Solid state forms of trisodium valsartan: sacubitril

Patent metadata

Field	Value
Publication number	US-10689352-B2
Application number	US-201615735717-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Jun 12, 2015
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

Solid state forms of trisodium vaisartan:sacubitril, processes for their preparation, pharmaceutical compositions containing such solid state forms and treatment methods using the pharmaceutical compositions are described.

First claim

The invention claimed is:

1. Crystalline form II of trisodium valsartan: sacubitril characterized by an X-ray powder diffraction pattern having peaks at: 7.3, 16.5, 9.4, 10.9 and 14.7 degrees two theta±0.2 degrees two theta, and an absence of a peak at 12.4 degrees two theta±0.2 degrees two theta.

2. A crystalline form according to claim 1 , which is characterized by an X-ray powder diffraction pattern as depicted in FIG. 1 .

3. A crystalline form according to claim 1 , which is characterized by the X-ray powder diffraction pattern having additional peaks at: 4.3, 5.8, 10.0, 12.9, 15.9 and 18.6 two theta±0.2 degrees two theta.

4. A crystalline form according to claim 1 , which is further characterized by the X-ray powder diffraction pattern having peaks at 4.3, 5.8, 7.3, 9.4, 10.0, 10.9, 12.9, 14.7, 15.9, 16.5, and 18.6 two theta±0.2 degrees two theta±0.2 degrees two theta.

5. A crystalline form according to claim 1 , further characterized by an X-ray powder diffraction pattern having peaks at: 4.3, 5.0, 5.5, 5.8, 7.3, 8.5, 8.9, 9.4, 10.0, 10.9, 11.6, 12.9, 13.7, 13.9, 14.7, 14.8, 15.1, 15.3, 15.9, 16.5, 17.3, 17.6, 18.6, 19.1, 19.5, 20.3, 21.2, 21.9 and 23.1 degrees two theta±0.2 degrees two theta.

6. A crystalline form according to claim 1 , wherein the crystalline form contains from 5.2 to 5.7 wt % water.

7. A crystalline form according to claim 1 , comprising agglomerates having spherical morphology, wherein at least 50% of the agglomerates have spherical morphology.

8. A crystalline form according to claim 1 , further characterized by a solid state 13 C NMR spectrum having peaks at 176.8, 161.9, 141.1, 139.5, 138.6, 137.2, 129.3, 128.7, 126.3, 124.9, 64.2, 60.6, 47.5, 46.1, 40.1, 39.0, 38.1, 34.3, 32.7, 29.8, 28.2, 22.4, 20.2, 17.8, 16.5, 13.7, 11.7 ppm±0.2 ppm.

9. A crystalline form according to claim 1 , which contains 20% (w/w) or less of a trisodium valsartan: sacubitril polymorph that is different from crystalline form II.

10. A crystalline form according to claim 1 , which contains 10% (w/w) or less of a trisodium valsartan: sacubitril polymorph that is different from crystalline form II.

11. A crystalline form according to claim 1 , which contains 5% (w/w) or less of a trisodium valsartan: sacubitril polymorph that is different from crystalline form II.

12. A crystalline form according to claim 1 , further characterized by X-ray powder diffraction d-spacings at: 20.341, 15.261, 12.068, 9.397, 8.826, 8.092, 6.863, 6.024, 5.583, 5.353 and 4.773 ű0.1 Å.

13. A pharmaceutical composition or formulation comprising a crystalline form II of trisodium valsartan: sacubitril as defined in claim 1 and at least one pharmaceutically acceptable excipient.

14. A process for preparing a pharmaceutical composition or formulation according claim 13 comprising combining form II of trisodium valsartan: sacubitril with at least one pharmaceutically acceptable excipient.

15. A method of treating hypertension or heart failure in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of trisodium valsartan: sacubitril form II as defined in claim 1 ; or a pharmaceutical formulation comprising the therapeutically amount of trisodium valsartan: sacubitril form II as defined in claim 1 and at least one pharmaceutically acceptable excipient.

16. A process for preparing a crystalline form II of trisodium valsartan: sacubitril comprising:
combining trisodium valsartan: sacubitril with an aromatic solvent and heating to about 80° C. to about 150° C. to form a solution, wherein the aromatic solvent is toluene, chlorobenzene, fluorobenzene, m-xylene, o-xylene, p-xylene, anisole, or methyl benzoate;
cooling the solution to about 4° C. to about 28° C. to form a mixture; and
isolating the crystalline form from the mixture;
wherein the crystalline form II of trisodium valsartan: sacubitril is characterized by an X-ray powder diffraction pattern having peaks at: 7.3, 16.5, 9.4, 10.9 and 14.7 degrees two theta±0.2 degrees two theta, and an absence of a peak at 12.4 degrees two theta±0.2 degrees two theta.

17. A process for preparing a crystalline form II of trisodium valsartan: sacubitril comprising:
combining disodium valsartan and sacubitril sodium with an aromatic solvent and heating to about 80° C. to about 150° C. to form a solution, wherein the aromatic solvent is toluene, chlorobenzene, fluorobenzene, m-xylene, o-xylene, p-xylene, anisole, or methyl benzoate;
cooling the solution to about 4° C. to about 28° C. and/or removing at least a portion of the solvent to obtain a mixture, and
isolating the crystalline form from the mixture;
wherein the crystalline form II of trisodium valsartan: sacubitril is characterized by an X-ray powder diffraction pattern having peaks at: 7.3, 16.5, 9.4, 10.9 and 14.7 degrees two theta±0.2 degrees two theta, and an absence of a peak at 12.4 degrees two theta±0.2 degrees two theta.

18. The process of claim 17 , wherein the solvent is toluene.

19. A process for preparing a crystalline form II of trisodium valsartan: sacubitril comprising:
providing a solution of sacubitril in a solvent that is ethyl acetate and/or toluene, optionally wherein the solution of sacubitril in a solvent is prepared by combining an alkali or alkali earth metal salt of sacubitril in the solvent and acidifying with an aqueous mineral acid;
adding valsartan acid and a sodium base to the solution to form a mixture;
optionally removing the solvent and adding toluene and water to form the mixture, heating the mixture up to 80° C. and then cooling the mixture to about 20° C.; and
isolating the crystalline form;
wherein the crystalline form II of trisodium valsartan: sacubitril is characterized by an X-ray powder diffraction pattern having peaks at: 7.3, 16.5, 9.4, 10.9 and 14.7 degrees two theta±0.2 degrees two theta, and an absence of a peak at 12.4 degrees two theta±0.2 degrees two theta.

20. A crystalline form II of trisodium valsartan: sacubitril obtainable by a process according to claim 16 .

21. A crystalline form II of trisodium valsartan: sacubitril obtainable by a process according to claim 17 .

22. A crystalline form II of trisodium valsartan: sacubitril obtainable by a process according to claim 19 .

Assignees

• Teva Pharmaceuticals Int Gmbh

Inventors

• Leksic Edislav
• Samec Dijana Skalec
• Sahnic Damir
• Kisicek Dejan
• Hrkovac Martina
• Topic Edi

Classifications

• C07D257/04 Primary

  Five-membered rings · CPC title

• C07C233/47

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61K31/41

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• A61K31/225

  Polycarboxylic acids · CPC title