Stable crystalline hydrate of clazosentan disodium salt

Patent metadata

Field	Value
Publication number	US-12534449-B2
Application number	US-202118251814-A
Country	US
Kind code	B2
Filing date	Nov 4, 2021
Priority date	Nov 5, 2020
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

The present invention relates to a stable hydrate of clazosentan disodium salt, pharmaceutical formulations manufactured using the same and their use as medicaments.

First claim

The invention claimed is:

1 . A crystalline hydrate of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt, wherein said hydrate is characterized by the presence of peaks in the X-ray powder diffractogram at the following angles of refraction 2θ:7.6°, 24.3°, and 25.0°.

2 . The crystalline hydrate according to claim 1 , wherein said hydrate is characterized by the presence of peaks in the X-ray powder diffractogram at the following angles of refraction 2θ:7.6°, 10.6°, 18.5°, 24.3°, and 25.0°.

3 . The crystalline hydrate according to claim 1 , wherein said hydrate is characterized by the presence of peaks in the X-ray powder diffractogram at the following angles of refraction 2θ:7.4°, 7.6°, 10.6°, 12.0°, 16.7°, 18.5°, 22.8°, 24.3°, 25.0° and 25.4°.

4 . The crystalline hydrate according to claim 1 , which shows the X-ray powder diffraction pattern as depicted in FIG. 3 .

5 . A process of manufacture of the crystalline hydrate according to claim 1 , wherein the process comprises exposing a first crystalline hydrate of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt to a relative ambient humidity of at least 70% until the crystalline hydrate according to claim 1 is formed, said first crystalline hydrate comprising from about 1 to about 4 equivalents of coordinated water.

6 . A process of manufacture of the crystalline hydrate according to claim 1 , said process comprising precipitating 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt from an aqueous solution by adding at least one water miscible organic solvent to said solution, such that the water activity in the mixture of water and the water miscible organic solvent(s) is at least 0.2.

7 . A pharmaceutical composition comprising the crystalline hydrate according to claim 1 , and at least one pharmaceutically acceptable carrier material.

8 . A process of manufacture of an aqueous pharmaceutical composition, said process comprising the step of dissolving the crystalline hydrate according to claim 1 .

9 . A method for the prevention/prophylaxis and/or treatment of a disease or disorder, where endothelin receptors are involved, said prevention/prophylaxis and/or treatment comprising administering to a subject in need of such prevention/prophylaxis and/or treatment a pharmaceutical composition, said composition comprising an effective amount of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide in the form of an aqueous solution of the crystalline hydrate according to claim 1 .

10 . A process of manufacture of the crystalline hydrate according to claim 2 , wherein the process comprises exposing a first crystalline hydrate of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt to a relative ambient humidity of at least 70% until the crystalline hydrate according to claim 2 is formed, said first crystalline hydrate comprising from about 1 to about 4 equivalents of coordinated water.

11 . A process of manufacture of the crystalline hydrate according to claim 2 , said process comprising precipitating 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt from an aqueous solution by adding at least one water miscible organic solvent to said solution, such that the water activity in the mixture of water and the water miscible organic solvent(s) is at least 0.2.

12 . A process of manufacture of the crystalline hydrate according to claim 3 , wherein the process comprises exposing a first crystalline hydrate of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt to a relative ambient humidity of at least 70% until the crystalline hydrate according to claim 3 is formed, said first crystalline hydrate comprising from about 1 to about 4 equivalents of coordinated water.

13 . A process of manufacture of the crystalline hydrate according to claim 3 , said process comprising precipitating 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt from an aqueous solution by adding at least one water miscible organic solvent to said solution, such that the water activity in the mixture of water and the water miscible organic solvent(s) is at least 0.2.

14 . A process of manufacture of an aqueous pharmaceutical composition, said process comprising the step of dissolving the crystalline hydrate according to claim 2 .

15 . A process of manufacture of an aqueous pharmaceutical composition, said process comprising the step of dissolving the crystalline hydrate according to claim 3 .

16 . A process of manufacture of an aqueous pharmaceutical composition, said process comprising the step of dissolving the crystalline hydrate according to claim 4 .

17 . A method for the prevention/prophylaxis and/or treatment of a disease or disorder, where endothelin receptors are involved, said prevention/prophylaxis and/or treatment comprising administering to a subject in need of such prevention/prophylaxis and/or treatment a pharmaceutical composition, said composition comprising an effective amount of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide in the form of an aqueous solution of the crystalline hydrate according to claim 2 .

18 . A method for the prevention/prophylaxis and/or treatment of a disease or disorder, where endothelin receptors are involved, said prevention/prophylaxis and/or treatment comprising administering to a subject in need of such prevention/prophylaxis and/or treatment a pharmaceutical composition, said composition comprising an effective amount of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide in the form of an aqueous solution of the crystalline hydrate according to claim 3 .

19 . A method for the prevention/prophylaxis and/or treatment of a disease or disorder, where endothelin receptors are involved, said prevention/prophylaxis and/or treatment comprising administering to a subject in need of such prevention/prophylaxis and/or treatment a pharmaceutical composition, said composition comprising an effective amount of 5-methyl-pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide in the form of an aqueous solution of the crystalline hydrate according to claim 4 .

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Rager Timo
• Von Raumer Markus

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title