TW201811734A - New crystal form of sacubitril sodium salts especially a neprilysinase inhibitor used for the treatment of heart failure, hypertension, and cardiomyopathy - Google Patents

Abstract

The present invention relates to the field of pharmaceutical synthesis, in particular to the new crystal forms A, B, C, D and E of sacubitril sodium salts and a preparation method thereof. The pharmaceutical composition can be used, for example, for the prevention or treatment of neprilysinase-related diseases or disorders, and is mainly used for heart failure, hypertension, and cardiomyopathy.

Description

New crystalline form of sacurbitone sodium salt

The present invention relates to the field of pharmaceutical synthesis, in particular to new crystal forms A, B, C, D, and E of sacurbitone sodium salt, and a method for preparing the same.

Sacubitril, chemical name 4-{[((2S, 4R) -1-([1,1'-biphenyl] -4-yl) -5-ethoxy-4-methyl -5-oxopent-2-yl] amino} -4-oxobutanoic acid, an enkephalinase inhibitor, has the following structure: .

Enkephalinase (NEP) is a metalloproteinase, which is expressed in multiple tissues in the body, most in the kidney, and can catalyze the degradation of many endogenous peptides, such as NP, bradykinin, substance P, etc. Therefore, NEP inhibitor May increase the amount of natriuretic peptide (NP). NP plays an important role in body fluid balance. There are three subtypes of NP, A (ANP), B (BNP), and C (CNP). When the atrial pressure increases due to vascular blood volume overload, the atrial releases ANP, which is also called atrial natriuretic peptide. Increased left ventricular filling pressure can promote the release of BNP. ANP and BNP can relax blood vessels, expel sodium, and diuretic. CNP is mainly manifested in the central nervous system, kidneys and vascular endothelial cells, and has an antithrombotic effect. Excessive plasma volume and left ventricular filling pressure can stimulate the release of NP, and the upregulation of NP in patients with heart failure is particularly obvious. The direct vasodilation of NP can reduce preventricular load, systemic vascular resistance, and arterial pressure. NP can exert a direct vasodilation effect by reducing preventricular load, systemic vascular resistance, and arterial pressure. In addition, NP can also increase the filtration rate of glomeruli and promote the excretion of sodium and water. NP can also reduce the release of renin, reduce the amount of plasma angiotensin II, and relax the blood vessels.

Angiotensin II (AngII) is a potent vasoconstrictor. It is the most important active hormone in the renin-angiotensin-aldosterone system (RAAS). It plays a major role in cardiovascular disease and can exert a direct boosting effect. There are at least two subtypes of AngII receptor, AT1 and AT2. AngII is highly selective for AT1 receptor, which is 300 times higher than AT2 receptor. After binding AngII to AT1 receptor, it will activate the corresponding cell channels, thereby showing the main effects of AngII, such as vasoconstriction, aldosterone secretion, renal tubular sodium, water reabsorption and so on. AT1 receptor antagonists can inhibit AngII-mediated vasoconstriction, renal tubular sodium, water reabsorption and other effects; and inhibit RAAS on the reflex regulation of baroreceptors, and inhibit sympathetic nerve excitation. AT1 receptor antagonists have been widely used in the treatment of hypertension.

When sacurbitux or its salt is combined with angiotensin II AT1 receptor antagonists, such as valsartan, it can simultaneously inhibit enkephalinase and angiotensin receptor, that is, it can simultaneously act on the kidney -Angiotensin system and promote brain natriuretic peptide loop, acting on the neuroendocrine system of the heart in a variety of ways, blocking receptors exerting harmful effects, and promoting protective mechanisms. LCZ-696 (Entresto), developed by Novartis, is a eutectic composed of sacurbitra sodium and valsartan disodium. It is used to treat chronic heart failure and / or hypertension. It has significant effects and good safety. At present, the drug has applied for marketing authorization for new drugs in the United States, the European Union and other countries, and has been approved by the FDA, becoming the first new drug approved for chronic heart failure in nearly 10 years.

Novartis developed eutectic LCZ-696 with sacurbitum sodium and valsartan disodium. One of the reasons is that the hygroscopicity of LCZ-696 is lower than that of sacurbitra sodium, which is more conducive to production and storage. Although the LCZ-696 eutectic has improved in physical properties, its fixed composition ratio limits the use of sacurbitra sodium with different proportions of valsartan or its pharmaceutically acceptable salts, or other AT1 receptor antagonists. Combination medication is not conducive to the adjustment of medication according to different situations in the clinic. Sakubituric free acid is not suitable for preparations, especially oral solid preparations, because of its low melting point and poor water solubility. Sacur in amorphous form is more hygroscopic and difficult to prepare. US 5217996 discloses a solid form of sacurbitux sodium salt X, which is prepared in accordance with the method, and has been found to have strong hygroscopicity. Therefore, it is necessary to further study the solid state form of sacurbitum sodium salt in order to obtain a sacurbitum sodium salt with simple preparation process and improved physical properties such as hygroscopicity.

It has been proven that it is very difficult to form the sacurbitum sodium salt with the desired advantageous properties. In most cases, it is obtained in the form of a sodium salt with poor stability. advantageous.

It is an object of the present invention to provide crystal forms A, B, C, D, and E of sacurbitone sodium salt.

Another object of the present invention is to provide a method for preparing crystalline forms A, B, C, D and E of sacurbitone sodium salt.

The crystalline form A of sacurbitum sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 6.0 ± 0.2, 7.0 ± 0.2, 11.8 ± 0.2 There are peaks at 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± 0.2; preferably at about 6.0 ± 0.2, 7.0 ± 0.2, 11.8 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± There is a peak at 0.2.

In a specific embodiment, under the condition of a heating rate of 10 ° C./min, the Sacurbitum sodium salt crystal form A has an endothermic peak near 168 ° C.

In a specific embodiment, under the condition of a heating rate of 10 ° C./min, the Sacurbitum sodium salt form A has an endothermic peak at 166-169 ° C.

In a specific embodiment, the crystalline form A of Sakubitux sodium salt has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG. 1.

In a specific embodiment, under the condition that the heating rate is 10 ° C./min, the crystalline form A of sacurbitone sodium salt has an endothermic curve substantially the same as the endothermic curve of the differential thermal analysis shown in FIG. 2.

The DSC chart of Sakubiqu Form A shows an endothermic peak around 166 ° C with an enthalpy of 98.31 J / g. Higher endothermic peak temperature and enthalpy value indicate that the crystal lattice of this crystal form has high stability. It is worth noting that the crystal form is kept in an open container at a temperature of 25 ° C and a relative humidity of 43.5% for 3 hours, and the water absorption is 1.4%, while the amorphous form under the same conditions has a water absorption of up to 12.8%.

The crystalline form B of the sacurbitum sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 5.1 ± 0.2, 10.4 ± 0.2, 11.2 ± There are peaks at 0.2, 19.2 ± 0.2, 19.7 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2; preferably at about 5.1 ± 0.2, 8.6 ± 0.2, 10.4 ± 0.2, 11.2 ± 0.2, 12.1 ± 0.2, 19.2 ± 0.2, 19.7 There are peaks at ± 0.2, 21.3 ± 0.2, and 21.8 ± 0.2.

In a specific embodiment, under the condition that the heating rate is 10 ° C./min, the crystal form B of the sacurbitum sodium salt has an endothermic peak near 133 ° C. and near 159 ° C.

In a specific embodiment, the crystalline form B of the sacurbitum sodium salt has an endotherm at 130-134 ° C and 149-160 ° C at a heating rate of 10 ° C / min. peak.

In a specific embodiment, the crystal form B of the sacurbitum sodium salt B has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG. 3.

In a specific embodiment, under the condition that the heating rate is 10 ° C./min, the crystalline form B of sacurbitone sodium salt has an endothermic curve substantially the same as the endothermic curve of the differential thermal analysis shown in FIG. 4.

The crystalline form C of sacurbitum sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2 There are peaks at 19.3 ± 0.2, 21.4 ± 0.2, 22.0 ± 0.2; preferably at about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2, 12.7 ± 0.2, 14.5 ± 0.2, 16.8 ± 0.2, 19.3 ± 0.2, 21.4 ± There are peaks at 0.2, 22.0 ± 0.2, and 27.2 ± 0.2.

In a specific embodiment, the sacurbitum sodium salt form C has a melting point of about 136 ± 5 ° C.

In a specific embodiment, the crystalline form C of Sakubitrol sodium salt has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG. 5.

It is worth noting that the crystal form is kept in an open container at a temperature of 25 ° C and a relative humidity of 43.5% for 3 hours and the water absorption is 2.4%, while the amorphous form under the same conditions has a water absorption of up to 12.8%.

The crystalline form D of sacurbitum sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 5.2 ± 0.2, 8.7 ± 0.2, 10.4 ± 0.2 There are peaks at 12.2 ± 0.2 and 15.7 ± 0.2.

In a specific embodiment, the crystal form D of sacurbitone sodium salt has a melting point of about 117 ± 5 ° C.

In a specific embodiment, the crystal form D of the sacurbitum sodium salt D has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG. 6.

The salicylate sodium salt crystal form E provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 8.2 ± 0.2, 10.4 ± 0.2, 11.0 ± 0.2 There are peaks at 13.9 ± 0.2, 16.7 ± 0.2, and 21.3 ± 0.2.

In a specific embodiment, the crystalline form E of sacurbitone sodium salt has a melting point of about 130 ± 5 ° C.

In a specific embodiment, the crystal form E of the sacurbitum sodium salt E has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG. 7.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form A, B, C, D or E of sacurbitone sodium salt of the present invention in combination with a pharmaceutically acceptable carrier. Gastrointestinal administration can be in the form of tablets, capsules, solutions, suspensions, etc. to the patient.

The crystalline form A, B, C, D or E of the sacurbitone sodium salt of the present invention, or a pharmaceutical composition comprising the same, can be used, for example, to prevent or treat a disease or disorder related to enkephalinase.

Major applications include heart failure, hypertension, and cardiomyopathy.

Those with ordinary knowledge in the technical field are fully capable of selecting relevant standard animal experimental models to prove the therapeutic indications and beneficial effects indicated by the context.

In the present invention, "the same powder X-ray diffraction spectrum" means that the positions of the peaks expressed in degrees 2θ are substantially the same, and the relative intensities of the peak positions are substantially the same. The relative intensity refers to the ratio of the intensity of the other peak to the intensity of the strongest peak when the intensity of the highest intensity peak among all diffraction peaks of the powder X-ray diffraction spectrum is 100%. It should be noted that the 2θ angle in the X-ray powder diffraction spectrum sometimes has some measurement errors due to various factors. The measured value will usually appear as ± 0.3, preferably ± 0.2, and more preferably ± 0.1. Degree of change. Therefore, in this specification, the 2θ angle based on the measured value of a specific sample should be understood to include the meaning of these allowable errors. In the present invention, "substantially the same as the powder X-ray diffraction pattern shown in Fig. 1" means that 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.

It should be noted that the absorption peak in differential scanning calorimetry is an inherent physical property of each crystal form of the present invention. However, in actual measurement, in addition to measurement error, an allowable amount of impurities may be mixed in. The possibility that the melting point varies due to reasons is also undeniable. Therefore, those with ordinary knowledge in the technical field can fully understand to what extent the measured value of the endothermic peak temperature in the present invention can be changed. For example, the error that can be conceived is about ± 5 ° C in some cases. It is preferably about ± 3 ° C, more preferably about ± 2 ° C, and even more preferably about ± 1 ° C.

The "melting point" in the present invention refers to an initial melting temperature at which a crystal form is melted.

Analysis method used in the present invention:

(1) X-ray powder diffraction

Bruker D8 advance diffractometer, Cu Ka filled tube (40 kV, 40 mA) at room temperature as X light source with wide-angle goniometer, 0.6 mm divergence slit, 2.5 ° primary Sola slit, 2.5 ° times Grade Sola slit, 8 mm anti-scatter slit, 0.1 mm detector slit and LynxEye detector. In the 2θ continuous scanning mode, the data acquisition is completed at a scanning speed of 2.4 ° / min and a scanning step of 0.02 ° in the range of 3 ° -40 °.

(2) Differential scanning calorimeter

Using TA Q200 and Mettler DSC 1+, under the protection of N2 at a flow rate of 50 mL / min, the temperature was acquired from room temperature to degradation temperature at 10 ° C / min before completing the acquisition.

(3) Thermogravimetric analyzer

Using TA Q500, under the protection of N ₂ at a flow rate of 50 mL / min, the temperature was raised from room temperature to degradation below 30% at 10 ° C./min to complete the data acquisition.

The above description of the present invention will be further described in detail in the following embodiments. However, it should not be construed that the content of the present invention is limited to the following embodiments. Any invention made based on the above content of the present invention belongs to The scope of the invention.

Comparative Example 1: Preparation of Sacurbitone Sodium Salt X

The sacurbitum sodium salt X is prepared according to the method of Example 1 in US5217996. The obtained sacurbitra sodium salt X has a melting point of 159-160 ° C.

Comparative Example 2: Preparation of Amorphous Sodium Salt

1.0 g of Sacbicuric free acid was suspended in 10 mL of water, an aqueous sodium hydroxide solution (97 mg / 1 mL) was added dropwise, and the solution was stirred at room temperature for 0.5 h. The solution was lyophilized to obtain a white powdery solid.

Example 1: Preparation of Sacurbitum Sodium Salt Form A

Dissolve 112 mg of sacurbicide in 2 mL of ethanol, add dropwise an ethanol solution containing 10.9 mg of sodium hydroxide per 0.1 mL, stir for 0.5 hours, and concentrate under reduced pressure. The obtained residue is ethanol / n-heptane (1/19 (Volume ratio) 300 mL of suspension and stirring overnight, filtration, and vacuum drying at 40 ° C to obtain a solid. The solid was added to 10 mL of isopropanol, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 40 ° C. to obtain a white solid, that is, a type of sacurbic sodium salt.

X-ray powder diffraction and differential scanning calorimetry were used to characterize the solid form A of Sacurbitum sodium salt A, and its solid-state characterization parameters and spectra are described in this paper.

As measured by a melting point apparatus, the melting point of the sodium salt of acucurbitate type A appeared at about 167-168 ° C.

Example 2: Preparation of Sacurbitum Sodium Salt Form B

Dissolve 112 mg of sacurbicid in 2 mL of ethanol, dropwise add 0.5 mL of an ethanol solution containing 9.29 mg of sodium hydroxide, stir for 0.5 hours, and concentrate under reduced pressure to obtain a dry solid. Dissolve 30 mg of this dry solid in 0.6 mL of ethanol, seal the small glass bottle where the solution is located with a parafilm, poke the hole and place it in a glass bottle containing 5 mL of ethyl acetate, and screw the cap tightly. After being left at room temperature for 15 days, the small glass bottle was taken out, and the supernatant was discarded by centrifugation to obtain a white solid, that is, a type B sacurbitum sodium salt.

X-ray powder diffraction and differential scanning calorimetry were used to characterize the solid form B of Sacurbitum sodium salt B, and its solid-state characterization parameters and spectra are as described herein.

As measured by a melting point apparatus, the type B sacurbitum sodium salt melted at about 133-136 ° C.

Example 3: Preparation of Sacurbitum Sodium Salt Form C

Dissolve 112 mg of sacurbicid in 2 mL of ethanol, dropwise add 0.5 mL of an ethanol solution containing 9.29 mg of sodium hydroxide, stir for 0.5 hours, and concentrate under reduced pressure to obtain a dry solid. 30 mg of this dry solid was added to 1 mL of isopropyl alcohol, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 40 ° C to obtain a white solid, namely, C-type sacurbitum sodium salt.

X-ray powder diffraction was used to characterize the solid form of sacurbitum sodium salt form C, and its solid-state characterization parameters and spectra are described in this paper.

As measured by a melting point apparatus, the melting point of the C-type sacurbitum sodium salt appeared at about 136 ± 5 ° C.

Example 4: Preparation of Sacurbitum Sodium Salt Form D

Dissolve 112 mg of sacurbicid in 2 mL of ethanol, dropwise add 0.5 mL of an ethanol solution containing 9.29 mg of sodium hydroxide, stir for 0.5 hours, and concentrate under reduced pressure to obtain a dry solid. 30 mg of this solid was added to 1 mL of 3-pentanone, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 40 ° C to obtain a white solid, namely, D-sakubitra sodium salt.

X-ray powder diffraction was used to characterize the solid form of sacurbitum sodium salt D, and its solid-state characterization parameters and spectra are as described herein.

As measured by the melting point apparatus, the melting point of D-type sacurbitum sodium salt appeared at about 117 ± 5 ° C.

Example 5: Preparation of Sacurbitum Sodium Salt Form E

Dissolve 112 mg of sacurbicid in 2 mL of ethanol, dropwise add 0.5 mL of an ethanol solution containing 9.29 mg of sodium hydroxide, stir for 0.5 hours, and concentrate under reduced pressure to obtain a dry solid. 30 mg of this dry solid was added to 1 mL of 2-butanone, dissolved, and ethyl acetate was added dropwise until turbidity appeared. The turbid solution was centrifuged to discard the supernatant. The obtained solid was dried in an oven at 40 ° C to obtain White solid, that is, E-type Sacurbitone sodium salt.

X-ray powder diffraction was used to characterize the solid form of sacurbitum sodium salt E, and its solid-state characterization parameters and spectra are as described herein.

As measured by a melting point apparatus, the melting point of the E-type sacurbitum sodium salt appeared at about 130 ± 5 ° C.

Example 6 Determination of Hygroscopicity of Crystal Forms of Sacurbitum Sodium in the Present Invention

test methods:

1. Take a dry glass weighing bottle with a stopper (50mm outer diameter and 15mm high) and place it in an artificial climate box (set temperature 25 ± 1 ℃, relative humidity 43.5 ± 2%) the day before and weigh it. (M1).

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

3. Open the weighing bottle and place it at the same temperature and humidity (the set temperature is 25 ± 1 ℃ and the relative humidity is 43.5 ± 2%) with the bottle cap.

4. Cap the weighing bottle before weighing and weigh (m3). Calculate the percentage of water absorption at each time point. The percentage of water absorption = (m3-m2) / (m2-m1) × 100%.

Results: Table 1

From the hygroscopic data in Table 1, it can be known that the crystalline form of the present invention has significantly improved water absorption capacity compared with the amorphous form of sacurbitone sodium salt X, which is suitable for further development.

The above is only a preferred embodiment of the present invention. It should be noted that, for those with ordinary knowledge in the technical field, without departing from the spirit of the present invention, a number of improvements and retouches can be made. These improvements and retouches It should also be regarded as the protection scope of the present invention.

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Fig. 1 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form A of sacurbitux sodium salt.

FIG. 2 is a differential scanning calorimeter (DSC chart) of crystalline form A of sacurbitux sodium salt.

FIG. 3 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form B of sacurbitum sodium salt B. FIG.

FIG. 4 is a differential scanning calorimeter (DSC chart) of crystalline form B of sacurbitux sodium salt.

FIG. 5 is a thermogravimetric analysis chart (TGA chart) of crystalline form B of sacurbitux sodium salt.

FIG. 6 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form C of sacurbitux sodium salt.

Fig. 7 is a powder X-ray diffraction pattern (XRD pattern) of crystalline form D of sacurbitux sodium salt.

Fig. 8 is a powder X-ray diffraction pattern (XRD pattern) of the salt form E of sacurbitux sodium salt.

Claims (15)

A form of sacurbitum sodium salt form A, wherein the form has the following properties: it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 6.0 ± 0.2, 7.0 ± 0.2, 11.8 ± There are peaks at 0.2, 18.2 ± 0.2, 19.7 ± 0.2, and 23.5 ± 0.2. For example, in the first range of the patent application, Sacurbitum sodium salt crystal form A, in which the differential scanning calorimeter has an endothermic peak near 168 ° C under the condition that the heating rate is 10 ° C / min. For example, in the case of the crystalline form A of sacurbitum sodium salt A in the scope of the patent application, the differential scanning calorimetry has an endothermic peak at 166-169 ° C under the condition that the heating rate is 10 ° C / min. A form of sacurbitum sodium salt form B, wherein the form has the following properties: it uses Cu-Ka radiation, the X-ray powder diffraction spectrum expressed in degrees 2θ is about 5.1 ± 0.2, 10.4 ± 0.2, 11.2 ± There are peaks at 0.2, 19.2 ± 0.2, 19.7 ± 0.2, 21.3 ± 0.2, and 21.8 ± 0.2. For example, in the case of the fourth form of the patent application, Sacurbitum sodium salt crystal form B, under the condition of a heating rate of 10 ° C / min, the differential scanning calorimetry has endothermic peaks near 133 ° C and near 159 ° C. . For example, in the case of the application of the fourth scope of the patent Sakubitra sodium salt crystal form B, where the heating rate is 10 ° C / min, the differential scanning calorimetry diagrams are at 130-134 ° C and 149-160 ° C. Endothermic peak. A form of sacurbitum sodium salt form C, wherein the form has the following properties: it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± There are peaks at 0.2, 19.3 ± 0.2, 21.4 ± 0.2, and 22.0 ± 0.2. For example, the crystalline form C of Sacurbitone sodium salt in item 7 of the scope of patent application has a melting point of about 136 ± 5 ° C. A form of sacurbitum sodium salt crystal form D, wherein the crystal form has the following properties: it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 5.2 ± 0.2, 8.7 ± 0.2, 10.4 ± There are peaks at 0.2, 12.2 ± 0.2, and 15.7 ± 0.2. For example, the crystalline form D of sacurbitum sodium salt in item 9 of the scope of patent application has a melting point of about 117 ± 5 ° C. A form of sacurbitum sodium salt form E, wherein the form has the following properties: it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is about 8.2 ± 0.2, 10.4 ± 0.2, 11.0 ± There are peaks at 0.2, 13.9 ± 0.2, 16.7 ± 0.2, and 21.3 ± 0.2. For example, the crystalline form E of sacurbitum sodium salt in the scope of the patent application No. 11 has a melting point of about 130 ± 5 ° C. A pharmaceutical composition comprising the crystalline form of sacurbitum sodium salt and any one of the pharmaceutically acceptable carriers in any one of claims 1-12. For example, the use of the sacurbitum crystal form of any one of the scope of application patents 1-12 for the preparation of a medicine for treating enkephalinase-related diseases. For example, the application in the scope of patent application No. 14 wherein the disease includes heart failure, hypertension and cardiomyopathy.