WO2018040065A1 - 缬沙坦二钠盐的晶型 - Google Patents

缬沙坦二钠盐的晶型 Download PDF

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WO2018040065A1
WO2018040065A1 PCT/CN2016/097926 CN2016097926W WO2018040065A1 WO 2018040065 A1 WO2018040065 A1 WO 2018040065A1 CN 2016097926 W CN2016097926 W CN 2016097926W WO 2018040065 A1 WO2018040065 A1 WO 2018040065A1
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Prior art keywords
disodium salt
crystal form
valsartan disodium
valsartan
salt crystal
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PCT/CN2016/097926
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English (en)
French (fr)
Inventor
刘飞
吴刚
姜伟明
林成刚
蔡璇
林萍
陆玉玲
刘立湘
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诺瑞特国际药业股份有限公司
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Application filed by 诺瑞特国际药业股份有限公司 filed Critical 诺瑞特国际药业股份有限公司
Priority to US16/329,992 priority Critical patent/US10745363B2/en
Priority to EP16914631.3A priority patent/EP3508479A4/en
Priority to CN201680088890.3A priority patent/CN109641856B/zh
Priority to PCT/CN2016/097926 priority patent/WO2018040065A1/zh
Publication of WO2018040065A1 publication Critical patent/WO2018040065A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 synthesis, in particular to new crystal forms A, B, D, E, F, G and H of valsartan disodium salt and a preparation method thereof.
  • Valsartan (Structure I) is a specific angiotensin (AT) II receptor antagonist that selectively acts on the AT 1 receptor subtype without any partial agonist at the AT 1 receptor. active.
  • AT angiotensin
  • Valsartan is a drug that has very low bulk density and is insoluble in water.
  • the melting point of the free acid form of valsartan is such that it is 80-95 ° C in the closed mash, 105-110 ° C in the open mash, and the enthalpy of fusion is 12 kJ / mol.
  • the melting point and the measured melting enthalpy of 12 kJ/mol confirmed the poor stability of the valsartan particles in the free acid form.
  • Valsartan is a free acid with two acidic hydrogen atoms, a hydrogen atom of a carboxyl group and a hydrogen atom of a tetrazole ring. Therefore, an acidic hydrogen atom or two acidic hydrogen atoms can be replaced with a monovalent or divalent cation.
  • Valsartan sodium salt can improve the solubility of valsartan in solution, but it is highly hygroscopic and needs to be stored in a cool and dry environment.
  • the valsartan disodium salt disclosed in CN01813039.9 is known to have a melting point starting from 260 and becoming brown at 295.
  • the sodium salt is analyzed by elemental analysis, and the obtained substance (hygroscopic) can be equilibrated in air (C 24 H 27 N 5 O 3 Na 2 , 5.36 mol H 2 O, molar mass 576.05), from which it is known that The sodium salt has a hygroscopicity of up to 20%. It is necessary to further study the solid form of valsartan sodium salt in order to obtain valsartan sodium salt with improved physical properties such as solubility and hygroscopicity.
  • Another object of the present invention is to provide a process for the preparation of crystalline forms A, B, D, E, F, G and H of valsartan disodium salt.
  • the valsartan disodium salt crystal form A provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2 ⁇ is about 4.7 ⁇ 0.2, 8.5 ⁇ 0.2, 9.5 ⁇ 0.2.
  • the valsartan disodium salt crystal form A has an endothermic peak at a temperature close to 183 ° C at a heating rate of 10 ° C / min.
  • the valsartan disodium salt crystal form A has an endothermic peak at 182-184 ° C at a heating rate of 10 ° C / min.
  • valsartan disodium salt crystal form A has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.
  • the valsartan disodium salt crystal form A has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG. 2 at a heating rate of 10 ° C/min.
  • valsartan disodium salt crystal form A is an asolvate of valsartan disodium salt.
  • the DSC chart of valsartan disodium salt crystal form A shows an endothermic peak at around 183 °C, and the enthalpy value is 335.53 J/g.
  • the crystal form has a high endothermic peak temperature and a enthalpy value.
  • the crystal lattice of the crystal form With high stability. It is worth noting that the crystal form is maintained in an open container at a temperature of 25 ⁇ 1 ° C and a relative humidity of 43.5 ⁇ 2% for 3 hours, and the water absorption is only 2.6%.
  • the valsartan disodium salt crystal form B provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2 ⁇ has peaks at about 4.4 ⁇ 0.2 and 8.8 ⁇ 0.2.
  • the valsartan disodium salt crystal form B has a melting point of about 198 ⁇ 5 °C.
  • the valsartan disodium salt crystal form B at a heating rate of 10 ° C / min, did not observe significant debinding solvent characteristics on the thermogravimetric analyzer.
  • the valsartan disodium salt crystal form B is an unsolvate of the valsartan disodium salt.
  • valsartan disodium salt crystal form B has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.
  • valsartan disodium salt crystal form B has substantially the same weight loss curve as the thermogravimetric analysis weight loss curve shown in FIG. 4 at a heating rate of 10 ° C/min.
  • the valsartan disodium salt crystal form D provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2 ⁇ is about 4.4 ⁇ 0.2, 9.0 ⁇ 0.2, 14.9 ⁇ 0.2. 21.4 ⁇ 0.2, 22.4 ⁇ 0.2 has a peak; preferably at about 4.4 ⁇ 0.2, 9.0 ⁇ 0.2, 12.6 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.3 ⁇ 0.2, 17.8 ⁇ 0.2, 21.4 ⁇ 0.2, 22.4 ⁇ 0.2, There is a peak at 23.8 ⁇ 0.2.
  • the valsartan disodium salt crystal form D has a melting point of about 207 ⁇ 5 °C.
  • valsartan disodium salt crystal form D has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.
  • valsartan disodium salt crystal form D is an unsolvate of valsartan disodium salt.
  • the valsartan disodium salt crystal form E provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2 ⁇ is about 6.3 ⁇ 0.2, 12.3 ⁇ 0.2, 14.7 ⁇ 0.2, There is a peak at 16.5 ⁇ 0.2, 17.4 ⁇ 0.2; preferably at 6.3 ⁇ 0.2, 9.8 ⁇ 0.2, 12.3 ⁇ 0.2, 14.7 ⁇ 0.2, 16.5 ⁇ 0.2, 17.4 ⁇ 0.2, 20.4 ⁇ 0.2, 22.0 ⁇ 0.2.
  • the valsartan disodium salt crystal form E has an endothermic peak at a temperature close to 127 ° C at a heating rate of 10 ° C / min.
  • the valsartan disodium salt crystal form E has a differential scanning calorimetry at a heating rate of 10 ° C / min. The figure has an endothermic peak at 107-127 °C.
  • the valsartan disodium salt crystal form E has a thermal weight loss of not less than 15% at 64-200 ° C, preferably a thermal weight loss of not less than 16%, more preferably a thermal weight of not less than 17%. The loss is most preferably a thermal weight loss of not less than 18%.
  • valsartan disodium salt crystal form E has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.
  • the valsartan disodium salt crystal form E has substantially the same weight loss curve as the thermogravimetric analysis weight loss curve shown in FIG. 7 at a heating rate of 10 ° C/min.
  • the valsartan disodium salt crystal form E has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG. 8 at a heating rate of 10 ° C/min.
  • valsartan disodium salt crystal form E is a dioxane solvate of valsartan disodium salt.
  • the ratio of valsartan disodium salt to dioxane in crystalline form E of valsartan disodium salt is 1:1.
  • valsartan disodium salt crystal form E has a liquid nuclear magnetic spectrum as shown in FIG.
  • the valsartan disodium salt crystal form F provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2 ⁇ is at about 6.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 18.3 ⁇ 0.2. There is a peak, preferably at 6.2 ⁇ 0.2, 9.6 ⁇ 0.2, 12.3 ⁇ 0.2, 14.9 ⁇ 0.2, 16.6 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 20.0 ⁇ 0.2, 22.2 ⁇ 0.2.
  • the valsartan disodium salt crystal form F has an endothermic peak at a temperature close to 116 ° C at a heating rate of 10 ° C / min.
  • the valsartan disodium salt crystal form F has an endothermic peak at 104-117 ° C at a heating rate of 10 ° C / min.
  • the valsartan disodium salt crystalline form F has a thermal weight loss of not less than 8.4% at 55-150 ° C, preferably a thermal weight loss of not less than 10%, more preferably a thermal weight of not less than 11%. loss.
  • valsartan disodium salt form F has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.
  • the valsartan disodium salt form F has substantially the same weight loss curve as the thermogravimetric analysis weight loss curve shown in FIG. 11 at a heating rate of 10 ° C/min.
  • the valsartan disodium salt crystal form F has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG. 12 at a heating rate of 10 ° C/min.
  • the crystalline form F of valsartan disodium salt is an ethyl acetate solvate of valsartan disodium salt.
  • the ratio of valsartan disodium salt to ethyl acetate in crystalline Form F of valsartan disodium salt is 1:0.5.
  • valsartan disodium salt crystal form F has a liquid nuclear magnetic spectrum as shown in FIG.
  • the valsartan disodium salt crystal form G provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2 ⁇ is about 6.4 ⁇ 0.2, 8.3 ⁇ 0.2, 9.5 ⁇ 0.2. There are peaks at 17.3 ⁇ 0.2, 19.4 ⁇ 0.2, preferably at 6.4 ⁇ 0.2, 8.3 ⁇ 0.2, 8.5 ⁇ 0.2, 9.5 ⁇ 0.2, 12.8 ⁇ 0.2, 17.3 ⁇ 0.2, 19.4 ⁇ 0.2, 26.0 ⁇ 0.2.
  • the valsartan disodium salt crystal form G has a superposition of degradation and melting signals in the differential scanning calorimetry curve at a heating rate of 10 ° C/min.
  • the valsartan disodium salt crystal form G has a powder substantially identical to the powder diffraction pattern shown in FIG. Final X-ray diffraction spectrum.
  • the valsartan disodium salt crystal form G has substantially the same weight loss curve as the thermogravimetric analysis weight loss curve shown in FIG. 15 at a heating rate of 10 ° C/min.
  • the valsartan disodium salt crystal form G has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG. 16 at a heating rate of 10 ° C/min.
  • valsartan disodium salt crystal form G is an asolvate of valsartan disodium salt.
  • the valsartan disodium salt crystal form H provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2 ⁇ is about 4.5 ⁇ 0.2, 8.7 ⁇ 0.2, 9.0 ⁇ 0.2. There are peaks; preferably at 4.5 ⁇ 0.2, 8.7 ⁇ 0.2, 9.0 ⁇ 0.2, 15.4 ⁇ 0.2, 18.3 ⁇ 0.2, 22.2 ⁇ 0.2; more preferably 4.5 ⁇ 0.2, 8.7 ⁇ 0.2, 9.0 ⁇ 0.2, 15.4 ⁇ 0.2 , 15.6 ⁇ 0.2, 18.3 ⁇ 0.2, 21.8 ⁇ 0.2, 22.2 ⁇ 0.2, 26.3 ⁇ 0.2 peak.
  • the valsartan disodium salt crystal form H at a heating rate of 10 ° C / min, no significant debinding solvent characteristics were observed on the thermogravimetric analyzer.
  • valsartan disodium salt form H has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.
  • the valsartan disodium salt crystal form H has a weight loss curve substantially the same as the thermogravimetric analysis weight loss curve shown in FIG. 18 at a heating rate of 10 ° C/min.
  • the valsartan disodium salt crystalline form H is an asolvate of the valsartan disodium salt.
  • the crystalline form of the valsartan disodium salt of the present invention has surprisingly advantageous characteristics, and the crystalline salt has a clear endothermic peak with a significant endothermic enthalpy under given conditions.
  • the crystalline salt of the present invention is stable, has good quality during storage, and does not change significantly in water content.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A, B, D, E, F, G and H of the valsartan disodium salt of the present invention in admixture with a pharmaceutically acceptable carrier, the pharmaceutical composition being For parenteral administration or parenteral administration, it can be administered to a patient in the form of a tablet, capsule, solution, suspension or the like.
  • a disease or condition such as a disease or condition selected from the group consisting of:
  • Hypertension congestive heart failure, acute renal failure, chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; atherosclerosis, insulin resistance and syndrome X , type 2 diabetes, obesity, kidney disease, hypothyroidism, survival after myocardial infarction, coronary heart disease, senile hypertension, familial dyslipidemia, increased collagen formation, remodeling after fibrosis and hypertension, and high All of these diseases or conditions associated with or unrelated to blood pressure; endothelial dysfunction with or without hypertension; hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia; glaucoma.
  • the main application is in the treatment of hypertension and congestive heart failure as well as post-myocardial infarction.
  • the same powder X-ray diffraction spectrum means that the positions of the peaks represented by degrees 2 ⁇ are substantially the same, and the relative intensities of the peak positions are substantially the same.
  • the relative intensity is the ratio of the intensity of the other peaks to the intensity of the strongest peak when the intensity of the peak having the highest intensity among all the diffraction peaks of the powder X-ray diffraction spectrum is 100%.
  • the 2 ⁇ angle in the X-ray powder diffraction spectrum sometimes causes several measurement errors due to various factors, and the measured value may vary to a degree generally of ⁇ 0.3, preferably ⁇ 0.2, more preferably ⁇ 0.1.
  • the 2 ⁇ angle based on the measured value of a specific sample is understood to mean the meaning including these allowable errors.
  • substantially the same as the powder X-ray diffraction pattern shown in Figure 1 in the present invention means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90 in the powder X-ray diffraction spectrum. %, or at least 95%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern.
  • the absorption peak in differential scanning calorimetry is an inherent physical property of each crystal form of the present invention.
  • impurities may be mixed in an allowable amount.
  • the possibility of a change in the melting point is also undeniable. Therefore, those skilled in the art can fully understand to what extent the measured value of the endothermic peak temperature in the present invention can be varied.
  • the conceivable error is, in some cases, about ⁇ 5 ° C, preferably It is about ⁇ 3 ° C, more preferably about ⁇ 2 ° C, and most preferably about ⁇ 1 ° C.
  • the "melting point" in the present invention means the initial melting temperature at which the crystal form is melted.
  • a Cu Ka filled tube (40 kV, 40 mA) was used as an X-ray source with a wide-angle goniometer, a 0.6 mm divergence slit, a 2.5° primary Sora slit, and a 2.5° secondary sora at room temperature.
  • data acquisition was performed at a scan speed of 2.4°/min, in a range of 3°-40° with a scan step of 0.02°.
  • Data acquisition was accomplished using TA Q200 and Mettler DSC 1+ under N 2 protection at a flow rate of 50 mL/min, before ramping from room temperature to degradation temperature at 10 °C/min.
  • Data collection was accomplished using TA Q500 at a flow rate of 50 mL/min under N 2 protection from 10 ° C/min to room temperature to 30% or less.
  • Figure 3 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form B of valsartan disodium salt.
  • Fig. 4 Thermogravimetric analysis chart (TGA chart) of crystalline form B of valsartan disodium salt.
  • Figure 5 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form D of valsartan disodium salt.
  • Fig. 7 Thermogravimetric analysis chart (TGA chart) of crystalline form E of valsartan disodium salt.
  • Figure 10 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form F of valsartan disodium salt.
  • Figure 12 is a differential scanning calorimetry map (DSC chart) of crystalline form F of valsartan disodium salt.
  • Figure 13 is a liquid nuclear magnetic resonance spectrum (H NMR chart) of crystalline form F of valsartan disodium salt.
  • Fig. 14 Powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form G.
  • Fig. 15 Thermogravimetric analysis chart (TGA chart) of crystalline form G of valsartan disodium salt.
  • Fig. 18 Thermogravimetric analysis chart (TGA chart) of crystalline form H of valsartan disodium salt.
  • valsartan 8.71 mg was dissolved in 0.87 mL of isopropanol, and 0.2 mL of 2 mmol of sodium hydroxide aqueous solution was added dropwise at room temperature, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give n-heptane/ethanol (19/1, volume ratio). The mixture was stirred overnight, filtered, and dried under vacuum at 40 ° C to give a solid.
  • the crystalline form A of valsartan disodium salt was characterized by X-ray powder diffraction and differential scanning calorimetry. The solid state characterization parameters and maps are as described herein.
  • the crystalline form B of valsartan disodium salt was characterized by X-ray powder diffraction and thermogravimetric analysis. The solid state characterization parameters and maps are as described herein.
  • valsartan 8.71 mg was dissolved in 0.87 mL of isopropyl alcohol, 0.2 mL of 2 mmol of sodium hydroxide solution was added dropwise at room temperature, stirred for 0.5 hour, and concentrated under reduced pressure to give a solid. The solid was stirred with n-heptane/ethanol (19/1, by volume) overnight, filtered, and dried in vacuo at 40 ° C to afford valsartan disodium salt solid.
  • the crystalline form D of valsartan disodium salt was characterized by X-ray powder diffraction.
  • the solid state characterization parameters and maps are as described herein.
  • the valsartan disodium salt crystal form E was characterized by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry and liquid nuclear magnetic resonance. The solid state characterization parameters and maps are as described herein.
  • the valsartan disodium salt crystal form F was characterized by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry and liquid nuclear magnetic resonance. The solid state characterization parameters and maps are as described herein.
  • the valsartan disodium salt crystal form G was characterized by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and its solid state characterization parameters and maps are as described herein.
  • valsartan 10 mg was added to 0.3 mL of water, 0.3 mL of 2 mmol of sodium hydroxide solution was added dropwise, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give a solid.
  • 0.2 mL of 2-butanone was added, stirred for 0.5 h, and refrigerated at 4 ° C to precipitate a solid, which was dried in an oven at 0 ° C to obtain a white solid, i.e., type H valsartan disodium salt.
  • the valsartan disodium salt crystal form H was characterized by X-ray powder diffraction, thermogravimetric analysis and differential scanning calorimetry. The solid state characterization parameters and maps are as described herein.
  • Example 8 Determination of the hygroscopicity of each valsartan disodium salt in the present invention
  • the thickness of the test sample is generally about 1 mm and weighed (m 2 ).

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Abstract

提供一类缬沙坦二钠盐的晶型A、B、D、E、F、G和H及其制备方法。

Description

[根据细则37.2由ISA制定的发明名称]　缬沙坦二钠盐的晶型 技术领域
本发明涉及药物合成领域，尤其涉及缬沙坦二钠盐的新晶型A、B、D、E、F、G和H及其制备方法。
背景技术
缬沙坦(结构式I)是一种特异性强的血管紧张素(AT)II受体拮抗剂，它选择性地作用于AT1受体亚型，对AT1受体没有任何部分激动剂的活性。
Figure PCTCN2016097926-appb-000001
缬沙坦是一种堆密度极小且在水中难溶的药物。游离酸形式的缬沙坦的熔点是这样的，在封闭的坩埚中为80-95℃，在敞口的坩埚中为105-110℃，并且熔化焓为12kJ/mol。熔点以及测定的12kJ/mol的熔化焓证实了游离酸形式的缬沙坦颗粒稳定性差。
在产品干燥或研磨过程中，以及在制剂的制备过程中需要更稳定形式的缬沙坦。缬沙坦是游离酸，具有两个酸性氢原子，羧基的氢原子和四唑环的氢原子。因此，可用一价或二价阳离子替代一个酸性氢原子或两个酸性氢原子。缬沙坦钠盐可以改善缬沙坦在溶液中的溶解度，但其吸湿性强，需要保存在阴凉干燥的环境中。已知CN01813039.9中公开的缬沙坦二钠盐，熔点从260开始，在295变为棕色。该钠盐通过测定元素分析，所得到的物质(吸湿性的)可在空气中达到平衡(C24H27N5O3Na2,5.36摩尔H2O,摩尔质量576.05)，由此可知，该钠盐吸湿性高达20％。有必要进一步对缬沙坦钠盐的固态形式进行研究，以期获得溶解度，吸湿性等物理性质改善的缬沙坦钠盐。
形成具有所需有利性质的缬沙坦的盐很困难，而本发明的缬沙坦二钠盐的晶型表现出所需的改善的性质。
发明内容
本发明的目的在于提供了缬沙坦二钠盐的晶型A、B、D、E、F、G和H。
本发明的另一目的在于提供了缬沙坦二钠盐的晶型A、B、D、E、F、G和H的制备方法。
本发明所提供的缬沙坦二钠盐晶型A的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.7±0.2，8.5±0.2，9.5±0.2，13.6±0.2，15.4±0.2，16.5±0.2，18.1±0.2，19.9±0.2，22.0±0.2，22.4±0.2，23.3±0.2，23.8±0.2，25.3±0.2，27.8±0.2处有峰；优选在4.7±0.2，8.5±0.2，9.5±0.2，10.8±0.2，11.0±0.2，13.6±0.2，13.8±0.2，14.4±0.2，15.4±0.2，16.5±0.2，18.1±0.2，19.9±0.2，22.0±0.2，22.4±0.2，23.3±0.2，23.8±0.2，25.3±0.2，27.8±0.2，28.9±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型A，在加热速度为10℃/分的条件下，其差示扫描量热图在接近183℃处有吸热峰。
在一实施例中，缬沙坦二钠盐晶型A，在加热速度为10℃/分的条件下，其差示扫描量热图在182-184℃处有吸热峰。
在一实施例中，缬沙坦二钠盐晶型A具有基本上与图1所示的粉末衍射图谱相同的粉末X射线衍射光谱。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型A具有基本上与图2所示的差热分析吸热曲线相同的吸热曲线。
在一实施例中，缬沙坦二钠盐晶型A是缬沙坦二钠盐的非溶剂化物。
缬沙坦二钠盐晶型A的DSC图显示183℃左右出现吸热峰，焓值是335.53J/g，该晶型具有高的吸热峰温度和焓值说明，该晶型的晶格具有高稳定性。值得注意的是，该晶型在敞口容器中，温度为25±1℃，相对湿度为43.5±2％的条件下，保持3小时，吸水程度仅为2.6％。
本发明所提供的缬沙坦二钠盐晶型B的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.4±0.2和8.8±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型B，熔点在约198±5℃。
在一实施例中，缬沙坦二钠盐晶型B，在加热速度为10℃/分的条件下，在热重分析仪上未观察到明显的脱结合溶剂的特征。
在一实施例中，缬沙坦二钠盐晶型B，该晶型是缬沙坦二钠盐的非溶剂合物。
在一实施例中，缬沙坦二钠盐晶型B具有基本上与图3所示的粉末衍射图谱相同的粉末X射线衍射光谱。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型B具有基本上与图4所示的热重量分析失重曲线相同的失重曲线。
本发明所提供的缬沙坦二钠盐晶型D的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.4±0.2，9.0±0.2，14.9±0.2，21.4±0.2，22.4±0.2处有峰；优选在约4.4±0.2，9.0±0.2，12.6±0.2，14.9±0.2，15.4±0.2，16.3±0.2，17.8±0.2，21.4±0.2，22.4±0.2，23.8±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型D，熔点在约207±5℃。
在一实施例中，缬沙坦二钠盐晶型D具有基本上与图5所示的粉末衍射图谱相同的粉末X射线衍射光谱。
在一实施例中，缬沙坦二钠盐晶型D是缬沙坦二钠盐的非溶剂化物。
本发明所提供的缬沙坦二钠盐晶型E的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约6.3±0.2，12.3±0.2，14.7±0.2，16.5±0.2，17.4±0.2处有峰；优选在6.3±0.2，9.8±0.2，12.3±0.2，14.7±0.2，16.5±0.2，17.4±0.2，20.4±0.2，22.0±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型E，在加热速度为10℃/分的条件下，其差示扫描量热图在接近127℃处有吸热峰。
在一实施例中，缬沙坦二钠盐晶型E，在加热速度为10℃/分的条件下，其差示扫描量热 图在107-127℃处有吸热峰。
在一实施例中，缬沙坦二钠盐晶型E，在64-200℃有不小于15％的热重量损失，优选不小于16％的热重量损失，更优选不小于17％的热重量损失，最优选不小于18％的热重量损失。
在一实施例中，缬沙坦二钠盐晶型E具有基本上与图6所示的粉末衍射图谱相同的粉末X射线衍射光谱。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型E具有基本上与图7所示的热重量分析失重曲线相同的失重曲线。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型E具有基本上与图8所示的差热分析吸热曲线相同的吸热曲线。
在一实施例中，缬沙坦二钠盐晶型E是缬沙坦二钠盐的二氧六环溶剂合物。
在一实施例中，缬沙坦二钠盐晶型E中缬沙坦二钠盐与二氧六环的比例为1：1。
在一实施例中，缬沙坦二钠盐晶型E具有如图9所示的液态核磁图谱。
本发明所提供的缬沙坦二钠盐晶型F的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约6.2±0.2，14.9±0.2和18.3±0.2处有峰，优选在6.2±0.2，9.6±0.2，12.3±0.2，14.9±0.2，16.6±0.2，17.2±0.2，18.3±0.2，20.0±0.2，22.2±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型F，在加热速度为10℃/分的条件下，其差示扫描量热图在接近116℃处有吸热峰。
在一实施例中，缬沙坦二钠盐晶型F，在加热速度为10℃/分的条件下，其差示扫描量热图在104-117℃处有吸热峰。
在一实施例中，缬沙坦二钠盐晶型F，在55-150℃有不小于8.4％的热重量损失，优选不小于10％的热重量损失，更优选不小于11％的热重量损失。
在一实施例中，缬沙坦二钠盐晶型F具有基本上与图10所示的粉末衍射图谱相同的粉末X射线衍射光谱。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型F具有基本上与图11所示的热重量分析失重曲线相同的失重曲线。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型F具有基本上与图12所示的差热分析吸热曲线相同的吸热曲线。
在一实施例中，缬沙坦二钠盐晶型F是缬沙坦二钠盐的乙酸乙酯溶剂合物。
在一实施例中，缬沙坦二钠盐晶型F中缬沙坦二钠盐与乙酸乙酯的比例为1：0.5。
在一实施例中，缬沙坦二钠盐晶型F具有如图13所示的液态核磁图谱。
本发明所提供的缬沙坦二钠盐晶型G的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约6.4±0.2，8.3±0.2，9.5±0.2，17.3±0.2，19.4±0.2处有峰，优选在6.4±0.2，8.3±0.2，8.5±0.2，9.5±0.2，12.8±0.2，17.3±0.2，19.4±0.2，26.0±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型G，在加热速度为10℃/分的条件下，其差示扫描量热图曲线中降解和熔融信号有重叠。
在一实施例中，缬沙坦二钠盐晶型G具有基本上与图14所示的粉末衍射图谱相同的粉 末X射线衍射光谱。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型G具有基本上与图15所示的热重量分析失重曲线相同的失重曲线。
在一实施例中，在加热速度为10℃/分的条件下，缬沙坦二钠盐晶型G具有基本上与图16所示的差热分析吸热曲线相同的吸热曲线。
在一实施例中，缬沙坦二钠盐晶型G是缬沙坦二钠盐的非溶剂化物。
本发明所提供的缬沙坦二钠盐晶型H的特征在于：其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.5±0.2，8.7±0.2，9.0±0.2处有峰；优选在4.5±0.2，8.7±0.2，9.0±0.2，15.4±0.2，18.3±0.2，22.2±0.2处有峰；更优选在4.5±0.2，8.7±0.2，9.0±0.2，15.4±0.2，15.6±0.2，18.3±0.2，21.8±0.2，22.2±0.2，26.3±0.2处有峰。
在一实施例中，缬沙坦二钠盐晶型H，在加热速度为10℃/分的条件下，在热重分析仪上未观察到明显的脱结合溶剂的特征
在一实施例中，缬沙坦二钠盐晶型H具有基本上与图17所示的粉末衍射图谱相同的粉末X射线衍射光谱。
在一实施例中，缬沙坦二钠盐晶型H，在加热速度为10℃/分的条件下，其具有基本上与图18所示的热重量分析失重曲线相同的失重曲线。
在一实施例中，缬沙坦二钠盐晶型H是缬沙坦二钠盐的非溶剂化物。
本发明的缬沙坦二钠盐晶型具有出人意料的有利特征，在给定条件下，结晶盐具有清楚的吸热峰，伴有显著的吸热焓。本发明的结晶盐是稳定的，在贮藏期间具有良好的质量，水含量改变不显著。
本发明提供包含治疗有效量的本发明所述的缬沙坦二钠盐的晶型A、B、D、E、F、G和H与药用载体混合形成的药物组合物，药物组合物可以使用胃肠给药或非胃肠给药，可以是片剂、胶囊、溶液、悬浮液等形式向病人给药。
本发明的缬沙坦二钠盐的晶型A、B、D、E、F、G和H，或包含其的药物组合物，可用于例如预防或治疗可通过阻断AT1受体得到抑制的疾病或病症，例如选自下列的疾病或病症：
高血压，充血性心力衰竭，急性肾衰竭，慢性肾衰竭，经皮经腔血管成形术后的再狭窄和冠状动脉旁路手术后的再狭窄；动脉粥样硬化，胰岛素抗性和X综合症，2型糖尿病，肥胖，肾病，甲状腺功能减退，心肌梗塞后存活，冠心病，老年高血压，家族性异常血脂症性高血压，胶原形成增加，纤维变性和高血压后的重构，与高血压有关或无关的所有这些疾病或病症；伴有或不伴有高血压的内皮机能障碍；高脂血症，高脂蛋白血症，动脉粥样硬化和高胆固醇血症；青光眼。
主要应用是治疗高血压和充血性心力衰竭以及心肌梗塞后病症。
本领域技术人员完全能够选择相关的标准动物实验模型来证明上下文所指出的治疗适应症和有益效果。
本发明中“相同的粉末X射线衍射光谱”，是指以度2θ表示的峰的位置实质上相同，峰位置的相对强度实质上相同。其中相对强度是指，粉末X-射线衍射光谱的所有衍射峰中强度最高的峰的强度为100％时，其他峰的强度与最强峰的强度进行比较的比值。需要说明的是， X-射线粉末衍射光谱中的2θ角有时由于各种因素会出现的若干测定误差，该实测值会出现通常为±0.3，优选地±0.2，更优选地±0.1的程度变动。因此，本说明书中，基于对特定样品的实测值的2θ角应理解为包含这些可容许的误差的含义。本发明中“基本上与图1所示的粉末X射线衍射图谱相同”是指粉末X-射线衍射光谱中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在所给出的粉末X射线衍射图谱中。
需要说明的是，差示扫描量热分析中的吸收峰是本发明各晶型具有的固有物性，但在实际的测定中，除了测定误差外，有时会由于混入可容许的量的杂质等原因导致熔点发生变动，这种可能性也是不能否定的。因此，本领域技术人员能够充分理解本发明中的吸热峰温度的实测值可以以何种程度发生变动，举例来说，可以设想的误差是，某些情况下为±5℃左右，优选地为±3℃左右，更优选地为±2℃左右，最优选地为±1℃左右。
本发明中的“熔点”是指晶型熔化的初始熔融温度。
本发明使用的分析方法：
1)X射线粉末衍射
使用Bruker D8 advance衍射仪，室温下使用Cu Ka填充管(40kV,40mA)作为具有广角测角仪的X射线源、0.6mm发散狭缝、2.5°初级索拉狭缝、2.5°次级索拉狭缝、8mm防散射狭缝、0.1mm探测器狭缝和LynxEye探测器。在2θ连续扫描模式下，以2.4°/分的扫描速度、在3°-40°的范围内以0.02°的扫描步长完成数据采集。
2)差示扫描量热仪
使用TA Q200和Mettler DSC 1+，在50mL/min的流速的N2保护下，以10℃/min从室温升温至降解温度前，完成数据采集。
3)热重分析仪
使用TA Q500，在50mL/min的流速的N2保护下，以10℃/min从室温升温至降解至30％以下，完成数据采集。
附图说明
图1缬沙坦二钠盐晶型A的粉末X-射线衍射图(XRD图)。
图2缬沙坦二钠盐晶型A的差示扫描量热图(DSC图)。
图3缬沙坦二钠盐晶型B的粉末X-射线衍射图(XRD图)。
图4缬沙坦二钠盐晶型B的热重分析图(TGA图)。
图5缬沙坦二钠盐晶型D的粉末X-射线衍射图(XRD图)。
图6缬沙坦二钠盐晶型E的粉末X-射线衍射图(XRD图)。
图7缬沙坦二钠盐晶型E的热重分析图(TGA图)。
图8缬沙坦二钠盐晶型E的差示扫描量热图(DSC图)。
图9缬沙坦二钠盐晶型E的液态核磁氢谱(H NMR图)。
图10缬沙坦二钠盐晶型F的粉末X-射线衍射图(XRD图)。
图11缬沙坦二钠盐晶型F的热重分析图(TGA图)。
图12缬沙坦二钠盐晶型F的差示扫描量热图(DSC图)。
图13缬沙坦二钠盐晶型F的液态核磁氢谱(H NMR图)。
图14缬沙坦二钠盐晶型G的粉末X-射线衍射图(XRD图)。
图15缬沙坦二钠盐晶型G的热重分析图(TGA图)。
图16缬沙坦二钠盐晶型G的差示扫描量热图(DSC图)。
图17缬沙坦二钠盐晶型H的粉末X-射线衍射图(XRD图)。
图18缬沙坦二钠盐晶型H的热重分析图(TGA图)。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述发明内容做进一步详细说明，但不应理解为本发明的内容仅限于以下实施例，凡基于本发明上述内容所做出的发明均属于本发明的范围。
实施例1 缬沙坦二钠盐晶型A的制备
将缬沙坦8.71mg溶解于0.87mL异丙醇中，室温下滴加2mmol氢氧化钠水溶液0.2mL，搅拌0.5小时，减压浓缩，得固体用正庚烷/乙醇(19/1，体积比)搅拌过夜，过滤，40℃下真空干燥，得到固体。将3mg该固体加入至0.1mL甲基叔丁基醚中，搅拌72小时后，离心弃上清，得到的固体放在30℃烘箱中，干燥得到白色固体，即A型缬沙坦二钠盐。
利用X-射线粉末衍射和差示扫描量热法对缬沙坦二钠盐晶型A进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例2 缬沙坦二钠盐晶型B的制备
将10mg缬沙坦加入到含有1.84mg氢氧化钠的0.3mL水中，减压浓缩干燥得固体。将3mg该盐加入至0.1mL 3-戊酮中，搅拌72小时后，离心弃上清，得到的固体放在30℃烘箱中，干燥得到白色固体，即B型缬沙坦二钠盐。
利用X-射线粉末衍射和热重分析法对缬沙坦二钠盐晶型B进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例3 缬沙坦二钠盐晶型D的制备
将缬沙坦8.71mg溶解于0.87mL异丙醇中，室温下滴加2mmol氢氧化钠溶液0.2mL，搅拌0.5小时，减压浓缩，得固体。该固体用正庚烷/乙醇(19/1，体积比)搅拌过夜，过滤，40℃下真空干燥，得到缬沙坦二钠盐固体。将3mg该固体加入至0.1mL正庚烷中，搅拌72小时后，离心弃上清，得到的固体放在30℃烘箱中，干燥得到白色固体，即D型缬沙坦二钠盐。
利用X-射线粉末衍射对缬沙坦二钠盐晶型D进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例4 缬沙坦二钠盐晶型E的制备
将缬沙坦8.71mg溶解于0.87mL异丙醇中，室温下滴加2mmol氢氧化钠溶液0.2mL，搅拌0.5小时，减压浓缩至干燥，得固体。该固体用正庚烷/乙醇(19/1，体积比)搅拌过夜，过滤，40℃下真空干燥，得固体。将5mg该固体加入至0.4mL 1,4-二氧六环中，搅拌48小时后，离心弃上清，得到的固体放在30℃烘箱中烘干，得到白色固体，即E型缬沙坦二钠盐。
利用X-射线粉末衍射，热重量分析，差示扫描量热法和液态核磁对缬沙坦二钠盐晶型E进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例5 缬沙坦二钠盐晶型F的制备
将缬沙坦8.71mg溶解于0.87mL异丙醇中，室温下滴加2mmol氢氧化钠溶液0.2mL，搅拌0.5小时，减压浓缩，干燥得固体。该固体用正庚烷/乙醇(19/1，体积比)搅拌过夜，过滤，40℃下真空干燥，得固体。将5mg该固体加入至0.4mL乙酸乙酯中，搅拌72小时后，离心弃上清，得到的固体放在30℃烘箱中烘干，得到白色固体，即F型缬沙坦二钠盐。
利用X-射线粉末衍射，热重量分析，差示扫描量热法和液态核磁对缬沙坦二钠盐晶型F进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例6 缬沙坦二钠盐晶型G的制备
将4.35mg缬沙坦溶解于0.3mL丙酮中，滴加2mmol氢氧化钠溶液0.1mL，搅拌0.5小时，减压浓缩干燥，得到的固体用15倍体积的乙酸乙酯重结晶，得到白色固体，即G型缬沙坦二钠盐。
利用X-射线粉末衍射，热重量分析，差示扫描量热法对缬沙坦二钠盐晶型G进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例7 缬沙坦二钠盐晶型H的制备
在0.3mL水中加入10mg缬沙坦，滴加2mmol氢氧化钠溶液0.3mL，搅拌0.5小时，减压浓缩干燥，得固体。向1mg该盐中加入0.2mL 2-丁酮，搅拌0.5h，4℃条件下冷藏，析出固体，置0℃烘箱干燥，得到白色固体，即H型缬沙坦二钠盐。
利用X-射线粉末衍射，热重量分析，差示扫描量热法对缬沙坦二钠盐晶型H进行了固态表征，其固态表征参数及图谱如本文中所述。
实施例8 本发明中各缬沙坦二钠盐晶型吸湿性的测定
测定方法：
1.取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)于前一天置于人工气候箱(设定温度为25±1℃，相对湿度为43.5±2％)内，称重(m1)。
2.取本发明晶型适量，置上述称量瓶中并平铺于称量瓶内，供试品厚度一般约为1mm，称重(m2)。
3.将称量瓶敞口，并与瓶盖同置于恒温恒湿(设定温度为25±1℃，相对湿度为43.5±2％)条件下。
4.称重前盖好称量瓶盖子，称重(m3)，计算各时间点的水分吸收百分率，水分吸收百分率＝(m3-m2)/(m2-m1)×100％。
结果：
表-1
时间 晶型 水分吸收，％
2h 晶型A 1.6％
2h 晶型B 1.9％
2h 晶型D 1.3％
2h 晶型E 2.1％
2h 晶型F 1.7％
2h 晶型G 0.7％
2h 晶型H 2.0％
4h 晶型A 2.0％
4h 晶型B 2.3％
4h 晶型D 1.9％
4h 晶型E 2.9％
4h 晶型F 2.2％
4h 晶型G 1.3％
4h 晶型H 2.8％
24h 晶型A 2.4％
24h 晶型B 3.0％
24h 晶型D 2.7％
24h 晶型E 3.6％
24h 晶型F 2.8％
24h 晶型G 1.5％
24h 晶型H 4.0％
由表-1吸湿性数据可知，本发明缬沙坦二钠盐晶型具有显著改善的吸湿性，适于进一步开发。
以上所述仅是本发明的优选实施方式，应当指出，对于本领域技术的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (26)

  1. 一种缬沙坦二钠盐晶型A，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.7±0.2，8.5±0.2，9.5±0.2，13.6±0.2，15.4±0.2，16.5±0.2，18.1±0.2，19.9±0.2，22.0±0.2，22.4±0.2，23.3±0.2，23.8±0.2，25.3±0.2，和27.8±0.2处有峰。
  2. 如权利要求1所述的缬沙坦二钠盐晶型A，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图在182-184℃处有吸热峰。
  3. 如权利要求2所述的缬沙坦二钠盐晶型A，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图在接近183℃处有吸热峰。
  4. 一种缬沙坦二钠盐晶型B，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.4±0.2和8.8±0.2处有峰。
  5. 如权利要求4所述的缬沙坦二钠盐晶型B，该晶型熔点在约198±5℃。
  6. 一种缬沙坦二钠盐晶型D，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.4±0.2，9.0±0.2，14.9±0.2，21.4±0.2，和22.4±0.2处有峰。
  7. 如权利要求6所述的缬沙坦二钠盐晶型D，该晶型熔点在约207±5℃。
  8. 一种缬沙坦二钠盐晶型E，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约6.3±0.2，12.3±0.2，14.7±0.2，16.5±0.2，和17.4±0.2处有峰。
  9. 如权利要求8所述的缬沙坦二钠盐晶型E，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图在接近127℃处有吸热峰。
  10. 如权利要求8所述的缬沙坦二钠盐晶型E，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图在107-127℃处有吸热峰。
  11. 如权利要求8所述的缬沙坦二钠盐晶型E，其特征在于，在加热速度为10℃/分的条件下，在64-200℃有不小于15％的热重量损失。
  12. 如权利要求8所述的缬沙坦二钠盐晶型E，其特征在于，该晶型是缬沙坦二钠盐的二氧六环溶剂合物。
  13. 如权利要求12所述的缬沙坦二钠盐晶型E，其特征在于，该晶型中中缬沙坦二钠盐与二氧六环的比例为1：1。
  14. 一种缬沙坦二钠盐晶型F，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约6.2±0.2，14.9±0.2和18.3±0.2处有峰。
  15. 如权利要求14所述的缬沙坦二钠盐晶型F，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图在接近116℃处有吸热峰。
  16. 如权利要求14所述的缬沙坦二钠盐晶型F，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图在104-117℃处有吸热峰。
  17. 如权利要求14所述的缬沙坦二钠盐晶型F，其特征在于，在加热速度为10℃/分的条件下，在55-150℃有不小于8.4％的热重量损失。
  18. 如权利要求14所述的缬沙坦二钠盐晶型F，其特征在于，该晶型是缬沙坦二钠盐的乙酸乙酯溶剂合物。
  19. 如权利要求18所述的缬沙坦二钠盐晶型F，其特征在于，该晶型中缬沙坦二钠盐与乙酸乙酯的比例为1：0.5。
  20. 一种缬沙坦二钠盐晶型G，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约6.4±0.2，8.3±0.2，9.5±0.2，17.3±0.2，和19.4±0.2处有峰。
  21. 如权利要求20所述的缬沙坦二钠盐晶型G，其特征在于，在加热速度为10℃/分的条件下，其差示扫描量热图曲线中降解和熔融信号有重叠。
  22. 一种缬沙坦二钠盐晶型H，其特征在于，该晶型具有如下性质：
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在约4.5±0.2，8.7±0.2，9.0±0.2有峰。
  23. 如权利要求22所述的缬沙坦二钠盐晶型H，其特征在于，在加热速度为10℃/分的条件下，在热重分析仪上未观察到明显的脱结合溶剂的特征。
  24. 一种药物组合物，其包含权利要求1-23中任意一项所述的缬沙坦二钠盐晶型和药用载体。
  25. 如权利要求1-23中任意一项所述的缬沙坦二钠盐在制备治疗通过阻断AT1受体得到抑制的疾病或病症的药物中的应用。
  26. 如权利要求25所述的应用，其中该疾病或病症包括高血压，充血性心力衰竭，急性肾衰竭，慢性肾衰竭，经皮经腔血管成形术后的再狭窄和冠状动脉旁路手术后的再狭窄；动脉粥样硬化，胰岛素抗性和X综合症，2型糖尿病，肥胖，肾病，甲状腺功能减退，心肌梗塞后存活，冠心病，老年高血压，家族性异常血脂症性高血压，胶原形成增加，纤维变性和高血压后的重构，与高血压有关或无关的所有这些疾病或病症；伴有或不伴有高血压的内皮机能障碍；高脂血症，高脂蛋白血症，动脉粥样硬化和高胆固醇血症；青光眼。
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