Arni compound calcium-sodium complex as well as crystal forms thereof, preparation method therefor and use thereof

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry polycrystalline forms, and particularly relates to an ARNi compound calcium-sodium complex as well as crystal forms A and B thereof, a preparation method therefor and the use thereof.

Description

ARNi compound calcium sodium complex and its crystal form as well as preparation method and application Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical polymorphs, and particularly relates to a calcium-sodium complex of an ARNi compound, a crystal form thereof, a preparation method thereof, and an application thereof. Background Art

[0002] Alisartan medoxomil (CAS: 947331-05-7), chemical name: 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropyloxy)-carbonyloxy]-methyl ester, trade name: Xinlitan, is a novel angiotensin II receptor (AT1) antagonist, or ARB. Its structural formula was first disclosed in Chinese patent CN200610023991.0, along with its use in the preparation of antihypertensive medications. Compared to other antihypertensive products of the same type (such as losartan), alisartan medoxomil offers reduced toxicity and superior antihypertensive efficacy.

[0003] The ARB olmesartan medoxomil is metabolized in vivo through hydrolysis to produce EXP3174, which then exerts its therapeutic effects. However, EXP3174 alone has low bioavailability and poor therapeutic efficacy. This is primarily due to its highly polar molecular structure, which makes it difficult to cross cell membranes through passive absorption methods such as diffusion. Structural modification is necessary to improve its passive absorption. However, existing technologies have reported that various methods, such as chemical modification and formulation optimization, have failed to effectively improve the bioavailability of EXP3174.

[0004] Neprilysin (NEP) is a neutral endopeptidase that can degrade a variety of endogenous vasoactive peptides including natriuretic peptides and bradykinin, and can also reduce the level of adrenomedullin. Neprilysin inhibitors (NEPi) can increase the levels of these substances to counteract vasoconstriction, sodium retention and overactivation of the neuroendocrine system.

[0005] Neprilysin inhibitors (NEPi) such as AHU377 (Sacubitril, CAS: 149709-62-6), chemical formula: C 24 H 29 NO5, its structure is as follows:

[0006] Patent WO2007056546 discloses a sodium salt complex of valsartan-sacubitril (LCZ696) and a preparation method thereof.

[0007] Patent WO2017 / 125031 discloses a series of complexes composed of angiotensin receptor antagonist metabolites and NEP inhibitors, characterized in that the structural unit of the complex is as follows: (aEXP3174·bAHU377)·xCa·nA, wherein a:b = 1:0.25~4; x is a value between 0.5 and 3; A refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, acetonitrile, toluene, dichloromethane; and n is a value between 0 and 3.

[0008] Patent WO2021143898 discloses the (aEXP3174·bAHU377)·xCa·nA crystal form, but the physical and chemical properties still need to be improved.

[0009] Summary of the Invention

[0010] The present invention first provides a calcium-sodium complex of ARNi and a crystal form thereof.

[0011] Specifically, ARNi is a complex composed of ARB and NEPi, wherein the ARB is EXP3174, and the chemical formula is: C 22 H 21 ClN6O2, its structure is as follows:

[0012] The neprilysin inhibitor (NEPi) is AHU377 (Sacubitril, CAS: 149709-62-6), and its chemical formula is: C 24 H 29 NO5, its structure is as follows:

[0013] Specifically, the structural units of the complex are as follows:

[0014] (EXP3174·AHU377)·X Ca·Y Na·nH2O, where 2X+Y=3.

[0015] Preferably, the structural units of the complex are as follows:

[0016] (EXP3174·AHU377)·1Ca·1Na·nH2O;

[0017] (EXP3174·AHU377)·0.5Ca·2Na·nH2O.

[0018] The specific structure is as follows: an ARNi compound calcium sodium complex, the structure of the complex is as follows:

[0019] Wherein, 2X+Y=3, and n is any value from 0 to 5.

[0020] As a preferred technical solution, n=0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5.

[0021] As a preferred technical solution, X=0.5 or 1; Y=1 or 2.

[0022] As a preferred technical solution of the present invention, n=1.

[0023] As a preferred technical solution of the present invention, X=1, Y=1, n=1, that is:

[0024] As a preferred technical solution of the present invention, X=1, Y=1, n=1, the calcium-sodium complex is a crystalline solid, the crystal form is crystal form A of the complex, and its X-ray powder diffraction spectrum has strong absorption diffraction peaks at 2θ of 4.08°, 5.76°, 15.93°, and 18.70°, with an acceptable error range of ±0.2°.

[0025] As a preferred technical solution of the present invention, X=1, Y=1, n=1, the crystal form is the crystal form A of the complex, and its X-ray powder diffraction spectrum is at 4.08°, 5.76°, 8.10°, 11.25°, 11.41°, 11.99°, 13.23°, 13.51°, 14.13°, 14.89°, 15.19°, 15.93°, 16.15°, 16.72°, 17.11°, 1 There are diffraction peaks with strong absorption at 7.54°, 18.70°, 19.22°, 19.68°, 19.89°, 20.69°, 20.98°, 21.50°, 22.82°, 23.09°, 23.71°, 24.84°, 25.34°, 25.90°, 26.40°, 27.11°, 28.15°, 29.16°, and 29.86°, with an acceptable error range of ±0.2°.

[0026] As a preferred technical solution of the present invention, the X-ray powder diffraction spectrum of the crystalline form A of the composite is shown in FIG2 or 3 .

[0027] As a preferred technical solution of the present invention, the complex is a crystalline solid, X=1, Y=1, n=1, the crystal form is crystal form A of the complex, and its DSC spectrum has endothermic peaks at 182.4±5°C and 227.1±5°C.

[0028] As a preferred technical solution of the present invention, the DSC spectrum of the crystalline form A of the complex is shown in FIG4 .

[0029] As a preferred technical solution of the present invention, the TG spectrum of the crystalline form A of the complex is shown in FIG5 .

[0030] As a preferred technical solution of the present invention, the calcium-sodium complex is a crystalline solid, X=1, Y=1, n=1, and the crystal form is crystal form B of the complex. Its X-ray powder diffraction spectrum has strong absorption diffraction peaks at 4.60°, 5.08°, 5.89°, 14.67°, 15.84°, 18.57°, 18.88°, and 19.95°, with an acceptable error range of ±0.2°.

[0031] As a preferred technical solution of the present invention, X=1, Y=1, n=1, the crystal form is the crystal form B of the complex, and its X-ray powder diffraction spectrum is at 4.60°, 5.08°, 5.89°, 9.96°, 11.57°, 12.14°, 13.70°, 14.17°, 14.67°, 15.52°, 15.84°, 16.37°, 17.42°, 18.57°, 18.88°, 19.56°, 19.95°, 20.30°, 20.53°, 21.27°, 21.93°, 22.57°, 23.04°, 23.50°, 24.10°, 24.85°, 25.02°, 25.93°, 26.45°, 26.62°, 27. There are diffraction peaks with strong absorption at 27.53°, 27.89°, 28.49°, 29.45°, 30.50°, 31.96°, 33.22°, 34.86°, 35.74°, 37.23°, 38.08°, 38.81°, 39.58°, 40.45°, 41.06°, 41.68°, and 43.98°, with an acceptable error range of ±0.2°.

[0032] As a preferred technical solution of the present invention, the X-ray powder diffraction spectrum of the crystalline form B of the composite is shown in FIG7 or 8 .

[0033] As a preferred technical solution of the present invention, the complex is a crystalline solid, X=1, Y=1, n=1, the crystal form is crystal form B of the complex, and its DSC spectrum has endothermic peaks at 179.4±5°C and 230.6±5°C.

[0034] As a preferred technical solution of the present invention, the DSC spectrum of the crystalline form B of the complex is shown in FIG9 .

[0035] As a preferred technical solution of the present invention, the TG spectrum of the crystalline form B of the complex is shown in FIG10 .

[0036] It will be understood by those skilled in the art that in the unit cell of the complex, the allisartan medoxomil metabolite (EXP3174), AHU377, calcium ions (Ca 2+) and solvent molecules will be filled in it in the form of several structural units.

[0037] The complex of the present invention is distinguished from a mixture obtained by simple physical mixing of two active ingredients.

[0038] A second object of the present invention is to provide a use of the complex of the present invention for the preparation of a medicament for treating a range of cardiovascular diseases and other complications, including hypertension and heart failure. Specifically, the diseases / complications treated include, but are not limited to, hypertension, essential hypertension, acute and chronic heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with intermediate ejection fraction, and heart failure with preserved ejection fraction.

[0039] The present invention further provides a pharmaceutical composition comprising the aforementioned ARNi compound calcium-sodium complex and one or more pharmaceutically acceptable carriers, wherein the mass percentage of the calcium-sodium complex in the pharmaceutical composition is 0.1 to 99.9%.

[0040] The pharmaceutical composition can be further used in combination with one or more antihypertensive drugs for hypertension or drug-resistant hypertension, for example, diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin-converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril; ACE / NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; β-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; positive inotropic drugs such as digoxin, babutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem , felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors. The most preferred combination ingredients are diuretics (e.g., hydrochlorothiazide) and / or calcium channel blockers (e.g., amlodipine or a salt thereof, levamlodipine or a salt thereof).

[0041] The pharmaceutical composition can be further used in combination with one or more heart failure drugs for heart failure or drug-resistant heart failure, for example, sodium-glucose co-transporter 2 inhibitors (SGLT2i), such as dapagliflozin, empagliflozin, canagliflozin, ertogliflozin and hengagliflozin.

[0042] Solid matter can be categorized into two main states: crystalline (also known as crystals) and amorphous (also known as amorphous, glassy, ​​etc.). The molecules, atoms, or ions in a crystalline substance (crystal) are arranged in a periodic, orderly pattern in three-dimensional space. The smallest repeating unit is called a unit cell, a parallelepiped defined by three axial lengths a, b, and c, and three angles α, β, and γ (unit cell parameters).

[0043] Single-crystal X-ray diffraction is currently the most established analytical method for determining the three-dimensional structure of crystalline complexes. It can independently analyze the structure of crystalline complexes, as well as the composition and ratio of cocrystals, solvates, hydrates, and salts. However, this method places extremely high demands on the quality and size of the crystals. Generally, the shortest dimension of the crystal must be at least 10 microns to obtain usable data using a laboratory-grade single-crystal X-ray diffractometer.

[0044] Electrons interact with matter millions of times more efficiently than X-rays, making it possible to study micron- and nanometer-scale crystals much smaller than those required for X-ray diffraction. By continuously tilting the crystal to collect electron diffraction data in different directions, data reduction can yield electron diffraction data similar to those of a single crystal. Currently, a large number of organic and inorganic crystals have been successfully resolved, ranging from relatively simple organic small molecules and inorganic crystals to highly complex structures such as zeolites, metal-organic frameworks (MOFs), and covalent organic frameworks (COFs). Combined with cryo-EM, protein crystal structures have also been successfully resolved. However, during data collection, electrons transfer energy to the material and slowly heat the sample, disrupting intermolecular interactions and chemical bonds within the material, leading to a decrease in crystallinity. This condition is known as radiation damage. For electron-beam-sensitive samples, special methods are required during data collection, such as cryogenic conditions and high-speed cameras, to minimize electron damage and obtain high-quality electron diffraction data. MicroED (micro-electron diffraction) is a new structural elucidation method. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 Crystal structure of the sample molecule of the composite crystal form A obtained in Example 1 (ball-and-stick diagram)

[0046] Figure 2 XRD spectrum of the composite crystal form A obtained in Example 1

[0047] Figure 3 XRD spectrum of the composite crystal form A obtained in Example 2

[0048] Figure 4 DSC spectrum of the composite crystal form A obtained in Example 1

[0049] Figure 5 TG spectrum of the composite crystal form A obtained in Example 1

[0050] FIG6 shows the crystal structure of the sample molecule of the complex crystal form B obtained in Example 3 (ball-and-stick diagram)

[0051] Figure 7 XRD spectrum of the composite crystal form B obtained in Example 3

[0052] FIG8 XRD spectrum of the composite crystal form B obtained in Example 4

[0053] FIG9 DSC spectrum of the composite crystal form A obtained in Example 3

[0054] Figure 10 TG spectrum of the composite crystal form A obtained in Example 3

[0055] Figure 11 TEM image of Form A

[0056] Figure 12 TEM image of Form B DETAILED DESCRIPTION

[0057] The present invention will be described in further detail below with reference to the embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0058] In the following embodiments:

[0059] X-ray powder diffraction (XRD) spectra were obtained using a PANalytical Empyrean X-ray diffractometer. The detection conditions were Cu-Kα radiation, wavelength The divergence slit was 1 / 4°, the X-ray tube voltage was 45 kV, the X-ray tube current was 40 mA, the scanning range was 3-60° (2θ), the step size was 0.0262606°, and the dwell time per step was 33.915 s.

[0060] DSC was performed using a NETZSCH DSC 214 differential scanning calorimeter (Germany). The experimental atmosphere was nitrogen at 40 ml / min. The scanning program was a temperature increase from room temperature to 250°C at 10°C / min, using an aluminum sample pan.

[0061] TG was performed using a NETZSCH TG 209F1 thermogravimetric analyzer (Germany). The experimental atmosphere was air at 20 ml / min. The scanning procedure was to increase the temperature from room temperature to 700°C at 10°C / min, using a platinum sample pan.

[0062] MicroED: Electron diffraction patterns were collected using a JEM-2100 Plus transmission electron microscope (TEM) manufactured by JEOL Ltd., with an accelerating voltage of 200 kV and equipped with a Merelin EM high-speed direct electron camera. QUANTIFOIL copper mesh (R1.2 / 1.3) and a Fischone 2550 cryotransfer rod were used, at an ambient temperature of 77 K. PELCOeasiGlow TM Glow discharge assembly. MicroED data collection, XDS for diffraction data reduction, SHELXT for initial structure analysis, and SHELXL and OLEX 2 for assisted refinement.

[0063] Example 1 Preparation of Calcium-Sodium Complex Crystal Form A Sample

[0064] Preparation method: Weigh 230 mg of sacubitril calcium and 234 mg of EXP3174, add 2 ml of acetone, stir at room temperature to dissolve, then add 20 mg of sodium hydroxide and 18 mg of calcium hydroxide. Continue stirring at room temperature for 4 days, filter under nitrogen protection, and vacuum dry at 50°C for 3 days to obtain Form A.

[0065] The MicroED of this composite is shown in Figure 1.

[0066] The X-ray powder diffraction spectrum of the complex is shown in Figure 2, and the DSC and TG spectra are shown in Figures 4 and 5, respectively. The TEM image of Form A is shown in Figure 11.

[0067] Crystal structure analysis reveals that sacubitril and EXP3174 combine in a 1:1 molar ratio to form a calcium-sodium complex crystal. Within a unit cell, there are four sacubitril molecules, four EXP3174 molecules, four calcium ions, four sodium ions, and four water molecules. Each of the four water molecules forms a hydrate with the calcium and sodium ions, namely (EXP3174·AHU377)·1Ca·1Na·1H2O. Specific crystal data are shown in Table 1 below.

[0068] Table 1

[0069] Example 2 Preparation of Calcium-Sodium Complex Crystal Form A Sample

[0070] Preparation method: Weigh 4.6g of sacubitril calcium and 4.68g of EXP3174, add 40ml of acetone, stir at room temperature to dissolve, then add 400mg of sodium hydroxide, 360mg of calcium hydroxide, and 0.6ml of water. Continue stirring at room temperature for 2 days, filter under nitrogen, and vacuum dry at 50°C for 3 days to obtain a white crystalline solid. Add 200mg of the prepared solid to 2ml of ethyl formate, stir at room temperature for 2 days, filter under nitrogen, and then vacuum dry at 45°C for 2 days to obtain Form A with a purity of 99.94%, a calcium content of 4.32%, a sodium content of 2.45%, and a moisture content of 2.7%.

[0071] The X-ray powder diffraction spectrum of the composite is shown in FIG3 .

[0072] The X-ray powder diffraction peaks of Examples 1 and 2 are summarized in Table 2 below, with an error range of ±0.2°:

[0073] Table 2

[0074] Among them, Rel.Int.=Relative Intensity, Pos.[ 。 2Th.]=Position[ 。 2Theta], with an error of ±0.2°. Rel.Int.=Relative Intensity only indicates the approximate intensity of the characteristic peak and should not be used as a limitation on the specific crystal form.

[0075] Summary: According to the XRD spectra and characteristic peak data in Figures 2 and 3, the strongest characteristic absorption peak is at 4.08° in 2θ angle, with an error of ±0.2° and a relative absorption intensity of 100%.

[0076] Furthermore, the crystal form has characteristic peaks at 4.08°, 5.76°, 15.93°, and 18.70°, with an error of ±0.2° and a relative absorption intensity greater than 20%;

[0077] Further, the crystal form has the following parameters: 4.08°, 5.76°, 8.10°, 11.25°, 11.41°, 11.99°, 13.23°, 13.51°, 14.13°, 14.89°, 15.19°, 15.93°, 16.15°, 16.72°, 17.11°, 17.54°, 18.70°, 19.22°, 19.68°, There are characteristic peaks at 19.89°, 20.69°, 20.98°, 21.50°, 22.82°, 23.09°, 23.71°, 24.84°, 25.34°, 25.90°, 26.40°, 27.11°, 28.15°, 29.16°, and 29.86°, with an error of ±0.2°, which can distinguish other substances representing this crystal form in more detail. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystal form.

[0078] Example 3 Preparation of Calcium-Sodium Complex Crystal Form B Sample

[0079] Preparation method: Weigh 460 mg of sacubitril calcium and 468 mg of EXP3174, add 4 ml of acetone, stir at room temperature to dissolve, then add 40 mg of sodium hydroxide, 36 mg of calcium hydroxide, and 60 μl of water. Continue stirring at room temperature for 4 days, filter under nitrogen protection, and vacuum dry at 50°C for 3 days to obtain Form B.

[0080] The MicroED of this composite is shown in Figure 6.

[0081] The X-ray powder diffraction spectrum of the complex is shown in Figure 7, and the DSC and TG spectra are shown in Figures 9 and 10, respectively. The TEM image of Form B is shown in Figure 12.

[0082] Crystal structure analysis reveals that sacubitril and EXP3174 combine in a 1:1 molar ratio to form a calcium-sodium complex crystal. Within each unit cell, there are two sacubitril molecules, two EXP3174 molecules, two calcium ions, two sodium ions, and two water molecules. Both water molecules form hydrates with the calcium and sodium ions, namely (EXP3174·AHU377)·1Ca·1Na·1H2O. The specific results are shown in Table 3 below.

[0083] Table 3

[0084] Example 4 Preparation of Calcium-Sodium Complex Crystal Form B Sample

[0085] Preparation: Weigh 4.6g of sacubitril calcium and 4.68g of EXP3174, add 40ml of acetone, and stir at room temperature to dissolve. Then, add 400mg of sodium hydroxide, 360mg of calcium hydroxide, and 0.6ml of water. Continue stirring at room temperature for 2 days, filter under nitrogen, and vacuum dry at 50°C for 3 days to obtain a white crystalline solid. Add 200mg of this prepared solid to 2ml of ethyl acetate, stir at room temperature for 2 days, filter under nitrogen, and vacuum dry at room temperature for 3 days to obtain Form B with a purity of 99.95%, a calcium content of 4.38%, a sodium content of 2.48%, and a moisture content of 2.8%.

[0086] The X-ray powder diffraction spectrum of the composite is shown in FIG8 .

[0087] The X-ray powder diffraction peaks of Examples 3 and 4 are summarized in Table 4 below, with an error range of ±0.2°:

[0088] Table 4

[0089] Among them, Rel.Int.=Relative Intensity, Pos.[ 。 2Th.]=Position[ 。 2Theta], with an error of ±0.2°. Rel.Int.=Relative Intensity only indicates the approximate intensity of the characteristic peak and should not be used as a limitation on the specific crystal form.

[0090] Summary: According to the XRD spectra and characteristic peak data in Figures 7 and 8, the strongest characteristic absorption peak is at 5.89° in 2θ angle, with an error of ±0.2° and a relative absorption intensity of 100%.

[0091] Further, the crystal form has characteristic peaks at 4.60°, 5.08°, 5.89°, 14.67°, 15.84°, 18.57°, 18.88°, and 19.95°, with an error of ±0.2° and a relative absorption intensity greater than 20%;

[0092] Further, the crystal form has the following peaks: 4.60°, 5.08°, 5.89°, 9.96°, 11.57°, 12.14°, 13.70°, 14.17°, 14.67°, 15.52°, 15.84°, 16.37°, 17.42°, 18.57°, 18.88°, 19.56°, 19.95°, 20.30°, 20.53°, 21.27°, 21.93°, 22.57°, 23.04°, 23.50°, 24.10°, 24.8 There are characteristic peaks at 5°, 25.02°, 25.93°, 26.45°, 26.62°, 27.53°, 27.89°, 28.49°, 29.45°, 30.50°, 31.96°, 33.22°, 34.86°, 35.74°, 37.23°, 38.08°, 38.81°, 39.58°, 40.45°, 41.06°, 41.68°, and 43.98°, with an error of ± 0.2°, which can distinguish other substances representing the present crystal form in more detail. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing the present crystal form.

[0093] From the TEM (transmission electron microscope) images, it can be seen that the crystal form A and crystal form B obtained from this product are both solids with good crystallinity.

[0094] Example 5 Stability Study

[0095] Solid powders of the calcium sodium complex crystal form A and crystal form B were placed naked under conditions of 60° C. and 75% RH, and then samples were taken for testing at specific times.

[0096] Table 5

[0097] It can be seen that the calcium-sodium complex crystal form A and crystal form B obtained in the present invention have very good stability.

[0098] Among them, the crystal form γ of (EXP3174·AHU377)·1.5Ca·2H2O of WO2021143898A1 is converted into crystal form ɑ during the drying process, and its stability is inferior to that of calcium sodium crystal form A and crystal form B.

[0099] Example 6

[0100] The solubility test used the sacubitril content as the solubility test indicator. The solubility of each crystal form was measured under near-neutral conditions. The results are as follows:

[0101] Table 6

[0102] From the above results, it can be seen that the solubility of the component sacubitril in the calcium sodium complex crystal form A and crystal form B is higher than that in the calcium complex crystal form ɑ and crystal form ζ under near-neutral conditions.

[0103] Example 7

[0104] After crystallization, the crystalline solid needs to be quickly filtered and the solvent residue removed. How to quickly filter and remove the solvent is crucial for industrialization. The present invention unexpectedly found that sodium calcium crystal form A and crystal form B are easier to filter and remove the solvent than calcium crystal form ɑ and calcium crystal form ζ. The results are as follows:

[0105] Table 7

[0106] Note: The qualified standards for residual solvents refer to ICH Q3C.

[0107] Example 8 Preparation of complexes under different conditions:

[0108] The applicant tried to prepare complexes using a variety of solvents and different metal ions. It was found that it was difficult to form sodium-potassium complexes and calcium-potassium complexes. The calcium-sodium complex can only be prepared under the aforementioned specific conditions. Therefore, obtaining the corresponding complexes is somewhat difficult, as follows:

[0109] Table 8

[0110] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. ARNi complex calcium sodium complex, characterized in that The structure of the complex is as follows: Wherein, 2X+Y=3, and n is any value from 0 to 5.

2. The ARNi compound calcium sodium complex according to claim 1, characterized in that n=0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5 or 5.

3. The ARNi compound calcium sodium complex according to claim 1, characterized in that X=0.5 or 1; Y=1 or 2, preferably X=1; Y=1.

4. The ARNi compound calcium sodium complex according to claim 1, characterized in that The complex is a crystalline solid, X=1, Y=1, n=1, the crystal form is crystal form A of the complex, and its X-ray powder diffraction spectrum has diffraction peaks with strong absorption at 2θ of 4.08°, 5.76°, 15.93°, and 18.70°, with an acceptable error range of ±0.2°.

5. The ARNi compound calcium sodium complex according to claim 4, characterized in that The X-ray powder diffraction spectrum of the crystalline form A has 2θ values ​​of 4.08°, 5.76°, 8.10°, 11.25°, 11.41°, 11.99°, 13.23°, 13.51°, 14.13°, 14.89°, 15.19°, 15.93°, 16.15°, 16.72°, 17.11°, 17.54°, 18.70°, 19.2 There are diffraction peaks with strong absorption at 2°, 19.68°, 19.89°, 20.69°, 20.98°, 21.50°, 22.82°, 23.09°, 23.71°, 24.84°, 25.34°, 25.90°, 26.40°, 27.11°, 28.15°, 29.16°, and 29.86°, and the acceptable error range is ±0.2°.

6. The ARNi compound calcium sodium complex according to claim 4 or 5, characterized in that The X-ray powder diffraction spectrum of the crystal form A is shown in Figure 2 or 3.

7. The ARNi compound calcium sodium complex according to claim 1, characterized in that The complex is a crystalline solid, X=1, Y=1, n=1, the crystal form is crystal form A of the complex, and its DSC spectrum has endothermic peaks at 182.4±5°C and 227.1±5°C.

8. The ARNi compound calcium sodium complex according to claim 7, characterized in that The DSC spectrum of the crystal form A is shown in FIG4 .

9. The ARNi compound calcium sodium complex according to claim 1, characterized in that The complex is a crystalline solid, X=1, Y=1, n=1, the crystal form is crystal form B of the complex, and its X-ray powder diffraction spectrum has diffraction peaks with strong absorption at 4.60°, 5.08°, 5.89°, 14.67°, 15.84°, 18.57°, 18.88°, and 19.95°, with an acceptable error range of ±0.2°.

10. The ARNi compound calcium sodium complex according to claim 9, characterized in that The X-ray powder diffraction spectrum of the crystalline form B is 4.60°, 5.08°, 5.89°, 9.96°, 11.57°, 12.14°, 13.70°, 14.17°, 14.67°, 15.52°, 15.84°, 16.37°, 17.42°, 18.57°, 18.88°, 19.56°, 19.95°, 20.30°, 20.53°, 21.27°, 21.93°, 22.57°, 23.04°, 23.50°, 24. There are diffraction peaks with strong absorption at .10°, 24.85°, 25.02°, 25.93°, 26.45°, 26.62°, 27.53°, 27.89°, 28.49°, 29.45°, 30.50°, 31.96°, 33.22°, 34.86°, 35.74°, 37.23°, 38.08°, 38.81°, 39.58°, 40.45°, 41.06°, 41.68°, and 43.98°, and the acceptable error range is ±0.2°.

11. The ARNi compound calcium sodium complex according to claim 9 or 10, characterized in that The X-ray powder diffraction spectrum of the crystalline form B is shown in FIG7 or 8 .

12. The ARNi compound calcium sodium complex according to claim 1, characterized in that The complex is a crystalline solid, X=1, Y=1, n=1, the crystal form is crystal form B of the complex, and its DSC spectrum has endothermic peaks at 179.4±5°C and 230.6±5°C.

13. The ARNi compound calcium sodium complex according to claim 12, characterized in that The DSC spectrum of the crystal form B is shown in Figure 9.

14. Use of the ARNi compound calcium sodium complex according to any one of claims 1 to 13 for preparing a drug for treating heart failure and / or hypertension.

15. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the ARNi compound calcium sodium complex as described in any one of claims 1-13, and one or more pharmaceutically acceptable carriers.

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