WO2015051546A1 - Formes cristallines de l'ester d'azilsartan et leur procédé de préparation - Google Patents

Formes cristallines de l'ester d'azilsartan et leur procédé de préparation Download PDF

Info

Publication number
WO2015051546A1
WO2015051546A1 PCT/CN2013/085089 CN2013085089W WO2015051546A1 WO 2015051546 A1 WO2015051546 A1 WO 2015051546A1 CN 2013085089 W CN2013085089 W CN 2013085089W WO 2015051546 A1 WO2015051546 A1 WO 2015051546A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
azilsartan
room temperature
crystal
crystalline form
Prior art date
Application number
PCT/CN2013/085089
Other languages
English (en)
Chinese (zh)
Inventor
沈涛
盛晓霞
盛晓红
Original Assignee
杭州领业医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州领业医药科技有限公司 filed Critical 杭州领业医药科技有限公司
Priority to PCT/CN2013/085089 priority Critical patent/WO2015051546A1/fr
Priority to CN201380059509.7A priority patent/CN104812752B/zh
Publication of WO2015051546A1 publication Critical patent/WO2015051546A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of azilsartan ester and a preparation method thereof.
  • Azisartan is a novel angiotensin II receptor blocker developed by Takeda Pharmaceuticals, Japan, and was approved by the US FDA in February 2011 under the trade name Edabi.
  • the drug is also a prodrug of a novel angiotensin II receptor blocker, azilsartan, for the treatment of hypertension and related complications.
  • the drug is administered orally and can be used alone or in combination with other antihypertensive drugs for the treatment of hypertension and related complications.
  • phase III clinical trial of 20-80 mg of azilsartan administered once daily its safety and efficacy were confirmed, and it was higher in comparison with losartan and olmesartan medoxomil. The blood pressure lowering effect.
  • azilsartan 1-[[2,-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) [1,1,- Biphenyl]-4-yl]fluorenyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid (5-mercapto-2-oxo-1,3-dioxol-4-yl) ) Ester;
  • English name Azilsartan Medoxomil, aka TAK-491, chemical formula: C 3 . H 24 N 4 0 8 ; molecular weight: 568.53;
  • Patent document US 2005/018726 discloses the confirmation, preparation and use of azilsartan. Specifically, the confirmation and preparation of azilsartan medolate were disclosed in Examples 1 and 2, and it was pointed out that the product was in a crystalline state, but no crystal form data was provided. For convenience, the crystal forms in Examples 1 to 2 will be described below. It is called "known crystal form"; a pharmaceutical composition of azilsartan is disclosed in Formulation Examples 1 to 6; and the use of azilsartan is disclosed in Test Examples 1 and 2.
  • Example 1 The identification, preparation and use of azilsartan medolate are disclosed in the patent document WO 2012/090043 A1. Specifically, in Examples 1 to 15, J2, J3, J4, J5, J6, J7, J8, J9 are disclosed. Crystalline morphology and amorphous azilsartan ester and its preparation method. Among them, a crystal form and preparation thereof are disclosed in Example 1. Methods, and XRPD patterns, DSC patterns, TGA patterns, and IR patterns of the crystal form are disclosed. For convenience, the crystal form in Example 1 is hereinafter referred to as "known crystal form J2".
  • Examples 3, 4 and 5 Another crystal form and its preparation method are disclosed in Examples 3, 4 and 5, and an XRPD pattern, a DSC chart, a TGA spectrum and an IR spectrum of the crystal form are disclosed.
  • the crystal forms in Examples 3, 4 and 5 are hereinafter referred to as "known crystal form J4".
  • the patent document also discloses that azilsartan has a therapeutic effect on hypertension and its complications.
  • crystal form J2 disclosed in the patent document WO2012/090043A1 is an anhydride and is superior to other crystal forms. It is known that the crystal form J4 is a dihydrate and is superior to others. Hydrate.
  • Polymorphs are properties of some molecular and molecular compositions. The same molecules may form different crystals due to different arrangements.
  • the polymorphs have different crystal structures and physical properties such as solubility, stability, thermal properties, mechanical properties, purification capabilities, X-ray diffraction patterns, infrared absorption patterns, Raman spectra, and solid state nuclear magnetics.
  • One or more analytical assays can be used to distinguish between different crystal forms of the same compound.
  • New crystalline forms of pharmaceutically active ingredients have been found to provide materials with advantageous processing properties, and new amorphous forms and solvates have been found to provide materials with better physicochemical properties, such as Better bioavailability, storage stability, easy processing, easy purification or as an intermediate crystal form that promotes conversion to other crystal forms.
  • New crystal forms of pharmaceutically useful compounds can also help improve drug performance. It expands the types of raw materials that formulation scientists can use to optimize formulation performance, such as improved dissolution, improved shelf life, and easier processing.
  • the known crystal form J2 mentioned in the patent document WO2012/090043A1 has a low solubility in water, affects the dissolution of the drug, thereby affecting the bioavailability, and the melting point is too high, which is not suitable for the hot melt extrusion method to obtain a preparation, and The crystal form particles are small, which is disadvantageous for the compressibility of the tablet;
  • the known crystal form J4 mentioned is a hydrate having a low dehydration temperature and poor thermal stability.
  • the new crystalline form is an anhydrate having a higher solubility, a lower melting point and a room temperature stability, or a more stable hydrate at room temperature, and a method of preparing these novel crystal forms, as well as pharmaceutical compositions and uses thereof.
  • the present invention provides Form 3 of azilsartan (hereinafter referred to as "Form 3", using Cu- ⁇ radiation, which is represented by 2 ⁇ angle
  • Form 3 The X-ray powder diffraction pattern has characteristic peaks at the following positions: 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 X-ray powder diffraction pattern of the crystal form 3 expressed at an angle of 2 ⁇ has a characteristic peak at the following position: 5 ⁇ 1 ⁇ 0 ⁇ 2. , 8 ⁇ 6 ⁇ 0 ⁇ 2. , 10 ⁇ 2 ⁇ 0 ⁇ 2. , 11 ⁇ 5. ⁇ 0 ⁇ 2.
  • the X-ray powder diffraction pattern of the crystal form 3 represented by a 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 3 has an X-ray powder diffraction pattern as shown in Fig. 1.
  • the thermogravimetric analysis (TGA) pattern of Form 3 showed that the sample was anhydrate; the decomposition temperature was 234 °C.
  • the differential scanning calorimetry (DSC) pattern of Form 3 showed a melting point of 151 ° C and crystallized during melting to a known crystalline form J2 having a melting point of about 170 °C.
  • the crystal form 3 is prepared by the following method: a suspension of a known crystal form J2 in dichlorosilane is stirred and crystallized at room temperature, and then the precipitated crystal is separated to obtain a crystal form 6, and then the crystal form is obtained. 6 The temperature was raised until the solvent was completely removed, and then cooled to room temperature to obtain the crystal form 3.
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in dichlorosilane at room temperature; the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the temperature rise is to a temperature of 140 ° C at a rate of 10 ° C / min, and the cooling rate of the cooling is 10 ° C / min.
  • the crystal form 3 has the following beneficial effects:
  • the crystal form 3 has a solubility in water at room temperature of 4. ( ⁇ g/g, which is higher than the known crystal form J2 (0.5 g/g);
  • the crystal form 3 is left at room temperature (40% ⁇ 75% RH) for 4 months, the crystal form and the melting point are unchanged, and has good stability;
  • crystal form 4 The crystalline form 3 has a lower melting point and is more suitable for use in a formulation for hot melt extrusion than the known crystalline form J2. According to an object of the present invention, the present invention provides a crystal form 4 of azilsartan (hereinafter referred to as "crystal form 4,").
  • the X-ray powder diffraction pattern of the Form 4 at 2 ⁇ angle has characteristic peaks at: 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 °.
  • the X-ray powder diffraction pattern of the crystal form 4 represented by a 2 ⁇ angle has characteristic peaks at the following positions: 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. .
  • the X-ray powder diffraction pattern of the crystal form 4 at an angle of 2 ⁇ has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 4 has an X-ray powder diffraction pattern as shown in Fig. 6.
  • the thermogravimetric analysis (TGA) pattern of Form 4 showed that the sample was anhydrate; the decomposition temperature was 231 °C.
  • the differential scanning calorimetry (DSC) pattern of Form 4 showed a melting point of 154 ° C and was crystallized at 160 ° C to form a known crystalline form J2 having a melting point of about 170 ° C.
  • the Form 4 is prepared by any of the following methods:
  • the organic solvent is preferably acetonitrile, ethanol, n-propanol, butanol, diisopropyl ether, mercapto tert-butyl ether, heptane, nonylcyclohexane, more preferably acetonitrile;
  • the amount of the amorphous substance is 1 to 20 times, preferably 2 to 10 times, more preferably 2 to 5 times, in the organic solvent at room temperature; the crystallization time is 0.5 to 3 Days, preferably 0.5 to 1 day.
  • the organic solvent is preferably acetonitrile, acetone, 2-butanone and tetrahydrofuran, more preferably acetonitrile; in the organic solvent solution of the crystal form J2, the amount of the crystal form J2 is known to be 0.1 to 1 in its solubility in acetonitrile.
  • the ratio is preferably 0.5 to 1 time, more preferably 0.8 to 1 time; and the time for the crystallization is 0.5 to 2 days.
  • the solution formation temperature is 40 to 80 ° C, preferably 70 to 80 ° C; and the temperature after cooling is 0 to 30 ° C, preferably 0 ° C.
  • the crystal form 4 has the following beneficial effects:
  • the crystal form 4 has a solubility in water at room temperature of 6. ( ⁇ g/g, which is higher than the known crystal form J2 (0.5 g/g);
  • the crystalline form 4 has a lower melting point and is more suitable for the hot melt extrusion process than the known crystalline form J2. Agent
  • the crystal form 4 has a larger particle size and has better tablet compressibility
  • the crystal form 4 was left at room temperature (40% ⁇ 75% RH) for 4 months, and the crystal form and the melting point were unchanged, and the stability was good.
  • the present invention provides a crystalline form 14 of azilsartan (hereinafter referred to as "Form 14").
  • the Form 14 is a hydrate and contains about 0.5 moles of water per mole of Form 14.
  • the X-ray powder diffraction pattern of the crystal form 14 represented by a 2 ⁇ angle has a characteristic peak at the following position: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form 14 represented by a 2 ⁇ angle has characteristic peaks at the following positions: 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°,
  • the X-ray powder diffraction pattern of the crystalline form 14 at a 2 ⁇ angle has characteristic peaks and relative intensities at:
  • a typical example of the crystal form 14 has an X-ray powder diffraction pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of the crystalline form 14 shows that the sample has a weight loss of 2.2% at 125 ° C, about 0.5 water molecules, is a hemihydrate, and its dehydration temperature is higher than J4 (95 ° C). The decomposition temperature was 221 °C.
  • the differential scanning calorimetry (DSC) pattern of Form 14 shows that after solvent loss, an anhydrous known crystalline form J2 having a melting point of about 170 ° C is formed.
  • the crystal form 14 is prepared by the following method: at room temperature, the known crystal form J2 is dissolved in a mixed solution of an organic solvent and water to form a solution, and then polydecyl methacrylate is added, followed by natural volatilization, Obtaining the crystal form 14;
  • the organic solvent is preferably acetone, 2-butanone and tetrahydrofuran, more preferably acetone;
  • the volume fraction of water is 1 to 5%
  • the poly(mercapto methacrylate) (PMMA) is used in an amount of 5% or less, preferably 4% or less, more preferably less than 3% by weight based on the known crystal form J2.
  • the amount of the crystal form J2 is known to be 0.2 to 1 times, preferably 0.5 to 1 time, more preferably 0.8 to 1 times the solubility in the organic solvent and water mixed solution at room temperature. .
  • the crystal form 14 has the following beneficial effects:
  • the crystal form 14 is relatively stable, and is left at room temperature (40% ⁇ 75% RH) for 4 months, and the melting point is unchanged;
  • the crystal form 14 has a higher dehydration temperature than the known crystal form J4, and has good thermal stability;
  • crystal form 6 has a larger particle size and has better tablet compressibility. Further, in accordance with the purpose of the present invention, the present invention provides a crystal form 6 of azilsartan (hereinafter referred to as "crystal form 6,").
  • the crystalline form 6 is a dichloromethane complex and contains 1 mole of dichlorodecane per mole of the crystalline form 6.
  • the X-ray powder diffraction pattern of the Form 6 at 2 ⁇ angle has a characteristic peak at the following position: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form 6 represented by a 2 ⁇ angle has characteristic peaks at the following positions: 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 °.
  • the X-ray powder diffraction pattern of the crystal form 6 represented by a 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 6 has an X-ray powder diffraction pattern as shown in Fig. 13.
  • thermogravimetric analysis (TGA) pattern of Form 6 showed a 4.8% weight loss before the sample at 150 ° C, about one molecule of dichloromethane, which was a dichloromethane complex; the decomposition temperature was 229 ° C.
  • the differential scanning calorimetry (DSC) pattern of Form 6 shows that it lost solvent at 127 ° C to give an amorphous form 3 having a melting point of about 151 °C.
  • the crystal form 6 is prepared by the following method: stirring a crystal suspension of a known crystal form J2 in methylene chloride at room temperature, and then separating the precipitated crystal to obtain the crystal form 6;
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in dichlorosilane at room temperature; the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the present invention provides a crystal form 5 of azilsartan (hereinafter referred to as "crystal form 5,").
  • the crystalline form 5 is a dioxane compound and contains 1 mole of dioxane per mole of the crystalline form 5.
  • the X-ray powder diffraction pattern of the Form 5 at 2 ⁇ angle has a characteristic peak at the following position: 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. .
  • the X-ray powder diffraction pattern of the Form 5 represented by a 2 ⁇ angle has a characteristic peak at the 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. .
  • the X-ray powder diffraction pattern of the crystal form 5 expressed at an angle of 2 ⁇ has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 5 has an X-ray powder diffraction pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of Form 5 showed a 10.1% weight loss before the sample at 150 ° C, which is about 1 dioxane molecule, which is a dioxane; the decomposition temperature is 238 ° C.
  • the differential scanning calorimetry (DSC) pattern of Form 5 shows that it lost solvent at 137 ° C to form a known Form J2 having a melting point of about 170 °C.
  • the Form 5 can be prepared by any of the following methods:
  • the amount of the crystal form J2 is known to be 0.2-1 times, preferably 0.5 to 1 time, more preferably 0.8 to 1 times the solubility in dioxane at room temperature.
  • the volume of the sec-butanol or water is 5 to 20 times, preferably 10 to 15 times the volume of the dioxane.
  • the crystallization time is l ⁇ 24h, preferably l ⁇ 5h.
  • a dioxane solution of a known crystal form J2 is formed at a certain temperature, and crystallizes naturally at the same temperature to obtain the crystal form 5.
  • the temperature is 30 to 50 ° C, preferably 40 ° C.
  • the amount of the crystal form J2 is known to be room temperature and its solubility in the dioxane
  • the present invention provides a crystalline form 7 of azilsartan (hereinafter referred to as "crystalline form 7,").
  • the crystalline form 7 is a nonylbenzene compound and contains 1 per mole of crystal form 7. Molar's toluene.
  • the X-ray powder diffraction pattern of the crystal form 7 at an angle of 2 ⁇ has a characteristic peak at the following position: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form 7 represented by a 2 ⁇ angle has a characteristic peak at the following position: 4 ⁇ 5 ⁇ 0 ⁇ 2. , 7 ⁇ 7 ⁇ 0 ⁇ 2. , 9 ⁇ 0 ⁇ 0 ⁇ 2. , 9.4. Soil 0.2. , 10.7. ⁇ 0 ⁇ 2. , 11 ⁇ 2 ⁇ 0 ⁇ 2. , 12 ⁇ 5 ⁇ 0 ⁇ 2 ⁇ ,
  • the X-ray powder diffraction pattern of the crystal form 7 expressed at an angle of 2 ⁇ has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 7 has an X-ray powder diffraction pattern as shown in Fig. 16.
  • thermogravimetric analysis (TGA) pattern of Form 7 showed a 7.7% weight loss before the sample at 150 ° C, which is about 1 benzene molecule, which is a quinone; the decomposition temperature is 231 °C.
  • the differential scanning calorimetry (DSC) pattern of Form 7 shows that it lost solvent at 131 ° C to form an anhydrous known crystalline form J2 having a melting point of about 170 °C.
  • the crystal form 7 can be produced by a method in which a suspension of a known crystal form J2 in toluene is stirred and crystallized at room temperature, and then the precipitated crystal is separated to obtain the crystal form 7.
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in toluene at room temperature.
  • the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the present invention provides a crystalline form 8 of azilsartan (hereinafter referred to as "crystal form 8,").
  • the crystalline form 8 is an etherate and contains 1 mole per mole of the crystalline form 8. The ether.
  • the X-ray powder diffraction pattern of the Form 8 at 2 ⁇ angle has a characteristic peak at the following position: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form 8 represented by a 2 ⁇ angle has characteristic peaks at the following positions: 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. .
  • the X-ray powder diffraction pattern of the crystal form 8 represented by a 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 8 has an X-ray powder diffraction pattern as shown in Fig. 19.
  • thermogravimetric analysis (TGA) pattern of Form 8 showed a sample weight loss of 9.3% before 150 °C, about one ether molecule, which was diethyl ether; the decomposition temperature was 222 °C.
  • the crystal form 8 can be produced by a method in which a suspension of a known crystal form J2 in diethyl ether is stirred and crystallized at room temperature, and then the precipitated crystals are separated to obtain the crystal form 8.
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in diethyl ether at room temperature.
  • the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the present invention provides a crystalline form 9 of azilsartan ester (hereinafter referred to as "crystal form 9,").
  • the crystalline form 9 is a chloroform and contains 1 mole per mole of the crystalline form 9. Chloroform.
  • the X-ray powder diffraction pattern of the crystal form 9 at an angle of 2 ⁇ has a characteristic peak at the following position: 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. .
  • the X-ray powder diffraction pattern of the crystal form 9 at an angle of 2 ⁇ has characteristic peaks at the following positions: 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. Division 0.2. 22.6 ⁇ 0.2 and 23.0. Division 0.2. .
  • the X-ray powder diffraction pattern of the crystal form 9 represented by a 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 9 has an X-ray powder diffraction pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of the Form 9 showed a 19.7% weight loss before the sample at 150 ° C, which is about one chloroform molecule, which is a chloroform; the decomposition temperature is 219 ° C.
  • the differential scanning calorimetry (DSC) pattern of Form 9 shows that it loses solvent at 120 ° C, forms an amorphous form and then crystallizes at 143 ° C to form a water-free known crystal form having a melting point of about 170 ° C. J2.
  • the crystal form 9 can be produced by a method in which a suspension of a known crystal form J2 in chloroform is stirred and crystallized at room temperature, and then the precipitated crystals are separated to obtain the crystal form 9.
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in chloroform at room temperature.
  • the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the present invention provides a crystal form 10 of azilsartan (hereinafter referred to as "crystal form 10").
  • the crystalline form 10 is a hydrate and contains 3 moles of water per mole of the crystalline form 10.
  • the X-ray powder diffraction pattern of the crystal form 10 at an angle of 2 ⁇ has characteristic peaks at the following positions: 4.6 ⁇ 0.2°, 8.9 ⁇ 0.2°, 9.5 ⁇ 0.2°, and 16.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form 10 at an angle of 2 ⁇ has characteristic peaks at the following positions: 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 °.
  • the X-ray powder diffraction pattern of the crystalline form 10 at a 2 ⁇ angle has characteristic peaks and relative intensities at:
  • a typical example of the crystal form 10 has an X-ray powder diffraction pattern as shown in Fig. 24.
  • thermogravimetric analysis (TGA) pattern of the Form 10 showed a 6.21% weight loss before the sample at 150 ° C, about three water molecules, being a trihydrate; the decomposition temperature was 230 ° C.
  • the crystal form 10 can be produced by volatilizing a solution of a nitro silane of a known crystal form J2 at a certain temperature, and then separating the precipitated crystals to obtain the crystal form 10.
  • the amount of the crystal form J2 is known to be 0.1 to 1 times, preferably 0.5 to 1 time, more preferably 0.8 to 1 times the solubility in nitrodecane at room temperature.
  • the volatile crystallization temperature is 30 to 50 °C.
  • the present invention provides a crystalline form 11 of azilsartan (hereinafter referred to as "crystal form"
  • the crystalline form 11 is an isopropyl ether compound and contains about 0.5 mole of isopropyl ether per mole of the crystalline form 11.
  • the X-ray powder diffraction pattern of the crystal form 11 represented by a 2 ⁇ angle has a characteristic peak at the following position: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystalline form 11 represented by a 2 ⁇ angle has Characteristic peaks: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystalline form 11 at an angle of 2 ⁇ has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 11 has an X-ray powder diffraction pattern as shown in Fig. 26.
  • thermogravimetric analysis (TGA) pattern of Form 11 showed a 6.7% weight loss before the sample at 150 °C, about 0.5 isopropyl ether molecules, which was isopropoxide; the decomposition temperature was 223 °C.
  • the differential scanning calorimetry (DSC) pattern of the crystalline form 11 shows that it loses solvent at 115 ° C to form an amorphous type.
  • the crystal was crystallized at 127 ° C to form an anhydrous known crystal form J2 having a melting point of about 170 ° C.
  • the crystal form 11 can be produced by a method in which a suspension of a known crystal form J2 in isopropyl ether is stirred and crystallized at room temperature, and then the precipitated crystals are separated to obtain the crystal form 11.
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in isopropyl ether at room temperature.
  • the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the present invention provides a crystalline form 15 of azilsartan (hereinafter referred to as "crystal form 15").
  • the crystalline form 15 is an ethyl acetate compound and contains 0.5 mole of ethyl acetate per mole of the crystalline form 15.
  • the X-ray powder diffraction pattern of the Form 15 at 2 ⁇ angle has a characteristic peak at the following position: 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 ⁇ .
  • the X-ray powder diffraction pattern of the crystalline form 15 expressed at an angle of 2 ⁇ has characteristic peaks at: 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°.
  • the X-ray powder diffraction pattern of the crystalline form 15 expressed in terms of 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form 15 has an X-ray powder diffraction pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of the Form 15 showed that the sample had a weight loss of 7.4% before 150 °C, about 0.5 ethyl acetate molecules, and was an ethyl acetate compound; the decomposition temperature was 223 °C.
  • the crystal form 15 can be prepared by the following method: stirring a crystal suspension of a known crystal form J2 in ethyl acetate at room temperature, and then separating the precipitated crystal to obtain the crystal form 15;
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in ethyl acetate at room temperature.
  • the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the present invention provides a crystalline form 16 of azilsartan (hereinafter referred to as "crystal form 16").
  • the crystalline form 16 is an isopropyl acetate and contains 0.5 moles of isopropyl acetate per mole of the crystalline form 16.
  • the X-ray powder diffraction pattern of the crystal form 16 at an angle of 2 ⁇ has a characteristic peak at the following position: 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. .
  • the X-ray powder diffraction pattern of the crystalline form 16 at a 2 ⁇ angle has characteristic peaks at: 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. .
  • the X-ray powder diffraction pattern of the crystalline form 16 at an angle of 2 ⁇ has characteristic peaks and relative intensities at:
  • a typical example of the crystal form 16 has an X-ray powder diffraction pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of the Form 16 showed a 6.2% weight loss before the sample at 150 ° C, about 0.5 isopropyl acetate molecules, which was an isopropyl acetate; the decomposition temperature was 223 °C.
  • the crystal form 16 can be produced by a method in which a suspension of a known crystal form J2 in isopropyl acetate is stirred and crystallized at room temperature, and then the precipitated crystals are separated to obtain the crystal form 16.
  • the amount of the crystal form J2 is known to be 1 to 20 times, preferably 1.5 to 10 times, more preferably 2 to 5 times the solubility in isopropyl acetate at room temperature.
  • the crystallization time is 0.5 to 7 days, preferably 0.5 to 3 days.
  • the "room temperature” means 10 to 30 °C.
  • the agitation is specifically performed as follows: magnetic stirring at 50 to 1800 rpm, preferably magnetic stirring at 300 to 900 rpm.
  • the separation includes filtration or centrifugation.
  • the specific operation of the centrifugation is as follows: The sample to be separated is placed in a 2 mL centrifuge tube, centrifuged at a rate of 6000 rpm, and the solid is completely settled to the bottom of the centrifuge tube to remove the supernatant.
  • the crystalline form described in the present invention may be subjected to a drying step unless otherwise specified.
  • the drying can be carried out by conventional techniques in the art, such as drying at room temperature, drying by air or drying under reduced pressure, in a fume hood, a blast oven or a vacuum oven; it can be carried out under reduced pressure or under reduced pressure, preferably The pressure is less than 0.09 Mpa; the drying temperature is about 30 to 50 ° C; the drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours.
  • the operation of the ultrasonic is: placing the container in an ultrasonic cleaner at room temperature, and performing ultrasonication for 1 to 30 minutes at an ultrasonic working power of 20 Khz to 40 Khz.
  • the operation of the rotary steaming is: at room temperature ⁇ boiling point of the solvent, less than atmospheric pressure (preferably pressure)
  • the force is less than 0.08 MPa), and is carried out at a rotation speed of 10 to 180 rpm (preferably 50 to 100 rpm).
  • the invention mainly relates to a new type of crystal form 3, crystal form 4, crystal form 14 and form 6 of azilsartan, and further relates to a new form of crystal form 5, crystal form 7, crystal form 8, crystal of azilsartan Form 9, Form 10, Form 11, Form 15 and Form 16.
  • crystal or “crystal form” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction patterns typically vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the only or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2 is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • anhydrous herein means that the crystal form contains not more than 1.5% by weight, or not more than 1.0% by weight, of water as measured by TGA.
  • the crystallization method employed in the present invention includes a method of volatilization, crystal slurry, polymer template volatilization recrystallization, and cooling recrystallization and solvent recrystallization.
  • Volatilization is to place the sample clear solution in an open 5 mL glass vial, open or capped, and volatilized at specific temperatures. It can be evaporated by a nitrogen gas or directly at room temperature.
  • the crystal slurry is a mixture of a supersaturated solution of the sample (in the presence of insoluble solids) in a different solvent system, usually from 2 hours to 2 weeks.
  • the polymer template experiment was consistent with the room temperature evaporation method except that a certain amount of insoluble polymer material was added to the sample solution.
  • the amount of the polymer substance used is not more than 5% by weight of the azilsartan ester, preferably not more than 4%, more preferably less than 3%.
  • a high molecular substance was used in the experiment to aid in crystal crystallization, and the high molecular substance used in the present invention was polydecyl methacrylate (PMMA).
  • the PMMA used in the present invention is amorphous, and the DSC does not show a melting point. Since the amount of the polymer substance is strictly controlled to 5% or less, the polymer substance does not affect the judgment of the crystal form in the experiment.
  • Cooling recrystallization is to dissolve the sample in a suitable solvent under specific high temperature conditions and place it in 5mL glass. In the glass vial, place it on a variable temperature shaker, cool down according to a certain cooling rate, and stir at room temperature overnight.
  • the experimental temperature may range from 0 to 75 ° C, preferably from 15 to 50 ° C.
  • the sample solution is incubated for 1 hour to 2 days at each specific temperature.
  • the anti-solvent recrystallization is, for example, dissolving the sample in a good solvent, solubilizing it by ultrasonication, adding an appropriate amount of the anti-solvent, and stirring at room temperature.
  • the raw material used in the present invention can be produced according to the method described in the patent document WO2012/090043A1, and the raw material used in the present invention is generally the known crystal form J2 described in the patent document.
  • the azilsartan ester amorphous form in the present invention can be produced according to the following method: Acetone is added to the known crystal form J2, and then rapidly spin-dried to obtain an amorphous form of azilsartan.
  • the present invention solves the problems of prior art crystal forms by providing new Form 3, Form 4, Form 14 and Form 6, which have at least one or more than known crystal forms.
  • Advantageous properties in particular, one or more of the following advantages: higher crystallinity, solubility, dissolution rate, good particle morphology, less prone to polymorphic transformation and/or dehydration, thermal and mechanical stability Good properties, low moisture absorption, better flowability, compressibility and apparent density, storage stability, low residual solvents, etc.
  • the present invention solves the prior art crystal form by providing a new Form 5, Form 7, Form 8, Form 9, Form 10, Form 11, Form 15 or Form 16.
  • the new crystal form has advantageous properties selected from at least one of the following: higher crystallinity, solubility, dissolution rate, good particle morphology, polymorphic transformation and/or dehydration, Good thermal and mechanical stability, low moisture absorption, better flow, compressibility and apparent density, storage stability, low residual solvents, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more of said azilsartan ester crystal form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 14, Form 15 or Form 16, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition may also comprise other crystalline forms or amorphous forms of pharmaceutically acceptable azilsartan, including but not limited to known crystalline forms J2 and known crystalline forms J4.
  • the pharmaceutical composition can be solid or liquid. If the pharmaceutical composition is in a liquid state, one or more of the crystalline forms of the azilsartan ester can be maintained as a solid in the liquid composition, for example as a suspension.
  • the present invention provides the crystalline form 3, crystalline form 4, crystalline form 5, crystalline form 6, crystalline form 7, crystalline form 8, crystalline form 9, crystalline form 10, crystalline form 11, crystalline form of the azilsartan Use of Form 14, Form 15 or Form 16 in the manufacture of a medicament for the treatment of hypertension and complications.
  • the present invention provides a method for treating hypertension and complications, comprising administering to a patient in need thereof an effective amount of the crystal form 3, Form 4, Form 5, crystal of the azilsartan Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 14, Form 15 or Form 16, or the pharmaceutical composition.
  • Such patients include, but are not limited to, mammals.
  • Figure 1 is an XRPD pattern of Form 3 of the present invention.
  • Figure 2 is a DSC diagram of Form 3 of the present invention.
  • Figure 3 is a TGA diagram of Form 3 of the present invention.
  • Figure 4 is an XRPD pattern of an amorphous material.
  • Figure 5 is an XRPD pattern of the crystal form 3 stability test of the present invention. Among them, the figure below is measured immediately after preparation; the above figure is measured after 4 months.
  • Figure 6 is an XRPD pattern of Form 4 of the present invention.
  • Figure 7 is a DSC chart of Form 4 of the present invention.
  • Figure 8 is a TGA diagram of Form 4 of the present invention.
  • Figure 9 is a PLM diagram of Form 4 of the present invention.
  • Figure 10 is an XRPD pattern of Form 5 of the present invention.
  • Figure 11 is a DSC chart of Form 5 of the present invention.
  • Figure 12 is a TGA diagram of Form 5 of the present invention.
  • Figure 13 is an XRPD pattern of Form 6 of the present invention.
  • Figure 14 is a DSC chart of Form 6 of the present invention.
  • Figure 15 is a TGA diagram of Form 6 of the present invention.
  • Figure 16 is an XRPD pattern of Form 7 of the present invention.
  • Figure 17 is a DSC chart of Form 7 of the present invention.
  • Figure 18 is a TGA diagram of Form 7 of the present invention.
  • Figure 19 is an XRPD pattern of the crystal form 8 of the present invention.
  • Figure 20 is a TGA diagram of Form 8 of the present invention.
  • Figure 21 is an XRPD pattern of the crystal form 9 of the present invention.
  • Figure 22 is a DSC chart of Form 9 of the present invention.
  • Figure 23 is a TGA diagram of Form 9 of the present invention.
  • Figure 24 is an XRPD pattern of the crystal form 10 of the present invention.
  • Figure 25 is a TGA diagram of the crystalline form 10 of the present invention.
  • Figure 26 is an XRPD pattern of the crystal form 11 of the present invention.
  • Figure 27 is a DSC chart of the crystalline form 11 of the present invention.
  • Figure 28 is a TGA diagram of Form 11 of the present invention.
  • Figure 29 is an XRPD pattern of the crystal form 14 of the present invention.
  • Figure 30 is a DSC diagram of Form 14 of the present invention.
  • Figure 31 is a TGA diagram of Form 14 of the present invention.
  • Figure 32 is a PLM diagram of a crystalline form 14 of the present invention.
  • Figure 33 is an XRPD pattern of the form 15 of the present invention.
  • Figure 34 is a TGA diagram of the crystalline form 15 of the present invention.
  • Figure 35 is an XRPD pattern of the crystal form 16 of the present invention.
  • Figure 36 is a TGA diagram of Form 16 of the present invention.
  • Figure 37 is an XRPD pattern of the known crystal form J2.
  • Figure 38 is a DSC chart of the known crystal form J2.
  • Figure 39 is a TGA diagram of the known crystal form J2.
  • Figure 40 is a PLM diagram of the known crystal form J2.
  • Figure 41 is an XRPD pattern of a known crystal form J4.
  • Figure 42 is a DSC chart of the known crystal form J4.
  • Figure 43 is a TGA diagram of the known crystal form J4. detailed description
  • the instrument used for X-ray powder diffraction was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target of 1.54 nm, an operating temperature of 40 kV and 40 mA, a ⁇ -2 ⁇ goniometer, Mo single. Colorimeter, Lynxeye detector.
  • the instrument is calibrated with the standard (usually corundum) supplied with the instrument before use.
  • the acquisition software is Diffrac Plus XRPD Commander and the analysis software is MDI Jade 5.0.
  • the sample was tested at room temperature and the sample to be tested was placed on a SiP non-reflective plate. The detailed test conditions are as follows: Angle range: 3 ⁇ 40°2 ⁇ ; Step size: 0.02°2 ⁇ ; Speed: 0.2s/step. Samples were not ground prior to testing unless otherwise stated.
  • the polarized light microscope (PLM) image was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the XP-500E polarized light microscope. The magnification of the sample is observed at a magnification and photographed.
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis.
  • a sample of 1-1 Omg was typically placed in an uncapped (unless otherwise specified) aluminum crucible. The sample was raised from 0 ° C to 250 ° C under the protection of 40 mL/min dry N 2 at a heating rate of 10 ° C/min, while the TA software recorded the heat of the sample during the heating process. The amount changes. In the present application, the melting point is reported as the starting temperature.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually 5-15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 by a stepwise high-resolution detection method at a heating rate of 10 ° C/min under the protection of 40 mL/min dry N 2 . °C, while the TA software records the weight change of the sample during the heating process.
  • the known crystalline form J2 of azilsartan medoxomil can be prepared according to the method described in Example 1 of the patent document WO2012/090043A1.
  • the azilsartan ester is known to be prepared by crystal form J2: at a temperature of 15 to 20 ° C, 0.5 g of azartanol ester known crystal form I is dissolved in 50 mL of methanol, and the solution is filtered and volatilized. , the known crystal form J2 is obtained.
  • the XRPD pattern of the crystal form J2 is known as shown in Fig. 37.
  • the DSC chart is shown in Figure 38, which shows a melting point of 170 °C.
  • the TGA pattern is shown in Figure 39 and is shown as an anhydride with a decomposition temperature of 229 °C.
  • the PLM diagram is shown in Figure 40, showing very small particles.
  • the known crystalline form J4 of azilsartan is prepared by dissolving 0.5 g of azilsartan ester form I in acetone (7.5 mL) and ethyl acetate (7.5) at 40-50 °C. In a mixed solution of mL), the temperature is lowered to 0 to 5 V and stirred, and the known crystal form J4 is obtained by filtration.
  • the XRPD pattern of the crystal form J4 is known as shown in Fig. 41.
  • the DSC chart is shown in Figure 42, which shows that after desolvation, it is crystallized at 146 ° C to form a water-free known crystal form J2 having a melting point of about 170 ° C.
  • the TGA plot is shown in Figure 43 and shows a 6.4% weight loss starting at 95 °C, about 2 water molecules, a dihydrate with a decomposition temperature of 222 °C.
  • the XRPD pattern of the amorphous material is shown in Fig. 4, and there is no XRPD diffraction peak, which is amorphous.
  • the DSC chart is shown in Figure 2. It shows: the melting point is 151 °C, and it undergoes crystal transformation during the melting process, and turns into a water-free known crystal form J2 having a melting point of about 170 °C.
  • the TGA diagram is shown in Figure 3. Display: As an anhydrate, the decomposition temperature is 234 °C.
  • the amorphous material prepared by the method of Example 3 was weighed, then 40 mL of acetonitrile was added, and the mixture was stirred at room temperature for 1 day, filtered and dried to obtain Form 4.
  • the yield was 0.92 g; the molar yield was 92%.
  • the DSC chart is shown in Figure 7.
  • the TGA diagram is shown in Figure 8. Display: As an anhydrate, the decomposition temperature is 231 °C.
  • the PLM diagram is shown in Figure 9. Display: Compared with the known crystal form J2 (Fig. 40), the crystal form 4 has a larger particle size and a better morphology.
  • the crystal form 4 was further stirred for 5 days or more to obtain a crystal form 3.
  • Example 11 100 mg of the amorphous material prepared by the method of Example 3 was weighed, added to a 5 mL glass bottle, and then 1.0 mL of ethanol was added thereto, and the mixture was stirred at room temperature for 1 day, filtered and dried to obtain Form 4. The yield was 65 mg; the molar yield was 65%.
  • Example 11 100 mg of the amorphous material prepared by the method of Example 3 was weighed, added to a 5 mL glass bottle, and then 1.0 mL of ethanol was added thereto, and the mixture was stirred at room temperature for 1 day, filtered and dried to obtain Form 4. The yield was 65 mg; the molar yield was 65%.
  • Example 11 100 mg of the amorphous material prepared by the method of Example 3 was weighed, added to a 5 mL glass bottle, and then 1.0 mL of ethanol was added thereto, and the mixture was stirred at room temperature for 1 day, filtered and dried to obtain Form 4. The yield was 65 mg; the molar yield was
  • amorphous material prepared in the method of Example 3 was weighed, added to a 10 mL glass vial, and then 5.0 mL of decyl tert-butyl ether was added thereto, and the mixture was stirred at room temperature for 1 day, filtered and dried to obtain a crystal form 4.
  • the yield was 0.38 g; the molar yield was 76%.
  • Example 6 The samples prepared in Examples 6 to 22 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 5.
  • the examples 6 to 22 were prepared in the same manner as in Example 5.
  • the DSC chart is shown in Figure 11. It shows: 137 ° C lost solvent, forming a crystal-free J2 melting point of about 170 ° C.
  • the TGA diagram is shown in Figure 12. It shows: The sample has 10.1% weight loss before 150 °C, about one dioxane molecule, which is dioxane; the decomposition temperature is 238 °C.
  • Example 25 to 33 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 24.
  • Illustrative Examples 25 to 33 were prepared in the same manner as in Example 24.
  • the DSC chart is shown in Figure 14. It is shown that the solvent is lost at 127 ° C to obtain an amorphous type 3 having a melting point of about 151 ° C.
  • the TGA chart is shown in Figure 15. It shows: 4.8% weight loss before 150 °C, about one molecule of dichloromethane, which is dichloromethane; the decomposition temperature is 229 °C.
  • Example 35 to 39 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 34.
  • Illustrative Examples 35 to 39 were prepared in the same manner as in Example 34.
  • the DSC chart is shown in Figure 17. It shows: Loss of solvent at 131 °C gives an amorphous J2 with a melting point of about 170 °C.
  • the TGA diagram is shown in Figure 18. It shows: 7.7% weight loss before 150 °C, about one molecule of fluorene, which is benzene benzene; decomposition temperature is 231 °C.
  • Example 41 to 45 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 40.
  • Illustrative Examples 41 to 45 were prepared in the same manner as in Example 40.
  • the TGA diagram is shown in Figure 20. It shows: 9.3% weight loss before 150 °C, about one ether molecule, which is etherified; the decomposition temperature is 222 °C.
  • Example 47 to 51 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 46.
  • the examples 47 to 51 were prepared in the same manner as in Example 46.
  • the DSC chart is shown in Figure 22. Display: It is crystal-free at 120 °C, and then crystallized at 143 °C to form crystal-free J2 with a melting point of 169 °C.
  • the TGA map is shown in Figure 23. It shows: 19.7% weight loss before 150 °C, about one chloroform molecule, which is chloroform; the decomposition temperature is 219 °C.
  • Example 53 to 57 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 52.
  • Illustrative Examples 53 to 57 were prepared in the same manner as in Example 52.
  • the TGA is shown in Figure 25. It shows: 6.21% weight loss before 150 °C, it is trihydrate; decomposition temperature is 230 °C.
  • the DSC chart is shown in Figure 27. It is shown that the solvent is lost at 115 ° C to form an anhydrous crystal form at 127 ° C to form a water-free known crystal form J2 having a melting point of 173 ° C.
  • the TGA diagram is shown in Figure 28. It shows: 6.7% weight loss before 150 °C, about 0.5 isopropyl ether molecules, is isopropyl ether; decomposition temperature is 223 °C.
  • Example 63 to 67 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 62. DESCRIPTION OF THE EXAMPLES 63 to 67 were prepared in the same manner as in Example 62.
  • the XRPD diagram is shown in Figure 29.
  • the DSC chart is shown in Figure 30. It is shown that after the solvent is lost, an anhydrous known crystal form J2 having a melting point of 170 ° C is formed.
  • the TGA diagram is shown in Figure 31. It shows: The sample has a weight loss of 2.2% at 125 °C, about 0.5 water, which is a hemihydrate. The dehydration temperature is higher than J4 (95 °C), and the decomposition temperature is 221 °C.
  • the PLM diagram is shown in Figure 32, which shows: Compared with the known crystal form J2 (Fig. 40), the crystal form 14 has larger particles and better morphology.
  • Example 69 to 73 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 68.
  • the examples 69 to 73 were prepared in the same manner as in Example 68.
  • the TGA diagram is shown in Figure 34. It shows: 7.4% weight loss before 150 °C, about 0.5 ethyl acetate molecule, which is ethyl acetate; the decomposition temperature is 223 °C.
  • Example 75 10 mg of the known crystal form J2 was weighed into a 5 mL glass bottle, 1.0 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 5 days, and filtered to obtain a crystal form 15. The yield was 7 mg; the molar yield was 65%.
  • Example 75 to 79 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 74. Description of Examples 75 to 79 were prepared in the same manner as in Example 74.
  • the TGA diagram is shown in Figure 36. It shows: 6.2% weight loss before 150 °C, about 0.5 isopropyl acetate molecules, is isopropyl acetate; decomposition temperature is 223 V.
  • Example 84 1.5 mg of the known crystal form J2 was weighed and added to a 5 mL glass bottle, 1.0 mL of isopropyl acetate was added, and the mixture was stirred at room temperature for 1 day, and filtered to obtain a crystal form 16. The yield was 1 mg; the yield was 62%.
  • Example 81 to 85 had the same or similar XRPD patterns, TGA patterns, and DSC patterns (not shown) as in Example 80. DESCRIPTION OF THE EXAMPLES 81 to 85 were prepared in the same manner as in Example 80.
  • the formulation of the capsule is shown in Table 1.
  • Example 86 The "Azilsartan membrane crystal form 3" prepared in the present invention was replaced by "the azilsartan ester crystal form 4" prepared in the present invention in Example 86, and the same procedure as in Example 86 was carried out to prepare a capsule.
  • Example 86 The "Azilsartan membrane form 3" prepared in the present invention was replaced with "Azisartan ester crystal form 14" prepared in the present invention in Example 86, and the same procedure as in Example 86 was carried out to prepare a capsule.
  • Example 89 The "Azilsartan membrane crystal form 3" prepared in the present invention was replaced with "Azisartantan ester crystal form 4" prepared in the present invention in Example 89, and the same procedure as in Example 89 was carried out to prepare a tablet.
  • Example 89 The "Azilsartan membrane crystal form 3" prepared in the present invention was replaced with "Azisartantan ester crystal form 14" prepared in the present invention in Example 89, and the same procedure as in Example 89 was carried out to prepare a tablet.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des formes cristallines d'un ester d'azilsartan et leur procédé de préparation. La présente invention concerne, en particulier, diverses formes cristallines inédites du composé qu'est l'ester (5-méthyl-2-oxo-1,3-dioxolan-4-yl)méthylique de l'acide 1-[[2'-2,5-dihydrogen-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-diphényl]-4-yl]méthyl]-2-éthoxy-1H-benzimidazole-7-carboxylique et leur procédé de préparation. Par rapport à l'état de la technique, les formes cristallines inédites de la présente invention montrent une meilleure solubilité dans l'eau et un point de fusion inférieur et, en conséquence, par rapport aux formes cristallines existantes, lesdites formes cristallines inédites présentent un meilleur taux de dissolution et une meilleure biodisponibilité, et elles favorisent l'obtention de préparations pharmaceutiques par un procédé d'extrusion à chaud.
PCT/CN2013/085089 2013-10-12 2013-10-12 Formes cristallines de l'ester d'azilsartan et leur procédé de préparation WO2015051546A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2013/085089 WO2015051546A1 (fr) 2013-10-12 2013-10-12 Formes cristallines de l'ester d'azilsartan et leur procédé de préparation
CN201380059509.7A CN104812752B (zh) 2013-10-12 2013-10-12 阿齐沙坦酯的晶型及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2013/085089 WO2015051546A1 (fr) 2013-10-12 2013-10-12 Formes cristallines de l'ester d'azilsartan et leur procédé de préparation

Publications (1)

Publication Number Publication Date
WO2015051546A1 true WO2015051546A1 (fr) 2015-04-16

Family

ID=52812465

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/085089 WO2015051546A1 (fr) 2013-10-12 2013-10-12 Formes cristallines de l'ester d'azilsartan et leur procédé de préparation

Country Status (2)

Country Link
CN (1) CN104812752B (fr)
WO (1) WO2015051546A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1946717A (zh) * 2004-02-25 2007-04-11 武田药品工业株式会社 苯并咪唑衍生物及其作为aⅱ受体拮抗剂的用途
WO2012107814A1 (fr) * 2011-02-08 2012-08-16 Jubilant Life Sciences Limited Procédé amélioré pour la préparation d'azilsartan médoxomil
WO2013042066A1 (fr) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Procédé de préparation d'azilsartan médoxomil
WO2013042067A1 (fr) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Procédé de préparation d'un sel de potassium de l'azilsartan médoxomil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1946717A (zh) * 2004-02-25 2007-04-11 武田药品工业株式会社 苯并咪唑衍生物及其作为aⅱ受体拮抗剂的用途
WO2012107814A1 (fr) * 2011-02-08 2012-08-16 Jubilant Life Sciences Limited Procédé amélioré pour la préparation d'azilsartan médoxomil
WO2013042066A1 (fr) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Procédé de préparation d'azilsartan médoxomil
WO2013042067A1 (fr) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Procédé de préparation d'un sel de potassium de l'azilsartan médoxomil

Also Published As

Publication number Publication date
CN104812752B (zh) 2016-09-28
CN104812752A (zh) 2015-07-29

Similar Documents

Publication Publication Date Title
KR20080089659A (ko) 아프레피탄트의 비정질 및 결정 형태 및 그것의 제조 방법
CN111164085B (zh) 瑞博西林的共晶和瑞博西林单琥珀酸盐的共晶、其制备方法、组合物和用途
WO2015180060A1 (fr) Sel d'un composé de diazacycloheptane et ses dérivés forme cristalline et substance amorphe
WO2018049632A1 (fr) Forme cristalline d'ozanimod, procédé de préparation et composition pharmaceutique associés
WO2015139386A1 (fr) Canagliflozine monohydratée et sa forme cristalline, son procédé de préparation et son utilisation
WO2015014315A1 (fr) Forme cristalline d'inhibiteur et son procédé de préparation et son utilisation
EP4153551A1 (fr) Formes à l'état solide de tapinarof
WO2015007206A1 (fr) Sels d'addition d'acide de l'afatinib et leurs formes cristallines, procédé de préparation et composition pharmaceutique correspondants
WO2015081566A1 (fr) Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation
CN110582497B (zh) Galunisertib的晶型及其制备方法和药物组合物
CN111868054A (zh) 呋喹替尼的共晶、其制备方法、组合物和用途
US20020107275A1 (en) Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation
JP2022542159A (ja) 固体形態レルゴリクス（Ｒｅｌｕｇｏｌｉｘ）
WO2019028689A1 (fr) Forme cristalline d'odm-201, son procédé de préparation et composition pharmaceutique correspondante
EP3867264A1 (fr) Formes à l'état solide de la voclosporine
WO2014036865A1 (fr) Procédé de préparation de mucate de fingolimod et cristal correspondant et application du mucate de fingolimod et du cristal correspondant
WO2015158202A1 (fr) Forme cristalline d'antibiotiques à base d'oxazolidinione, son procédé de préparation, sa composition pharmaceutique et son utilisation
WO2014016842A1 (fr) Coprécipités amorphes du rivaroxaban
TWI662031B (zh) １－｛２－氟－４－［５－（４－異丁基苯基）－１，２，４－噁二唑－３－基］－苄基｝－３－吖丁啶羧酸的晶型
WO2015051546A1 (fr) Formes cristallines de l'ester d'azilsartan et leur procédé de préparation
WO2008044102A1 (fr) Forme polymorphe d'aprépitant et procédé de préparation de celle-ci
WO2014169770A1 (fr) Forme cristalline de dabrafénid et procédé de préparation et d'utilisation de celui-ci
CN105949182B (zh) 阿齐沙坦酯的晶型及其制备方法
WO2022144042A1 (fr) Forme cristalline de tas-116, son procédé de préparation, sa composition pharmaceutique et son utilisation
WO2015096119A1 (fr) Sels de lorcasérine et leurs cristaux, leurs procédés de préparation et utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13895260

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13895260

Country of ref document: EP

Kind code of ref document: A1