17) In a sub-embodiment of any one of embodiments 11), 12), 14) and 15), the water miscible organic solvent/s is/are added until precipitation is formed.

The isolation step v) in embodiments 12) or 15) may be performed by any method known in the art used for separation of solid material from a liquid, preferably by filtration.

It is understood that exposing a crystalline hydrate of COMPOUND as disclosed herein to relative ambient humidity means to allow the a crystalline hydrate of COMPOUND to come into contact with a carrier gas (moving or stationary), said carrier gas comprising air, nitrogen or argon, said carrier gas exhibiting more than 70%; in particular more than 80% relative humidity.

The crystalline hydrates of COMPOUND according to any one of the embodiments disclosed herein may be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral, especially injectable administration.

18) Another embodiment relates to a crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use as a medicament.

The crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) may be used as single crystalline hydrate or as a mixture with other crystalline stoichiometric or non-stoichiometric hydrates and/or amorphous material of COMPOUND.

19) A further embodiment relates to pharmaceutical compositions comprising as active ingredient a crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9), and at least one pharmaceutically acceptable carrier material (notably water).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the crystalline form of the present invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

20) A further embodiment relates to the use of the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) in the manufacture of an aqueous pharmaceutical composition.

21) A further embodiment relates to a process of manufacture an aqueous pharmaceutical composition, said process comprising dissolving the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) (notably in a solvent such as water).

22) A further embodiment relates to the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, wherein said pharmaceutical composition is used as a medicament.

23) A further embodiment relates to the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, wherein said pharmaceutical composition is used for the prevention/prophylaxis and/or treatment of cerebral vasospasm and its subsequent ischemic effects and/or symptoms after aneurysmal subarachnoid hemorrhage (aSAH).

24) A further embodiment relates to the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, wherein said pharmaceutical composition is used for the prevention/prophylaxis and/or treatment of clinical deterioration due to vasospasm-related delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage (aSAH).

25) A further embodiment relates to the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, wherein said pharmaceutical composition is used for the prevention/prophylaxis and/or treatment of clinical deterioration due to vasospasm-related delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage (aSAH).

The term “clinical deterioration” as used herein refers to a worsening of at least two points compared to the reference score, on the mGCS or the aNIHSS scales, lasting for at least 2 hours, which cannot be entirely attributed to causes other than cerebral vasospasm. Clinical deterioration due to delayed cerebral ischemia may be adjudicated based on review of clinical data, case narratives, angiograms and/or CT scans. The term “mGCS” refers to the Glasgow Coma Scale, which is a neurological scale aiming to give a reliable and objective way of recording the state of a person's consciousness. The term “aNIHSS” refers to the abbreviated National Institutes of Health Stroke Scale: a tool used by healthcare providers to objectively quantify the impairment caused by a stroke.

26) A further embodiment relates to the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, wherein said pharmaceutical composition is used for the prevention/prophylaxis and/or treatment of cerebral infarction.

The term “cerebral infarction” as used herein refers to all-cause new or worsened cerebral infarction (notably said infraction having a total volume of more than about 5 cm³). New or worsened cerebral infarctions may be determined by central radiology review comparing CT scans performed 16 days after initiation of therapy with a drug with the CT scan performed before said initiation of therapy.

27) A further embodiment relates to the crystalline hydrate of COMPOUND according to any one of embodiments 1) to 9) for use as a medicament; notably for use in the prevention/prophylaxis and/or treatment of a disease or disorder, where endothelin receptors are involved; especially for use for the prevention/prophylaxis and/or treatment of cerebral vasospasm and its subsequent ischemic effects and/or symptoms after aneurysmal subarachnoid hemorrhage (aSAH).

The present invention also relates to a method for the prevention/prophylaxis and/or treatment of a disease or disorder, where endothelin receptors are involved, especially in the prevention/prophylaxis and/or treatment of cerebral vasospasm and its subsequent ischemic effects and/or symptoms after aneurysmal subarachnoid hemorrhage (aSAH), 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, as an active ingredient, 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 of COMPOUND according to any one of embodiments 1) to 9).

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 (clazosentan free acid), as used herein, refers to the compound of Formula 2

[Image Omitted]

The term “effective amount” as used herein refers to a dose from about 5 mg/day to about 20 mg/day (especially from about 10 mg/day to about 15 mg/day) administered to a subject for up to 20 days (especially for up to 14 days). The effective amount is preferably administered intravenously and more preferably intravenously as a solution in water.

The term “solvate(s)” either used alone or in combination is understood in the context of the present invention to mean an aggregate comprising a compound or a salt thereof as defined herein and one or more molecules of a solvent. Hydrates are a special form of solvates, wherein the one or more solvent molecules comprised in said aggregate are water molecules.

The term “wt.” signifies weight (e.g. in kg) of a substance (e.g. reactant) per weight (e.g. in kg) of a starting material (such as COMPOUND) or a solvent (such as water).

The term “equivalent(s)”, also abbreviated “eq.”, refers to the number of moles of a compound that reacts with (or is equivalent to) an arbitrary number of moles of another compound in a given chemical reaction. In the case of solvates/hydrates of COMPOUND as disclosed herein, said term refers to the number of molecules of solvent/water per one molecule of COMPOUND.

The term “prevention” as used herein also means prophylaxis.

COMPOUND in its crystalline forms as disclosed herein may be present in different isomeric/tautomeric forms with respect to the position of the sodium atom in the tetrazole ring and/or in the sulfonamide group as depicted below.

[Image Omitted]

It is thus understood that all possible isomers/tautomers of COMPOUND in its crystalline hydrate forms are within the scope of the present invention, even though only one isomer/tautomer may be described herein (e.g. Formula 1). In solution, said isomers/tautomers exist usually as mixtures of different isomeric/tautomeric forms; in the solid state typically one form predominates. The asterisks “*” and “**” in the formulas hereinabove denote the point of attachment of the corresponding group to the rest of the molecule of COMPOUND.

Based on the dependencies of the different embodiments 1) to 27) as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form:

2+1, 3+1, 4+1, 5+1, 5+2+1, 5+3+1, 6+1, 6+2+1, 6+3+1, 6+4+1, 6+5+1, 6+5+2+1, 6+5+3+1, 7+1, 7+2+1, 7+3+1, 7+4+1, 7+5+1, 7+5+2+1, 7+5+3+1, 8+1, 8+2+1, 8+3+1, 8+4+1, 8+5+1, 8+5+2+1, 8+5+3+1, 9+1, 9+2+1, 9+3+1, 9+4+1, 9+5+1, 9+5+2+1, 9+5+3+1, 10+1, 10+2+1, 10+3+1, 10+4+1, 10+5+1, 10+5+2+1, 10+5+3+1, 10+6+1, 10+6+2+1, 10+6+3+1, 10+6+4+1, 10+6+5+1, 10+6+5+2+1, 10+6+5+3+1, 10+7+1, 10+7+2+1, 10+7+3+1, 10+7+4+1, 10+7+5+1, 10+7+5+2+1, 10+7+5+3+1, 10+8+1, 10+8+2+1, 10+8+3+1, 10+8+4+1, 10+8+5+1, 10+8+5+2+1, 10+8+5+3+1, 10+9+1, 10+9+2+1, 10+9+3+1, 10+9+4+1, 10+9+5+1, 10+9+5+2+1, 10+9+5+3+1, 11+1, 11+2+1, 11+3+1, 11+4+1, 11+5+1, 11+5+2+1, 11+5+3+1, 11+6+1, 11+6+2+1, 11+6+3+1, 11+6+4+1, 11+6+5+1, 11+6+5+2+1, 11+6+5+3+1, 11+7+1, 11+7+2+1, 11+7+3+1, 11+7+4+1, 11+7+5+1, 11+7+5+2+1, 11+7+5+3+1, 11+8+1, 11+8+2+1, 11+8+3+1, 11+8+4+1, 11+8+5+1, 11+8+5+2+1, 11+8+5+3+1, 11+9+1, 11+9+2+1, 11+9+3+1, 11+9+4+1, 11+9+5+1, 11+9+5+2+1, 11+9+5+3+1, 12+1, 12+2+1, 12+3+1, 12+4+1, 12+5+1, 12+5+2+1, 12+5+3+1, 12+6+1, 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22+9+3+1,22+9+4+1, 22+9+5+1, 22+9+5+2+1,22+9+5+3+1, 23+1, 23+2+1, 23+3+1, 23+4+1, 23+5+1, 23+5+2+1, 23+5+3+1, 23+6+1, 23+6+2+1, 23+6+3+1, 23+6+4+1, 23+6+5+1, 23+6+5+2+1, 23+6+5+3+1, 23+7+1, 23+7+2+1, 23+7+3+1, 23+7+4+1, 23+7+5+1, 23+7+5+2+1, 23+7+5+3+1, 23+8+1, 23+8+2+1, 23+8+3+1, 23+8+4+1, 23+8+5+1, 23+8+5+2+1, 23+8+5+3+1, 23+9+1, 23+9+2+1, 23+9+3+1, 23+9+4+1, 23+9+5+1, 23+9+5+2+1,23+9+5+3+1, 24+1, 24+2+1,24+3+1, 24+4+1,24+5+1,24+5+2+1,24+5+3+1,24+6+1,24+6+2+1, 24+6+3+1, 24+6+4+1, 24+6+5+1, 24+6+5+2+1, 24+6+5+3+1, 24+7+1, 24+7+2+1, 24+7+3+1, 24+7+4+1, 24+7+5+1, 24+7+5+2+1, 24+7+5+3+1, 24+8+1, 24+8+2+1, 24+8+3+1, 24+8+4+1, 24+8+5+1, 24+8+5+2+1, 24+8+5+3+1, 24+9+1, 24+9+2+1, 24+9+3+1, 24+9+4+1, 24+9+5+1, 24+9+5+2+1, 24+9+5+3+1, 25+1, 25+2+1, 25+3+1, 25+4+1, 25+5+1, 25+5+2+1, 25+5+3+1, 25+6+1, 25+6+2+1, 25+6+3+1, 25+6+4+1, 25+6+5+1, 25+6+5+2+1, 25+6+5+3+1, 25+7+1, 25+7+2+1, 25+7+3+1, 25+7+4+1, 25+7+5+1, 25+7+5+2+1, 25+7+5+3+1, 25+8+1, 25+8+2+1, 25+8+3+1, 25+8+4+1, 25+8+5+1,25+8+5+2+1,25+8+5+3+1, 25+9+1,25+9+2+1, 25+9+3+1,25+9+4+1, 25+9+5+1, 25+9+5+2+1,25+9+5+3+1, 26+1, 26+2+1, 26+3+1, 26+4+1, 26+5+1, 26+5+2+1, 26+5+3+1, 26+6+1, 26+6+2+1, 26+6+3+1, 26+6+4+1, 26+6+5+1, 26+6+5+2+1, 26+6+5+3+1, 26+7+1, 26+7+2+1, 26+7+3+1, 26+7+4+1, 26+7+5+1, 26+7+5+2+1, 26+7+5+3+1, 26+8+1, 26+8+2+1, 26+8+3+1, 26+8+4+1, 26+8+5+1, 26+8+5+2+1, 26+8+5+3+1, 26+9+1, 26+9+2+1, 26+9+3+1, 26+9+4+1, 26+9+5+1, 26+9+5+2+1,26+9+5+3+1, 27+1, 27+2+1,27+3+1, 27+4+1,27+5+1,27+5+2+1,27+5+3+1,27+6+1,27+6+2+1, 27+6+3+1, 27+6+4+1, 27+6+5+1, 27+6+5+2+1, 27+6+5+3+1, 27+7+1, 27+7+2+1, 27+7+3+1, 27+7+4+1, 27+7+5+1, 27+7+5+2+1, 27+7+5+3+1, 27+8+1, 27+8+2+1, 27+8+3+1, 27+8+4+1, 27+8+5+1, 27+8+5+2+1, 27+8+5+3+1, 27+9+1, 27+9+2+1,27+9+3+1,27+9+4+1,27+9+5+1,27+9+5+2+1, or27+9+5+3+1.