Co-crystal of sacubitril or salt thereof and azilsartan or salt thereof

Abstract

The present disclosure relates to co-crystals of sacubitril (or a salt of sacubitril, in particular an alkaline earth metal salt or alkali metal salt) and azilsartan (or a salt of azilsartan, in particular an alkaline earth metal salt or alkali metal salt) and methods of preparation thereof, pharmaceutical compositions containing the co-crystals and uses of the co-crystals, in particular for the treatment of cardiovascular system diseases.

Description

Technical Field

[0001] This disclosure relates to a cocrystal of sacubitril (or a salt of sacubitril, particularly an alkaline earth metal salt or an alkali metal salt) and azisartan (or a salt of azisartan, particularly an alkaline earth metal salt or an alkali metal salt), methods for preparing the same, pharmaceutical compositions containing the cocrystal, and uses of the cocrystal, particularly for the treatment of cardiovascular diseases. Background Technology

[0002] Cardiovascular diseases (such as hypertension and heart failure) are a type of disease that poses a significant threat to human health.

[0003] Sacubitril's IUPAC name is 4-{[(2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentane-2-yl]amino}-4-oxobutyric acid. Sacubitril is an enkephalinase inhibitor that exerts vasodilatory and anti-fibrotic effects by enhancing the diuretic natriuretic peptide system. Azilsartan's IUPAC name is 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl]methyl}-1H-benzi[d]imidazole-7-carboxylic acid. Azilsartan is an angiotensin II receptor antagonist (ARB) that potently blocks the renin-angiotensin system. Theoretically, combining sacubitril with azisartan has a synergistic and complementary mechanism, which can exert a stronger clinical effect and improve cardiovascular function. However, there is currently no mature compound preparation on the market.

[0004] Drug cocrystals refer to a single crystalline phase formed by the non-covalent bonding (such as hydrogen bonding) of two or more different components (usually including one active pharmaceutical ingredient and one or more cocrystal forming agents), which is of great value in drug development. In the prior art, KR20230024188A discloses a cocrystal of sacubitril and azisartan. However, the cocrystal system disclosed in this document has the following significant drawbacks: 1) The cocrystal forming agent needs to be added: In addition to the two active pharmaceutical ingredients (APIs), an additional cocrystal forming agent (such as polyethylene glycol, nicotinamide, salicylic acid, ethyl cellulose, or caffeic acid) needs to be introduced into the cocrystal, increasing the complexity of the formulation and the potential risk of instability; 2) Predominantly amorphous: Most of the cocrystals prepared by this prior art are amorphous, with poor physicochemical properties, which is not conducive to industrial production and long-term storage.

[0005] Therefore, there is an urgent need to develop a sacubitril-azilsartan eutectic system that does not contain eutectic forming agents and has excellent physicochemical properties, so as to further expand its application potential in the treatment of cardiovascular diseases and provide new formulation options for related drug compositions. Summary of the Invention

[0006] In view of the above-mentioned needs in the art, the inventors have provided a eutectic of sacubitril (or a salt of sacubitril, particularly an alkaline earth metal salt or an alkali metal salt) and azisartan (or a salt of azisartan, particularly an alkaline earth metal salt or an alkali metal salt), wherein the eutectic is free of a eutectic forming agent and has at least one (preferably all) of the following properties: good chemical and physical stability (e.g., low hygroscopicity, high stability under long-term storage, high temperature, high humidity, light and / or pressure conditions), high solubility (thereby having high bioavailability), and high compatibility with excipients.

[0007] Therefore, in a first aspect, this disclosure provides a eutectic of sacubitril or a salt thereof with azisartan or a salt thereof.

[0008] In a preferred embodiment, the salt of Sakubachu is an alkaline earth metal salt or an alkali metal salt of Sakubachu.

[0009] In a preferred embodiment, the salt of azisartan is an alkaline earth metal salt or an alkali metal salt of azisartan.

[0010] In a preferred embodiment, the salt of sacubitril is selected from: sacubitril sodium, sacubitril potassium, and sacubitril calcium.

[0011] In a preferred embodiment, the salt of azisartan is selected from: azisartan sodium, azisartan potassium, and azisartan calcium.

[0012] In one embodiment, in the eutectic of this disclosure, the molar ratio of sacubitril or its salt to azisartan or its salt is 0.1:1 to 2:1, for example 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2:1.

[0013] In one embodiment, the eutectic of this disclosure is a eutectic of sacubitril sodium and azisartan. Preferably, in the eutectic of sacubitril sodium and azisartan, the molar ratio of sacubitril sodium to azisartan is 0.9:1 to 1.1:1, for example, 1:1.

[0014] In one embodiment, the eutectic of this disclosure is selected from the group consisting of:

[0015] (1) The eutectic crystal form 1 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the crystal form 1 contains characteristic peaks at 2θ angles of 8.1°±0.2°, 14.7°±0.2°, 16.3°±0.2°, and 24.5°±0.2°;

[0016] (2) The eutectic crystal form 2 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the crystal form 2 contains characteristic peaks at 2θ angles of 10.5°±0.2°, 10.9°±0.2°, 20.8°±0.2°, and 21.0°±0.2°;

[0017] (3) The eutectic crystal form 3 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the crystal form 3 contains characteristic peaks at 2θ angles of 5.1°±0.2°, 8.7°±0.2°, 15.8°±0.2°, and 20.4°±0.2°;

[0018] (4) The eutectic crystal form 4 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the crystal form 4 contains characteristic peaks at 2θ angles of 7.9°±0.2°, 14.0°±0.2°, 15.8°±0.2°, and 21.5°±0.2°;

[0019] (5) The eutectic crystal form 5 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the crystal form 5 contains characteristic peaks at 2θ angles of 8.0°±0.2°, 14.6°±0.2°, 15.9°±0.2°, and 24.1°±0.2°;

[0020] (6) The eutectic form 6 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the eutectic form 6 contains characteristic peaks at 2θ angles of 7.6°±0.2°, 8.3°±0.2°, 15.2°±0.2°, and 22.0°±0.2°;

[0021] (7) The eutectic crystal form 7 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the crystal form 7 contains characteristic peaks at 2θ angles of 5.2°±0.2°, 8.8°±0.2°, 17.7°±0.2°, and 20.7°±0.2°;

[0022] (8) A eutectic form 8 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of form 8 contains characteristic peaks at 2θ angles of 7.5°±0.2°, 14.7°±0.2°, 21.9°±0.2°, and 24.5°±0.2°; and

[0023] (9) The eutectic form 9 of sacubitril sodium and azisartan, wherein the X-ray powder diffraction pattern of the eutectic form 9 contains characteristic peaks at 2θ angles of 8.1°±0.2°, 15.3°±0.2°, 16.2°±0.2° and 21.6°±0.2°.

[0024] In one embodiment, the X-ray powder diffraction pattern of crystal form 1 further includes one or more characteristic peaks selected from the following 2θ angles: 5.3°±0.2°, 8.9°±0.2°, 9.7°±0.2°, 13.4°±0.2°, 16.5°±0.2°, 19.1°±0.2°, 21.3°±0.2°, and 22.3°±0.2°.

[0025] In one embodiment, the X-ray powder diffraction pattern of crystal form 2 further includes one or more characteristic peaks selected from the following 2θ angles: 5.6°±0.2°, 6.3°±0.2°, 11.6°±0.2°, 12.5°±0.2°, 14.8°±0.2°, 17.5°±0.2°, 19.9°±0.2°, and 21.9°±0.2°.

[0026] In one embodiment, the X-ray powder diffraction pattern of crystal form 3 further includes one or more characteristic peaks selected from the following 2θ angles: 7.8°±0.2°, 13.8°±0.2°, 16.1°±0.2°, 17.5°±0.2°, 18.4°±0.2°, 21.7°±0.2°, 23.8°±0.2°, and 27.0°±0.2°.

[0027] In one embodiment, the X-ray powder diffraction pattern of crystal form 4 further includes one or more characteristic peaks selected from the following 2θ angles: 3.8°±0.2°, 9.5°±0.2°, 15.2°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 19.2°±0.2°, 20.3°±0.2°, and 24.8°±0.2°.

[0028] In one embodiment, the X-ray powder diffraction pattern of crystal form 5 further includes one or more characteristic peaks selected from the following 2θ angles: 7.6°±0.2°, 9.6°±0.2°, 10.2°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 21.6°±0.2°, 22.1°±0.2°, and 27.9°±0.2°.

[0029] In one embodiment, the X-ray powder diffraction pattern of crystal form 6 further includes one or more characteristic peaks selected from the following 2θ angles: 4.9°±0.2°, 10.2°±0.2°, 14.7°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 20.7°±0.2°, 21.4°±0.2°, and 24.8°±0.2°.

[0030] In one embodiment, the X-ray powder diffraction pattern of crystal form 7 further includes one or more characteristic peaks selected from the following 2θ angles: 7.9°±0.2°, 13.8°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 18.4°±0.2°, 21.0°±0.2°, 23.6°±0.2°, and 26.9°±0.2°.

[0031] In one embodiment, the X-ray powder diffraction pattern of crystal form 8 further includes one or more characteristic peaks selected from the following 2θ angles: 8.1°±0.2°, 10.2°±0.2°, 16.3°±0.2°, 20.6°±0.2°, 22.6°±0.2°, 25.3°±0.2°, 28.5°±0.2°, and 30.8°±0.2°.

[0032] In one embodiment, the X-ray powder diffraction pattern of crystal form 9 further includes one or more characteristic peaks selected from the following 2θ angles: 11.4°±0.2°, 13.4°±0.2°, 15.6°±0.2°, 22.9°±0.2°, 24.2°±0.2°, 24.4°±0.2°, 26.8°±0.2°, and 29.1°±0.2°.

[0033] In one embodiment, the X-ray powder diffraction pattern of crystal form 1 is as follows: Figure 1 As shown.

[0034] In one embodiment, the X-ray powder diffraction pattern of crystal form 2 is as follows: Figure 2 As shown.

[0035] In one embodiment, the X-ray powder diffraction pattern of crystal form 3 is as follows: Figure 3 As shown.

[0036] In one embodiment, the X-ray powder diffraction pattern of crystal form 4 is as follows: Figure 4 As shown.

[0037] In one embodiment, the X-ray powder diffraction pattern of crystal form 5 is as follows: Figure 5 As shown.

[0038] In one embodiment, the X-ray powder diffraction pattern of crystal form 6 is as follows: Figure 6 As shown.

[0039] In one embodiment, the X-ray powder diffraction pattern of crystal form 7 is as follows: Figure 7 As shown.

[0040] In one embodiment, the X-ray powder diffraction pattern of crystal form 8 is as follows: Figure 8 As shown.

[0041] In one embodiment, the X-ray powder diffraction pattern of crystal form 9 is as follows: Figure 9 As shown.

[0042] In one embodiment, the eutectic (crystal form 2) has a melting initiation temperature of 120°C ± 2°C as determined by differential scanning calorimetry.

[0043] In one embodiment, the eutectic (crystal type 2) is anhydrous or tunnel hydrate.

[0044] In one embodiment, the eutectic contains crystallization solvent molecules selected from H2O, alcohols, ketones, or esters.

[0045] In one embodiment, the number of solvent molecules is 0-5, preferably 1-3.

[0046] In a preferred embodiment, the solvent molecules are H2O, and the eutectic contains 0 to 5, preferably 1 to 3 molar equivalents of H2O.

[0047] In one embodiment, the eutectic (crystal form 2) has a weight loss of 3.8% ± 0.5% below 150°C as determined by thermogravimetric analysis, and / or a decomposition temperature in the range of 250°C ± 10°C.

[0048] In a second aspect, this disclosure provides a method for preparing the eutectic according to the first aspect, comprising the following steps:

[0049] (1) Sacubitril or its salt is mixed with azisartan or its salt in a solvent to form a suspension, wherein the solvent is selected from: methanol, ethanol, trifluoroethanol, isopropanol, n-propanol, sec-butanol, n-butanol, water, acetone, butanone, isopropyl ether, diethyl ether, ethyl acetate, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, toluene, n-heptane, methylcyclohexane, dimethyl sulfoxide and butyl acetate;

[0050] (2) The suspension obtained in step (1) is subjected to crystallization treatment, wherein the crystallization treatment is selected from: manual grinding method, mechanical ball milling method, solvent evaporation method, rotary evaporation method, crystal slurry conversion method, cooling crystallization method, amorphous conversion crystallization method or alkali-adjusted crystallization method;

[0051] (3) Separate the eutectic formed in step (2).

[0052] In one embodiment, in step (1), sacubitril or its salt is mixed with azisartan or its salt in a 1:1 molar ratio.

[0053] In one embodiment, the method for preparing a eutectic according to this disclosure includes the following steps:

[0054] (1) Sacubitril or its salt and azisartan or its salt are reacted in a solvent system containing acetonitrile or isopropyl acetate at a 1:1 molar ratio by a slurry conversion method to form a eutectic of sacubitril or its salt and azisartan or its salt; and

[0055] (2) The eutectic obtained by separation.

[0056] In a third aspect, this disclosure provides the use of the eutectic according to the first aspect in the preparation of a medicament for treating cardiovascular diseases.

[0057] In a preferred embodiment, cardiovascular diseases include hypertension and heart failure.

[0058] In a fourth aspect, this disclosure provides a pharmaceutical composition comprising:

[0059] - The eutectic as described in the first aspect; and

[0060] - One or more additional ingredients, said additional ingredients being selected from diluents, pharmaceutically acceptable carriers, pharmaceutically acceptable excipients, solubilizers, and solvents.

[0061] In a fifth aspect, this disclosure provides a method for treating cardiovascular diseases, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition according to the fourth aspect, preferably, the cardiovascular diseases including hypertension and heart failure. Attached Figure Description

[0062] The accompanying drawings described herein are for illustrative purposes only. The drawings are not intended to limit the scope of this disclosure.

[0063] Figure 1 The XRPD diagram of the eutectic crystal form 1 of sacubitril sodium and azisartan is shown.

[0064] Figure 2 The XRPD diagram of the eutectic form 2 of sacubitril sodium and azisartan is shown.

[0065] Figure 3 The XRPD diagram of the eutectic crystal form 3 of sacubitril sodium and azisartan is shown.

[0066] Figure 4 The XRPD diagram of the eutectic form 4 of sacubitril sodium and azisartan is shown.

[0067] Figure 5 The XRPD diagram of the eutectic crystal form 5 of sacubitril sodium and azisartan is shown.

[0068] Figure 6 The XRPD diagram of the eutectic crystal form 6 of sacubitril sodium and azisartan is shown.

[0069] Figure 7 The XRPD diagram of the eutectic crystal form 7 of sacubitril sodium and azisartan is shown.

[0070] Figure 8 The XRPD diagram of the eutectic crystal form 8 of sacubitril sodium and azisartan is shown.

[0071] Figure 9 The XRPD diagram of the eutectic form 9 of sacubitril sodium and azisartan is shown.

[0072] Figure 10 The TGA diagram of the eutectic form 2 of sacubitril sodium and azisartan is shown.

[0073] Figure 11 The DSC diagram of the eutectic form 2 of sacubitril sodium and azisartan is shown.

[0074] Figure 12 The hot-stage XRPD diagram of the eutectic crystal form 2 of sacubitril sodium and azisartan is shown.

[0075] Figure 13 The eutectic crystal form 2 of sacubitril sodium and azisartan is shown. 1 H-NMR spectrum (DMSO-d6).

[0076] Figure 14 The DVS diagram of the eutectic crystal form 2 of sacubitril sodium and azisartan is shown.

[0077] Figure 15 The PLM diagram of the eutectic form 2 of sacubitril sodium and azisartan is shown.

[0078] Figure 16 The XRPD plot of sacubitril sodium is shown.

[0079] Figure 17 The DSC plot of sacubitril sodium is shown.

[0080] Figure 18 The TGA chromatogram of sacubitril sodium is shown.

[0081] Figure 19 The XRPD plot of azisartan is shown.

[0082] Figure 20 The DSC chart for azisartan is shown.

[0083] Figure 21 The TGA graph of azisartan is shown. Detailed Implementation

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0085] In this document, "therapeutic effective dose" refers to a dose of pharmaceutical composition that, when administered to a patient, produces a therapeutic effect on the disease or at least one of its clinical symptoms. This dose effectively relieves, improves, or eliminates the disease or symptoms. It should be understood that the specific therapeutic effective dose varies depending on a variety of factors, including but not limited to: the specific type and severity of the disease being treated, the patient's individual circumstances (such as age, weight, and overall health status), and the physician's professional judgment. Those skilled in the art can determine the appropriate dose for a specific situation based on these factors through routine experiments.

[0086] In one embodiment, the eutectic of the present invention is a eutectic of sacubitril sodium and azisartan, and the X-ray powder diffraction pattern of the eutectic contains characteristic peaks at 2θ angles of 10.5°±0.2°, 10.9°±0.2°, 20.8°±0.2°, and 21.0°±0.2°.

[0087] The eutectic of the present invention has the following significant beneficial effects:

[0088] 1. The eutectic composition of the present invention is fixed and the preparation has excellent reproducibility, which can be successfully scaled up, fully meeting the core requirements of quality uniformity and production reproducibility for pharmaceutical raw materials.

[0089] 2. The eutectic of the present invention maintains its crystal structure, thermodynamic properties and physical state essentially unchanged under conditions such as high temperature, high humidity and light, exhibiting excellent physical and chemical stability.

[0090] 3. The cocrystal of the present invention can maintain its structural integrity in a pH 6.8 buffer solution that simulates the intestinal environment and dissolve synchronously in a synergistic manner, with both components having high concentrations and a stable molar ratio of about 1:1.

[0091] 4. The eutectic of the present invention exhibits better compressibility and formability than physical mixtures (manifested as lower tablet hardness), and can be directly pressed into shape.

[0092] In one embodiment, a method for preparing a eutectic (crystal form 2) is also provided, comprising the following steps:

[0093] (1) Sacubitril sodium and azilsartan are reacted in a solvent system containing acetonitrile or isopropyl acetate at a 1:1 molar ratio via a slurry conversion method to form a eutectic of sacubitril sodium and azilsartan; and

[0094] (2) The eutectic obtained by separation.

[0095] The inventors conducted extensive research on various conditions (including crystallization methods and solvents) for the formation of eutectic of these two APIs (i.e., sacubitril sodium and azisartan), and found that a eutectic with good stability can only be formed when a slurry conversion method is used and a specific solvent (acetonitrile or isopropyl acetate) is used.

[0096] In one embodiment, the slurry conversion method includes solvent-mediated crystallization starting from an amorphous solid or from a crystalline mixture.

[0097] The pharmaceutical compositions disclosed herein can be formulated for any suitable route of administration, including, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or local administration.

[0098] The pharmaceutical compositions disclosed herein can be formulated into oral dosage forms, such as tablets, capsules, suspensions, and oral instant films. The pharmaceutical compositions disclosed herein can also be formulated into injectable dosage forms, such as lyophilized powder for injection and suspension for injection.

[0099] The cocrystal of this disclosure or its pharmaceutical composition may be included in a kit for administering the pharmaceutical composition to a patient for therapeutic purposes. The kit may include the pharmaceutical composition and instructions for administering the pharmaceutical composition to a patient. The kit may be used to treat cardiovascular diseases such as hypertension and heart failure. The kit may include the cocrystal of this disclosure, a pharmaceutically acceptable medium for administering the cocrystal, and instructions for administering a formulation comprising the cocrystal to a patient.

[0100] The present disclosure will now be described in further detail with reference to the accompanying drawings and embodiments. The following embodiments are for illustrative purposes only and are not intended to limit the scope of the disclosure. Experimental methods in the embodiments that do not specify specific conditions are performed under conventional conditions known in the art or under conditions recommended by the manufacturer.

[0101] The instruments, reagents, etc. used in the following examples and comparative examples are all commercially available.

[0102] Characterization instruments and methods

[0103] X-ray powder diffraction (XRPD) and hot-stage XRPD patterns were obtained from a Bruker D8 Advancediffractometer. Parameters were as follows: Cu target; wavelength 1.54 Å; current and voltage: 40 kV, 40 mA; angle range: 3–40˚2θ.

[0104] Thermogravimetric analysis (TGA) data were acquired using a TA Instruments Q500 TGA. Parameters were as follows: Mode: High-resolution mode; Heating rate: 10 °C / min; Protective gas: N2; Sample pan: Platinum crucible.

[0105] Differential scanning calorimetry (DSC) data were acquired using a METTLER TOLEDO DSC 3. Parameters were as follows: heating rate: 10℃ / min; protective gas: N2; sample dish: a perforated aluminum crucible with a lid.

[0106] Proton nuclear magnetic resonance (NMR) 1 The H-NMR spectrum was acquired from a Bruker Ascend 500. The parameters were as follows: full-frequency excitation, 30 ppm single pulse spectrum, 16 scans at a 30° angle, digital orthogonal detection, and temperature control at 298K.

[0107] Dynamic moisture adsorption (DVS) plots were obtained from a TA Instruments Q5000 SA. Parameters were as follows: gas flow rate: 10 ml / min; protective gas: N2; sample tray: platinum crucible.

[0108] The polarized light microscope (PLM) image was taken from an XP-500E. Parameters are as follows: 10x eyepiece, 4x objective lens.

[0109] reagents

[0110] Sacubitril sodium: purchased from Zhejiang Tianyu Pharmaceutical Co., Ltd. Its X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) spectra are shown below. Figure 16 , Figure 17 and Figure 18 As shown.

[0111] Azisartan: Purchased from Zhejiang Tianyu Pharmaceutical Co., Ltd. Its X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) spectra are as follows: Figure 19 , Figure 20 and Figure 21 As shown.

[0112] Example 1: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 1)

[0113] Sacubitril sodium (50 mg) and azisartan (53 mg) were mixed in a 1:1 molar ratio, and 1.0 mL of acetone was added. The mixture was stirred at room temperature for 2 days to form a crystal slurry. After centrifugation, the mixture was vacuum dried at 40 °C overnight to obtain a eutectic of sacubitril sodium and azisartan.

[0114] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 1As shown.

[0115] Example 2: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 2)

[0116] Sacubitril sodium (50 mg) and azisartan (52.65 mg) were mixed in a 1:1 molar ratio, and 1.0 mL of acetonitrile was added. The mixture was stirred at room temperature for 2 days to form a crystal slurry. After centrifugation, the slurry was dried under vacuum at 40 °C overnight to obtain a eutectic of sacubitril sodium and azisartan.

[0117] The obtained eutectic was characterized, and its X-ray powder diffraction (XRPD) pattern is shown below. Figure 2 As shown, the thermogravimetric analysis (TGA) results are as follows: Figure 10 As shown, the differential scanning calorimetry (DSC) analysis results are as follows: Figure 11 As shown, the XRPD analysis results of the hot stage are as follows: Figure 12 As shown, 1 The H-NMR (DMSO-d6) analysis results are as follows: Figure 13 As shown, the DVS analysis results are as follows: Figure 14 As shown, the PLM characterization results are as follows: Figure 15 As shown.

[0118] Example 3: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 3)

[0119] Sacubitril sodium (180 mg) and azisartan (189.54 mg) were mixed in a 1:1 molar ratio, and 9.0 mL of ethanol was added. After dissolving and clarifying at 70 °C, the mixture was divided into 6 equal portions. One portion was rapidly rotary evaporated at 70 °C to obtain an amorphous product. The transparent sample obtained by rotary evaporation was taken, and 0.5 mL of 1,4-dioxane was added for crystallization. If no crystals precipitated, the mixture was sonicated and stirred overnight at 8 °C without precipitation. Then, 1 mL of methyl tert-butyl ether was added, and the mixture was stirred for 0.5 hours to precipitate an oil. After stirring overnight, the oil precipitated. The mixture was centrifuged and vacuum dried at 40 °C for 2 hours to obtain a eutectic of sacubitril sodium and azisartan.

[0120] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 3 As shown.

[0121] Example 4: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 4)

[0122] Sacubitril sodium (100 mg) and azilsartan (105.30 mg) were mixed in a 1:1 molar ratio and dissolved in 1.0 mL of acetone at 60 °C. Separately, sodium carbonate (1.2 equivalents) was dissolved in 0.1 mL of water. This sodium carbonate aqueous solution was added dropwise to the acetone solution of the sample, stirred overnight at 40 °C, centrifuged, and vacuum dried at 40 °C for 2 hours to obtain a eutectic of sacubitril sodium and azilsartan.

[0123] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 4 As shown.

[0124] Example 5: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 5)

[0125] Sacubitril sodium (100 mg) and azisartan (105.30 mg) were mixed in a 1:1 molar ratio and dissolved in 2.0 mL of acetone at 40 °C. Separately, potassium hydroxide (1.2 equivalents) was dissolved in 0.05 mL of water. This potassium hydroxide aqueous solution was added dropwise to the acetone solution of the sample, stirred overnight at 40 °C, centrifuged, and vacuum dried at 40 °C for 2 hours to obtain a eutectic of sacubitril sodium and azisartan.

[0126] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 5 As shown.

[0127] Example 6: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 6)

[0128] Sacubitril sodium (100 mg) and azilsartan (105.30 mg) were mixed in a 1:1 molar ratio and dissolved in 2.0 mL of acetone at 40 °C. Separately, sodium hydroxide (1.2 equivalents) was dissolved in 0.1 mL of methanol. This methanol solution of sodium hydroxide was added dropwise to the acetone solution of the sample, stirred overnight at 40 °C, centrifuged, and vacuum dried at 40 °C for 2 hours to obtain a eutectic of sacubitril sodium and azilsartan.

[0129] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 6 As shown.

[0130] Example 7: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 7)

[0131] Sacubitril sodium (100 mg) and azisartan (105.30 mg) were mixed in a 1:1 molar ratio, and 2.0 mL of toluene was added. The mixture was stirred at 40 °C until it did not dissolve. Separately, potassium hydroxide (1.2 equivalents) was dissolved in 0.1 mL of methanol. The methanol solution of potassium hydroxide was added dropwise to the toluene suspension of the sample, and the mixture was stirred overnight at 40 °C to obtain a gel-like solid. The solid was centrifuged and vacuum dried at 40 °C for 2 hours to obtain a eutectic of sacubitril sodium and azisartan.

[0132] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 7 As shown.

[0133] Example 8: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 8)

[0134] Weigh 50 mg of sacubitril sodium and 52.65 mg of azisartan (1:1 molar ratio). Add solid azisartan to 4.0 mL of butanone. Stir at 70 °C until dissolved. Add solid sacubitril sodium and continue stirring until completely dissolved. Then add 1.5 mL of methyl tert-butyl ether as an antisolvent. Stir overnight at 6 °C until solid precipitates. Centrifuge and vacuum dry overnight at 40 °C to obtain a eutectic of sacubitril sodium and azisartan.

[0135] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 8 As shown.

[0136] Example 9: Preparation of a eutectic of sacubitril sodium and azisartan (crystal form 9)

[0137] Weigh 50 mg of sacubitril sodium and 52.65 mg of azilsartan (1:1 molar ratio). Add the solid sacubitril sodium to 4.0 mL of methanol and stir to dissolve at 70 °C. Then add the solid azilsartan and continue stirring until completely dissolved. Subsequently, add 4.0 mL of isopropyl acetate and 5.0 mL of n-heptane as antisolvents. Stir overnight at 6 °C to precipitate the solid. Centrifuge and vacuum dry overnight at 40 °C to obtain a eutectic of sacubitril sodium and azilsartan.

[0138] The obtained eutectic was characterized by X-ray powder diffraction (XRPD), and its characteristic diffraction pattern is shown below. Figure 9 As shown.

[0139] Example 10: Reproducibility verification and characterization of sacubitril sodium and azisartan eutectic (crystal forms 1 to 9)

[0140] To verify the structural stability and reproducibility of the crystal forms described in the above embodiments, repeated preparation and characterization were performed, and the results are as follows:

[0141] 1. Nuclear magnetic resonance (NMR) and high-performance liquid chromatography (HPLC) analyses were performed on multiple batches of crystal form 1 samples. The results showed that the ratio of sacubitril sodium to azisartan varied significantly among different batches of samples, fluctuating between 0:1 and 0.4:1, indicating that the sample composition was unstable.

[0142] 2. NMR and HPLC analyses were performed on multiple batches of crystal form 2 samples. The results of all batches consistently showed that the ratio of sacubitril sodium to azisartan remained stable at approximately 1:1 (between 0.9:1 and 1.1:1), indicating that this crystal form has good reproducibility and compositional stability.

[0143] 3. NMR and HPLC analyses were performed on multiple batches of crystal form 3 samples. The results showed that the NMR detection ratio was approximately 0.1:1, while the HPLC detection ratio was approximately 0.3:1, which was inconsistent with the NMR ratio. Furthermore, the sodium sacubitril content was extremely low, indicating that a stable eutectic structure had not been formed.

[0144] 4. HPLC analysis was performed on multiple batches of crystal form 4 samples. The results showed that the ratio of sacubitril sodium to azisartan varied significantly among different batches (from 0.4:1 to 0.9:1), indicating that the sample composition was not fixed and had poor reproducibility.

[0145] 5. NMR and HPLC analyses were performed on multiple batches of samples with crystal forms 5, 6, and 7. The results showed that, for samples with crystal forms 5 to 7, although the NMR and HPLC detection ratios were basically consistent within a single batch, the samples were unstable when the raw material ratios were changed, and a stable eutectic with a fixed composition could not be obtained.

[0146] 6. NMR and HPLC analyses were performed on multiple batches of samples with crystal forms 8 and 9. The results showed that the content of sacubitril sodium was extremely low or undetectable in samples with crystal forms 8 and 9 (NMR and HPLC ratios were 0:1 and 0.2:1, respectively).

[0147] The results of eutectic screening of sacubitril sodium and azisartan under various crystallization conditions (including different solvents, additives and antisolvents) showed that crystal form 1 and crystal forms 3-9 all had problems with poor reproducibility and unstable composition.

[0148] In contrast, crystal form 2 consistently yielded a cocrystal product with a molar ratio of approximately 1:1 for sacubitril sodium and azithromycin in repeated experiments across different batches, and its preparation could be scaled up. These results strongly demonstrate that crystal form 2 possesses significant structural stability and reproducibility, exhibiting superior physicochemical properties compared to other crystal forms and demonstrating its potential as a crystal form for pharmaceutical active ingredients.

[0149] Example 11: Solid-state stability of sacubitril sodium and azithrostan eutectic crystal form 2 and physical mixture

[0150] 1. Experimental Methods

[0151] Test samples: Sacubitril sodium and azisartan eutectic (crystal form 2), and equimolar physical mixtures of sacubitril sodium and azisartan.

[0152] Stability conditions:

[0153] Long-term: 25℃±2℃, 60%±5%RH, open and protected from light.

[0154] Lighting: 25℃±5℃, 30%RH-70%RH, illuminance not less than 4500lx±500lx, open.

[0155] High temperature: 50℃±5℃, <30%RH, open and protected from light.

[0156] Sampling time: 0 days, 5 days, 10 days, 30 days.

[0157] Characterization methods: X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and visual inspection.

[0158] 2. Experimental Results

[0159] Table 1.

[0160]

[0161] The above experimental results show that the sacubitril sodium and azithartan eutectic (crystal form 2) of the present invention maintains essentially unchanged crystal form, thermodynamic properties, and physical state under high temperature, high humidity, and light stress conditions, exhibiting excellent solid-state stability. In contrast, their equimolar physical mixtures exhibit significant instability under the same conditions.

[0162] Therefore, eutectic (crystal form 2) has obvious advantages over simple physical mixtures in storage and formulation processing, and is more suitable as an active pharmaceutical ingredient for developing stable and reliable drug formulations.

[0163] Example 12: Solid-state stability of sacubitril sodium and azithrostan eutectic crystal form 2 and physical mixture

[0164] 1. Experimental Methods

[0165] Test samples: Sacubitril sodium and azisartan eutectic (crystal form 2), and equimolar physical mixtures of sacubitril sodium and azisartan.

[0166] Stability conditions:

[0167] Temperature: Room temperature (approximately 25°C), 40°C oven.

[0168] Packaging: Sealed and open storage.

[0169] Sampling time: 0 days, 7 days, 14 days.

[0170] Characterization methods: X-ray powder diffraction (XRPD) and visual inspection.

[0171] 2. Experimental Results

[0172] Table 2.

[0173]

[0174] The above experimental results show that the sacubitril sodium and azisartan eutectic (crystal form 2) of the present invention exhibits excellent crystal form physical stability under thermal stress conditions, and its crystal structure remains unchanged under various conditions. In contrast, its equimolar physical mixture exhibits obvious solid-phase instability, and its tendency to agglomerate also increases the difficulty of the production process.

[0175] In summary, the eutectic (crystal form 2) is significantly superior to physical mixtures in terms of physical state and crystal stability, and is more suitable for developing stable and reliable solid pharmaceutical formulations.

[0176] Example 13: Equilibrium solubility of sacubitril sodium and azithrostan eutectic crystal form 2 and physical mixture

[0177] 1. Experimental Methods

[0178] Test samples: Sacubitril sodium and azisartan eutectic (crystal form 2), and equimolar physical mixtures of sacubitril sodium and azisartan.

[0179] Solution medium: pH 6.8 buffer (a key pH that mimics the intestinal environment).

[0180] Experimental conditions: constant temperature oscillation at 37℃.

[0181] Sampling time: 4 hours, 24 hours.

[0182] Test items: The concentrations (mg / mL) of azisartan and sacubitril sodium were determined by HPLC, and their molar ratio was calculated.

[0183] 2. Experimental Results

[0184] Table 3.

[0185]

[0186] The above experimental results show that, in a pH 6.8 buffer solution, the sacubitril sodium and azilsartan cocrystal (crystal form 2) of the present invention maintains structural stability for both 4 and 24 hours, and achieves synergistic dissolution of the two components. The concentrations of sacubitril sodium and azilsartan in the solution remain consistently high and close to each other, with a stable molar ratio of approximately 1:1. This indicates that at this physiologically relevant pH, the cocrystal of the present invention can maintain its structural integrity and dissolve synchronously in a synergistic manner.

[0187] In contrast, the physical mixture exhibited severe dissolution asynchrony in the pH 6.8 buffer. The molar ratio of the two components in solution consistently deviated significantly from 1:1. Of particular importance, the solubility of azisartan in the physical mixture was significantly lower than that in the eutectic form (1.91 mg / mL vs 4.54 mg / mL at 24 h).

[0188] Therefore, the cocrystal (crystal form 2) of the present invention has significant advantages and outstanding effects in ensuring the synchronous release of the two active ingredients in the intestinal environment and improving the bioavailability of combined medication when developing oral solid dosage forms.

[0189] Example 14: Tableting performance of sacubitril sodium and azisartan eutectic crystal form 2 and physical mixture

[0190] To evaluate the tableting performance of eutectic form 2, tableting experiments were conducted on eutectic form 2 and physical mixtures under excipient-free conditions. The experimental results are shown in Table 4 below.

[0191] Table 4.

[0192]

[0193] Experimental results show that, without the participation of excipients, both the eutectic and the physical mixture of the present invention can be compressed into solid tablets with a white appearance, and XRPD analysis revealed no change in crystal form. Notably, the hardness of the eutectic tablets after compression is lower than that of the physical mixtures, indicating that the eutectic of the present invention has better compressibility and formability. These results demonstrate that the eutectic of the present invention can be directly compressed into tablets without the need for additional excipients, exhibiting good process adaptability and application potential.

[0194] Example 15: Hygroscopicity of sacubitril sodium and azithrostan eutectic crystal form 2 and physical mixture

[0195] This embodiment compares the behavior of eutectic (crystal form 2) and physical mixture under low humidity conditions through dynamic moisture adsorption (DVS) experiments.

[0196] 1. Experimental Methods

[0197] Test samples: Sacubitril sodium and azisartan eutectic (crystal form 2), and equimolar physical mixtures of sacubitril sodium and azisartan.

[0198] Experimental conditions: Desorption experiments were conducted at 10% relative humidity (RH) for 72 hours.

[0199] Test items: Sample mass change (used to calculate desorption amount); X-ray powder diffraction (XRPD) analysis of solid residues after the experiment to determine crystal form.

[0200] 2. Experimental Results

[0201]

[0202] The above experimental results show that the sacubitril sodium and azisartan cocrystal (crystal form 2) of the present invention has a definite solid form and stability, while the physical mixture undergoes an uncontrollable solid-phase transformation during the hygroscopic process, further proving the superiority of the cocrystal of the present invention as a pharmaceutical raw material.

[0203] All publications, patent applications, patents and other references mentioned in this disclosure are incorporated herein by reference in their entirety.

[0204] While this disclosure has been illustrated and described with reference to certain preferred embodiments, those skilled in the art should understand that the above description is a further detailed explanation of the disclosure in conjunction with specific embodiments, and should not be construed as limiting the specific implementation of this disclosure to these descriptions. Various changes in form and detail can be made by those skilled in the art, including some simple deductions or substitutions, without departing from the spirit and scope of this disclosure.

Claims

1. A co-crystal of sacubitril or a salt thereof and azilsartan or a salt thereof.

2. The co-crystal of claim 1, wherein, the salt of sacubitril is an alkaline earth metal salt or an alkali metal salt of sacubitril; and / or, the salt of azilsartan is an alkaline earth metal salt or an alkali metal salt of azilsartan.

3. The co-crystal of claim 1 or 2, wherein, the salt of sacubitril is selected from the group consisting of sodium sacubitril, potassium sacubitril, calcium sacubitril; the salt of azilsartan is selected from the group consisting of sodium azilsartan, potassium azilsartan, calcium azilsartan.

4. The co-crystal of any one of claims 1 to 3, wherein, the molar ratio of sacubitril or a salt thereof to azilsartan or a salt thereof is 0.1:1 to 2:1, for example 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2:

1.

5. The co-crystal of any one of claims 1 to 4, wherein, the X-ray powder diffraction pattern of the co-crystal comprises characteristic peaks at 2-theta angles of 10.5°±0.2°, 10.9°±0.2°, 20.8°±0.2°, 21.0°±0.2°.

6. The co-crystal of claim 5, wherein, the X-ray powder diffraction pattern of the co-crystal further comprises one or more characteristic peaks at 2-theta angles selected from the group consisting of 5.6°±0.2°, 6.3°±0.2°, 11.6°±0.2°, 12.5°±0.2°, 14.8°±0.2°, 17.5°±0.2°, 19.9°±0.2°, 21.9°±0.2°.

7. The co-crystal of claim 5 or 6, wherein, the co-crystal has an X-ray powder diffraction pattern as shown in Figure 2.

8. The co-crystal of any one of claims 1 to 7, wherein, the co-crystal has a melting onset temperature of 120°C±2°C as determined by differential scanning calorimetry.

9. The co-crystal of any one of claims 1 to 8, wherein, the co-crystal contains crystallization solvent molecules selected from the group consisting of H2O, alcohols, ketones or esters; preferably, the solvent molecules are H2O, the co-crystal comprises 0 to 5, preferably 1 to 3 molar equivalents of H2O.

10. The co-crystal according to any one of claims 1 to 9, wherein, the co-crystal has a weight loss of 3.8%±0.5% below 150°C and / or a decomposition temperature in the range of 250°C±10°C as determined by thermogravimetric analysis.

11. A method for preparing the co-crystal of any one of claims 1 to 10, comprising the steps of: (1) reacting sacubitril or a salt thereof and azilsartan or a salt thereof in a 1:1 molar ratio in a solvent system comprising acetonitrile or isopropyl acetate by a slurry conversion process to form a co-crystal of sacubitril or a salt thereof and azilsartan or a salt thereof; and (2) isolating the resulting co-crystal.

12. Use of the co-crystal of any one of claims 1 to 10 for the manufacture of a medicament for the treatment of cardiovascular diseases, preferably the cardiovascular diseases comprise hypertension and heart failure.

13. A pharmaceutical composition comprising: - the co-crystal of any one of claims 1 to 10; and - one or more additional ingredients selected from the group consisting of diluents, pharmaceutically acceptable carriers, pharmaceutically acceptable excipients, solubilizers and solvents.

14. A method for treating cardiovascular diseases, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 13, preferably, the cardiovascular diseases comprise hypertension and heart failure.

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