TWI648267B - Valsartan disodium salt new crystal form - Google Patents

Abstract

The present invention relates to novel crystalline forms A, B, D, E, F, G and H of valsartan disodium salt and a process for the preparation thereof.

Description

Valsartan disodium salt new crystal form

The invention relates to the field of pharmaceutical synthesis, in particular to a new crystalline form 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 AT1 receptor subtype without any partial agonist activity on the AT1 receptor. (I)

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.

A more stable form of valsartan is required during product drying or grinding, as well as during preparation of the formulation. Valsartan is a free acid having 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 was analyzed by elemental analysis, and the obtained substance (hygroscopic) was equilibrated in air (C24H27N5O3Na2, 5.36 mol H2O, molar mass 576.05), and it was found that the sodium salt had 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.

It is difficult to form a salt of valsartan having the desired advantageous properties, while the crystalline form of the valsartan disodium salt of the present invention exhibits the desired improved properties.

It is an object of the present invention to provide crystal forms A, B, D, E, F, G and H of valsartan disodium salt.

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 2θ is about 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 with peaks; At 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 There are peaks at ±0.2, 22.4±0.2, 23.3±0.2, 23.8±0.2, 25.3±0.2, 27.8±0.2, and 28.9±0.2.

In one embodiment, 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.

In one embodiment, the valsartan disodium salt crystal form A has an endothermic peak at 182-184 ° C at a heating rate of 10 ° C / min.

In a specific embodiment, valsartan disodium salt crystal form A has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, 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.

In a specific embodiment, the valsartan disodium salt crystal form A is an asolvate of the 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 has a high lattice. 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 by degree 2θ has peaks at about 4.4 ± 0.2 and 8.8 ± 0.2.

In one embodiment, the valsartan disodium salt crystal form B has a melting point of about 198 ± 5 °C.

In one embodiment, 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.

In a specific embodiment, the valsartan disodium salt crystal form B is an unsolvate of the valsartan disodium salt.

In a specific embodiment, valsartan disodium salt crystal form B has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, the 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 2θ is about 4.4±0.2, 9.0±0.2, 14.9±0.2. , 21.4 ± 0.2, 22.4 ± 0.2 with peaks; preferably 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 ± There are peaks at 0.2, 23.8 ± 0.2.

In one embodiment, the valsartan disodium salt crystal form D has a melting point of about 207 ± 5 °C.

In a specific embodiment, valsartan disodium salt crystal form D has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.

In one embodiment, the valsartan disodium salt crystalline form D is an asolvate of the 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 diffraction spectrum of the X-ray powder expressed by degree 2θ is about 6.3 ± 0.2, 12.3 ± 0.2, 14.7 ± 0.2 There are peaks 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.

In one embodiment, 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.

In one embodiment, the crystalline form E of valsartan disodium salt has an endothermic peak at 107-127 ° C at a heating rate of 10 ° C / min.

In a specific embodiment, 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 not less than 17%. The thermal weight loss is better than not less than 18% of the thermal weight loss.

In a specific embodiment, valsartan disodium salt crystal form E has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, the valsartan disodium salt crystalline form E is a dioxane solvate of valsartan disodium salt.

In one embodiment, the ratio of valsartan disodium salt to dioxane in crystalline form E of valsartan disodium salt is 1:1.

In a specific embodiment, valsartan disodium salt crystal form E has a liquid nuclear magnetic spectrum as shown in FIG.

The crystalline form F of the valsartan disodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is about 6.2 ± 0.2, 14.9 ± 0.2, and 18.3 ± 0.2. There are peaks, 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.

In one embodiment, 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.

In one embodiment, the valsartan disodium salt crystal form F has an endothermic peak at 104-117 ° C at a heating rate of 10 ° C / min.

In a specific embodiment, the valsartan disodium salt crystal 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 not less than 11%. Thermal weight loss.

In a specific embodiment, valsartan disodium salt form F has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, the valsartan disodium salt crystalline form F is an ethyl acetate solvate of valsartan disodium salt.

In one embodiment, the ratio of valsartan disodium salt to ethyl acetate in crystalline Form F of valsartan disodium salt is 1:0.5.

In a specific embodiment, 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 diffraction spectrum of the X-ray powder expressed by degree 2θ 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.

In one embodiment, the valsartan disodium salt crystal form G has an overlap in degradation and melting signals in the differential scanning calorimetry curve at a heating rate of 10 ° C/min.

In a specific embodiment, valsartan disodium salt crystal form G has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, the valsartan disodium salt crystalline form G is an asolvate of the 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 2θ 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, There are peaks at 15.4±0.2, 15.6±0.2, 18.3±0.2, 21.8±0.2, 22.2±0.2, and 26.3±0.2.

In a specific embodiment, the valsartan disodium salt crystal form H, at a heating rate of 10 ° C / min, showed no significant debinding solvent characteristics on the thermogravimetric analyzer.

In a specific embodiment, valsartan disodium salt crystal form H has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, 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.

In a specific embodiment, 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 under given conditions, the crystalline salt has a clear endothermic peak with significant endothermic enthalpy. 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 comprising a therapeutically effective amount of the 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 can be used in the gastrointestinal composition. For administration or parenteral administration, it may be administered to a patient in the form of a tablet, a capsule, a solution, a suspension or the like.

The crystalline forms A, B, D, E, F, G and H of the valsartan disodium salt of the present invention, or a pharmaceutical composition comprising the same, can be used, for example, for the prevention or treatment of inhibition by blocking the AT1 receptor. 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 X syndrome Type 2 diabetes, obesity, kidney disease, hypothyroidism, survival after myocardial infarction, coronary heart disease, senile hypertension, familial dyslipidemia, increased collagen formation, fibrosis, remodeling after 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 and post-myocardial infarction.

Those of ordinary skill in the art are well able to select relevant standard animal experimental models to demonstrate the therapeutic indications and benefits indicated by the context.

In the present invention, "the same powder X-ray diffraction spectrum" means that the positions of the peaks represented by degrees 2θ 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%. It should be noted that the 2θ angle in the diffraction spectrum of the X-ray powder sometimes has several measurement errors due to various factors, and the measured value may appear to be usually ±0.3, preferably ±0.2, more preferably ±0.1. The degree of change. Therefore, in the present specification, the 2θ angle based on the measured value of a specific sample is understood to mean the meaning including these allowable errors. In the present invention, "substantially the same as the powder X-ray diffraction pattern shown in FIG. 1" means at least 50%, or at least 60%, or at least 70%, or at least 80% of the powder X-ray diffraction spectrum, or At least 90%, or at least 95%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern.

In addition, the absorption peak in the differential scanning calorimetry is an inherent physical property of each crystal form of the present invention. However, in actual measurement, in addition to the measurement error, impurities may be mixed in an allowable amount. Causes the melting point to change,

This possibility cannot be denied. 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. For example, the conceivable error is, in some cases, about ±5 ° C. Preferably, it is about ± 3 ° C, more preferably about ± 2 ° C, and even more preferably about ± 1 ° C.

The "melting point" in the present invention means the initial melting temperature at which the crystal form is melted.

Analytical methods used in the present invention:

(1) X-ray powder diffraction

Using a Bruker D8 advance diffractometer, use a Cu Ka fill tube (40 kV, 40 mA) at room temperature as an X-ray source with a wide-angle goniometer, 0.6 mm divergence slit, 2.5° primary cable slit, 2.5° Secondary cable slits, 8 mm anti-scatter slits, 0.1 mm detector slits and LynxEye detectors. In the 2θ continuous scan mode, data acquisition was performed at a scan speed of 2.4°/min and a scan step of 0.02° in the range of 3°-40°.

(2) Differential scanning calorimeter

Data acquisition was accomplished using TA Q200 and Mettler DSC 1+ under N ₂ protection at a flow rate of 50 mL/min and warming from room temperature to degradation temperature at 10 ° C/min.

(3) Thermogravimetric analyzer

Data acquisition was accomplished using TA Q500 at a flow rate of 50 mL/min under N2 protection from 10 ° C/min to room temperature to 30% or less.

The above description of the present invention will be further described in detail by the specific embodiments of the present invention, but it should be understood that the invention is limited to the following specific embodiments. It is within the scope of the invention.

Example 1: Preparation of valsartan disodium salt crystal form A.

8.71 mg of valsartan 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). The mixture was stirred overnight, filtered, and dried under vacuum at 40 ° C to give a solid. 3 mg of this solid was added to 0.1 mL of methyl tert-butyl ether, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was placed in an oven at 30 ° C, and dried to obtain a white solid, ie, type A valsartan disodium salt. .

The valsartan disodium salt crystal form A was characterized by X-ray powder diffraction and differential scanning calorimetry. The solid state characterization parameters and maps are as described herein.

Example 2: Preparation of crystalline form B of valsartan disodium salt.

10 mg of valsartan was added to 0.3 mL of water containing 1.84 mg of sodium hydroxide, and concentrated under reduced pressure to give a solid. 3 mg of this salt was added to 0.1 mL of 3-pentanone, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was placed in an oven at 30 ° C, and dried to obtain a white solid, B-valsartan disodium salt.

The valsartan disodium salt crystal form B was characterized by X-ray powder diffraction and thermogravimetric analysis. The solid state characterization parameters and maps are as described herein.

Example 3: Preparation of crystalline form D of valsartan disodium salt.

8.71 mg of valsartan was dissolved in 0.87 mL of isopropanol, 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. 3 mg of this solid was added to 0.1 mL of n-heptane, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was placed in an oven at 30 ° C, and dried to obtain a white solid, D-valsartan disodium salt.

The valsartan disodium salt crystal form D was characterized by X-ray powder diffraction, and its solid state characterization parameters and maps are as described herein.

Example 4: Preparation of crystalline form E of valsartan disodium salt.

8.71 mg of valsartan was dissolved in 0.87 mL of isopropanol, 0.2 mL of 2 mmol of sodium hydroxide solution was added dropwise at room temperature, stirred for 0.5 hour, and concentrated to dryness 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 to give a solid. 5 mg of this solid was added to 0.4 mL of 1,4-dioxane, and after stirring for 48 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 30 ° C to obtain a white solid, ie, E-type valsartan. Disodium salt.

The solid state characterization parameters and maps of valsartan disodium salt crystal form E were 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.

Example 5: Preparation of crystalline form F of valsartan disodium salt.

8.71 mg of valsartan was dissolved in 0.87 mL of isopropanol, 0.2 mL of 2 mmol of sodium hydroxide solution was added dropwise at room temperature, stirred for 0.5 hour, concentrated under reduced pressure and dried to give a solid. The solid was stirred with n-heptane/ethanol (19/1, by volume) overnight, filtered, and dried in vacuo to give a solid. 5 mg of this solid was added to 0.4 mL of ethyl acetate, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 30 ° C to obtain a white solid, that is, F-type valsartan disodium salt.

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.

Example 6: Preparation of valsartan disodium salt crystal form G.

4.35 mg of valsartan was dissolved in 0.3 mL of acetone, 0.1 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. The obtained solid was recrystallized from 15 volumes of ethyl acetate to give white solid. , that is, G-type valsartan disodium salt.

The valsartan disodium salt crystal form G 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 7: Preparation of crystalline form H of valsartan disodium salt.

10 mg of valsartan 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. To 1 mg of this salt, 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 the crystalline form of each valsartan disodium salt in the present invention.

test methods:

1. Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm) in the artificial climate chamber (set temperature 25±1 °C, relative humidity 43.5±2%) on the previous day, weigh (m1).

2. Take the appropriate amount of the crystal form of the present invention, place it in the above weighing bottle and lay it in the weighing bottle. The thickness of the test sample is generally about 1 mm and weighed (m2).

3. Open the weighing bottle and place it in constant temperature and humidity (set temperature is 25±1°C, relative humidity is 43.5±2%).

4. Cover the weighing bottle cap before weighing, weigh (m3), calculate the percentage of water absorption at each time point, and the percentage of water absorption = (m3-m2) / (m2-m1) × 100%.

Results: Table-1

From the hygroscopicity data of Table-1, it is understood that the crystalline form of the valsartan disodium salt of the present invention has remarkably improved hygroscopicity and is suitable for further development.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make some improvements and refinements without departing from the principles of the present invention. These improvements and modifications should also be considered as protection of the present invention.

no

Figure 1 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form A.

Figure 2 is a differential scanning calorimetry (DSC chart) of valsartan disodium salt crystal form A.

Figure 3 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form B.

Figure 4 is a thermogravimetric analysis (TGA diagram) of valsartan disodium salt crystal form B.

Figure 5 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form D.

Figure 6 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form E.

Figure 7 is a thermogravimetric analysis (TGA diagram) of valsartan disodium salt crystal form E.

Figure 8 is a differential scanning calorimetry (DSC chart) of crystalline form E of valsartan disodium salt.

Figure 9 is a liquid nuclear magnetic resonance spectrum (H NMR chart) of crystalline form E of valsartan disodium salt.

Figure 10 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form F.

Figure 11 is a thermogravimetric analysis (TGA diagram) of crystalline form F of valsartan disodium salt.

Figure 12 is a differential scanning calorimetry (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.

Figure 14 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form G.

Figure 15 is a thermogravimetric analysis (TGA diagram) of valsartan disodium salt crystal form G.

Figure 16 is a differential scanning calorimetry (DSC chart) of valsartan disodium salt crystal form G.

Figure 17 is a powder X-ray diffraction pattern (XRD pattern) of valsartan disodium salt crystal form H.

Figure 18 is a thermogravimetric analysis (TGA diagram) of valsartan disodium salt crystal form H.

Claims (24)

A crystalline form A of valsartan disodium salt, wherein the crystalline form has the property of using Cu-Ka radiation, the diffraction spectrum of the X-ray powder expressed in degrees 2θ is about 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, and 27.8 ± 0.2 peaks. The crystalline form A of valsartan disodium salt of claim 1 wherein the differential scanning calorimetry has an endothermic peak at 182-184 ° C at a heating rate of 10 ° C / min. The valsartan disodium salt crystal form A of claim 2, wherein the differential scanning calorimetry has an endothermic peak at a temperature close to 183 ° C at a heating rate of 10 ° C / min. A crystalline form D of valsartan disodium salt, wherein the crystalline form has the property of using Cu-Ka radiation, the diffraction spectrum of the X-ray powder expressed in degrees 2θ is about 4.4 ± 0.2, 9.0 ± 0.2, 14.9 ± There are peaks at 0.2, 21.4 ± 0.2, and 22.4 ± 0.2. The crystalline form of valsartan disodium salt of claim 4 has a melting point of about 207 ± 5 °C. A crystalline form E of valsartan disodium salt, wherein the crystalline form has the property of using Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is about 6.3 ± 0.2, 12.3 ± 0.2, 14.7 ± There are peaks at 0.2, 16.5 ± 0.2, and 17.4 ± 0.2. The valsartan disodium salt crystal form E of claim 6 wherein the differential scanning calorimetry has an endothermic peak at a temperature close to 127 ° C at a heating rate of 10 ° C / min. The crystalline form E of valsartan disodium salt of claim 6 wherein the differential scanning calorimetry has an endothermic peak at 107-127 ° C at a heating rate of 10 ° C / min. The crystalline form E of valsartan disodium salt of claim 6 wherein there is a thermal weight loss of not less than 15% at 64-200 ° C at a heating rate of 10 ° C / min. The crystalline form E of valsartan disodium salt of claim 6, wherein the crystalline form is a dioxane solvate of valsartan disodium salt. The valsartan disodium salt crystal form E of claim 10, wherein the ratio of valsartan disodium salt to dioxane in the crystal form is 1:1. A crystalline form F of valsartan disodium salt, wherein the crystalline form has the property of using Cu-Ka radiation, the diffraction spectrum of the X-ray powder expressed in degrees 2θ is about 6.2 ± 0.2, 14.9 ± 0.2, and 18.3 ± There is a peak at 0.2. The valsartan disodium salt crystal form F of claim 12, wherein the differential scanning calorimetry 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 of claim 12, wherein the differential scanning calorimetry has an endothermic peak at 104-117 ° C at a heating rate of 10 ° C / min. The valsartan disodium salt crystal form F of claim 12, wherein the heating weight is 10 ° C / min, and the thermal weight loss is not less than 8.4% at 55-150 ° C. The crystalline form F of valsartan disodium salt of claim 12, wherein the crystalline form is an ethyl acetate solvate of valsartan disodium salt. The crystalline form F of valsartan disodium salt of claim 16, wherein the ratio of valsartan disodium salt to ethyl acetate in the crystalline form is 1:0.5. A crystalline form G of valsartan disodium salt, wherein the crystalline form has the following properties: It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at about 6.4 ± 0.2, 8.3 ± 0.2, 9.5 ± 0.2, 17.3 ± 0.2, and 19.4 ± 0.2. The valsartan disodium salt crystal form G of claim 18, wherein the degradation and melting signals in the differential scanning calorimetry curve overlap at a heating rate of 10 ° C / min. A crystalline form H of valsartan disodium salt, wherein the crystalline form has the property of using Cu-Ka radiation, the diffraction spectrum of the X-ray powder expressed in degrees 2θ is about 4.5 ± 0.2, 8.7 ± 0.2, 9.0 ± 0.2 has a peak. The valsartan disodium salt crystal form H of claim 20, wherein no significant debinding solvent characteristics were observed on the thermogravimetric analyzer at a heating rate of 10 ° C/min. A pharmaceutical composition comprising the crystalline form of valsartan disodium salt of any one of claims 1-21, and a pharmaceutically acceptable carrier. Use of a valsartan disodium salt according to any one of claims 1 to 21 for the manufacture of a medicament for treating a disease or condition which is inhibited by blocking the AT1 receptor. The use of claim 23, wherein the disease or condition comprises 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 X syndrome, type 2 diabetes, obesity, nephropathy, hypothyroidism, survival after myocardial infarction, coronary heart disease, senile hypertension, familial dyslipidemia, increased collagen formation , fibrosis and remodeling after hypertension, all of these diseases or conditions associated with or unrelated to hypertension; endothelial dysfunction with or without hypertension; hyperlipidemia, hyperlipoproteinemia, arterial atherosclerosis Sclerotherapy and hypercholesterolemia; glaucoma.