Crystalline form of sacubitril sodium salt

Abstract

Provided are new crystalline forms A, B, C, D and E of sacubitril sodium salt and a method for preparation thereof, pharmaceutical compositions thereof, and application thereof in preparing drugs for enkephalinase-related diseases.

Claims

1. A crystalline form A of sacubitril sodium salt, wherein, the crystalline form has the following properties: by using a Cu-Ka radiation, its X-ray powder diffraction spectrum shows peaks at about 6.00.2, 7.00.2, 11.80.2, 18.20.2, 19.70.2, and 23.50.2, expressed in degrees 2.

2. The crystalline form A of sacubitril sodium salt according to claim 1, wherein, at a heating rate of 10 C./min, a differential scanning calorimetry thermogram of said crystalline form A of sacubitril sodium salt shows an endothermic peak at around 168 C.

3. The crystalline form A of sacubitril sodium salt according to claim 1, wherein, at a heating rate of 10 C./min, a differential scanning calorimetry thermogram of said crystalline form A of sacubitril sodium salt shows an endothermic peak at around 166-169 C.

4. A crystalline form B of sacubitril sodium salt, wherein, the crystalline form has the following properties: by using a Cu-Ka radiation, its X-ray powder diffraction spectrum shows peaks at about 5.10.2, 10.40.2, 11.20.2, 19.20.2, 19.70.2, 21.30.2, and 21.80.2, expressed in degrees 2.

5. The crystalline form B of sacubitril sodium salt according to claim 4, wherein, at a heating rate of 10 C./min, a differential scanning calorimetry thermogram of said crystalline form B of sacubitril sodium salt shows endothermic peaks at around 133 C. and 159 C.

6. The crystalline form B of sacubitril sodium salt according to claim 4, wherein, at a heating rate of 10 C./min, a differential scanning calorimetry thermogram of said crystalline form B of sacubitril sodium salt shows endothermic peaks at 130-134 C. and 149-160 C.

7. A crystalline form C of sacubitril sodium salt, wherein, the crystalline form has the following properties: by using a Cu-Ka radiation, its X-ray powder diffraction spectrum shows peaks at about 6.50.2, 10.50.2, 11.20.2, 19.30.2, 21.40.2, 22.00.2, expressed in degree 20.

8. The crystalline form C of the sacubitril sodium salt according to claim 7, which has a melting point of about 1365 C.

9. A crystalline form D of sacubitril sodium salt, wherein, the crystalline form has the following properties: by using a Cu-Ka radiation, its X-ray powder diffraction spectrum shows peaks at about 5.20.2, 8.70.2, 10.40.2, 12.20.2, and 15.70.2, expressed in degrees 2.

10. The crystalline form D of the sacubitril sodium salt according to claim 9, which has a melting point of about 1175 C.

11. A crystalline form E of sacubitril sodium salt, wherein, the crystalline form has the following properties: by using a Cu-Ka radiation, its X-ray powder diffraction spectrum shows peaks at about 8.20.2, 10.40.2, 11.00.2, 13.90.2, 16.70.2, and 21.30.2, expressed in degree 2.

12. The crystalline form E of the sacubitril sodium salt according to claim 11, which has a melting point of about 1305 C.

13. A pharmaceutical composition, comprising: the crystalline form A of sacubitril sodium salt according to claim 1; and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition, comprising: the crystalline form B of sacubitril sodium salt according to claim 4; and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition, comprising: the crystalline form C of sacubitril sodium salt according to claim 7; and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition, comprising: the crystalline form D of sacubitril sodium salt according to claim 9; and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition, comprising: the crystalline form E of sacubitril sodium salt according to claim 11; and a pharmaceutically acceptable carrier.

18. A method for treating enkephalinase-related disease, comprising: administering the crystalline form A of sacubitril sodium salt according to claim 1 to a subject in need thereof.

19. The method according to claim 18, wherein the disease comprises heart failure, hypertension, and cardiomyopathy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows an X-ray powder diffraction (XRD) pattern of a crystalline form A of sacubitril sodium salts.

(2) FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form A of sacubitril sodium salts.

(3) FIG. 3 shows an X-ray powder diffraction (XRD) pattern of a crystalline form B of sacubitril sodium salts.

(4) FIG. 4 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form B of sacubitril sodium salts.

(5) FIG. 5 shows a thermogravimetric analysis (TGA) thermogram of a crystalline form B of sacubitril sodium salts.

(6) FIG. 6 shows an X-ray powder diffraction (XRD) pattern of a crystalline form C of sacubitril sodium salts.

(7) FIG. 7 shows an X-ray powder diffraction (XRD) pattern of a crystalline form D of sacubitril sodium salts.

(8) FIG. 8 shows an X-ray powder diffraction (XRD) pattern of a crystalline form E of sacubitril sodium salts.

DETAILED DESCRIPTION OF THE INVENTION

(9) The above summary of the present invention will be further described with reference to the embodiments of the following examples. However, it should not be understood that the content of the present invention is only limited to the following embodiments, and all the inventions based on the above-mentioned contents of the present invention belong to the scope of the present invention.

COMPARISON EXAMPLE 1

Preparation of Sacubitril Sodium Salt X

(10) The sacubitril sodium salt X was prepared according to the method of Example 1 of U.S. Pat. No. 5,217,996, and the resulting sacubitril sodium salt X had a melting point of 159-160 C.

COMPARISON EXAMPLE 2

Preparation of Amorphous Form of Sacubitril Sodium Salts

(11) 1.0 g of sacubitril free acid was suspended in 10 mL of water, and sodium hydroxide solution (97 mg/1 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 h, and the solution was lyophilized to obtain a white powdery solid.

EXAMPLE 1

Preparation of the Crystalline Form A of Sacubitril Sodium Salt

(12) 112 mg of sacubitril was dissolved in 2 mL of ethanol, and an ethanol solution containing 10.9 mg of sodium hydroxide per 0.1 mL was added dropwise. The mixture was stirred for 0.5 h, and concentrated under reduced pressure, and the obtained residue was suspended with 300 mL of ethanol/n-heptane ( 1/19, by volume) and stirred overnight, filtered, and vacuum dried at 40 C. to yield a solid. The solid was added to 10 mL of isopropanol, and after stirring for 72 hours, the supernatant was discarded after centrifugation, and the obtained solid was dried in an oven at 40 C. to yield a white solid, which is a type A sacubitril sodium salt.

(13) This sacubitril sodium salt crystalline form A was subjected to a solid-state characterization by X-ray powder diffraction and differential scanning calorimetry. The solid-state characterization parameters and spectrums are as described herein.

(14) By using a melting point apparatus, the melting of the crystalline form A of sacubitril sodium salts was observed at around 167-168 C.

EXAMPLE 2

Preparation of Crystalline Form B of Sacubitril Sodium Salt

(15) 112 mg of sacubitril was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise. The mixture was stirred for 0.5 hour, and concentrated under reduced pressure to obtain a dry solid. 30 mg of the dry solid was dissolved in 0.6 mL of ethanol, and the small glass bottle in which the solution was placed was sealed with a sealing film, and the hole was punched, placed in a glass bottle containing 5 mL of ethyl acetate, and the cap was screwed. After standing at room temperature for 15 days, the small glass bottle was taken out, and the supernatant was discarded after centrifugation to yield a white solid, which is a type B sacubitril sodium salt.

(16) This sacubitril sodium salt crystalline form B was subjected to a solid-state characterization by X-ray powder diffraction and differential scanning calorimetry. The solid-state characterization parameters and spectrums are as described herein.

(17) By using a melting point apparatus, the melting of the crystalline form B of sacubitril sodium salts was observed at around 133-136 C.

EXAMPLE 3

Preparation of Crystalline Form C of Sacubitril Sodium Salt

(18) 112 mg of sacubitril was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise. The mixture was stirred for 0.5 hour, and concentrated under reduced pressure to obtain a dry solid. 30 mg of the dry solid was added to 1 mL of isopropanol, and after stirring for 72 hours, the supernatant was discarded after centrifugation, and the obtained solid was dried in an oven at 40 C. to yield a white solid, which is a type C sacubitril sodium salt.

(19) This sacubitril sodium salt crystalline form C was subjected to a solid-state characterization by X-ray powder diffraction. The solid-state characterization parameters and spectrums are as described herein.

(20) By using a melting point apparatus, the melting of the crystalline form C of sacubitril sodium salts was observed at around 1365 C.

EXAMPLE 4

Preparation of Crystalline Form D of Sacubitril Sodium Salt

(21) 112 mg of sacubitril was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise. The mixture was stirred for 0.5 hour, and concentrated under reduced pressure to obtain a dry solid. 30 mg of the dried solid was added to 1 mL of 3-pentanone, and after stirring for 72 hours, the supernatant was discarded after centrifugation, and the obtained solid was dried in an oven at 40 C. to yield a white solid, which is a type D sacubitril sodium salt.

(22) This sacubitril sodium salt crystalline form D was subjected to a solid-state characterization by X-ray powder diffraction. The solid-state characterization parameters and spectrums are as described herein.

(23) By using a melting point apparatus, the melting of the crystalline form D of sacubitril sodium salts was observed at around 1175 C.

EXAMPLE 5

Preparation of the Crystalline Form E of Sacubitril Sodium Salt

(24) 112 mg of sacubitril was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise. The mixture was stirred for 0.5 hour, and concentrated under reduced pressure to obtain a dry solid. 30 mg of the dried solid was added to 1 mL of 2-butanone, dissolved, and ethyl acetate was added dropwise until turbidity appeared. The supernatant was discarded after centrifugation, and the obtained solid was dried in an oven at 40 C. to yield a white solid, which is a type E sacubitril sodium salt.

(25) This sacubitril sodium salt crystalline form E was subjected to a solid-state characterization by X-ray powder diffraction. The solid-state characterization parameters and spectrums are as described herein.

(26) By using a melting point apparatus, the melting of the crystalline form E of sacubitril sodium salts was observed at around 1305 C.

EXAMPLE 6

Determination of the Hygroscopicity of Each Crystalline Form of Sacubitril Sodium Salt of the Present Invention

(27) Analysis method:

(28) 1. Take a dry stuffed glass weighing bottle (outer diameter 50 mm, height 15 mm) in the artificial climate chamber (set temperature is 251 C., relative humidity is 43.52%) and weight it (m.sub.1).

(29) 2. Take the appropriate amount of the crystalline form in the present invention, and place it in the abovementioned weighing bottle and lay it inside the weighing bottle. The thickness of the test sample is generally about 1 mm. Weight the sample (m.sub.2).

(30) 3. Uncover the weighing bottle and place it with the bottle cap under constant temperature and humidity (set temperature is 251 C., relative humidity is 43.52%).

(31) 4. Put the cap back on the weighing bottle before weighing, and then weight it (m.sub.3). The water absorption percentage for each time point is calculated by the formula=(m.sub.3m.sub.2)/(m.sub.2m.sub.1)100%.

(32) Results:

(33) TABLE-US-00001 TABLE 1 Time Crystalline form Water absorption, % 1.5 h amorphous form 7.1% 1.5 h sacubitril sodium salt X 8.3% 1.5 h A 0.6% 1.5 h B 0.5% 1.5 h C 1.2% 1.5 h D 1.5% 1.5 h E 2.4% 3 h amorphous form 12.8% 3 h sacubitril sodium salt X 11.0% 3 h A 1.4% 3 h B 1.0% 3 h C 2.4% 3 h D 3.2% 3 h E 4.3%

(34) From the hygroscopicity data shown in Table 1, the crystalline form of the present invention has significantly improved hygroscopicity than the amorphous form as well as the disclosed sacubitril sodium salt X, and is suitable for further development.

(35) The above description merely relates to preferred embodiments in the present invention, and it should be pointed out that, for a person of ordinary skill in the art, some improvements and modifications can also be made under the premise of not departing from the principle of the present invention, and these improvements and modifications should also be considered to be within the scope of protection of the present invention.