CN105949182B - Crystal form of Azilsartan and preparation method thereof - Google Patents

Abstract

The present invention relates to crystal forms of Azilsartan and preparation method thereof.Specifically, the present invention relates to compound 1- [[2 '-(2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) [1,1 '-biphenyl] -4- base] methyl] and -2- ethyoxyl -1H- benzimidazole -7- carboxylic acid (5- methyl -2- oxo -1,3- bis- dislikes cyclopentadienyl -4- base) methyl esters a variety of novel crystal forms and preparation method thereof.Solubility is high compared with the prior art in novel crystal forms water of the present invention and has lower fusing point, therefore relative to existing crystal form, has better dissolution rate and bioavilability and be more conducive to obtain pharmaceutical preparation using hot-melt extruded method.

Description

Crystal form of Azilsartan and preparation method thereof

Technical field

The present invention relates to medicine crystal technical fields.In particular to the crystal form and preparation method thereof of Azilsartan.

Background technique

Azilsartan is a kind of novel hypertension element II receptor resistance of Japanese military field (Takeda) drugmaker exploitation Stagnant dose, U.S. FDA approval listing, trade name Edabi were obtained in 2 months 2011.The medicine is also novel hypertension element II receptor The prodrug of retarding agent Azilsartan, the treatment for hypertension and related complication.The medicine is oral medication, can be both applied alone, also The treatment for hypertension and related complication can be combined with other depressor.In 20~80mg Azilsartan once a day In the III phase clinical trial of ester administration, confirm its safety and validity, and compared with Losartan and olmesartan medoxomil In experiment, there is higher hypotensive activity.The chemical name of Azilsartan are as follows: 1- [[2 '-(oxo -1 2,5- dihydro -5-, 2,4- oxadiazoles -3- base) [1,1 '-biphenyl] -4- base] methyl] -2- ethyoxyl -1H- benzimidazole -7- carboxylic acid (5- methyl -2- Oxo -1,3- two dislikes cyclopentadienyl -4- base) methyl esters；English name: Azilsartan Medoxomil also known as TAK-491, chemical formula are as follows: C₃₀H₂₄N₄O₈；Molecular weight are as follows: 568.53；Chemical structural formula is as follows:

Patent document US2005/018726 discloses the confirmation of Azilsartan, preparation and use.Specifically, implementing The confirmation and preparation of Azilsartan are disclosed in example 1~2, and point out that product is crystalline state, but do not provide crystal form data, in order to It is convenient, the crystal form in Examples 1 to 2 is known as " known crystal form I " below；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.

Confirmation, the preparation and use of Azilsartan are disclosed in patent document WO2012/090043A1, specifically, Disclosed in embodiment 1~15 more kinds of crystal habits of J2, J3, J4, J5, J6, J7, J8, J9 and amorphous Azilsartan and its Preparation method.Wherein, disclose a kind of crystal form and preparation method thereof in embodiment 1, and disclose the crystal form XRPD figure, DSC figure, TGA spectrogram and IR spectrogram.For convenience, the crystal form in embodiment 1 is known as " known crystal form J2 " below.In embodiment 3, another crystal form and preparation method thereof is disclosed in 4 and 5, and disclose XRPD figure, DSC figure, TGA spectrogram and the IR of the crystal form Spectrogram.For convenience, the crystal form in embodiment 3,4 and 5 is known as " known crystal form J4 " below.In addition, the patent document is also public Azilsartan has been opened with the therapeutic effect to hypertension and its complication.

Other three kinds of crystal forms that Azilsartan is disclosed in patent document WO2013/042066A1 are specifically being implemented Example 3~5 discloses the crystalline state and preparation method thereof of two kinds of Azilsartans.

Experiment and the study found that known crystal form disclosed in patent document WO2012/090043A1 are repeated through the present inventor J2 is anhydride, and is better than other crystal forms, it is known that crystal form J4 is then dihydrate, and is better than other hydrates.

Polymorphic is the property of some molecules and molecular composition.Identical molecule may due to different spread patterns shape At different crystal.The polymorphic have different crystal structure and physical property, as solubility, stability, thermal property, Engineering properties, purification capacity, X-ray diffractogram, infrared absorption figure, Raman spectrum and solid-state nmr etc..One or more analyses Detection mode can be used for distinguishing the different crystal forms of same compound.

It was found that the crystal form (including anhydride, hydrate, solvate) that active pharmaceutical ingredient is new can provide advantageous add The material of work property finds that new anhydrous crystal forms and solvate can provide the substance with more preferable physicochemical property, such as more Bioavilability well, stable storing, easy processing processing, the intermediate crystalline substance for being easily purified or being converted into as promotion other crystal forms Type.The novel crystal forms of the compound of pharmaceutically useful can also help improve the performance of drug.It expand formulation science man in order to Optimize the kenel of preparation performance and available raw material, such as improve dissolution rate, improve shelf life, be easier processing etc..

The solubility of the known crystal form J2 referred in patent document WO2012/090043A1 in water is lower, influences drug Dissolution, and then influence bioavilability, and fusing point is excessively high, is not suitable for hot-melt extruded method and obtains preparation, and the crystal form Grain is smaller, is unfavorable for the compressibility of tablet；The known crystal form J4 referred to is hydrate, and dehydration temperaturre is lower, and thermal stability is poor.

Therefore, it is still necessary to the new crystal form of Azilsartan, the crystal form will have good purity, while it should have it is lower Fusing point, be suitable for formulation application the features such as；Either at room temperature with the hydrate of more preferable stability.

Summary of the invention

In view of the deficiencies of 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.The novel crystal forms are that solubility is higher, fusing point is lower and the anhydride or room temperature of ambient-temp-stable are more stable Hydrate further relates to the preparation method and its pharmaceutical composition and purposes of these novel crystal forms.

Purpose according to the present invention, the present invention provide the crystal form 3 (hereinafter referred to as " crystal form 3 ") of Azilsartan.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 3 is indicated 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 collection that the crystal form 3 is indicated with 2 θ angles has 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 collection that the crystal form 3 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 3 has X-ray powder diffraction figure as shown in Figure 1.

Thermogravimetric analysis (TGA) map of the crystal form 3 shows that sample is anhydride；Decomposition temperature is 234 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 3 shows that its fusing point is 151 DEG C, and occurs to turn in melting process Crystalline substance switchs to the known crystal form J2 that fusing point is about 170 DEG C.

The crystal form 3 is prepared using following methods: at room temperature, the suspension that known crystal form J2 is formed in methylene chloride Then the crystal of precipitation is separated, obtains crystal form 6, then crystal form 6 is warming up to and sloughs solvent completely, then cool down by stirring and crystallizing To room temperature to get arrive the crystal form 3.

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of room temperature its solubility in methylene chloride, preferably It is 1.5~10 times, more preferably 2~5 times；Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

Preferably, to be warming up to 140 DEG C with the rate of 10 DEG C/min, the rate of temperature fall of the cooling is 10 for the heating ℃/min。

The crystal form 3 has the advantages that

1. it is 4.0 μ g/g that 3 room temperature of crystal form, which is lauched middle solubility, relatively known crystal form J2 (0.5 μ g/g) is high；

2. the crystal form 3 at room temperature (40%~75%RH), is placed 4 months, crystal form and fusing point are constant, have preferable Stability；

3. 3 fusing point of crystal form is lower, relative to known crystal form J2, it is particularly suited for the preparation of hot-melt extruded method.

Purpose according to the present invention, the present invention provide the crystal form 4 (hereinafter referred to as " crystal form 4 ") of Azilsartan.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 4 is indicated 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 collection that the crystal form 4 is indicated with 2 θ angles has 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 collection that the crystal form 4 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 4 has X-ray powder diffraction figure as shown in FIG. 6.

Thermogravimetric analysis (TGA) map of the crystal form 4 shows that sample is anhydride；Decomposition temperature is 231 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 4 shows that its fusing point is 154 DEG C, turns crystalline substance in 160 DEG C, forms fusing point About 170 DEG C of known crystal form J2.

The crystal form 4 is using any one preparation in following methods:

(1) in room temperature, then the suspension stirring and crystallizing that Azilsartan amorphous substance is formed in organic solvent will Crystal separation, the drying of precipitation, obtain the crystal form 4；

The organic solvent is preferably acetonitrile, ethyl alcohol, normal propyl alcohol, butanol, isopropyl ether, methyl tertiary butyl ether(MTBE), heptane, methyl Hexamethylene, more preferably acetonitrile；

In the suspension, the amount of amorphous substance is 1~20 times of solubility in organic solvent at room temperature, preferably It is 2~10 times, more preferably 2~5 times；Crystallization mixing time is 0.5~3 day, preferably 0.5~1 day.

(2) the cooling simultaneously stirring and crystallizing of the solution for known crystal form J2 being dissolved in organic solvent formation, then by the crystal of precipitation Separation, drying, obtain the crystal form 4；

The organic solvent is preferably acetonitrile, acetone, 2- butanone and tetrahydrofuran, more preferably acetonitrile；

In the organic solvent solution of the crystal form J2, it is known that the amount of crystal form J2 be its in acetonitrile solubility 0.1~1 Times, preferably 0.5~1 times, more preferably 0.8~1 times；The time of the crystallization is 0.5~2 day.

The solution formation temperature is 40~80 DEG C, preferably 70~80 DEG C；Temperature after cooling is 0~30 DEG C, preferably It is 0 DEG C.

The crystal form 4 has the advantages that

1. it is 6.0 μ g/g that 4 room temperature of crystal form, which is lauched middle solubility, relatively known crystal form J2 (0.5 μ g/g) is high；

2. the crystal form 4 has lower fusing point, relatively known crystal form J2 is particularly suited for the preparation of hot-melt extruded method；

3. 4 particle of crystal form is larger, there is preferable tablet compressibility；

4. the crystal form 4 is placed 4 months at room temperature (40%~75%RH), crystal form and fusing point are constant, have preferable Stability.

Purpose according to the present invention, the present invention provide the crystal form 14 (hereinafter referred to as " crystal form 14 ") of Azilsartan.

The crystal form 14 is hydrate, and every mole of crystal form 14 contains about 0.5 mole of water.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 14 is indicated 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 collection that the crystal form 14 is indicated 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 collection that the crystal form 14 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 14 has X-ray powder diffraction figure as shown in figure 29.

Thermogravimetric analysis (TGA) map of the crystal form 14 shows that sample begins with 2.2% weightlessness at 125 DEG C, is roughly equal to 0.5 A hydrone is semihydrate, and dehydration temperaturre is high compared with (95 DEG C) of J4, and decomposition temperature is 221 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 14 shows that forming fusing point after it loses solvent is about 170 DEG C anhydrous Known crystal form J2.

The crystal form 14 is prepared using following methods: at room temperature, known crystal form J2 being dissolved in the mixed of organic solvent and water It closes in solution, forms solution, add polymethyl methacrylate, then volatilize crystallization naturally, obtains the crystal form 14；

The organic solvent is preferably acetone, 2- butanone and tetrahydrofuran, more preferably acetone；

The in the mixed solvent of the organic solvent and water, the volume fraction of water are 1~5%；

The usage amount of the polymethyl methacrylate (PMMA) is less than or equal to the 5% of known crystal form J2 weight, preferably small In being equal to 4%, more preferably less than 3%.

In the solution of the crystal form J2, it is known that the amount of crystal form J2 is at room temperature, in organic solvent and water mixed solution 0.2~1 times of solubility, preferably 0.5~1 times, more preferably 0.8~1 times.

The crystal form 14 has the advantages that

1. the crystal form 14 is more stable, 4 months crystal forms are placed under room temperature (40%~75%RH) environment and fusing point is constant；

2. the relatively known crystal form J4 of the crystal form 14 has higher dehydration temperaturre, better heat stability；

3. 14 particle of crystal form is larger, there is preferable tablet compressibility.In addition, purpose according to the present invention, this hair It is bright that the crystal form 6 (hereinafter referred to as " crystal form 6 ") of Azilsartan is provided.

The crystal form 6 is that methylene chloride closes object, and every mole of crystal form 6 contains 1 mole of methylene chloride.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 6 is indicated 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 collection that the crystal form 6 is indicated with 2 θ angles has 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 collection that the crystal form 6 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 6 has X-ray powder diffraction figure as shown in fig. 13 that.

Thermogravimetric analysis (TGA) map of the crystal form 6 has 4.8% weightlessness before showing 150 DEG C of sample, be roughly equal to 1 two Chloromethanes molecule closes object for methylene chloride；Decomposition temperature is 229 DEG C.

It is about 151 DEG C that differential scanning calorimetric (DSC) figure of the crystal form 6, which shows that it loses solvent to obtain fusing point at 127 DEG C, Anhydrous crystal forms 3.

The crystal form 6 is prepared using following methods: at room temperature, the suspension that known crystal form J2 is formed in methylene chloride Then the crystal of precipitation is separated, obtains the crystal form 6 by stirring and crystallizing；

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of room temperature its solubility in methylene chloride, preferably It is 1.5~10 times, more preferably 2~5 times；Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In addition, purpose according to the present invention, the present invention provides the crystal form 5 (hereinafter referred to as " crystal form 5 ") of Azilsartan.

The crystal form 5 is that dioxane closes object, and every mole of crystal form 5 contains 1 mole of dioxane.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 5 is indicated 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 collection that the crystal form 5 is indicated with 2 θ angles has 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 collection that the crystal form 5 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 5 has X-ray powder diffraction figure as shown in Figure 10.

Thermogravimetric analysis (TGA) map of the crystal form 5 has 10.1% weightlessness before showing 150 DEG C of sample, be roughly equal to 1 dioxy Six toroidal molecules close object for dioxane；Decomposition temperature is 238 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 5 shows that it loses solvent at 137 DEG C, and forming fusing point is about 170 DEG C Known crystal form J2.

The crystal form 5 can be prepared by any one in following methods:

(1) in room temperature, sec-butyl alcohol and/or water are added to the dioxane solution of known crystal form J2, then stirring and crystallizing will The crystal of precipitation separates, and obtains the crystal form 5；

In the dioxane solution, it is known that the amount of crystal form J2 is the 0.2~1 of its solubility in dioxane of room temperature Times, preferably 0.5~1 times, more preferably 0.8~1 times.The volume of the sec-butyl alcohol or water is the 5~20 of dioxane volume Times, preferably 10~15 times.Crystallization mixing time be 1~for 24 hours, preferably 1~5h.

(2) at a certain temperature, the dioxane solution of known crystal form J2 is formed, under same temperature, volatilization is tied naturally Crystalline substance obtains the crystal form 5.The temperature is 30~50 DEG C, preferably 40 DEG C.

In the dioxane solution, it is known that the amount of crystal form J2 is the 0.2~1 of its solubility in dioxane of room temperature Times, preferably 0.5~1 times, more preferably 0.8~1 times.

In addition, purpose according to the present invention, the present invention provides the crystal form 7 (hereinafter referred to as " crystal form 7 ") of Azilsartan.

The crystal form 7 is toluene compound, and every mole of crystal form 7 contains 1 mole of toluene.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 7 is indicated 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 collection that the crystal form 7 is indicated with 2 θ angles has 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 collection that the crystal form 7 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 7 has X-ray powder diffraction figure as shown in figure 16.

Thermogravimetric analysis (TGA) map of the crystal form 7 has 7.7% weightlessness before showing 150 DEG C of sample, be roughly equal to 1 toluene Molecule is toluene compound；Decomposition temperature is 231 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 7 shows that it loses solvent at 131 DEG C, and forming fusing point is about 170 DEG C Anhydrous known crystal form J2.

The crystal form 7 can be prepared by following methods: in room temperature, the known crystal form J2 suspension formed in toluene being stirred Crystallization is mixed, then the crystal of precipitation is separated, obtains the crystal form 7.

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of its solubility in toluene of room temperature, preferably 1.5~10 times, more preferably 2~5 times.Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In addition, purpose according to the present invention, the present invention provides the crystal form 8 (hereinafter referred to as " crystal form 8 ") of Azilsartan.

The crystal form 8 is etherate, and every mole of crystal form 8 contains 1 mole of ether.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 8 is indicated 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 collection that the crystal form 8 is indicated with 2 θ angles has 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 collection that the crystal form 8 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 8 has X-ray powder diffraction figure as shown in figure 19.

Thermogravimetric analysis (TGA) map of the crystal form 8 has 9.3% weightlessness before showing 150 DEG C of sample, be roughly equal to 1 ether Molecule is etherate；Decomposition temperature is 222 DEG C.

The crystal form 8 can be prepared by following methods: in room temperature, the known crystal form J2 suspension formed in ether being stirred Crystallization is mixed, then the crystal of precipitation is separated, obtains the crystal form 8.

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of its solubility in ether of room temperature, preferably 1.5~10 times, more preferably 2~5 times.Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In addition, purpose according to the present invention, the present invention provides the crystal form 9 (hereinafter referred to as " crystal form 9 ") of Azilsartan.

The crystal form 9 is chloroform compound, and every mole of crystal form 9 contains 1 mole of chloroform.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 9 is indicated 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 collection that the crystal form 9 is indicated with 2 θ angles has 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 collection that the crystal form 9 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 9 has X-ray powder diffraction figure as shown in figure 21.

Thermogravimetric analysis (TGA) map of the crystal form 9 has 19.7% weightlessness before showing 150 DEG C of sample, about unify chlorine Imitative molecule is chloroform compound；Decomposition temperature is 219 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 9 shows that it loses solvent 120 DEG C at, after formation anhydrous crystal forms in 143 DEG C turn the brilliant anhydrous known crystal form J2 for forming fusing point and being about 170 DEG C.

The crystal form 9 can be prepared by following methods: in room temperature, the known crystal form J2 suspension formed in chloroform being stirred Crystallization is mixed, then the crystal of precipitation is separated, obtains the crystal form 9.

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of its solubility in chloroform of room temperature, preferably 1.5~10 times, more preferably 2~5 times.Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In addition, purpose according to the present invention, the present invention provides the crystal form 10 (hereinafter referred to as " crystal form 10 ") of Azilsartan.

The crystal form 10 is hydrate, and every mole of crystal form 10 contains 3 moles of water.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 10 is indicated 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 collection that the crystal form 10 is indicated 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 collection that the crystal form 10 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 10 has X-ray powder diffraction figure as of fig. 24.

Thermogravimetric analysis (TGA) map of the crystal form 10 has 6.21% weightlessness before showing 150 DEG C of sample, be roughly equal to three water Molecule is trihydrate；Decomposition temperature is 230 DEG C.

The crystal form 10 can be prepared by following methods: at a certain temperature, by the nitromethane solution of known crystal form J2 Volatilize crystallization, then separates the crystal of precipitation, obtains the crystal form 10.

In the nitromethane solution, it is known that the amount of crystal form J2 is the 0.1~1 of its solubility in nitromethane of room temperature Times, preferably 0.5~1 times, more preferably 0.8~1 times.The volatilization crystallization temperature is 30~50 DEG C.

In addition, purpose according to the present invention, the present invention provides the crystal form 11 (hereinafter referred to as " crystal form 11 ") of Azilsartan.

The crystal form 11 is isopropyl etherate, and every mole of crystal form 11 is about containing 0.5 mole of isopropyl ether.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 11 is indicated 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 collection that the crystal form 11 is indicated 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 collection that the crystal form 11 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 11 has X-ray powder diffraction figure as shown in figure 26.

Thermogravimetric analysis (TGA) map of the crystal form 11 has 6.7% weightlessness before showing 150 DEG C of sample, be roughly equal to 0.5 it is different Propyl ether molecule is isopropyl etherate；Decomposition temperature is 223 DEG C.

Differential scanning calorimetric (DSC) figure of the crystal form 11 shows that it loses solvent at 115 DEG C and forms anhydrous crystal forms in 127 DEG C turn the brilliant anhydrous known crystal form J2 for forming fusing point and being about 170 DEG C.

The crystal form 11 can be prepared by following methods: in room temperature, the suspension that known crystal form J2 is formed in isopropyl ether Then the crystal of precipitation is separated, obtains the crystal form 11 by liquid stirring and crystallizing.

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of its solubility in isopropyl ether of room temperature, preferably 1.5~10 times, more preferably 2~5 times.Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In addition, purpose according to the present invention, the present invention provides the crystal form 15 (hereinafter referred to as " crystal form 15 ") of Azilsartan.

The crystal form 15 is ethyl acetate compound, and every mole of crystal form 15 contains 0.5 mole of ethyl acetate.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 15 is indicated 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 collection that the crystal form 15 is indicated 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 collection that the crystal form 15 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 15 has X-ray powder diffraction figure as shown in figure 33.

Thermogravimetric analysis (TGA) map of the crystal form 15 has 7.4% weightlessness before showing 150 DEG C of sample, be roughly equal to 0.5 second Teos molecule closes object for ethyl acetate；Decomposition temperature is 223 DEG C.

The crystal form 15 can be prepared by following methods: in room temperature, known crystal form J2 be formed in ethyl acetate outstanding Then the crystal of precipitation is separated, obtains the crystal form 15 by supernatant liquid stirring and crystallizing；

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of its solubility in ethyl acetate of room temperature, preferably It is 1.5~10 times, more preferably 2~5 times.Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In addition, purpose according to the present invention, the present invention provides the crystal form 16 (hereinafter referred to as " crystal form 16 ") of Azilsartan.

The crystal form 16 is that isopropyl acetate closes object, and every mole of crystal form 16 contains 0.5 mole of isopropyl acetate.

It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form 16 is indicated 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 collection that the crystal form 16 is indicated 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 collection that the crystal form 16 is indicated with 2 θ angles has feature in following position Peak and relative intensity:

Without limitation, a representative instance of the crystal form 16 has X-ray powder diffraction figure as shown in figure 35.

Thermogravimetric analysis (TGA) map of the crystal form 16 has 6.2% weightlessness before showing 150 DEG C of sample, be roughly equal to 0.5 second Isopropyl propionate molecule closes object for isopropyl acetate；Decomposition temperature is 223 DEG C.

The crystal form 16 can be prepared by following methods: in room temperature, known crystal form J2 being formed in isopropyl acetate Then the crystal of precipitation is separated, obtains the crystal form 16 by suspension stirring and crystallizing.

In the suspension, it is known that the amount of crystal form J2 is 1~20 times of its solubility in isopropyl acetate of room temperature, excellent It is selected as 1.5~10 times, more preferably 2~5 times.Crystallization mixing time is 0.5~7 day, preferably 0.5~3 day.

In the preparation method of the above-mentioned all crystal forms being related to:

" room temperature " refers to 10~30 DEG C.

The stirring, concrete operations are as follows: with 50~1800 revs/min carry out magnetic agitation, preferably 300~900 revs/min into Capable magnetic agitation.

The separation, including filter or be centrifuged.The concrete operations of the centrifugation are as follows: be intended to isolated sample be placed in 2mL from It in heart pipe, is centrifuged with 6000 revs/min of rates, centrifugation bottom of the tube is all sink to solid, remove supernatant.

Unless stated otherwise, crystal form described in the present invention can pass through drying steps.The drying can use ability The routine techniques in domain is completed, such as air drying, forced air drying or is dried under reduced pressure, in draught cupboard, convection oven or vacuum drying oven In carry out；It can be carried out in the case where depressurizing or not depressurizing, preferably pressure is less than 0.09Mpa；About 30~50 DEG C of drying temperature；It is dry Time is 10~72 hours, preferably 10~48 hours, more preferably 10~24 hours.

In the application, ultrasonic operation are as follows: container is placed in ultrasonic cleaner at room temperature, it is super with 20Khz~40Khz Sound operating power carries out ultrasound 1~30 minute.

In the application, the operation of revolving are as follows: in room temperature~solvent boiling point, (preferably pressure is small less than under the pressure of atmospheric pressure In 0.08MPa), to be carried out under the conditions of 10~180rpm rotation speed (preferably 50~100rpm).

The invention mainly relates to the new crystal form 3 of Azilsartan, crystal form 4, crystal form 14 and crystal forms 6, are additionally related to A Qi Husky smooth ester new crystal form 5, crystal form 7, crystal form 8, crystal form 9, crystal form 10, crystal form 11, crystal form 15 and crystal form 16.

In the present invention, " crystal " or " crystal form " refers to what the characterization of the X-ray diffractogram by shown in was confirmed.This field 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.In particular, well known to those skilled in the art, X-ray diffractogram would generally be with instrument Condition and change.In particular, it should be pointed out that the relative intensity of X-ray diffractogram may also be with the variation of experiment condition And change, so the sequence of peak intensity cannot function as unique or deciding factor.In addition, the experimental error of peak angle degree usually exists 5% or less, the error of these angles should also be considered into, allow generally for ± 0.2 error.In addition, due to sample The influence of the empirical factors such as height, will cause the overall offset of peak angle degree, allows generally for certain offset.Thus, this field skill Art personnel are it is understood that the X-ray diffractogram of a crystal form need not be with the X-ray in example referred herein in the present invention Diffraction pattern is completely the same.It is any to belong to model of the invention with the crystal form with the same or similar figure of characteristic peak in these figures Within farmland.Those skilled in the art can compare the figure listed by the present invention with the figure of a unknown crystal form, with confirm this two Group picture reflection is identical to be also different crystal form.

Unless stated otherwise, " anhydride " refers to the crystal form through TGA measurement containing not more than 1.5% (weight here 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 With the method for anti-solvent recrystallization.

Volatilization is placed on sample clear solution in open 5mL vial, open or capping punching, in specific temperature Under the conditions of volatilize.The method or the volatilization of direct room temperature that nitrogen is blown can be used.

Magma is to stir the supersaturated solution (with the presence of undissolved solid) of sample in different solvents system, usually 2 hours~2 weeks.

Polymeric stencil experiment is consistent with room temperature evaporation method, is only added to a certain amount of insoluble polymer substance in sample In product solution.

In the present invention, in polymeric stencil experiment, the usage amount of polymer substance is no more than Azilsartan weight 5%, preferably more than 4%, more preferably less than 3%.In some cases, during the experiment using polymer substance to help The crystallization of crystallization in motion type, the polymer substance being used in the present invention are polymethyl methacrylate (PMMA).

PMMA used is amorphous in the present invention, and DSC does not show fusing point.Due to the use of polymer substance Amount is strictly controlled 5% hereinafter, therefore the polymer substance will not influence the judgement of crystal form in an experiment.

Cooling recrystallization is dissolved a sample in appropriate solvent under specific hot conditions, and 5mL vial is placed on In, it is placed in alternating temperature shaking table, successively cools down according to certain rate of temperature fall, is 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 keeps the temperature 1 hour~2 days.

Anti-solvent recrystallization is, for example, that sample is dissolved in good solvent, and ultrasound makes it dissolve, then adds appropriate anti-solvent, room Temperature stirring.

Raw material used in the present invention can the method according to described in patent document WO2012/090043A1 preparation, Usually raw material used in the present invention is known crystal form J2 described in the patent document.

Heretofore described Azilsartan amorphous substance can be prepared according to following methods: be added into known crystal form J2 Then acetone is quickly spin-dried for, it is amorphous to obtain Azilsartan.

The present invention is solved by offer new crystal form 3, crystal form 4, crystal form 14 and crystal form 6 and is asked existing for prior art crystal form Topic, the new crystal form have at least one or more of favorable property compared with known crystal form, are especially in the presence of one of following advantages Or it is several: higher crystallinity, dissolution rate, good particle shape, is less prone to polymorphic inversion and/or dehydration at solubility Kenel, calorifics and good mechanical stability, agent of low hygroscopicity, better mobility, compressibility and apparent density, stable storing Property, low-residual solvent etc..

In some embodiments, the present invention is by providing new crystal form 5, crystal form 7, crystal form 8, crystal form 9, crystal form 10, crystalline substance Type 11, crystal form 15 or crystal form 16 solve the problems, such as that prior art crystal form exists, which, which has, is selected from following at least one Favorable property: higher crystallinity, solubility, dissolution rate, good particle shape, be less prone to polymorphic inversion and/ Or kenel, calorifics and good mechanical stability, agent of low hygroscopicity, better mobility, compressibility and the apparent density, storage being dehydrated Stability, low-residual solvent etc..

In addition, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes one kind or more of therapeutically effective amount Crystal form 3, crystal form 4, crystal form 5, crystal form 6, crystal form 7, crystal form 8, crystal form 9, crystal form 10, crystal form 11, the crystalline substance of the kind Azilsartan Type 14, crystal form 15 or crystal form 16, and at least one pharmaceutically acceptable excipient.

Described pharmaceutical composition can also include the crystal form or amorphous substance of other pharmaceutical Azilsartans, these are brilliant Type includes but is not limited to known crystal form J2 and known crystal form J4.

Described pharmaceutical composition can be solid-state or liquid.If the pharmaceutical composition is liquid, one or more Ahs The crystal form of Qi Shatan ester can remain solid in the liquid composition, such as suspension.

In addition, the present invention provides crystal form 3, crystal form 4, crystal form 5, crystal form 6, crystal form 7, crystal form 8, the crystalline substance of the Azilsartan The use of type 9, crystal form 10, crystal form 11, crystal form 14, crystal form 15 or crystal form 16 in the drug of preparation treatment hypertension and complication On the way.

In addition, the present invention provides a kind of method for treating hypertension and complication, the method includes giving the trouble of needs Crystal form 3, crystal form 4, crystal form 5, crystal form 6, crystal form 7, crystal form 8, the crystal form 9, crystal form of the Azilsartan of person's therapeutically effective amount 10, crystal form 11, crystal form 14, crystal form 15 or crystal form 16 or described pharmaceutical composition.

The patient includes but is not limited to mammal.

Detailed description of the invention

Fig. 1 is that the XRPD of crystal form 3 of the present invention schemes.

Fig. 2 is that the DSC of crystal form 3 of the present invention schemes.

Fig. 3 is that the TGA of crystal form 3 of the present invention schemes.

Fig. 4 is that the XRPD of amorphous substance schemes.

Fig. 5 is the XRPD figure in 3 stability experiment of crystal form of the present invention.Wherein, the following figure is that measurement immediately obtains after preparing；On Figure is measured after being 4 months and is obtained.

Fig. 6 is that the XRPD of crystal form 4 of the present invention schemes.

Fig. 7 is that the DSC of crystal form 4 of the present invention schemes.

Fig. 8 is that the TGA of crystal form 4 of the present invention schemes.

Fig. 9 is that the PLM of crystal form 4 of the present invention schemes.

Figure 10 is that the XRPD of crystal form 5 of the present invention schemes.

Figure 11 is that the DSC of crystal form 5 of the present invention schemes.

Figure 12 is that the TGA of crystal form 5 of the present invention schemes.

Figure 13 is that the XRPD of crystal form 6 of the present invention schemes.

Figure 14 is that the DSC of crystal form 6 of the present invention schemes.

Figure 15 is that the TGA of crystal form 6 of the present invention schemes.

Figure 16 is that the XRPD of crystal form 7 of the present invention schemes.

Figure 17 is that the DSC of crystal form 7 of the present invention schemes.

Figure 18 is that the TGA of crystal form 7 of the present invention schemes.

Figure 19 is that the XRPD of crystal form 8 of the present invention schemes.

Figure 20 is that the TGA of crystal form 8 of the present invention schemes.

Figure 21 is that the XRPD of crystal form 9 of the present invention schemes.

Figure 22 is that the DSC of crystal form 9 of the present invention schemes.

Figure 23 is that the TGA of crystal form 9 of the present invention schemes.

Figure 24 is that the XRPD of crystal form 10 of the present invention schemes.

Figure 25 is that the TGA of crystal form 10 of the present invention schemes.

Figure 26 is that the XRPD of crystal form 11 of the present invention schemes.

Figure 27 is that the DSC of crystal form 11 of the present invention schemes.

Figure 28 is that the TGA of crystal form 11 of the present invention schemes.

Figure 29 is that the XRPD of crystal form 14 of the present invention schemes.

Figure 30 is that the DSC of crystal form 14 of the present invention schemes.

Figure 31 is that the TGA of crystal form 14 of the present invention schemes.

Figure 32 is that the PLM of crystal form 14 of the present invention schemes.

Figure 33 is that the XRPD of crystal form 15 of the present invention schemes.

Figure 34 is that the TGA of crystal form 15 of the present invention schemes.

Figure 35 is that the XRPD of crystal form 16 of the present invention schemes.

Figure 36 is that the TGA of crystal form 16 of the present invention schemes.

The XRPD that Figure 37 is known crystal form J2 schemes.

The DSC that Figure 38 is known crystal form J2 schemes.

The TGA that Figure 39 is known crystal form J2 schemes.

The PLM that Figure 40 is known crystal form J2 schemes.

The XRPD that Figure 41 is known crystal form J4 schemes.

The DSC that Figure 42 is known crystal form J4 schemes.

The TGA that Figure 43 is known crystal form J4 schemes.

Specific embodiment

The present invention with further reference to following embodiment limit, the preparation of the embodiment detailed description of the present invention crystal form and Application method.It will be apparent for a person skilled in the art that can not departed from for many changes of both material and method Implement in the case where the scope of the invention.

Acquire instrument and method used in data:

Instrument used in X-ray powder diffraction (XPRD) is Bruker D8Advance diffractometer, is adopted The Ka X-ray for being 1.54nm with copper target wavelength, under the operating condition of 40kV and 40mA, θ -2 θ angular instrument, Mo monochromator, Lynxeye detector.Instrument is calibrated using the preceding standard items (generally corundum) carried with instrument.Acquisition software is Diffrac Plus XRPD Commander, analysis software is MDI Jade 5.0.Sample is tested at room temperature, need The sample to be detected is placed on SiP areflexia plate.Detailed testing conditions are as follows: angular range: 3~40 ° of 2 θ；Step-length: 0.02 ° 2 θ；Speed: 0.2s/ step.Unless stated otherwise, sample is not ground before detection.

Polarization microscope (PLM) figure is picked up from XP-500E polarization microscope (the limited public affairs of the rectangular optical instrument in Shanghai Department).It takes a small amount of powder sample to be placed on glass slide, a small amount of mineral oil is added dropwise to better disperse powder sample, covered, Then sample is placed on the objective table of XP-500E polarization microscope, selects the shape of suitable amplification factor observing samples Looks are simultaneously taken pictures.

Differential thermal analysis (DSC) data are picked up from TA Instruments Q200MDSC, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.The sample of 1~10mg is usually taken to be placed in uncapped (unless special Do not mentionlet alone bright) aluminium crucible in, with the heating rate of 10 DEG C/min in the dry N of 40mL/min₂Protection under sample is risen to from 0 DEG C 250 DEG C, while thermal change of the TA software records sample in temperature-rise period.In this application, fusing point is come by initial temperature Report.

Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500TGA, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.It usually takes the sample of 5~15mg to be placed in platinum crucible, adopts With the mode of segmentation high resolution detection, N is dried in 40mL/min with the heating rate of 10 DEG C/min₂Protection under by sample from room Temperature rise is to 300 DEG C, while weight change of the TA software records sample in temperature-rise period.

Embodiment 1

The known crystal form J2 of Azilsartan can be according to described in embodiment 1 in patent document WO2012/090043A1 Method preparation.

Specifically, the J2's the preparation method comprises the following steps: at 15~20 DEG C, by 0.5g Azilsartan of crystal form known to Azilsartan Know that crystal form I is dissolved in 50mL methanol, volatilize after solution is filtered, obtains known crystal form J2.

The XRPD figure of known crystal form J2 is shown in Figure 37.

DSC figure is shown in that Figure 38, display fusing point are 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 that Figure 40, display particle are minimum.

Embodiment 2

The known crystal form J4 of Azilsartan can be according to described in embodiment 4 in patent document WO2012/090043A1 Method preparation.

Specifically, the known crystal form of Azilsartan J4's the preparation method comprises the following steps: at 40~50 DEG C, by 0.5g Azilsartan Crystal form I is dissolved in the mixed solution of acetone (7.5mL) and ethyl acetate (7.5mL), is cooled to 0~5 DEG C and is stirred, is obtained by filtration Known crystal form J4.

The XRPD figure of known crystal form J4 is shown in Figure 41.

DSC figure is shown in Figure 42, turns the brilliant anhydrous known crystal form for forming fusing point and being about 170 DEG C in 146 DEG C after showing its desolventizing J2。

TGA figure is shown in Figure 43, be shown in 95 DEG C begin with 6.4% weightlessness, be roughly equal to 2 hydrones, be dihydrate, decompose Temperature is 222 DEG C.

Embodiment 3

It weighs crystal form J2 known to 100mg to be added in 30mL single-necked flask, then adds 10mL acetone, be quickly spin-dried for, obtain To the solid amorphous object like foam-like.

The XRPD figure of amorphous substance is shown in Fig. 4, and no XRPD diffraction maximum is amorphous substance.

Embodiment 4

The crystal form 6 for weighing the preparation of 10mg (15.3mmol) embodiment 34 is put into TGA disk to be heated with the rate of 10 DEG C/min To 140 DEG C, room temperature is down to the rate of 10 DEG C/min after being kept for 0.5 minute, obtains crystal form 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 occurs to turn crystalline substance in melting process, and switching to fusing point is about 170 DEG C Anhydrous known crystal form J2.

TGA figure is shown in Fig. 3.Display: for anhydride, decomposition temperature is 234 DEG C.

Embodiment 5

The amorphous substance of 3 method of 1g embodiment preparation is weighed, 40mL acetonitrile is then added, capping is stirred at room temperature 1 day, filters After be dried to obtain crystal form 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 form J2 (Figure 40), 4 granularity of crystal form is larger, and pattern is preferable.

The crystal form 4 continues stirring 5 days or more, obtains crystal form 3.

Embodiment 6

The amorphous substance for weighing the preparation of 3 method of 20mg embodiment, is added in 5mL vial, then adds 2.0mL second Nitrile, capping are stirred at room temperature 2 days, and crystal form 4 is dried to obtain after filtering.Yield is 17mg, molar yield 85%.

Embodiment 7

The amorphous substance for weighing the preparation of 3 method of 20mg embodiment, is added in 5mL vial, then adds 4.0mL second Nitrile, capping are stirred at room temperature 0.5 day, and crystal form 4 is dried to obtain after filtering.Yield is 17mg；Molar yield is 85%.

Embodiment 8

The amorphous substance for weighing the preparation of 3 method of 20mg embodiment, is added in 5mL vial, then adds 1.0mL second Nitrile, capping are stirred at room temperature 3 days, and crystal form 4 is dried to obtain after filtering.Yield is 15mg；Molar yield is 75%.

Embodiment 9

The amorphous substance for weighing the preparation of 3 method of 200mg embodiment, is added in 5mL vial, then adds 2.0mL second Nitrile, capping are stirred at room temperature 3 days, and crystal form 4 is dried to obtain after filtering.Yield is 130mg；Molar yield is 65%.

Embodiment 10

The amorphous substance for weighing the preparation of 3 method of 100mg embodiment, is added in 5mL vial, then adds 1.0mL second Alcohol, capping are stirred at room temperature 1 day, and crystal form 4 is dried to obtain after filtering.Yield is 65mg；Molar yield is 65%.

Embodiment 11

The amorphous substance for weighing the preparation of 3 method of 100mg embodiment, is added in 5mL vial, then adds 1.0mL fourth Alcohol, capping are stirred at room temperature 1 day, and crystal form 4 is dried to obtain after filtering.Yield is 60mg；Molar yield is 60%.

Embodiment 12

The amorphous substance for weighing the preparation of 3 method of 100mg embodiment, is added in 5mL vial, and it is different then to add 1.0mL Propyl ether, capping are stirred at room temperature 1 day, and crystal form 4 is dried to obtain after filtering.Yield is 75mg；Molar yield is 75%.

Embodiment 13

The amorphous substance for weighing the preparation of 3 method of 0.5g embodiment, is added in 10mL vial, then adds 5.0mL first Base tertbutyl ether, capping are stirred at room temperature 1 day, and crystal form 4 is dried to obtain after filtering.Yield is 0.38g；Molar yield is 76%.

Embodiment 14

The amorphous substance for weighing the preparation of 3 method of 100mg embodiment, is added in 5mL vial, then adds 1.0mL heptan Alkane, capping are stirred at room temperature 1 day, and crystal form 4 is dried to obtain after filtering.Yield is 50mg；Molar yield is 50%.

Embodiment 15

The amorphous substance for weighing the preparation of 3 method of 100mg embodiment, is added in 5mL vial, then adds 1.0mL first Butylcyclohexane, capping are stirred at room temperature 1 day, and crystal form 4 is dried to obtain after filtering.Yield is 50mg；Molar yield is 50%.

Embodiment 16

Crystal form J2 known to 20mg is weighed, is added in 2mL vial, 0.4mL acetonitrile is added, room temperature ultrasound 1min is placed on After 80 DEG C of oil bath stirrings cause it to be completely dissolved, stirring 2 days in 0 DEG C of refrigerator are moved to.Crystal form 4 is dried to obtain after filtering.Yield is 12mg；Molar yield is 60%.

Embodiment 17

Crystal form J2 known to 16mg is weighed, is added in 2mL vial, 0.4mL acetonitrile is added, room temperature ultrasound 1min is placed on After 70 DEG C of oil bath stirrings cause it to be completely dissolved, stirring 1 day in 0 DEG C of refrigerator is moved to.Crystal form 4 is dried to obtain after filtering.Yield is 12mg；Molar yield is 75%.

Embodiment 18

Crystal form J2 known to 20mg is weighed, is added in 5mL vial, 4mL acetonitrile is added, room temperature ultrasound 1min is placed on 40 After DEG C oil bath stirring causes it to be completely dissolved, stirring 0.5 day in 0 DEG C of refrigerator is moved to.Crystal form 4 is dried to obtain after filtering.Yield is 11mg；Molar yield is 55%.

Embodiment 19

Crystal form J2 known to 20mg is weighed, is added in 2mL vial, 0.8mL acetonitrile is added, room temperature ultrasound 1min is placed on After 60 DEG C of oil bath stirrings cause it to be completely dissolved, stirring 1 day in 0 DEG C of refrigerator is moved to.Crystal form 4 is dried to obtain after filtering.Yield is 12mg；Molar yield is 60%.

Embodiment 20

Crystal form J2 known to 20mg is weighed, is added in 2mL vial, 0.8mL acetone is added, room temperature ultrasound 1min is placed on After 60 DEG C of oil bath stirrings cause it to be completely dissolved, stirring 1 day in 0 DEG C of refrigerator is moved to.Crystal form 4 is dried to obtain after filtering.Yield is 13mg；Molar yield is 65%.

Embodiment 21

Crystal form J2 known to 20mg is weighed, is added in 2mL vial, 0.8mL 2- butanone is added, after room temperature ultrasound 1min It is placed in after 60 DEG C of oil baths stirring causes it to be completely dissolved, moves to stirring 1 day in 0 DEG C of refrigerator.Crystal form 4 is dried to obtain after filtering.Yield For 12mg；Molar yield is 60%.

Embodiment 22

Crystal form J2 known to 20mg is weighed, is added in 2mL vial, 0.8mL tetrahydrofuran is added, after room temperature ultrasound 1min It is placed in after 60 DEG C of oil baths stirring causes it to be completely dissolved, moves to stirring 1 day in 0 DEG C of refrigerator.Crystal form 4 is dried to obtain after filtering.Yield For 10mg；Molar yield is 50%.

Sample prepared by embodiment 6~22 has same as Example 5 or similar XRPD map, TGA map, DSC figure Compose (not shown).Illustrate that embodiment 6~22 is prepared is and the identical substance of embodiment 5.

Embodiment 23

The crystal form 3 for weighing the preparation of 5mg embodiment 4, is placed under room temperature (40%~75%RH), takes out and carries out after 4 months XRPD detection is still crystal form 3.XRPD figure is shown in Fig. 5.

Embodiment 24

Crystal form J2 known to 2g is weighed, is dissolved in about 20mL dioxane, is filtered after ultrasonic 3min, filtrate is added about In 200mL water, 1h is stirred, crystal form 5 is obtained after filtering.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 of mistake solvents form the anhydrous crystal forms J2 that fusing point is about 170 DEG C.

TGA figure is shown in Figure 12.Display: having 10.1% weightlessness, be roughly equal to 1 dioxane molecule before 150 DEG C of sample, is dioxy Six cyclisation objects；Decomposition temperature is 238 DEG C.

Embodiment 25

Crystal form J2 known to 1.6g is weighed, is dissolved in about 40mL dioxane, is filtered after ultrasonic 3min, filtrate is added about In 200mL water, 1h is stirred, crystal form 5 is obtained after filtering.Yield is 1.4g；Molar yield is 61%.

Embodiment 26

Crystal form J2 known to 20mg is weighed, is dissolved in about 0.8mL dioxane, is filtered after ultrasonic 3min, filtrate is added about It in 6mL water, is stirred overnight, crystal form 5 is obtained after filtering.Yield is 14mg；Molar yield is 61%.

Embodiment 27

Crystal form J2 known to 20mg is weighed, is dissolved in about 2.0mL dioxane, is filtered after ultrasonic 3min, filtrate is added about In 8mL water, 10h is stirred, crystal form 5 is obtained after filtering.Yield is 15mg；Molar yield is 65%.

Embodiment 28

Crystal form J2 known to 20mg is weighed, is dissolved in about 0.4mL dioxane, is filtered after ultrasonic 3min, filtrate is added about In 4mL sec-butyl alcohol, stirring obtains crystal form 5 for 24 hours, after filtering.Yield is 15mg；Molar yield is 65%.

Embodiment 29

Crystal form J2 known to 20mg is weighed, is dissolved in about 0.4mL dioxane, is filtered after ultrasonic 3min, filtrate is added about In 6mL sec-butyl alcohol, 20h is stirred, crystal form 5 is obtained after filtering.Yield is 13mg；Molar yield is 56%.

Embodiment 30

Crystal form J2 known to 10mg is weighed, is dissolved in 1.5mL dioxane, is filtered after 40 DEG C of ultrasound 1min, filtrate is being opened 40 DEG C of volatilizations, volatilize to obtain crystal form 5 in lid bottle.Yield is 5mg；Molar yield is 43%.

Embodiment 31

Crystal form J2 known to 8mg is weighed, is dissolved in 1.5mL dioxane, is filtered after 30 DEG C of ultrasound 1min, filtrate is being uncapped 30 DEG C of volatilizations, volatilize to obtain crystal form 5 in bottle.Yield is 5mg；Molar yield is 54%.

Embodiment 32

Crystal form J2 known to 10mg is weighed, is dissolved in 3.0mL dioxane, is filtered after 40 DEG C of ultrasound 1min, filtrate is being opened 50 DEG C of volatilizations, volatilize to obtain crystal form 5 in lid bottle.Yield is 5mg；Molar yield is 43.3%.

Embodiment 33

Crystal form J2 known to 10mg is weighed, is dissolved in 7.5mL dioxane, is filtered after 50 DEG C of ultrasound 1min, filtrate is being opened 50 DEG C of volatilizations, volatilize to obtain crystal form 5 in lid bottle.Yield is 5mg；Molar yield is 43.3%.

Sample prepared by embodiment 25~33 has and the same or similar XRPD map of embodiment 24, TGA map, DSC Map (not shown).Illustrate that embodiment 25~33 is prepared is and the identical substance of embodiment 24.

Embodiment 34

It weighs crystal form J2 known to 25mg to be added in 5mL vial, then adds 1.0mL methylene chloride, cover room temperature and stir It mixes 3 days, crystal form 6 is obtained after filtering.Yield is 20mg；Yield is 70%.

XRPD figure is shown in Figure 13.

DSC figure is shown in Figure 14.Display: solvent is lost at 127 DEG C and obtains the anhydrous crystal forms 3 that fusing point is about 151 DEG C.

TGA figure is shown in Figure 15.Display: having 4.8% weightlessness, be roughly equal to 1 methylene chloride molecule before 150 DEG C, is dichloromethane Alkide；Decomposition temperature is 229 DEG C.

Embodiment 35

It weighs crystal form J2 known to 10mg to be added in 5mL vial, then adds 1.0mL methylene chloride, cover room temperature and stir It mixes 2 days, crystal form 6 is obtained after filtering.Yield is 8mg；Yield is 70%.

Embodiment 36

It weighs crystal form J2 known to 50mg to be added in 5mL vial, then adds 1.0mL methylene chloride, cover room temperature and stir It mixes 5 days, crystal form 6 is obtained after filtering.Yield is 38mg；Yield is 66%.

Embodiment 37

It weighs crystal form J2 known to 100mg to be added in 5mL vial, then adds 1.0mL methylene chloride, cover room temperature and stir It mixes 7 days, crystal form 6 is obtained after filtering.Yield is 75mg；Yield is 65%.

Embodiment 38

It weighs crystal form J2 known to 7.5mg to be added in 5mL vial, then adds 1.0mL methylene chloride, cover room temperature and stir It mixes 1 day, crystal form 6 is obtained after filtering.Yield is 5mg；Yield is 58%.

Embodiment 39

It weighs crystal form J2 known to 10mg to be added in 5mL vial, then adds 2.0mL methylene chloride, cover room temperature and stir It mixes 0.5 day, crystal form 6 is obtained after filtering.Yield is 7mg；Yield is 61%.

Sample prepared by embodiment 35~39 has and the same or similar XRPD map of embodiment 34, TGA map, DSC Map (not shown).Illustrate that embodiment 35~39 is prepared is and the identical substance of embodiment 34.

Embodiment 40

It weighs crystal form J2 known to 20mg to be added in 5mL vial, then adds 1.0mL toluene, capping is stirred at room temperature 7 It, obtains crystal form 7 after filtering.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 of mistake solvents obtain the anhydrous crystal forms J2 that fusing point is about 170 DEG C.

TGA figure is shown in Figure 18.Display: having 7.7% weightlessness, be roughly equal to 1 toluene molecule before 150 DEG C, is toluene compound；It decomposes Temperature is 231 DEG C.

Embodiment 41

It weighs crystal form J2 known to 10mg to be added in 5mL vial, then adds 1.0mL toluene, capping is stirred at room temperature 5 It, obtains crystal form 7 after filtering.Yield is 6mg；Molar yield is 52%.

Embodiment 42

It weighs crystal form J2 known to 50mg to be added in 20mL vial, then adds 10mL toluene, capping is stirred at room temperature 3 It, obtains crystal form 7 after filtering.Yield is 43mg；Molar yield is 74%.

Embodiment 43

It weighs crystal form J2 known to 10mg to be added in 20mL vial, then adds 5.0mL toluene, capping is stirred at room temperature 2 It, obtains crystal form 7 after filtering.Yield is 5mg；Molar yield is 43%.

Embodiment 44

It weighs crystal form J2 known to 10mg to be added in 20mL vial, then adds 6.5mL toluene, capping is stirred at room temperature 2 It, obtains crystal form 7 after filtering.Yield is 5mg；Molar yield is 43%.

Embodiment 45

It weighs crystal form J2 known to 8mg to be added in 20mL vial, then adds 8.0mL toluene, capping is stirred at room temperature 0.5 It, obtains crystal form 7 after filtering.Yield is 5mg；Molar yield is 54%.

Sample prepared by embodiment 41~45 has and the same or similar XRPD map of embodiment 40, TGA map, DSC Map (not shown).Illustrate that embodiment 41~45 is prepared is and the identical substance of embodiment 40.

Embodiment 46

It weighs crystal form J2 known to 20mg to be added in 5mL vial, adds 1.0mL ether, capping is stirred at room temperature 7 days, mistake Crystal form 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: having 9.3% weightlessness, be roughly equal to 1 ether molecule before 150 DEG C, is etherate；It decomposes Temperature is 222 DEG C.

Embodiment 47

It weighs crystal form J2 known to 10mg to be added in 5mL vial, adds 1.0mL ether, capping is stirred at room temperature 5 days, mistake The crystal form 8 obtained after filter.Yield is 6mg；Molar yield is 53%.

Embodiment 48

It weighs crystal form J2 known to 25mg to be added in 5mL vial, adds 5.0mL ether, capping is stirred at room temperature 3 days, mistake The crystal form 8 obtained after filter.Yield is 21mg；Molar yield is 74%.

Embodiment 49

It weighs crystal form J2 known to 20mg to be added in 20mL vial, adds 10mL ether, capping is stirred at room temperature 2 days, mistake The crystal form 8 obtained after filter.Yield is 15mg；Molar yield is 66%.

Embodiment 50

It weighing crystal form J2 known to 20mg to be added in 20mL vial, adds 13.5mL ether, capping is stirred at room temperature 1 day, The crystal form 8 obtained after filtering.Yield is 15mg；Molar yield is 66%.

Embodiment 51

It weighs crystal form J2 known to 25mg to be added in 50mL round-bottomed flask, adds 25mL ether, capping is stirred at room temperature 0.5 It, the crystal form 8 obtained after filtering.Yield is 15mg；Molar yield is 53%.

Sample prepared by embodiment 47~51 has and the same or similar XRPD map of embodiment 46, TGA map, DSC Map (not shown).Illustrate that embodiment 47~51 is prepared is and the identical substance of embodiment 46.

Embodiment 52

It weighs crystal form J2 known to 20mg to be added in 5mL vial, adds 1.0mL chloroform, capping is stirred at room temperature 2 days, mistake Crystal form 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: being formed for 120 DEG C of mistake solvents and turning the brilliant fusing point that formed in 143 DEG C after anhydrous crystal forms is 169 DEG C anhydrous crystal forms J2.

TGA figure is shown in Figure 23.Display: there is 19.7% weightlessness before 150 DEG C, about unify a chloroform molecule, be chloroform compound；Point Solving temperature is 219 DEG C.

Embodiment 53

It weighs crystal form J2 known to 50mg to be added in 5mL vial, adds 1.0mL chloroform, capping is stirred at room temperature 3 days, mistake Crystal form 9 is obtained after filter.Yield is 42mg；Molar yield is 69%.

Embodiment 54

It weighs crystal form J2 known to 100mg to be added in 5mL vial, adds 1.0mL chloroform, capping is stirred at room temperature 5 days, mistake Crystal form 9 is obtained after filter.Yield is 75mg；Molar yield is 62%.

Embodiment 55

It weighs crystal form J2 known to 200mg to be added in 5mL vial, adds 1.0mL chloroform, capping is stirred at room temperature 7 days, mistake Crystal form 9 is obtained after filter.Yield is 160mg；Molar yield is 66%.

Embodiment 56

It weighing crystal form J2 known to 10mg to be added in 5mL vial, adds 1.0mL chloroform, capping is stirred at room temperature 0.5 day, Crystal form 9 is obtained after filtering.Yield is 8mg；Molar yield is 66%.

Embodiment 57

It weighs crystal form J2 known to 15mg to be added in 5mL vial, adds 1.0mL chloroform, capping is stirred at room temperature 1 day, mistake Crystal form 9 is obtained after filter.Yield is 8mg；Molar yield is 44%.

Sample prepared by embodiment 53~57 has and the same or similar XRPD map of embodiment 52, TGA map, DSC Map (not shown).Illustrate that embodiment 53~57 is prepared is and the identical substance of embodiment 52.

Embodiment 58

It weighs crystal form J2 known to 10mg to be dissolved in 10mL nitromethane solvent, be filtered after 40 DEG C of ultrasound 1min, filtrate exists It uncaps 30 DEG C of volatilizations in bottle, volatilizes to obtain crystal form 10.Yield is 8mg；Molar yield is 73%.

XRPD figure is shown in Figure 24.

TGA is shown in Figure 25.Display: having 6.21% weightlessness before 150 DEG C, is trihydrate；Decomposition temperature is 230 DEG C.

Embodiment 59

It weighs crystal form J2 known to 8mg to be dissolved in 10mL nitromethane solvent, be filtered after 40 DEG C of ultrasound 1min, filtrate is being opened 40 DEG C of volatilizations, volatilize to obtain crystal form 10 in lid bottle.Yield is 6mg；Molar yield is 68%.

Embodiment 60

It weighs crystal form J2 known to 10mg to be dissolved in 20mL nitromethane solvent, be filtered after 40 DEG C of ultrasound 1min, filtrate exists It uncaps 40 DEG C of volatilizations in bottle, volatilizes to obtain crystal form 10.Yield is 6mg；Yield is 55%.

Embodiment 61

It weighs crystal form J2 known to 10mg to be dissolved in 10mL nitromethane solvent, be filtered after 40 DEG C of ultrasound 1min, filtrate exists It uncaps 50 DEG C of volatilizations in bottle, volatilizes to obtain crystal form 10.Yield is 6mg；Yield is 55%.

Sample prepared by embodiment 59~61 has and the same or similar XRPD map of embodiment 58, TGA map, DSC Map (not shown).Illustrate that embodiment 59~61 is prepared is and the identical substance of embodiment 58.

Embodiment 62

It weighing crystal form J2 known to 20mg to be added in 5mL vial, adds 1.0mL isopropyl ether, capping is stirred at room temperature 7 days, Crystal form 11 is obtained after filtering.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 to turn the brilliant fusing point that formed in 127 DEG C is 173 DEG C Anhydrous known crystal form J2.

TGA figure is shown in Figure 28.Display: having 6.7% weightlessness, be roughly equal to 0.5 isopropyl ether molecule before 150 DEG C, is etherified for isopropyl Object；Decomposition temperature is 223 DEG C.

Embodiment 63

It weighing crystal form J2 known to 10mg to be added in 5mL vial, adds 1.0mL isopropyl ether, capping is stirred at room temperature 5 days, Crystal form 11 is obtained after filtering.Yield is 7mg；Molar yield is 64%.

Embodiment 64

It weighing crystal form J2 known to 20mg to be added in 5mL vial, adds 4.0mL isopropyl ether, capping is stirred at room temperature 3 days, Crystal form 11 is obtained after filtering.Yield is 18mg；Molar yield is 83%.

Embodiment 65

It weighing crystal form J2 known to 20mg to be added in 20mL vial, adds 10mL isopropyl ether, capping is stirred at room temperature 2 days, Crystal form 11 is obtained after filtering.Yield is 15mg；Molar yield is 69%.

Embodiment 66

It weighs crystal form J2 known to 20mg to be added in 20mL vial, adds 13.5mL isopropyl ether, capping is stirred at room temperature 1 It, obtains crystal form 11 after filtering.Yield is 15mg；Molar yield is 69%.

Embodiment 67

It weighs crystal form J2 known to 10mg to be added in 20mL vial, adds 10mL isopropyl ether, capping is stirred at room temperature 0.5 It, obtains crystal form 11 after filtering.Yield is 6mg；Molar yield is 64%.

Sample prepared by embodiment 63~67 has and the same or similar XRPD map of embodiment 62, TGA map, DSC Map (not shown).Illustrate that embodiment 63~67 is prepared is and the identical substance of embodiment 62.

Embodiment 68

Crystal form J2 known to 2g is weighed, adds the solution (volume fraction of water is 1%) of 100mL acetone and water, dissolution, then add Add 60mg polymethyl methacrylate, room temperature of uncapping evaporates into the crystal form 14 that solvent is absolutely dry, obtains.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 form J2 that fusing point is 170 DEG C after losing solvent.

TGA figure is shown in Figure 31.Display: sample begins with 2.2% weightlessness at 125 DEG C, is roughly equal to 0.5 hydrone, is half water Object is closed, dehydration temperaturre is high compared with (95 DEG C) of J4, and decomposition temperature is 221 DEG C.

PLM figure is shown in Figure 32, and display: compared with known crystal form J2 (Figure 40), 14 particle of crystal form is larger, and pattern is preferable.

Embodiment 69

It weighs crystal form J2 known to 16mg to be added in 5mL vial, adds the solution (volume of water of 1.1mL acetone and water Score is 5%) dissolution, then adds 0.64mg polymethyl methacrylate, and room temperature of uncapping evaporates into the crystalline substance that solvent is absolutely dry, obtains Type 14.Yield is 13mg；Molar yield is 80%.

Embodiment 70 (0.5)

It weighs crystal form J2 known to 10mg to be added in 5mL vial, adds the solution (volume of water of 1.0mL acetone and water Score is 3%) dissolution, then adds 0.5mg polymethyl methacrylate, and room temperature of uncapping evaporates into the crystal form that solvent is absolutely dry, obtains 14.Yield is 7mg；Molar yield is 69%.

Embodiment 71

It weighs crystal form J2 known to 10mg to be added in 5mL vial, adds the solution (volume of water of 2.5mL acetone and water Score is 4%) dissolution, then adds 0.3mg polymethyl methacrylate, and room temperature of uncapping evaporates into the crystal form that solvent is absolutely dry, obtains 14.Yield is 7mg；Molar yield is 69%.

Embodiment 72

It weighs crystal form J2 known to 10mg to be added in 5mL vial, adds the solution (body of water of 2.5mL 2- butanone and water Fraction is 2%) dissolution, then adds 0.3mg polymethyl methacrylate, and room temperature of uncapping evaporates into the crystalline substance that solvent is absolutely dry, obtains Type 14.Yield is 7mg；Molar yield is 69%.

Embodiment 73

Crystal form J2 known to 10mg is weighed to be added in 5mL vial, add 2.5mL tetrahydrofuran and water solution (water Volume fraction is that 2%), dissolution then adds 0.3mg polymethyl methacrylate, and room temperature of uncapping evaporates into that solvent is absolutely dry, is obtained Crystal form 14.Yield is 7mg；Molar yield is 69%.

Sample prepared by embodiment 69~73 has and the same or similar XRPD map of embodiment 68, TGA map, DSC Map (not shown).Illustrate that embodiment 69~73 is prepared is and the identical substance of embodiment 68.

Embodiment 74

It weighs crystal form J2 known to 20mg to be added in 5mL vial, adds 1.0mL ethyl acetate, capping is stirred at room temperature 7 It, obtains crystal form 15 after filtering.Yield is 15mg；Molar yield is 70%.

XRPD figure is shown in Figure 33.

TGA figure is shown in Figure 34.Display: having 7.4% weightlessness, be roughly equal to 0.5 ethyl acetate molecule before 150 DEG C, is acetic acid second Ester closes object；Decomposition temperature is 223 DEG C.

Embodiment 75

It weighs crystal form J2 known to 10mg to be added in 5mL vial, adds 1.0mL ethyl acetate, capping is stirred at room temperature 5 It, obtains crystal form 15 after filtering.Yield is 7mg；Molar yield is 65%.

Embodiment 76

It weighing crystal form J2 known to 5mg to be added in 5mL vial, adds 1.0mL ethyl acetate, capping is stirred at room temperature 3 days, Crystal form 15 is obtained after filtering.Yield is 4mg；Molar yield is 74%.

Embodiment 77

It weighing crystal form J2 known to 2mg to be added in 5mL vial, adds 1.0mL ethyl acetate, capping is stirred at room temperature 2 days, Crystal form 15 is obtained after filtering.Yield is 1mg；Molar yield is 46%.

Embodiment 78

It weighs crystal form J2 known to 1.5mg to be added in 5mL vial, adds 1.0mL ethyl acetate, capping is stirred at room temperature 1 It, obtains crystal form 15 after filtering.Yield is 1mg；Molar yield is 62%.

Embodiment 79

It weighs crystal form J2 known to 4mg to be added in 5mL vial, adds 4.0mL ethyl acetate, capping is stirred at room temperature 0.5 It, obtains crystal form 15 after filtering.Yield is 3mg；Molar yield is 70%.

Sample prepared by embodiment 75~79 has and the same or similar XRPD map of embodiment 74, TGA map, DSC Map (not shown).Illustrate that embodiment 75~79 is prepared is and the identical substance of embodiment 74.

Embodiment 80

It weighs crystal form J2 known to 20mg to be added in 5mL vial, adds 1.0mL isopropyl acetate, capping is stirred at room temperature 7 It, obtains crystal form 16 after filtering.Yield is 16mg；Yield is 74%.

XRPD figure is shown in Figure 35.

TGA figure is shown in Figure 36.Display: having 6.2% weightlessness, be roughly equal to 0.5 isopropyl acetate ester molecule before 150 DEG C, is acetic acid Isopropyl ester closes object；Decomposition temperature is 223 DEG C.

Embodiment 81

It weighs crystal form J2 known to 10mg to be added in 5mL vial, adds 1.0mL isopropyl acetate, capping is stirred at room temperature 5 It, obtains crystal form 16 after filtering.Yield is 8mg；Yield is 74%.

Embodiment 82

It weighs crystal form J2 known to 20mg to be added in 5mL vial, adds 4.0mL isopropyl acetate, capping is stirred at room temperature 3 It, obtains crystal form 16 after filtering.Yield is 18mg；Yield is 84%.

Embodiment 83

It weighs crystal form J2 known to 2mg to be added in 5mL vial, adds 1.0mL isopropyl acetate, capping is stirred at room temperature 2 It, obtains crystal form 16 after filtering.Yield is 1mg；Yield is 46%.

Embodiment 84

It weighs crystal form J2 known to 1.5mg to be added in 5mL vial, adds 1.0mL isopropyl acetate, capping is stirred at room temperature 1 day, crystal form 16 is obtained after filtering.Yield is 1mg；Yield is 62%.

Embodiment 85

It weighs crystal form J2 known to 4mg to be added in 5mL vial, adds 4.0mL isopropyl acetate, capping is stirred at room temperature 0.5 day, crystal form 16 is obtained after filtering.Yield is 2mg；Yield is 46%.

Sample prepared by embodiment 81~85 has and the same or similar XRPD map of embodiment 80, TGA map, DSC Map (not shown).Illustrate that embodiment 81~85 is prepared is and the identical substance of embodiment 80.

Embodiment 86

Capsule agent prescription is as shown in table 1.

1 capsule agent prescription of table

Ingredient	It measures (mg/)
		Azilsartan crystal form 3 prepared by the present invention	10
Lactose	69.5
		Light silicon anhydride	0.2
Magnesium stearate	0.3

By 10g Azilsartan crystal form 3 prepared by the present invention, 69.5g lactose, 0.2g light silicon anhydride, 0.3g stearic acid Magnesium physical mixed is simultaneously inserted in capsule, and 1000 capsules are prepared into.

Embodiment 87

" Azilsartan crystal form 3 prepared by the present invention " in embodiment 86 is replaced with into " Azilsartan prepared by the present invention Ester crystal form 4 ", other operations prepare capsule with embodiment 86.

Embodiment 88

" Azilsartan crystal form 3 prepared by the present invention " in embodiment 86 is replaced with into " Azilsartan prepared by the present invention Ester crystal form 14 ", other operations prepare capsule with embodiment 86.

Embodiment 89

Tablet formulation is as shown in table 2.

2 tablet formulation of table

By 10g Azilsartan crystal form 3 prepared by the present invention, 35g lactose and 150g cornstarch and 20g microcrystalline cellulose Physical mixed is simultaneously pelletized, then 10g microcrystalline cellulose and 5g magnesium stearate physical mixed are added thereto, is pressed into 1000.

Embodiment 90

" Azilsartan crystal form 3 prepared by the present invention " in embodiment 89 is replaced with into " Azilsartan prepared by the present invention Ester crystal form 4 ", other operations prepare tablet with embodiment 89.

Embodiment 91

" Azilsartan crystal form 3 prepared by the present invention " in embodiment 89 is replaced with into " Azilsartan prepared by the present invention Ester crystal form 14 ", other operations prepare tablet with embodiment 89.

Comparative example 1

The crystal form 3 prepared by the present invention of crystal form J2,20mg known to 20mg and 20mg crystal form 4 prepared by the present invention are respectively put into It is filtered after being stirred overnight in 100mL water, weighs filtrate weight, then filtrate is spin-dried for, and acetonitrile dissolved clarification is added and is transferred to 10mL appearance Measuring bottle constant volume carries out HPLC detection after weighing.Experimental result is shown: the solubility of known crystal form J2 is 0.50 μ g/g, and crystal form 3 For 4.00 μ g/g, the solubility of crystal form 4 is 6.00 μ g/g, and the solubility of crystal form 3 and crystal form 4 is significantly higher than known crystal form J2.

It will be understood by those skilled in the art that some modifications can be made to the present invention under the introduction of this specification Or variation.These modifications and variations should also be as within the scope of the claims in the present invention.

Claims (11)

1. the crystal form 14 of structure Azilsartan as follows,

It is characterized in that, the crystal form 14 is hydrate, and every mole of crystal form 14 contains 0.5 mole of water；It is radiated using Cu-K α, The X-ray powder diffraction collection that the crystal form 14 is indicated with 2 θ angles has characteristic peak: 6.2 ± 0.2 °, 8.7 in following position ± 0.2 °, 9.0 ± 0.2 °, 13.5 ± 0.2 °, 16.2 ± 0.2 ° and 26.7 ± 0.2 °.

2. the crystal form 14 of Azilsartan according to claim 1, which is characterized in that the crystal form 14 is indicated with 2 θ angles X-ray powder diffraction collection following position have characteristic 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 °.

3. the crystal form 14 of Azilsartan according to claim 2, which is characterized in that the crystal form 14 is indicated with 2 θ angles X-ray powder diffraction collection following position have characteristic peak and relative intensity:

4. a kind of preparation method of the crystal form 14 of Azilsartan according to any one of claims 1 to 3, which is characterized in that The preparation method is that: at room temperature, known crystal form J2 is dissolved in the mixed solution of organic solvent and water, forms solution, then Polymethyl methacrylate is added, then volatilize crystallization naturally, obtains the crystal form 14；

The organic solvent is acetone, 2- butanone and tetrahydrofuran；

The in the mixed solvent of the organic solvent and water, the volume fraction of water are 1~5%；

The usage amount of the polymethyl methacrylate is less than or equal to the 5% of known crystal form J2 weight；

In the solution of the crystal form J2, it is known that the amount of crystal form J2 is at room temperature, to dissolve in organic solvent and water mixed solution 0.2~1 times of degree.

5. the preparation method of Azilsartan crystal form 14 according to claim 4, which is characterized in that the organic solvent is Acetone.

6. the preparation method of Azilsartan crystal form 14 according to claim 4, which is characterized in that the polymethyl The usage amount of sour methyl esters is less than or equal to the 4% of known crystal form J2 weight.

7. the preparation method of Azilsartan crystal form 14 according to claim 6, which is characterized in that the polymethyl The usage amount of sour methyl esters is less than the 3% of known crystal form J2 weight.

8. the preparation method of Azilsartan crystal form 14 according to claim 4, which is characterized in that the crystal form J2's is molten In liquid, it is known that the amount of crystal form J2 is 0.5~1 times of solubility in organic solvent and water mixed solution at room temperature.

9. the preparation method of Azilsartan crystal form 14 according to claim 8, which is characterized in that the crystal form J2's is molten In liquid, it is known that the amount of crystal form J2 is 0.8~1 times of solubility in organic solvent and water mixed solution at room temperature.

10. a kind of pharmaceutical composition, it includes the Azilsartans according to any one of claims 1 to 3 of therapeutically effective amount Crystal form 14, and at least one pharmaceutically acceptable excipient.

11. the crystal form 14 of Azilsartan according to any one of claims 1 to 3 is in preparation treatment hypertension and complication Purposes in drug.