomposition temperature is 229 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 6 shows that it loses solvent at 127 DEG C and obtains fusing point and be about 151 DEG C Anhydrous crystal forms 3.
Described crystal formation 6 uses following method to prepare: under room temperature, the suspension formed in dichloromethane by known crystal formation J2 Stirring and crystallizing, then separates the crystal separated out, obtains described crystal formation 6；
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in dichloromethane of room temperature, preferably It is 1.5～10 times, more preferably 2～5 times；Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 5 (hereinafter referred to as " crystal formation 5 ") of Azilsartan.
Described crystal formation 5 is dioxane compound, and every mole of crystal formation 5 is containing the dioxane of 1 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 5 represents with 2 θ angles has in following position Characteristic peak: 7.2 ± 0.2 °, 10.6 ± 0.2 °, 11.0 ± 0.2 °, 14.7 ± 0.2 °, 18.5 ± 0.2 ° and 19.2 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 5 represents with 2 θ angles has a characteristic peak in following position: 7.2±0.2°、7.6±0.2°、10.6±0.2°、11.0±0.2°、13.3±0.2°、14.7±0.2°、15.7±0.2°、 17.1 ± 0.2 °, 17.8 ± 0.2 °, 18.5 ± 0.2 °, 19.2 ± 0.2 ° and 22.3 ° ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 5 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 5 has X-ray powder diagram as shown in Figure 10.
There is the weightlessness of 10.1% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 5, be roughly equal to 1 dioxy Six toroidal molecules, for dioxane compound；Decomposition temperature is 238 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 5 shows that it loses solvent at 137 DEG C, forms fusing point and is about 170 DEG C Known crystal formation J2.
Described crystal formation 5 can be by following method, any one is prepared:
(1) in room temperature, add sec-butyl alcohol and/or water, stirring and crystallizing to the dioxane solution of known crystal formation J2, then will The crystal separated out separates, and obtains described crystal formation 5；
In described dioxane solution, it is known that the amount of crystal formation J2 is the 0.2～1 of its dissolubility in dioxane of room temperature Times, preferably 0.5～1 times, more preferably 0.8～1 times.The volume of described sec-butyl alcohol or water is the 5～20 of dioxane volume Times, preferably 10～15 times.Crystallize mixing time is 1～24h, preferably 1～5h.
(2) at a certain temperature, the dioxane solution of known crystal formation J2 is formed, under same temperature, volatilization knot naturally Crystalline substance, obtains described crystal formation 5.Described temperature is 30～50 DEG C, preferably 40 DEG C.
In described dioxane solution, it is known that the amount of crystal formation J2 is the 0.2～1 of its dissolubility in dioxane of room temperature Times, preferably 0.5～1 times, more preferably 0.8～1 times.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 7 (hereinafter referred to as " crystal formation 7 ") of Azilsartan.
Described crystal formation 7 is toluene compound, and every mole of crystal formation 7 is containing the toluene of 1 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 7 represents with 2 θ angles has in following position Characteristic peak: 4.5 ± 0.2 °, 9.4 ± 0.2 °, 10.7 ± 0.2 °, 17.1 ± 0.2 °, 18.1 ± 0.2 and 19.4 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 7 represents with 2 θ angles has a characteristic peak in following position: 4.5±0.2°、7.7±0.2°、9.0±0.2°、9.4°±0.2°、10.7°±0.2°、11.2±0.2°、12.5±0.2°、 13.7 ± 0.2 °, 17.1 ± 0.2 °, 18.1 ± 0.2 °, 19.4 ± 0.2 ° and 20.1 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 7 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 7 has X-ray powder diagram as shown in figure 16.
There is the weightlessness of 7.7% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 7, be roughly equal to 1 toluene Molecule, for toluene compound；Decomposition temperature is 231 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 7 shows that it loses solvent at 131 DEG C, forms fusing point and is about 170 DEG C Anhydrous known crystal formation J2.
Described crystal formation 7 can be prepared by following method: in room temperature, is stirred by the suspension that known crystal formation J2 is formed in toluene Mix crystallize, then the crystal separated out is separated, obtain described crystal formation 7.
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in toluene of room temperature, it is preferably 1.5～10 times, more preferably 2～5 times.Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 8 (hereinafter referred to as " crystal formation 8 ") of Azilsartan.
Described crystal formation 8 is etherate, and every mole of crystal formation 8 is containing the ether of 1 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 8 represents with 2 θ angles has in following position Characteristic peak: 4.5 ± 0.2 °, 9.0 ± 0.2 °, 9.6 ± 0.2 °, 10.8 ± 0.2 °, 12.7 ± 0.2 ° and 18.3 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 8 represents with 2 θ angles has a characteristic peak in following position: 4.5±0.2°、8.5±0.2°、9.0±0.2°、9.6±0.2°、10.8±0.2°、11.1±0.2°、12.7±0.2°、13.4 ± 0.2 °, 17.0 ± 0.2 °, 18.3 ± 0.2 °, 19.1 ± 0.2 and 22.9 ° ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 8 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 8 has X-ray powder diagram as shown in figure 19.
There is the weightlessness of 9.3% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 8, be roughly equal to 1 ether Molecule, for etherate；Decomposition temperature is 222 DEG C.
Described crystal formation 8 can be prepared by following method: in room temperature, is stirred by the suspension that known crystal formation J2 is formed in ether Mix crystallize, then the crystal separated out is separated, obtain described crystal formation 8.
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in ether of room temperature, it is preferably 1.5～10 times, more preferably 2～5 times.Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 9 (hereinafter referred to as " crystal formation 9 ") of Azilsartan.
Described crystal formation 9 is chloroform compound, and every mole of crystal formation 9 is containing the chloroform of 1 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 9 represents with 2 θ angles has in following position Characteristic peak: 4.5 ± 0.2 °, 11.0 ± 0.2 °, 12.5 ± 0.2 °, 16.6 ± 0.2 °, 19.0 ± 0.2 ° and 23.0 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 9 represents with 2 θ angles has a characteristic peak in following position: 4.5±0.2°、8.3±0.2°、8.9±0.2°、11.0±0.2°、12.5±0.2°、13.8±0.2°、14.7±0.2°、 15.6 ± 0.2 °, 16.6 ± 0.2 °, 19.0 ° ± 0.2 °, 22.6 ± 0.2 and 23.0 ° ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 9 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 9 has X-ray powder diagram as shown in figure 21.
The weightlessness of 19.7%, about unification chlorine is had before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 9 Imitative molecule, for chloroform compound；Decomposition temperature is 219 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 9 shows that it loses solvent 120 DEG C at, after formation anhydrous crystal forms in 143 DEG C turn crystalline substance and form the anhydrous known crystal formation J2 that fusing point is about 170 DEG C.
Described crystal formation 9 can be prepared by following method: in room temperature, is stirred by the suspension that known crystal formation J2 is formed in chloroform Mix crystallize, then the crystal separated out is separated, obtain described crystal formation 9.
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in chloroform of room temperature, it is preferably 1.5～10 times, more preferably 2～5 times.Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 10 (hereinafter referred to as " crystal formation 10 ") of Azilsartan.
Described crystal formation 10 is hydrate, and every mole of crystal formation 10 is containing the water of 3 moles.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 10 represents with 2 θ angles has in following position There is a characteristic peak: 4.6 ± 0.2 °, 8.9 ± 0.2 °, 9.5 ± 0.2 ° and 16.5 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 10 represents with 2 θ angles has feature in following position Peak: 4.6 ± 0.2 °, 4.8 ± 0.2 °, 8.9 ± 0.2 °, 9.5 ± 0.2 °, 10.7 ± 0.2 °, 12.7 ± 0.2 °, 16.5 ± 0.2 °, 16.9 ± 0.2 ° and 23.3 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 10 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 10 has X-ray powder diagram as of fig. 24.
There is the weightlessness of 6.21% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 10, be roughly equal to three water Molecule, for trihydrate；Decomposition temperature is 230 DEG C.
Described crystal formation 10 can be prepared by following method: at a certain temperature, by the nitromethane solution of known crystal formation J2 Volatilization crystallize, then separates the crystal separated out, obtains described crystal formation 10.
In described nitromethane solution, it is known that the amount of crystal formation J2 is the 0.1～1 of its dissolubility in nitromethane of room temperature Times, preferably 0.5～1 times, more preferably 0.8～1 times.Described volatilization recrystallization temperature is 30～50 DEG C.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 11 (hereinafter referred to as " crystal formation 11 ") of Azilsartan.
Described crystal formation 11 is diisopropyl ether compound, and every mole of crystal formation 11 about contains the diisopropyl ether of 0.5 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 11 represents with 2 θ angles has in following position There is a characteristic peak: 4.6 ± 0.2 °, 9.4 ± 0.2 °, 10.8 ± 0.2 °, 12.5 ± 0.2 °, 13.9 ± 0.2 ° and 18.4 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 11 represents with 2 θ angles has feature in following position Peak: 4.6 ± 0.2 °, 9.4 ± 0.2 °, 10.8 ± 0.2 °, 11.2 ± 0.2 °, 12.5 ± 0.2 °, 13.9 ± 0.2 °, 17.0 ± 0.2 °, 18.4 ± 0.2 °, 19.3 ± 0.2 °, 20.0 ± 0.2 °, 22.8 ± 0.2 ° and 28.0 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 11 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 11 has X-ray powder diagram as shown in figure 26.
Described crystal formation 11 thermogravimetric analysis (TGA) collection of illustrative plates display 150 DEG C of sample before have 6.7% weightlessness, be roughly equal to 0.5 different Propyl ether molecule, for diisopropyl ether compound；Decomposition temperature is 223 DEG C.
Differential scanning calorimetric (DSC) figure of described crystal formation 11 shows that it loses solvent at 115 DEG C and forms anhydrous crystal forms in 127 DEG C turn crystalline substance to form fusing point and be about the anhydrous known crystal formation J2 of 170 DEG C.
Described crystal formation 11 can be prepared by following method: in room temperature, the suspension formed in diisopropyl ether by known crystal formation J2 Liquid stirring and crystallizing, then separates the crystal separated out, obtains described crystal formation 11.
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in diisopropyl ether of room temperature, it is preferably 1.5～10 times, more preferably 2～5 times.Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 15 (hereinafter referred to as " crystal formation 15 ") of Azilsartan.
Described crystal formation 15 is ethyl acetate compound, and every mole of crystal formation 15 is containing the ethyl acetate of 0.5 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 15 represents with 2 θ angles has in following position There is a characteristic peak: 4.5 ± 0.2 °, 6.1 ± 0.2 °, 9.0 ± 0.2 °, 9.5 ± 0.2 °, 10.8 ± 0.2 ° and 18.2 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 15 represents with 2 θ angles has feature in following position Peak: 4.5 ± 0.2 °, 6.1 ± 0.2 °, 9.0 ± 0.2 °, 9.5 ± 0.2 °, 10.8 ± 0.2 °, 11.2 ± 0.2 °, 12.6 ± 0.2 °, 13.9 ± 0.2 °, 17.1 ± 0.2 °, 18.3 ± 0.2 °, 22.5 ± 0.2 and 23.0 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 15 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 15 has X-ray powder diagram as shown in figure 33.
There is the weightlessness of 7.4% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 15, be roughly equal to 0.5 second Teos molecule, for ethyl acetate compound；Decomposition temperature is 223 DEG C.
Described crystal formation 15 can be prepared by following method: in room temperature, formed in ethyl acetate by known crystal formation J2 is outstanding Supernatant liquid stirring and crystallizing, then separates the crystal separated out, obtains described crystal formation 15；
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in ethyl acetate of room temperature, preferably It is 1.5～10 times, more preferably 2～5 times.Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
Additionally, according to the purpose of the present invention, the present invention provides the crystal formation 16 (hereinafter referred to as " crystal formation 16 ") of Azilsartan.
Described crystal formation 16 is isopropyl acetate compound, and every mole of crystal formation 16 is containing the isopropyl acetate of 0.5 mole.
Using Cu-K α radiation, the X-ray powder diffraction spectrum that described crystal formation 16 represents with 2 θ angles has in following position There is a characteristic peak: 4.5 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 9.4 ± 0.2 °, 10.7 ± 0.2 ° and 18.2 ± 0.2 °.
Preferably, the X-ray powder diffraction spectrum that described crystal formation 16 represents with 2 θ angles has feature in following position Peak: 4.5 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 9.4 ± 0.2 °, 10.7 ± 0.2 °, 11.1 ± 0.2 °, 12.7 ± 0.2 °, 17.0 ± 0.2 °, 18.2 ± 0.2 °, 22.5 ± 0.2 °, 22.9 ± 0.2 ° and 23.4 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction spectrum that described crystal formation 16 represents with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of described crystal formation 16 has X-ray powder diagram as shown in figure 35.
There is the weightlessness of 6.2% before thermogravimetric analysis (TGA) collection of illustrative plates 150 DEG C of the sample of display of described crystal formation 16, be roughly equal to 0.5 second Isopropyl propionate molecule, for isopropyl acetate compound；Decomposition temperature is 223 DEG C.
Described crystal formation 16 can be prepared by following method: in room temperature, is formed by known crystal formation J2 in isopropyl acetate Suspension stirring and crystallizing, then separates the crystal separated out, obtains described crystal formation 16.
In described suspension, it is known that the amount of crystal formation J2 is 1～20 times of its dissolubility in isopropyl acetate of room temperature, excellent Elect 1.5～10 times as, more preferably 2～5 times.Crystallize mixing time is 0.5～7 day, preferably 0.5～3 day.
In the preparation method of the above-mentioned all crystal formations related to:
Described " room temperature " refers to 10～30 DEG C.
Described stirring, concrete operations are: with 50～1800 revs/min of magnetic agitation carried out, and preferably 300～900 revs/min are entered The magnetic agitation of row.
Described separation, including filtering or centrifugal.Described centrifugal concrete operations are: be intended to separate sample be placed in 2mL from In heart pipe, it is centrifuged with 6000 revs/min of speed, treats that solid is all sink to bottom centrifuge tube, remove supernatant.
Unless stated otherwise, the crystal formation described in the present invention can be through drying steps.Described dry, ability can be used The routine techniques in territory completes, such as normal temperature drying, forced air drying or drying under reduced pressure, at fume hood, convection oven or vacuum drying oven In carry out；Can carry out under reducing pressure or not reducing pressure, preferably pressure is less than 0.09Mpa；Baking temperature about 30～50 DEG C；It is dried Time is 10～72 hours, preferably 10～48 hours, more preferably 10～24 hours.
In the application, ultrasonic operation is: be placed in ultrasonic cleaner by container under room temperature, surpasses with 20Khz～40Khz Sound operating power carries out ultrasonic 1～30 minute.
In the application, the operation that rotation is steamed is: at room temperature～solvent boiling point, less than under the pressure of atmospheric pressure, (preferably pressure is little In 0.08MPa), to carry out under the conditions of 10～180rpm rotary speeies (preferably 50～100rpm).
The invention mainly relates to the new crystal formation of Azilsartan 3, crystal formation 4, crystal formation 14 and crystal formation 6, be additionally related to A Qi Crystal formation 5, crystal formation 7, crystal formation 8, crystal formation 9, crystal formation 10, crystal formation 11, crystal formation 15 and the crystal formation 16 that husky smooth ester is new.
In the present invention, " crystal " or " crystal formation " refers to be characterized by shown X-ray diffractogram and is confirmed.This area skill Art personnel it is understood that physicochemical property discussed herein can be characterized, experimental error therein depend on instrument condition, The preparation of sample and the purity of sample.Particularly, as well known to those skilled in the art, X-ray diffractogram would generally be along with instrument Condition and change.Special needs to be pointed out is, the relative intensity of X-ray diffractogram is likely to the change along with experiment condition And change, so the order of peak intensity cannot function as unique or deciding factor.It addition, the experimental error of peak angle degree generally exists 5% or less, the error of these angles also should be considered into, allows generally for ± the error of 0.2.Further, since sample The impact of the empirical factors such as height, can cause the overall offset of peak angle degree, allows generally for certain skew.Thus, this area skill Art personnel are it is understood that the X-ray diffractogram of a crystal formation need not be with the X-ray in example referred herein in the present invention Diffraction pattern is completely the same.Any crystal formation with figure same or analogous with the characteristic peak in these figures belongs to the model of the present invention Within farmland.Figure listed by the present invention can be compared by those skilled in the art with the figure of a unknown crystal formation, with confirm this two The reflection of group figure is identical or different crystal formation.
Unless stated otherwise, here " anhydride " refers to described crystal formation through TGA measurement containing not more than 1.5% (weight Than), or the water of not more than 1.0% (weight ratio).
The crystallization mode used in the present invention includes volatilization, magma, polymeric stencil volatilization recrystallization and cooling recrystallization Method with solvent resistant recrystallization.
Volatilization is to be placed on by sample settled solution in uncovered 5mL vial, uncovered or add a cover punching, at specified temp Under the conditions of volatilize.Method or directly room temperature volatilization that nitrogen blows can be used.
Magma is to be stirred in different solvents system by the supersaturated solution (with the presence of undissolved solid) of sample, it is common that 2 hours～2 time-of-weeks.
Polymeric stencil experiment is consistent with room temperature evaporation method, simply with the addition of a certain amount of insoluble polymer substance in sample In product solution.
In the present invention, in polymeric stencil is tested, the usage amount of polymer substance is less than Azilsartan weight 5%, preferably more than 4%, more preferably less than 3%.In some cases, use polymer substance with side in experimentation Crystallization in motion type crystallizes, and the polymer substance used in the present invention is polymethyl methacrylate (PMMA).
PMMA used in the present invention is amorphous, and DSC does not show fusing point.Use due to polymer substance Amount is strictly controlled below 5%, and this polymer substance does not interferes with the judgement of crystal formation the most in an experiment.
Cooling recrystallization is to dissolve a sample in appropriate solvent under specific hot conditions, is placed on 5mL vial In, it is placed in alternating temperature shaking table, lowers the temperature successively according to certain rate of temperature fall, stirred overnight at room temperature.The temperature of experiment can be 0～75 DEG C, preferably 15～50 DEG C.In each specific temperature, sample solution is incubated 1 hour～2 days.
Sample is e.g. dissolved in good solvent by solvent resistant recrystallization, ultrasonic makes it dissolve, then adds appropriate solvent resistant, room Temperature stirring.
Raw material used in the present invention can be prepared according to the method described in patent documentation WO2012/090043A1, The raw material generally used in the present invention is the known crystal formation J2 described by this patent documentation.
Heretofore described Azilsartan amorphous substance can be prepared according to following methods: adds in known crystal formation J2 Acetone, is the most quickly spin-dried for, and obtains Azilsartan amorphous.
The present invention solves asking of prior art crystal formation existence by providing new crystal formation 3, crystal formation 4, crystal formation 14 and crystal formation 6 Topic, this new crystal formation has at least one or multiple favorable property compared with known crystal formation, is especially in the presence of one of following advantage Or several: higher degree of crystallinity, dissolubility, dissolution rate, good particle shape, be difficult to that polymorphic inversion and/or dehydration occur Kenel, calorifics and good mechanical stability, agent of low hygroscopicity, more preferable mobility, compressibility and apparent density, stable storing Property, low-residual solvent etc..
In some embodiments, the present invention is by providing new crystal formation 5, crystal formation 7, crystal formation 8, crystal formation 9, crystal formation 10, brilliant Type 11, crystal formation 15 or crystal formation 16 solve the problem that prior art crystal formation exists, and this new crystal formation has selected from following at least one Favorable property: higher degree of crystallinity, dissolubility, dissolution rate, good particle shape, be difficult to occur polymorphic inversion and/ Or kenel, calorifics and good mechanical stability, agent of low hygroscopicity, more preferable mobility, compressibility and apparent density, the storage of dehydration Stability, low-residual solvent etc..
Additionally, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the one of therapeutically effective amount or many Plant the crystal formation 3 of described Azilsartan, crystal formation 4, crystal formation 5, crystal formation 6, crystal formation 7, crystal formation 8, crystal formation 9, crystal formation 10, crystal formation 11, crystalline substance Type 14, crystal formation 15 or crystal formation 16, and at least one pharmaceutically acceptable excipient.
Described pharmaceutical composition can also comprise crystal formation or the amorphous substance of other pharmaceutically useful Azilsartan, and these are brilliant Type includes but not limited to known crystal formation J2 and known crystal formation J4.
Described pharmaceutical composition can be solid-state or liquid.If this pharmaceutical composition is liquid, then one or more described Ah The crystal formation of Qi Shatan ester can remain solid, such as suspension in this fluid composition.
Additionally, the present invention provides the crystal formation 3 of described Azilsartan, crystal formation 4, crystal formation 5, crystal formation 6, crystal formation 7, crystal formation 8, crystalline substance Type 9, crystal formation 10, crystal formation 11, crystal formation 14, crystal formation 15 or crystal formation 16 use in the medicine of preparation treatment hypertension and complication On the way.
Additionally, the present invention provides a kind of method treating hypertension and complication, described method includes to the trouble with needs The crystal formation 3 of the described Azilsartan of person's therapeutically effective amount, crystal formation 4, crystal formation 5, crystal formation 6, crystal formation 7, crystal formation 8, crystal formation 9, crystal formation 10, crystal formation 11, crystal formation 14, crystal formation 15 or crystal formation 16, or described pharmaceutical composition.
Described patient includes but not limited to mammal.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of crystal formation 3 of the present invention.
Fig. 2 is the DSC figure of crystal formation 3 of the present invention.
Fig. 3 is the TGA figure of crystal formation 3 of the present invention.
Fig. 4 is the XRPD figure of amorphous substance.
Fig. 5 is the XRPD figure in crystal formation 3 stability experiment of the present invention.Wherein, figure below obtains for measuring immediately after preparation；On Figure is to measure after 4 months to obtain.
Fig. 6 is the XRPD figure of crystal formation 4 of the present invention.
Fig. 7 is the DSC figure of crystal formation 4 of the present invention.
Fig. 8 is the TGA figure of crystal formation 4 of the present invention.
Fig. 9 is the PLM figure of crystal formation 4 of the present invention.
Figure 10 is the XRPD figure of crystal formation 5 of the present invention.
Figure 11 is the DSC figure of crystal formation 5 of the present invention.
Figure 12 is the TGA figure of crystal formation 5 of the present invention.
Figure 13 is the XRPD figure of crystal formation 6 of the present invention.
Figure 14 is the DSC figure of crystal formation 6 of the present invention.
Figure 15 is the TGA figure of crystal formation 6 of the present invention.
Figure 16 is the XRPD figure of crystal formation 7 of the present invention.
Figure 17 is the DSC figure of crystal formation 7 of the present invention.
Figure 18 is the TGA figure of crystal formation 7 of the present invention.
Figure 19 is the XRPD figure of crystal formation 8 of the present invention.
Figure 20 is the TGA figure of crystal formation 8 of the present invention.
Figure 21 is the XRPD figure of crystal formation 9 of the present invention.
Figure 22 is the DSC figure of crystal formation 9 of the present invention.
Figure 23 is the TGA figure of crystal formation 9 of the present invention.
Figure 24 is the XRPD figure of crystal formation 10 of the present invention.
Figure 25 is the TGA figure of crystal formation 10 of the present invention.
Figure 26 is the XRPD figure of crystal formation 11 of the present invention.
Figure 27 is the DSC figure of crystal formation 11 of the present invention.
Figure 28 is the TGA figure of crystal formation 11 of the present invention.
Figure 29 is the XRPD figure of crystal formation 14 of the present invention.
Figure 30 is the DSC figure of crystal formation 14 of the present invention.
Figure 31 is the TGA figure of crystal formation 14 of the present invention.
Figure 32 is the PLM figure of crystal formation 14 of the present invention.
Figure 33 is the XRPD figure of crystal formation 15 of the present invention.
Figure 34 is the TGA figure of crystal formation 15 of the present invention.
Figure 35 is the XRPD figure of crystal formation 16 of the present invention.
Figure 36 is the TGA figure of crystal formation 16 of the present invention.
Figure 37 is the XRPD figure of known crystal formation J2.
Figure 38 is the DSC figure of known crystal formation J2.
Figure 39 is the TGA figure of known crystal formation J2.
Figure 40 is the PLM figure of known crystal formation J2.
Figure 41 is the XRPD figure of known crystal formation J4.
Figure 42 is the DSC figure of known crystal formation J4.
Figure 43 is the TGA figure of known crystal formation J4.
Detailed description of the invention
The present invention with further reference to following example limit, described embodiment describe in detail the present invention crystal formation preparation and Using method.It will be apparent for a person skilled in the art that for material and method many change can without departing from Implement in the case of the scope of the invention.
Gather instrument used by data and method:
The instrument that X-ray powder diffraction (XPRD) is used is Bruker D8 Advance diffractometer, adopts By the Ka X-ray that copper target wavelength is 1.54nm, under the operating condition of 40kV and 40mA, θ-2 θ clinometer, Mo monochromator, Lynxeye detector.Standard substance (generally corundum) calibration that instrument carries with instrument before use.Acquisition software is Diffrac Plus XRPD Commander, analyzing software is MDI Jade 5.0.Sample is tested at ambient temperature, needing Sample to be detected is placed on SiP areflexia plate.Testing conditions in detail is as follows: angular range: 3～40 ° of 2 θ；Step-length: 0.02 ° 2 θ；Speed: 0.2s/ walks.Unless stated otherwise, sample is the most ground.
Micropolariscope (PLM) figure picks up from XP-500E micropolariscope (the Shanghai limited public affairs of rectangular optical instrument Department).Take a small amount of powder sample to be placed on microscope slide, drip a small amount of mineral oil with preferably dispersed powders sample, covered, Then sample is placed on the object stage of XP-500E micropolariscope, selects the shape of suitable amplification observing samples Looks are also taken pictures.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200 MDSC, and instrument control software is Thermal Advantage, analyzing software is Universal Analysis.Generally take the sample of 1～10mg to be positioned over and do not add a cover (unless special Do not mentionlet alone bright) aluminum crucible in, be dried N with the programming rate of 10 DEG C/min at 40mL/min2Protection under sample is risen to from 0 DEG C 250 DEG C, TA software records sample thermal change in temperature-rise period simultaneously.In this application, fusing point is to come by initial temperature Report.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500 TGA, and instrument control software is Thermal Advantage, analyzing software is Universal Analysis.Generally take the sample of 5～15mg to be positioned in platinum crucible, adopt By the mode of segmentation high resolution detection, it is dried N with the programming rate of 10 DEG C/min at 40mL/min2Protection under by sample from room Temperature rise is to 300 DEG C, and TA software records sample weight in temperature-rise period changes simultaneously.
Embodiment 1
The known crystal formation J2 of Azilsartan can be according to described by embodiment 1 in patent documentation WO2012/090043A1 Prepared by method.
Specifically, the preparation method of Azilsartan known crystal formation J2 is: at 15～20 DEG C, by 0.5g Azilsartan Know that crystal formation I is dissolved in 50mL methanol, volatilize after solution is filtered, obtain known crystal formation J2.
The XRPD figure of known crystal formation J2 is shown in Figure 37.
DSC figure is shown in Figure 38, and display fusing point is 170 DEG C.
TGA figure is shown in Figure 39, is shown as anhydride, and decomposition temperature is 229 DEG C.
PLM figure is shown in Figure 40, and display granule is minimum.
Embodiment 2
The known crystal formation J4 of Azilsartan can be according to described by embodiment 4 in patent documentation WO2012/090043A1 Prepared by method.
Specifically, the preparation method of the known crystal formation J4 of Azilsartan is: at 40～50 DEG C, by 0.5g Azilsartan Crystal formation I is dissolved in the mixed solution of acetone (7.5mL) and ethyl acetate (7.5mL), is cooled to 0～5 DEG C and stirs, being filtrated to get Known crystal formation J4.
The XRPD figure of known crystal formation J4 is shown in Figure 41.
DSC figure is shown in Figure 42, turns crystalline substance in 146 DEG C and form the anhydrous known crystal formation that fusing point is about 170 DEG C after showing its desolventizing J2。
TGA figure is shown in Figure 43, show 95 DEG C begin with 6.4% weightlessness, be roughly equal to 2 hydrones, for dihydrate, decompose Temperature is 222 DEG C.
Embodiment 3
Weigh 100mg known crystal formation J2 and add in 30mL single port flask, then add 10mL acetone, be quickly spin-dried for, To the solid amorphous thing like cystose.
The XRPD figure of amorphous substance is shown in Fig. 4, without XRPD diffraction maximum, for amorphous substance.
Embodiment 4
Weigh the crystal formation 6 of 10mg (15.3mmol) embodiment 34 preparation to put in TGA dish and heat with the speed of 10 DEG C/min To 140 DEG C, it is down to room temperature with the speed of 10 DEG C/min after keeping 0.5 minute, obtains crystal formation 3.Yield is 8mg (14.1mmol)； Molar yield is 92%.
XRPD figure is shown in Fig. 1.
DSC figure is shown in Fig. 2.Display: fusing point is 151 DEG C, and occur to turn crystalline substance in melting process, transfer fusing point to and be about 170 DEG C Anhydrous known crystal formation J2.
TGA figure is shown in Fig. 3.Display: for anhydride, decomposition temperature is 234 DEG C.
Embodiment 5
Weigh amorphous substance prepared by 1g embodiment 3 method, then add 40mL acetonitrile, add a cover and be stirred at room temperature 1 day, filter After be dried to obtain crystal formation 4.Yield is 0.92g；Molar yield is 92%.
XRPD figure is shown in Fig. 6.
DSC figure is shown in Fig. 7.Display: fusing point is 154 DEG C, turns crystalline substance in 160 DEG C, forms the anhydrous crystal forms that fusing point is about 170 DEG C J2。
TGA figure is shown in Fig. 8.Display: for anhydride, decomposition temperature is 231 DEG C.
PLM figure is shown in Fig. 9.Display: compared with known crystal formation J2 (Figure 40), crystal formation 4 granularity is relatively big, and pattern is preferable.
Described crystal formation 4 continues stirring more than 5 days, obtains crystal formation 3.
Embodiment 6
Weigh amorphous substance prepared by 20mg embodiment 3 method, add in 5mL vial, then add 2.0mL second Nitrile, adds a cover and is stirred at room temperature 2 days, be dried to obtain crystal formation 4 after filtration.Yield is 17mg, and molar yield is 85%.
Embodiment 7
Weigh amorphous substance prepared by 20mg embodiment 3 method, add in 5mL vial, then add 4.0mL second Nitrile, adds a cover and is stirred at room temperature 0.5 day, be dried to obtain crystal formation 4 after filtration.Yield is 17mg；Molar yield is 85%.
Embodiment 8
Weigh amorphous substance prepared by 20mg embodiment 3 method, add in 5mL vial, then add 1.0mL second Nitrile, adds a cover and is stirred at room temperature 3 days, be dried to obtain crystal formation 4 after filtration.Yield is 15mg；Molar yield is 75%.
Embodiment 9
Weigh amorphous substance prepared by 200mg embodiment 3 method, add in 5mL vial, then add 2.0mL second Nitrile, adds a cover and is stirred at room temperature 3 days, be dried to obtain crystal formation 4 after filtration.Yield is 130mg；Molar yield is 65%.
Embodiment 10
Weigh amorphous substance prepared by 100mg embodiment 3 method, add in 5mL vial, then add 1.0mL second Alcohol, adds a cover and is stirred at room temperature 1 day, be dried to obtain crystal formation 4 after filtration.Yield is 65mg；Molar yield is 65%.
Embodiment 11
Weigh amorphous substance prepared by 100mg embodiment 3 method, add in 5mL vial, then add 1.0mL fourth Alcohol, adds a cover and is stirred at room temperature 1 day, be dried to obtain crystal formation 4 after filtration.Yield is 60mg；Molar yield is 60%.
Embodiment 12
Weigh amorphous substance prepared by 100mg embodiment 3 method, add in 5mL vial, then add 1.0mL different Propyl ether, adds a cover and is stirred at room temperature 1 day, be dried to obtain crystal formation 4 after filtration.Yield is 75mg；Molar yield is 75%.
Embodiment 13
Weigh amorphous substance prepared by 0.5g embodiment 3 method, add in 10mL vial, then add 5.0mL first Base tertbutyl ether, adds a cover and is stirred at room temperature 1 day, be dried to obtain crystal formation 4 after filtration.Yield is 0.38g；Molar yield is 76%.
Embodiment 14
Weigh amorphous substance prepared by 100mg embodiment 3 method, add in 5mL vial, then add 1.0mL heptan Alkane, adds a cover and is stirred at room temperature 1 day, be dried to obtain crystal formation 4 after filtration.Yield is 50mg；Molar yield is 50%.
Embodiment 15
Weigh amorphous substance prepared by 100mg embodiment 3 method, add in 5mL vial, then add 1.0mL first Butylcyclohexane, adds a cover and is stirred at room temperature 1 day, be dried to obtain crystal formation 4 after filtration.Yield is 50mg；Molar yield is 50%.
Embodiment 16
Weighing 20mg known crystal formation J2, add in 2mL vial, add 0.4mL acetonitrile, the ultrasonic 1min of room temperature is placed on 80 DEG C of oil baths stirring causes after it is completely dissolved, and moves to stirring 2 days in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield is 12mg；Molar yield is 60%.
Embodiment 17
Weighing 16mg known crystal formation J2, add in 2mL vial, add 0.4mL acetonitrile, the ultrasonic 1min of room temperature is placed on 70 DEG C of oil baths stirring causes after it is completely dissolved, and moves to stirring 1 day in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield is 12mg；Molar yield is 75%.
Embodiment 18
Weighing 20mg known crystal formation J2, add in 5mL vial, add 4mL acetonitrile, the ultrasonic 1min of room temperature is placed on 40 DEG C oil bath stirring causes after it is completely dissolved, and moves to stirring 0.5 day in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield is 11mg；Molar yield is 55%.
Embodiment 19
Weighing 20mg known crystal formation J2, add in 2mL vial, add 0.8mL acetonitrile, the ultrasonic 1min of room temperature is placed on 60 DEG C of oil baths stirring causes after it is completely dissolved, and moves to stirring 1 day in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield is 12mg；Molar yield is 60%.
Embodiment 20
Weighing 20mg known crystal formation J2, add in 2mL vial, add 0.8mL acetone, the ultrasonic 1min of room temperature is placed on 60 DEG C of oil baths stirring causes after it is completely dissolved, and moves to stirring 1 day in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield is 13mg；Molar yield is 65%.
Embodiment 21
Weigh 20mg known crystal formation J2, add in 2mL vial, add 0.8mL 2-butanone, after the ultrasonic 1min of room temperature It is placed in 60 DEG C of oil baths stirring and causes after it is completely dissolved, move to stirring 1 day in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield For 12mg；Molar yield is 60%.
Embodiment 22
Weigh 20mg known crystal formation J2, add in 2mL vial, add 0.8mL oxolane, after the ultrasonic 1min of room temperature It is placed in 60 DEG C of oil baths stirring and causes after it is completely dissolved, move to stirring 1 day in 0 DEG C of refrigerator.Crystal formation 4 it is dried to obtain after filtration.Yield For 10mg；Molar yield is 50%.
The sample of embodiment 6～22 preparation has same as in Example 5 or similar XRPD collection of illustrative plates, TGA collection of illustrative plates, DSC figure Spectrum (not shown).Illustrate that embodiment 6～22 prepares is the material identical with embodiment 5.
Embodiment 23
Weigh the crystal formation 3 of 5mg embodiment 4 preparation, be positioned under room temperature (40%～75%RH), take out after 4 months and carry out XRPD detection is still crystal formation 3.XRPD figure is shown in Fig. 5.
Embodiment 24
Weighing 2g known crystal formation J2, be dissolved in about 20mL dioxane, filter after ultrasonic 3min, filtrate is added about In 200mL water, stir 1h, after filtration, obtain crystal formation 5.Yield is 1.5g；Molar yield is 65%.
XRPD figure is shown in Figure 10.
DSC figure is shown in Figure 11.Display: 137 DEG C are lost solvent, form anhydrous crystal forms J2 that fusing point is about 170 DEG C.
TGA figure is shown in Figure 12.Display: have the weightlessness of 10.1% before 150 DEG C of sample, be roughly equal to 1 dioxane molecule, for dioxy Six cyclisation things；Decomposition temperature is 238 DEG C.
Embodiment 25
Weighing 1.6g known crystal formation J2, be dissolved in about 40mL-dioxane, filter after ultrasonic 3min, filtrate is added about In 200mL water, stir 1h, after filtration, obtain crystal formation 5.Yield is 1.4g；Molar yield is 61%.
Embodiment 26
Weighing 20mg known crystal formation J2, be dissolved in about 0.8mL dioxane, filter after ultrasonic 3min, filtrate is added about In 6mL water, it is stirred overnight, after filtration, obtains crystal formation 5.Yield is 14mg；Molar yield is 61%.
Embodiment 27
Weighing 20mg known crystal formation J2, be dissolved in about 2.0mL dioxane, filter after ultrasonic 3min, filtrate is added about In 8mL water, stir 10h, after filtration, obtain crystal formation 5.Yield is 15mg；Molar yield is 65%.
Embodiment 28
Weighing 20mg known crystal formation J2, be dissolved in about 0.4mL dioxane, filter after ultrasonic 3min, filtrate is added about In 4mL sec-butyl alcohol, stir 24h, after filtration, obtain crystal formation 5.Yield is 15mg；Molar yield is 65%.
Embodiment 29
Weighing 20mg known crystal formation J2, be dissolved in about 0.4mL dioxane, filter after ultrasonic 3min, filtrate is added about In 6mL sec-butyl alcohol, stir 20h, after filtration, obtain crystal formation 5.Yield is 13mg；Molar yield is 56%.
Embodiment 30
Weighing 10mg known crystal formation J2, be dissolved in 1.5mL dioxane, filter after 40 DEG C of ultrasonic 1min, filtrate is being opened In lid bottle, 40 DEG C of volatilizations, volatilize and obtain crystal formation 5.Yield is 5mg；Molar yield is 43%.
Embodiment 31
Weighing 8mg known crystal formation J2, be dissolved in 1.5mL dioxane, filter after 30 DEG C of ultrasonic 1min, filtrate is being uncapped In Ping, 30 DEG C of volatilizations, volatilize and obtain crystal formation 5.Yield is 5mg；Molar yield is 54%.
Embodiment 32
Weighing 10mg known crystal formation J2, be dissolved in 3.0mL dioxane, filter after 40 DEG C of ultrasonic 1min, filtrate is being opened In lid bottle, 50 DEG C of volatilizations, volatilize and obtain crystal formation 5.Yield is 5mg；Molar yield is 43.3%.
Embodiment 33
Weighing 10mg known crystal formation J2, be dissolved in 7.5mL dioxane, filter after 50 DEG C of ultrasonic 1min, filtrate is being opened In lid bottle, 50 DEG C of volatilizations, volatilize and obtain crystal formation 5.Yield is 5mg；Molar yield is 43.3%.
The sample of embodiment 25～33 preparation has XRPD collection of illustrative plates same or analogous with embodiment 24, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 25～33 prepares is the material identical with embodiment 24.
Embodiment 34
Weigh 25mg known crystal formation J2 and add in 5mL vial, then add 1.0mL dichloromethane, add a cover room temperature and stir Mix 3 days, after filtration, obtain crystal formation 6.Yield is 20mg；Productivity is 70%.
XRPD figure is shown in Figure 13.
DSC figure is shown in Figure 14.Display: lose solvent at 127 DEG C and obtain the anhydrous crystal forms 3 that fusing point is about 151 DEG C.
TGA figure is shown in Figure 15.Display: had the weightlessness of 4.8% before 150 DEG C, be roughly equal to 1 dichloromethane molecule, for dichloromethane Alkide；Decomposition temperature is 229 DEG C.
Embodiment 35
Weigh 10mg known crystal formation J2 and add in 5mL vial, then add 1.0mL dichloromethane, add a cover room temperature and stir Mix 2 days, after filtration, obtain crystal formation 6.Yield is 8mg；Productivity is 70%.
Embodiment 36
Weigh 50mg known crystal formation J2 and add in 5mL vial, then add 1.0mL dichloromethane, add a cover room temperature and stir Mix 5 days, after filtration, obtain crystal formation 6.Yield is 38mg；Productivity is 66%.
Embodiment 37
Weigh 100mg known crystal formation J2 and add in 5mL vial, then add 1.0mL dichloromethane, add a cover room temperature and stir Mix 7 days, after filtration, obtain crystal formation 6.Yield is 75mg；Productivity is 65%.
Embodiment 38
Weigh 7.5mg known crystal formation J2 and add in 5mL vial, then add 1.0mL dichloromethane, add a cover room temperature and stir Mix 1 day, after filtration, obtain crystal formation 6.Yield is 5mg；Productivity is 58%.
Embodiment 39
Weigh 10mg known crystal formation J2 and add in 5mL vial, then add 2.0mL dichloromethane, add a cover room temperature and stir Mix 0.5 day, after filtration, obtain crystal formation 6.Yield is 7mg；Productivity is 61%.
The sample of embodiment 35～39 preparation has XRPD collection of illustrative plates same or analogous with embodiment 34, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 35～39 prepares is the material identical with embodiment 34.
Embodiment 40
Weigh 20mg known crystal formation J2 and add in 5mL vial, then add 1.0mL toluene, add a cover and be stirred at room temperature 7 My god, obtain crystal formation 7 after filtration.Yield is 10mg；Molar yield is 43%.
XRPD figure is shown in Figure 16.
DSC figure is shown in Figure 17.Display: 131 DEG C are lost solvent and obtain anhydrous crystal forms J2 that fusing point is about 170 DEG C.
TGA figure is shown in Figure 18.Display: have the weightlessness of 7.7% before 150 DEG C, be roughly equal to 1 toluene molecule, for toluene compound；Decompose Temperature is 231 DEG C.
Embodiment 41
Weigh 10mg known crystal formation J2 and add in 5mL vial, then add 1.0mL toluene, add a cover and be stirred at room temperature 5 My god, obtain crystal formation 7 after filtration.Yield is 6mg；Molar yield is 52%.
Embodiment 42
Weigh 50mg known crystal formation J2 and add in 20mL vial, then add 10mL toluene, add a cover and be stirred at room temperature 3 My god, obtain crystal formation 7 after filtration.Yield is 43mg；Molar yield is 74%.
Embodiment 43
Weigh 10mg known crystal formation J2 and add in 20mL vial, then add 5.0mL toluene, add a cover and be stirred at room temperature 2 My god, obtain crystal formation 7 after filtration.Yield is 5mg；Molar yield is 43%.
Embodiment 44
Weigh 10mg known crystal formation J2 and add in 20mL vial, then add 6.5mL toluene, add a cover and be stirred at room temperature 2 My god, obtain crystal formation 7 after filtration.Yield is 5mg；Molar yield is 43%.
Embodiment 45
Weigh 8mg known crystal formation J2 and add in 20mL vial, then add 8.0mL toluene, add a cover and be stirred at room temperature 0.5 My god, obtain crystal formation 7 after filtration.Yield is 5mg；Molar yield is 54%.
The sample of embodiment 41～45 preparation has XRPD collection of illustrative plates same or analogous with embodiment 40, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 41～45 prepares is the material identical with embodiment 40.
Embodiment 46
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 1.0mL ether, add a cover and be stirred at room temperature 7 days, mistake Crystal formation 8 is obtained after filter.Yield is 15mg；Molar yield is 66%.
XRPD figure is shown in Figure 19.
TGA figure is shown in Figure 20.Display: have the weightlessness of 9.3% before 150 DEG C, be roughly equal to 1 ether molecule, for etherate；Decompose Temperature is 222 DEG C.
Embodiment 47
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 1.0mL ether, add a cover and be stirred at room temperature 5 days, mistake The crystal formation 8 obtained after filter.Yield is 6mg；Molar yield is 53%.
Embodiment 48
Weigh 25mg known crystal formation J2 and add in 5mL vial, add 5.0mL ether, add a cover and be stirred at room temperature 3 days, mistake The crystal formation 8 obtained after filter.Yield is 21mg；Molar yield is 74%.
Embodiment 49
Weigh 20mg known crystal formation J2 and add in 20mL vial, add 10mL ether, add a cover and be stirred at room temperature 2 days, mistake The crystal formation 8 obtained after filter.Yield is 15mg；Molar yield is 66%.
Embodiment 50
Weigh 20mg known crystal formation J2 and add in 20mL vial, add 13.5mL ether, add a cover and be stirred at room temperature 1 day, The crystal formation 8 obtained after filtration.Yield is 15mg；Molar yield is 66%.
Embodiment 51
Weigh 25mg known crystal formation J2 and add in 50mL round-bottomed flask, add 25mL ether, add a cover and be stirred at room temperature 0.5 My god, the crystal formation 8 obtained after filtration.Yield is 15mg；Molar yield is 53%.
The sample of embodiment 47～51 preparation has XRPD collection of illustrative plates same or analogous with embodiment 46, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 47～51 prepares is the material identical with embodiment 46.
Embodiment 52
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 1.0mL chloroform, add a cover and be stirred at room temperature 2 days, mistake Crystal formation 9 is obtained after filter.Yield is 16mg；Molar yield is 66%.
XRPD figure is shown in Figure 21.
DSC figure is shown in Figure 22.Display: be 120 DEG C and lose solvents and form that turn crystalline substance to form fusing points in 143 DEG C after anhydrous crystal forms be 169 DEG C anhydrous crystal forms J2.
TGA figure is shown in Figure 23.Display: have the weightlessness of 19.7%, about unification chloroform molecule before 150 DEG C, for chloroform compound；Point Solving temperature is 219 DEG C.
Embodiment 53
Weigh 50mg known crystal formation J2 and add in 5mL vial, add 1.0mL chloroform, add a cover and be stirred at room temperature 3 days, mistake Crystal formation 9 is obtained after filter.Yield is 42mg；Molar yield is 69%.
Embodiment 54
Weigh 100mg known crystal formation J2 and add in 5mL vial, add 1.0mL chloroform, add a cover and be stirred at room temperature 5 days, mistake Crystal formation 9 is obtained after filter.Yield is 75mg；Molar yield is 62%.
Embodiment 55
Weigh 200mg known crystal formation J2 and add in 5mL vial, add 1.0mL chloroform, add a cover and be stirred at room temperature 7 days, mistake Crystal formation 9 is obtained after filter.Yield is 160mg；Molar yield is 66%.
Embodiment 56
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 1.0mL chloroform, add a cover and be stirred at room temperature 0.5 day, Crystal formation 9 is obtained after filtration.Yield is 8mg；Molar yield is 66%.
Embodiment 57
Weigh 15mg known crystal formation J2 and add in 5mL vial, add 1.0mL chloroform, add a cover and be stirred at room temperature 1 day, mistake Crystal formation 9 is obtained after filter.Yield is 8mg；Molar yield is 44%.
The sample of embodiment 53～57 preparation has XRPD collection of illustrative plates same or analogous with embodiment 52, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 53～57 prepares is the material identical with embodiment 52.
Embodiment 58
Weighing 10mg known crystal formation J2 to be dissolved in 10mL nitromethane solvent, filter after 40 DEG C of ultrasonic 1min, filtrate exists Uncap 30 DEG C of volatilizations in bottle, volatilize and obtain crystal formation 10.Yield is 8mg；Molar yield is 73%.
XRPD figure is shown in Figure 24.
TGA is shown in Figure 25.Display: have the weightlessness of 6.21% before 150 DEG C, for trihydrate；Decomposition temperature is 230 DEG C.
Embodiment 59
Weighing 8mg known crystal formation J2 to be dissolved in 10mL nitromethane solvent, filter after 40 DEG C of ultrasonic 1min, filtrate is being opened In lid bottle, 40 DEG C of volatilizations, volatilize and obtain crystal formation 10.Yield is 6mg；Molar yield is 68%.
Embodiment 60
Weighing 10mg known crystal formation J2 to be dissolved in 20mL nitromethane solvent, filter after 40 DEG C of ultrasonic 1min, filtrate exists Uncap 40 DEG C of volatilizations in bottle, volatilize and obtain crystal formation 10.Yield is 6mg；Productivity is 55%.
Embodiment 61
Weighing 10mg known crystal formation J2 to be dissolved in 10mL nitromethane solvent, filter after 40 DEG C of ultrasonic 1min, filtrate exists Uncap 50 DEG C of volatilizations in bottle, volatilize and obtain crystal formation 10.Yield is 6mg；Productivity is 55%.
The sample of embodiment 59～61 preparation has XRPD collection of illustrative plates same or analogous with embodiment 58, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 59～61 prepares is the material identical with embodiment 58.
Embodiment 62
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 1.0mL diisopropyl ether, add a cover and be stirred at room temperature 7 days, Crystal formation 11 is obtained after filtration.Yield is 15mg；Molar yield is 69%.
XRPD figure is shown in Figure 26.
DSC figure is shown in Figure 27.Display: losing solvent at 115 DEG C and forming anhydrous crystal forms and turn crystalline substance to form fusing point in 127 DEG C is 173 DEG C Anhydrous known crystal formation J2.
TGA figure is shown in Figure 28.Display: have the weightlessness of 6.7% before 150 DEG C, be roughly equal to 0.5 diisopropyl ether molecule, is etherified for isopropyl Thing；Decomposition temperature is 223 DEG C.
Embodiment 63
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 1.0mL diisopropyl ether, add a cover and be stirred at room temperature 5 days, Crystal formation 11 is obtained after filtration.Yield is 7mg；Molar yield is 64%.
Embodiment 64
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 4.0mL diisopropyl ether, add a cover and be stirred at room temperature 3 days, Crystal formation 11 is obtained after filtration.Yield is 18mg；Molar yield is 83%.
Embodiment 65
Weigh 20mg known crystal formation J2 and add in 20mL vial, add 10mL diisopropyl ether, add a cover and be stirred at room temperature 2 days, Crystal formation 11 is obtained after filtration.Yield is 15mg；Molar yield is 69%.
Embodiment 66
Weigh 20mg known crystal formation J2 and add in 20mL vial, add 13.5mL diisopropyl ether, add a cover and be stirred at room temperature 1 My god, obtain crystal formation 11 after filtration.Yield is 15mg；Molar yield is 69%.
Embodiment 67
Weigh 10mg known crystal formation J2 and add in 20mL vial, add 10mL diisopropyl ether, add a cover and be stirred at room temperature 0.5 My god, obtain crystal formation 11 after filtration.Yield is 6mg；Molar yield is 64%.
The sample of embodiment 63～67 preparation has XRPD collection of illustrative plates same or analogous with embodiment 62, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 63～67 prepares is the material identical with embodiment 62.
Embodiment 68
Weigh 2g known crystal formation J2, add 100mL acetone and the solution (volume fraction of water is 1%) of water, dissolve, then add Adding 60mg polymethyl methacrylate, it is absolutely dry that room temperature of uncapping evaporates into solvent, the crystal formation 14 obtained.Yield is 1.8g；Mole receive Rate is 89%.
XRPD figure is shown in Figure 29.
DSC figure is shown in Figure 30.Display: it forms the anhydrous known crystal formation J2 that fusing point is 170 DEG C after losing solvent.
TGA figure is shown in Figure 31.Display: sample 125 DEG C begin with 2.2% weightlessness, be roughly equal to 0.5 hydrone, be half water Compound, its dehydration temperaturre relatively J4 (95 DEG C) is high, and decomposition temperature is 221 DEG C.
PLM figure is shown in Figure 32, display: compared with known crystal formation J2 (Figure 40), and crystal formation 14 granule is relatively big, and pattern is preferable.
Embodiment 69
Weigh 16mg known crystal formation J2 and add in 5mL vial, add 1.1mL acetone and the solution (volume of water of water Mark is 5%), to dissolve, then add 0.64mg polymethyl methacrylate, it is absolutely dry that room temperature of uncapping evaporates into solvent, the crystalline substance obtained Type 14.Yield is 13mg；Molar yield is 80%.
Embodiment 70 (0.5)
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 1.0mL acetone and the solution (volume of water of water Mark is 3%), to dissolve, then add 0.5mg polymethyl methacrylate, it is absolutely dry that room temperature of uncapping evaporates into solvent, the crystal formation obtained 14.Yield is 7mg；Molar yield is 69%.
Embodiment 71
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 2.5mL acetone and the solution (volume of water of water Mark is 4%), to dissolve, then add 0.3mg polymethyl methacrylate, it is absolutely dry that room temperature of uncapping evaporates into solvent, the crystal formation obtained 14.Yield is 7mg；Molar yield is 69%.
Embodiment 72
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 2.5mL 2-butanone and the solution (body of water of water Fraction is 2%), to dissolve, then add 0.3mg polymethyl methacrylate, it is absolutely dry that room temperature of uncapping evaporates into solvent, the crystalline substance obtained Type 14.Yield is 7mg；Molar yield is 69%.
Embodiment 73
Weighing 10mg known crystal formation J2 and add in 5mL vial, the solution of interpolation 2.5mL oxolane and water be (water Volume fraction is 2%), to dissolve, then add 0.3mg polymethyl methacrylate, it is absolutely dry that room temperature of uncapping evaporates into solvent, obtains Crystal formation 14.Yield is 7mg；Molar yield is 69%.
The sample of embodiment 69～73 preparation has XRPD collection of illustrative plates same or analogous with embodiment 68, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 69～73 prepares is the material identical with embodiment 68.
Embodiment 74
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 1.0mL ethyl acetate, add a cover and be stirred at room temperature 7 My god, obtain crystal formation 15 after filtration.Yield is 15mg；Molar yield is 70%.
XRPD figure is shown in Figure 33.
TGA figure is shown in Figure 34.Display: have the weightlessness of 7.4% before 150 DEG C, be roughly equal to 0.5 ethyl acetate molecule, for acetic acid second Ester compound；Decomposition temperature is 223 DEG C.
Embodiment 75
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 1.0mL ethyl acetate, add a cover and be stirred at room temperature 5 My god, obtain crystal formation 15 after filtration.Yield is 7mg；Molar yield is 65%.
Embodiment 76
Weigh 5mg known crystal formation J2 and add in 5mL vial, add 1.0mL ethyl acetate, add a cover and be stirred at room temperature 3 days, Crystal formation 15 is obtained after filtration.Yield is 4mg；Molar yield is 74%.
Embodiment 77
Weigh 2mg known crystal formation J2 and add in 5mL vial, add 1.0mL ethyl acetate, add a cover and be stirred at room temperature 2 days, Crystal formation 15 is obtained after filtration.Yield is 1mg；Molar yield is 46%.
Embodiment 78
Weigh 1.5mg known crystal formation J2 and add in 5mL vial, add 1.0mL ethyl acetate, add a cover and be stirred at room temperature 1 My god, obtain crystal formation 15 after filtration.Yield is 1mg；Molar yield is 62%.
Embodiment 79
Weigh 4mg known crystal formation J2 and add in 5mL vial, add 4.0mL ethyl acetate, add a cover and be stirred at room temperature 0.5 My god, obtain crystal formation 15 after filtration.Yield is 3mg；Molar yield is 70%.
The sample of embodiment 75～79 preparation has XRPD collection of illustrative plates same or analogous with embodiment 74, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 75～79 prepares is the material identical with embodiment 74.
Embodiment 80
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 1.0mL isopropyl acetate, add a cover and be stirred at room temperature 7 My god, obtain crystal formation 16 after filtration.Yield is 16mg；Productivity is 74%.
XRPD figure is shown in Figure 35.
TGA figure is shown in Figure 36.Display: have the weightlessness of 6.2% before 150 DEG C, be roughly equal to 0.5 isopropyl acetate ester molecule, for acetic acid Isopropyl ester compound；Decomposition temperature is 223 DEG C.
Embodiment 81
Weigh 10mg known crystal formation J2 and add in 5mL vial, add 1.0mL isopropyl acetate, add a cover and be stirred at room temperature 5 My god, obtain crystal formation 16 after filtration.Yield is 8mg；Productivity is 74%.
Embodiment 82
Weigh 20mg known crystal formation J2 and add in 5mL vial, add 4.0mL isopropyl acetate, add a cover and be stirred at room temperature 3 My god, obtain crystal formation 16 after filtration.Yield is 18mg；Productivity is 84%.
Embodiment 83
Weigh 2mg known crystal formation J2 and add in 5mL vial, add 1.0mL isopropyl acetate, add a cover and be stirred at room temperature 2 My god, obtain crystal formation 16 after filtration.Yield is 1mg；Productivity is 46%.
Embodiment 84
Weigh 1.5mg known crystal formation J2 and add in 5mL vial, add 1.0mL isopropyl acetate, add a cover and be stirred at room temperature 1 day, after filtration, obtain crystal formation 16.Yield is 1mg；Productivity is 62%.
Embodiment 85
Weigh 4mg known crystal formation J2 and add in 5mL vial, add 4.0mL isopropyl acetate, add a cover and be stirred at room temperature 0.5 day, after filtration, obtain crystal formation 16.Yield is 2mg；Productivity is 46%.
The sample of embodiment 81～85 preparation has XRPD collection of illustrative plates same or analogous with embodiment 80, TGA collection of illustrative plates, DSC Collection of illustrative plates (not shown).Illustrate that embodiment 81～85 prepares is the material identical with embodiment 80.
Embodiment 86
Capsule formula is as shown in table 1.
Table 1 capsule formula
Azilsartan crystal formation 3 prepared by the 10g present invention, 69.5g lactose, 0.2g light silicon anhydride, 0.3g stearic acid Magnesium physical mixed is also inserted in capsule, is prepared as 1000 seed lac capsules.
Embodiment 87
" Azilsartan crystal formation 3 prepared by the present invention " in embodiment 86 is replaced with " Azilsartan prepared by the present invention Ester crystal formation 4 ", other operation, with embodiment 86, prepares capsule.
Embodiment 88
" Azilsartan crystal formation 3 prepared by the present invention " in embodiment 86 is replaced with " Azilsartan prepared by the present invention Ester crystal formation 14 ", other operation, with embodiment 86, prepares capsule.
Embodiment 89
Tablet formulation is as shown in table 2.
Table 2 tablet formulation
Azilsartan crystal formation 3,35g lactose and 150g corn starch prepared by the 10g present invention and 20g microcrystalline Cellulose Physical mixed is also pelletized, then is added thereto to 10g microcrystalline Cellulose and 5g magnesium stearate physical mixed, is pressed into 1000.
Embodiment 90
" Azilsartan crystal formation 3 prepared by the present invention " in embodiment 89 is replaced with " Azilsartan prepared by the present invention Ester crystal formation 4 ", other operation, with embodiment 89, prepares tablet.
Embodiment 91
" Azilsartan crystal formation 3 prepared by the present invention " in embodiment 89 is replaced with " Azilsartan prepared by the present invention Ester crystal formation 14 ", other operation, with embodiment 89, prepares tablet.
Comparative example 1
Crystal formation 4 prepared by the crystal formation 3 and 20mg present invention known for 20mg crystal formation J2,20mg present invention prepared is respectively put into Filtering after being stirred overnight in 100mL water, weigh filtrate weight, then filtrate is spin-dried for, and addition acetonitrile is molten clear and is transferred to 10mL appearance Measuring bottle constant volume, carries out HPLC detection after weighing.Experimental result shows: the dissolubility of known crystal formation J2 is 0.50 μ g/g, and crystal formation 3 Being 4.00 μ g/g, the dissolubility of crystal formation 4 is 6.00 μ g/g, and the dissolubility of crystal formation 3 and crystal formation 4 is significantly higher than known crystal formation J2.
It will be understood by those skilled in the art that under the teaching of this specification, the present invention can be made some amendments Or change.These modifications and variations should also be as within the scope of the claims in the present invention.

Claims (13)

1. the crystal formation 3 of the Azilsartan that structure is as follows,
It is characterized in that, the X-ray powder diffraction spectrum that described crystal formation 3 represents with 2 θ angles has a characteristic peak in following position: 5.1 ± 0.2 °, 10.2 ± 0.2 °, 11.5 ± 0.2 °, 11.7 ± 0.2 °, 12.5 ± 0.2 ° and 17.2 ± 0.2 °.
The crystal formation 3 of Azilsartan the most according to claim 1, it is characterised in that described crystal formation 3 represents with 2 θ angles X-ray powder diffraction spectrum has a characteristic peak in following position: 5.1 ± 0.2 °, 8.6 ± 0.2 °, 10.2 ± 0.2 °, 11.5 ° ± 0.2°、11.7±0.2°、12.5±0.2°、13.6±0.2°、14.8±0.2°、15.7±0.2°、17.2±0.2°、19.7± 0.2 ° and 24.2 ± 0.2 °.
The crystal formation 3 of Azilsartan the most according to claim 2, it is characterised in that described crystal formation 3 represents with 2 θ angles X-ray powder diffraction spectrum has a characteristic peak and relative intensity in following position:
4. the preparation method of the crystal formation 3 of the Azilsartan according to any one of a claims 1 to 3, it is characterised in that institute Stating preparation method is: under room temperature, the suspension stirring and crystallizing formed in dichloromethane by known crystal formation J2, then by precipitation Crystal separates, then is warming up to slough completely solvent by this crystal, is then cooled to room temperature, i.e. obtains described crystal formation 3.
The preparation method of the crystal formation 3 of Azilsartan the most according to claim 4, it is characterised in that in described suspension, The amount of known crystal formation J2 is 1～20 times of its dissolubility in dichloromethane of room temperature.
The preparation method of the crystal formation 3 of Azilsartan the most according to claim 5, it is characterised in that in described suspension, The amount of known crystal formation J2 is 1.5～10 times of its dissolubility in dichloromethane of room temperature.
The preparation method of the crystal formation 3 of Azilsartan the most according to claim 6, it is characterised in that in described suspension, The amount of known crystal formation J2 is 2～5 times of its dissolubility in dichloromethane of room temperature.
The preparation method of the crystal formation 3 of Azilsartan the most according to claim 4, it is characterised in that described crystallize stirs Time is 0.5～7 day.
The preparation method of the crystal formation 3 of Azilsartan the most according to claim 8, it is characterised in that described crystallize stirs Time is 0.5～3 day.
The preparation method of the crystal formation 3 of Azilsartan the most according to claim 4, it is characterised in that described intensification be with The ramp of 10 DEG C/min is to 140 DEG C.
The preparation method of the crystal formation 3 of 11. Azilsartans according to claim 4, it is characterised in that the fall of described cooling Temperature speed is 10 DEG C/min.
12. 1 kinds of pharmaceutical compositions, it comprises according to any one of one or more claims 1 to 3 of therapeutically effective amount Or the crystal formation 3 of Azilsartan that the preparation method of claim 4 prepares, and at least one pharmaceutically acceptable figuration Agent.
The crystal formation 3 of the Azilsartan that according to any one of 13. claims 1 to 3 or claim 4 preparation methoies prepare Purposes in the medicine of preparation treatment hypertension and complication.
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