Stable crystalline hydrate of clazosentan disodium salt

Abstract

The present invention relates to stable hydrates of clazosentan disodium salt, pharmaceutical formulations prepared therewith and their use as medicaments.

Description

Technical Field

[0001] The present invention relates to a novel crystalline hydrate of clazosentan disodium salt, a method for producing the same, a pharmaceutical preparation having the crystalline hydrate, and use as an endothelin receptor antagonist in the treatment or prevention of diseases or disorders involving endothelin receptors. Particularly, it relates to their use in the manufacture of a medicament for use in the prevention and / or treatment of cerebral vasospasm and subsequent ischemic effects / symptoms after life-threatening aneurysmal subarachnoid hemorrhage (aSAH).

Background Art

[0002] Clazosentan disodium salt (hereinafter also referred to as "compound") is known by several systematic names such as N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyrimidin-4-yl]-pyridin-4-yl}-5-methyl-pyridine-2-sulfonic acid disodium salt or N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-5-methyl-pyridine-2-sulfonic acid hydrochloride (1:2). Clazosentan is also known in the art by its laboratory codes, ACT-108475 (free acid), AXV-034343 (free acid), AXV-034343A (disodium salt), ACT-108475A (disodium salt), VML 588 and Ro 61-1790. The "compound" may be represented by the following structure:

[0003]

Chemical Formula

[0004] WO9619459, EP0897914, and EP0979822 disclose several endothelin receptor antagonists, including clazosentan, and their synthesis. Clazosentan has been evaluated in several human clinical trials, e.g., NCT00940095, NCT03585270, JapicCTI-163369, and JapicCTI-163368, in the disease and / or pathology associated with aneurysmal subarachnoid hemorrhage (aSAH). [Brief explanation of the drawing]

[0005] [Figure 1] Figure 1 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 2]Figure 2 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 3] Figure 3 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 4] Figure 4 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 5]Figure 5 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 6] Figure 6 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 7] Figure 7 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 8]Figure 8 shows powder X-ray diffractograms of the corresponding crystalline solvate / hydrate forms of "compounds" shown in the table below, where the powder X-ray diffractogram is expressed as a function of the refraction angle 2θ of Cu Kα irradiation. The X-ray diffractogram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the indicated refraction angle of 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities of 10% or greater than 10% from 2theta in the range of 5-35° are reported). [Figure 9] Figure 9 shows the powder X-ray diffractogram of the solid product of Reference Example 1. [Figure 10] Figure 10 shows the gravimetric vapor adsorption (GVS) analysis of the corresponding crystalline hydrate forms of "compounds" (shown in the table below), with the relative change in mass (%) due to water absorption or release shown against relative humidity (%). [Figure 11] Figure 11 shows the gravimetric vapor adsorption (GVS) analysis of the corresponding crystalline hydrate forms of "compounds" (shown in the table below), with the relative change in mass (%) due to water absorption or release shown against relative humidity (%). [Figure 12] Figure 12 shows the gravimetric vapor adsorption (GVS) analysis of the corresponding crystalline hydrate forms of "compounds" (shown in the table below), with the relative change in mass (%) due to water absorption or release shown against relative humidity (%). [Figure 13] Figure 13 shows the gravimetric vapor adsorption (GVS) analysis of the corresponding crystalline hydrate forms of "compounds" (shown in the table below), with the relative change in mass (%) due to water absorption or release shown against relative humidity (%). [Figure 14] Figure 14 shows the gravimetric vapor adsorption (GVS) analysis of the corresponding crystalline hydrate forms of "compounds" (shown in the table below), with the relative change in mass (%) due to water absorption or release shown against relative humidity (%). [Figure 15] Figure 15 shows the gravimetric vapor adsorption (GVS) analysis of the corresponding crystalline hydrate forms of "compounds" (shown in the table below), with the relative change in mass (%) due to water absorption or release shown against relative humidity (%). [Figure 16]Figure 16 shows the thermogravimetric analysis (TGA) of the crystalline hydrate form C "compound," with the relative mass (percentage of the total mass of the sample) on the vertical axis relative to temperature (°C).

[0006] [Table 1]

[0007] [Table 2]

[0008] To avoid any doubt, the peaks described above describe the experimental results of powder X-ray diffraction shown in Figures 1 to 8. In contrast to the above list of peaks, it should be understood that only selected characteristic peaks are necessary to fully and clearly characterize each crystal form of the “compound” of the present invention. [Overview of the project]

[0009] Detailed description of the present invention 1) One aspect of the present invention relates to crystalline hydrates of "compounds". A crystalline hydrate according to any one aspect of this specification may contain, in addition to coordinating water, a non-coordinating solvent (especially water). In this specification, "non-coordinating solvent (especially water)" is used as a term for a physicoadsorbent or physicocapture solvent (especially water) (as defined in *Polymorphism in the Pharmaceutical Industry* (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Solvates). The crystalline hydrates described herein may contain non-coordinating water and / or one or more non-coordinating organic solvents. Furthermore, a crystalline hydrate according to any one aspect of this specification shall be a solid.

[0010] 2) Another aspect relates to a crystalline hydrate according to embodiment 1), wherein the crystalline hydrate has from about 4.5 to about 5.5 (especially from 4.7 to about 5.3; particularly from about 4.5 to about 5.0) equivalents of coordinated water.

[0011] 3) Another aspect relates to a crystalline hydrate according to embodiment 1), wherein the crystalline hydrate has about 5.0 equivalents [i.e., about 12.7% w / w (especially relative to the wet weight of the “compound”)] of coordinated water. The crystalline hydrate according to embodiment 3) can be regarded as the corresponding hydrate in a fully hydrated state.

[0012] 4) Another aspect relates to a crystalline hydrate according to embodiment 1), wherein the crystalline hydrate has from about 11.5% w / w to about 13.7% w / w (especially from about 12% w / w to about 13.3% w / w; particularly from about 11.5% w / w to about 12.7% w / w) of coordinated water (especially relative to the wet weight of the “compound”).

[0013] The amount of coordinated water expressed as “% w / w” as defined in any of the embodiments disclosed herein is calculated relative to the wet weight of the “compound”, i.e., relative to the weight of the “compound” in its corresponding hydrated form. The determination of the amount of coordinated water relative to the wet weight of the “compound” shall involve the steps of drying a specific amount of the “compound” in its hydrated form until all water is removed, and calculating the weight loss relative to that specific amount. The amount of coordinated water expressed as “% w / w” as defined in any of the embodiments disclosed herein may also be expressed relative to the dry weight of the “compound”, i.e., relative to the weight of the “compound” after all crystal water has been completely removed. The complete removal of this crystal water may be effected, for example, by exposing the hydrate of the “compound” described herein to 0% relative humidity at 25°C for 1 to 4 hours or longer (e.g., in the GVS apparatus described in the present application). Accordingly, embodiment 4) may also be expressed as relating to a crystalline hydrate according to embodiment 1), wherein the crystalline hydrate has from about 13.0% w / w to about 15.9% w / w (especially from about 13.6% w / w to about 15.4% w / w; particularly from about 13.0% w / w to about 14.5% w / w) of coordinated water relative to the dry weight of the “compound”.

[0014] 5) Another embodiment relates to a crystalline hydrate that substantially has the TGA curve shown in Figure 16; and / or the GVS curve shown in Figure 10, and conforms to any one of embodiments 1) to 3).

[0015] 6) Another embodiment relates to a crystalline hydrate according to any one of embodiments 1) to 5), characterized by the presence of peaks at the following refraction angles 2θ: 7.6°, 24.3°, and 25.0° in a powder X-ray diffractogram.

[0016] 7) Another embodiment relates to a crystalline hydrate according to any one of embodiments 1) to 5), characterized by the presence of peaks in the powder X-ray diffractogram at the following refraction angles 2θ: 7.6°, 10.6°, 18.5°, 24.3°, and 25.0°.

[0017] 8) Another embodiment relates to a crystalline hydrate according to any one of embodiments 1) to 5), characterized by the presence of peaks in the powder X-ray diffractogram at the following refraction angles 2θ: 7.4°, 7.6°, 10.6°, 12.0°, 16.7°, 18.5°, 22.8°, 24.3°, 25.0°, and 25.4°.

[0018] 9) Another embodiment relates to a crystalline hydrate that essentially exhibits the powder X-ray diffraction pattern shown in Figure 3, according to any one of embodiments 1) to 5).

[0019] To avoid any doubt, whenever one of the above embodiments refers to "a peak at the following refraction angle 2θ in a powder X-ray diffractogram," it should be understood that the powder X-ray diffractogram is obtained using coupled Cu Kα1 and Kα2 irradiation without removing Kα2; and the accuracy of the 2θ values ​​provided herein is within the range of + / -0.1 to 0.2°. In particular, when specifying a refraction angle 2theta (2θ) for a peak in the embodiments and claims of the present invention, the stated 2θ value should be understood to be between -0.2° and +0.2° (2θ+ / -0.2°); and preferably between -0.1° and +0.1° (2θ+ / -0.1°).

[0020] When the plural form is used for compounds, solids, crystalline forms, hydrates, compositions, diseases, etc., it is intended to also refer to the singular compound, solid, crystalline form, hydrate, composition, disease, etc.

[0021] The definitions set forth herein apply uniformly to the subject matter defined in any one of the embodiments disclosed herein, and apply throughout this specification and the claims with necessary modifications unless broader or narrower definitions are provided by specific definitions. Naturally, a definition or preferred definition of a term or expression may independently (and together with) define and replace any or all other terms or expressions defined herein or in any preferred definition.

[0022] For example, when defining the presence of a peak in a powder X-ray diffractogram, the usual method is to do so in terms of the signal-to-noise ratio (S=signal, N=noise). According to this definition, if we say that a peak must exist in a powder X-ray diffractogram, it is understood that the peak in the powder X-ray diffractogram is defined by having a signal-to-noise ratio (S=signal, N=noise) greater than x (where x is a number greater than 1), usually greater than 2, and especially greater than 3.

[0023] In the context of a crystal form essentially representing the powder X-ray diffraction pattern shown in a figure, the term “essentially” means that there must be at least one major peak in the diagram shown in the figure, i.e., a peak with a relative intensity greater than 20%, particularly greater than 10%, compared to the strongest peak in the diagram. However, those skilled in powder X-ray diffraction techniques should be aware that the relative intensity of a powder X-ray diffractogram can be subject to strong fluctuations due to favorable orientation effects, which can, for example, cause peak disappearance or fluctuations in the intensity of a single peak.

[0024] When not used in relation to temperature, the term "about" placed before a numerical value "X" in this application means between 10% of XX and 10% of X+X, preferably XX X most preferably represents a temperature ranging from 5% of to 5% of X+X. In the specific case of temperature, the term "about" placed before the temperature "Y" in this application represents a temperature ranging from Y-10°C to Y+10°C, preferably from Y-5°C to Y+5°C. Room temperature means a temperature of about 25°C.

[0025] Whenever terms such as "between X and Y," "X to Y," "X to Y," or "X~Y" are used to describe a numerical range, the endpoints of the indicated range, "X" and "Y," are explicitly included within that range. For example, if the temperature range is described as "between 40°C and 80°C" (or "40°C to 80°C"), it means that the endpoints, 40°C and 80°C, are included within that range. Another example of the use of the term "approximately" in combination with the above range definitions is the expression "approximately 4.5 to approximately 5.5" as used herein, where the endpoints, approximately 4.5 and approximately 5.5, are explicitly included within that range.

[0026] 10) Another aspect relates to a crystalline hydrate of a "compound" according to any one of embodiments 1) to 9), wherein the crystalline hydrate can be obtained by a method comprising the step of exposing a first crystalline hydrate of a "compound" to a relative ambient humidity of at least 70% (particularly at least 80%) until a crystalline hydrate according to any one of embodiments 1) to 9) is formed, the first crystalline hydrate having about 1 to about 4 equivalents of coordinating water.

[0027] 11) Another embodiment relates to a crystalline hydrate of a compound according to any one of embodiments 1) to 9), wherein the crystalline hydrate can be obtained by a method comprising the step of precipitating the compound from an aqueous solution, and the compound is precipitated from an aqueous solution by adding at least one water-miscible organic solvent to the aqueous solution such that the water activity of the mixture of water and the water-miscible organic solvent is at least about 0.2 (in particular at least about 0.3; especially at least about 0.6).

[0028] As used herein, the term "water activity" refers to the partial pressure of water vapor in a mixture of water and at least one water-miscible organic solvent, divided by the partial pressure of pure water vapor at the same temperature. For example, a solvent mixture containing about 4% water and about 96% isopropanol has a water activity of about 0.3.

[0029] 12) Another embodiment relates to a crystalline hydrate of a “compound” according to any one of embodiments 1) to 9), which can be obtained by the method of embodiment 11), wherein the above method comprises the following steps (in particular order below): i) The step of dissolving the "compound" in water under heating until a saturated solution (particularly one with a concentration of about 0.5 g / mL) is obtained; ii) The step of cooling the above solution (especially to room temperature); iii) Adding at least one water-miscible organic solvent such that the water activity in the mixture of water and the water-miscible organic solvent is at least about 0.2 (particularly at least about 0.3; especially at least about 0.6; preferably, about 10 to about 20 mL of 2-propanol per 1 g of “compound”); iv) Optionally, a stirring step (especially at room temperature for 1 or 2 weeks; particularly 2 weeks); and v) A step of isolating the solid residue by solid-liquid separation (especially by filtration).

[0030] 13) Another aspect relates to a method for producing a crystalline hydrate of a “compound” according to any one of embodiments 1) to 9), the method comprising the step of exposing a first crystalline hydrate of a “compound” to a relative ambient humidity of at least 70% (particularly at least 80%) until a crystalline hydrate according to any one of embodiments 1) to 9) is formed, the first crystalline hydrate having about 1 to about 4 equivalents of coordination water.

[0031] 14) Another embodiment relates to a method for producing a crystalline hydrate of a “compound” according to any one of embodiments 1) to 9), the method comprising the step of precipitating the “compound” from the aqueous solution by adding at least one water-miscible organic solvent to the aqueous solution such that the water activity of the mixture of water and the water-miscible organic solvent is at least 0.2 (in particular at least 0.3; especially at least 0.6).

[0032] 15) Another embodiment is a method according to embodiment 14), wherein the method comprises the following steps (in particular order): i) The step of dissolving the "compound" in water under heating until a saturated solution (particularly one with a concentration of about 0.5 g / mL) is obtained; ii) The step of cooling the above solution (especially to room temperature); iii) Adding at least one water-miscible organic solvent such that the water activity in the mixture of water and the water-miscible organic solvent is at least about 0.2 (particularly at least about 0.3; especially at least about 0.6; preferably, about 10 to about 20 mL of 2-propanol per 1 g of “compound”); iv) Optionally, a stirring step (especially at room temperature for 1 or 2 weeks; particularly 2 weeks); and v) A step of isolating the solid residue by solid-liquid separation (especially by filtration).

[0033] The compound has a solubility of approximately 25 g in 100 mL of water at room temperature.

[0034] The water-miscible organic solvents referred to in embodiments 11, 12, 14, and 15 are lower alcohols, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, acetone, dimethylformamide, 1,4-dioxane, diethylene glycol dimethyl ether, and 1,2-dimethoxyethane; in particular, lower alcohols (such as methanol, ethanol, 1-propanol, 2-propanol, and isobutanol), tetrahydrofuran, acetonitrile, dimethyl sulfoxide, acetone, and dimethylformamide; in particular, selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, isobutanol, tetrahydrofuran, acetonitrile, and dimethyl sulfoxide; especially 2-propanol.

[0035] The term "lower alcohol" refers to a 1, 2, or polyhydric alcohol, i.e., an alcohol having 1, 2, or 3 or more hydroxyl groups, wherein the hydroxyl groups are substituted by 1 or 2 or more hydrogen atoms. 1-5 - This refers to the alcohol that binds to an alkane. 1-5 The term "alkane" refers to a straight or branched saturated hydrocarbon chain consisting of 1 to 5 carbon atoms. Examples of lower alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, iso-butanol, 2-methyl-propan-2-ol, 2-methyl-propan-1-ol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, ethylene glycol, propylene glycol, and glycerol; in particular methanol, ethanol, 1-propanol, and 2-propanol; and especially 2-propanol.

[0036] 16) In either sub-embodiment of aspect 12) or 15), about 1 wt. of “compound” is dissolved in about 2 wt. of water (especially under heating).

[0037] 17) In any one of the sub- embodiments of aspects 11), 12), 14), and 15), the water-miscible organic solvent is added until a precipitate is formed.

[0038] The isolation step v) in embodiment 12) or 15) may be carried out using any method known in the art used to separate a solid substance from a liquid, preferably by filtration. ru.

[0039] Exposure of the crystalline hydrate of the "Compound" disclosed herein to relative ambient humidity is understood to mean contact of the crystalline hydrate of the "Compound" with a carrier gas (moving or stationary), wherein the carrier gas is air, nitrogen, or argon, and the carrier gas exhibits a relative humidity greater than 70%, particularly greater than 80%.

[0040] A crystalline hydrate of a "compound" according to any one of the embodiments disclosed herein may be used as a pharmaceutical, for example, in the form of a pharmaceutical composition for enteral or parenteral administration, particularly by injection.

[0041] 18) Another aspect relates to a crystalline hydrate of a “compound” according to any one of aspects 1) to 9) for use as a pharmaceutical.

[0042] A crystalline hydrate of a "compound" according to any one of embodiments 1) to 9) may be used as a single crystalline hydrate or as a mixture with other crystalline stoichiometric or non-stoichiometric hydrates and / or amorphous materials of the "compound".

[0043] 19) Further embodiments relate to pharmaceutical compositions having, as active ingredients, a crystalline hydrate of a "compound" according to any one of embodiments 1) to 9) and at least one pharmaceutically acceptable carrier material (particularly water).

[0044] The pharmaceutical composition can be manufactured by methods well known to those 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 combining the crystalline form of the present invention with optionally other therapeutically beneficial substances, along with a suitable non-toxic, inert, pharmaceutically acceptable solid or liquid carrier material and, if necessary, a conventional pharmaceutically acceptable adjuvant, to form a pharmaceutical dosage.

[0045] 20) Further embodiments relate to the use of crystalline hydrates of “compounds” according to any one of embodiments 1) to 9) in the manufacture of aqueous pharmaceutical compositions.

[0046] 21) A further embodiment relates to a method for producing an aqueous pharmaceutical composition, the method comprising the step of dissolving a crystalline hydrate of a "compound" according to any one of embodiments 1) to 9) in a solvent (particularly water).

[0047] 22) Further embodiments relate to crystalline hydrates of a “compound” according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, wherein the pharmaceutical composition is used as a pharmaceutical.

[0048] 23) Further embodiments relate to crystalline hydrates of “compounds” according to any one of embodiments 1) to 9) for use in the manufacture of aqueous pharmaceutical compositions, said pharmaceutical compositions to be used for the prevention / prophylaxis and / or treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) and its subsequent ischemic effects and / or symptoms.

[0049] 24) Further embodiments include embodiments 1) to 9) for use in the manufacture of aqueous pharmaceutical compositions. With respect to a crystalline hydrate of a "compound" conforming to any one of the above, the pharmaceutical composition is used for the prevention and / or treatment of clinical deterioration resulting from vasospasm-related delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage (aSAH).

[0050] 25) Further embodiments relate to crystalline hydrates of a “compound” according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, the pharmaceutical composition to be used for the prevention and / or treatment of clinical exacerbation resulting from vasospasm-associated delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage (aSAH).

[0051] As used herein, the term “clinical deterioration” means a deterioration of at least two points on the mGCS or aNIHSS scale compared to a reference score, lasting at least two hours, and not entirely attributable to causes other than cerebral vasospasm. Clinical deterioration due to delayed ischemia may be determined based on a review of clinical data, case narratives, angiography, and / or CT scans. The term “mGCS” refers to the Glasgow Coma Scale, a neurological scale intended to provide a reliable and objective means of recording a person’s state of consciousness. The term “aNIHSS” is an abbreviation for the National Institutes of Health Stroke Scale, a tool used by healthcare providers to objectively quantify the impairment caused by stroke.

[0052] 26) Further embodiments relate to crystalline hydrates of a “compound” according to any one of embodiments 1) to 9) for use in the manufacture of an aqueous pharmaceutical composition, the pharmaceutical composition being used for the prevention and / or treatment of cerebral infarction.

[0053] As used herein, the term "cerebral infarction" refers to a new or worsened cerebral infarction of any cause (in particular, the infarction being approximately 5 cm in size). 3This means having a larger overall volume. A new or worsened cerebral infarction may be determined by central radiology review by comparing a CT scan performed 16 days after the start of drug treatment with a CT scan performed before the start of said treatment.

[0054] 27) Further embodiments relate to crystalline hydrates of “compounds” according to any one of embodiments 1) to 9) for use as pharmaceuticals; in particular for use in the prevention and / or treatment of diseases or disorders involving endothelin receptors; and especially for use in the prevention and / or treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) and its subsequent ischemic effects and / or symptoms.

[0055] The present invention also relates to a method for the prevention and / or treatment of diseases or disorders involving endothelin receptors, particularly for the prevention and / or treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) and its subsequent ischemic effects and / or symptoms, wherein the prevention and / or treatment comprises administering a pharmaceutical composition to a subject in need of such prevention and / or treatment, the composition comprising an effective amount of 5-methylpyridine-2-sulfonic acid N-{6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl}amide as an active ingredient, in the form of an aqueous solution of a crystalline hydrate of a “compound” according to any one of embodiments 1) to 9).

[0056] The 5-methylpyridine-2-sulfonic acid used herein is N-{6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazo [Il-5-yl)-pyridine-4-yl]-pyrimidine-4-yl}amide (clazosentan free acid) refers to the compound of formula 2:

[0057] [ka]

[0058] As used herein, the term “effective dose” means a dose of approximately 5 mg / day to approximately 20 mg / day (particularly from approximately 10 mg / day to approximately 15 mg / day) administered to a subject for a maximum of 20 days (particularly a maximum of 14 days). This effective dose is preferably administered intravenously, more preferably as an aqueous solution.

[0059] The term "solvate," whether used alone or in combination, means, in the context of this invention, a compound or salt thereof as defined herein and an aggregate having one or more solvent molecules. A hydrate is a special form of solvate in which one or more solvent molecules contained in the aggregate are water molecules.

[0060] The term "wt." represents the weight (e.g., in kg) of a substance (e.g., reactants) per unit weight (e.g., in kg) of the starting material (e.g., compound) or solvent (e.g., water).

[0061] The term "equivalent" and its abbreviation "eq." mean the number of moles of a compound that react with (or are equivalent to) any number of moles of another compound in a given chemical reaction. In the case of solvates / hydrates of the "compounds" disclosed herein, the term means the number of solvent / water molecules per molecule of the "compound."

[0062] As used herein, the term "prevention" also means "prophylaxis."

[0063] The crystalline "compounds" disclosed herein may exist in different isomeric / tautomeric forms with respect to the position of the sodium atom in the tetrazole ring and / or sulfonamide group, as shown below.

[0064] [ka]

[0065] Therefore, even if only one isomer / tautomer is described herein (e.g., Formula 1), all possible isomers / tautomers of the crystalline hydrate form of the “compound” are considered to be within the scope of the present invention. In solution, the isomers / tautomers usually exist as a mixture of different isomer / tautomer types; in the solid state, typically one form is dominant. The asterisk in the above formula * " and " ** The symbol indicates the bonding point of the corresponding group to the rest of the molecule of the compound.

[0066] Accordingly, based on the dependencies of the different embodiments 1) to 27) disclosed herein, the following embodiments are possible, intended, and are specifically disclosed herein as individual embodiments: 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、12+6+2+1、12+6+3+1、12+6+4+1、12+6+5+1、12+6+5+2+1、12+6+5+3+1、12+7+1、12+7+2+1、12+7+3+1、12+7+4+1、12+7+5+1、12+7+5+2+1、12+7+5+3+1、12+8+1、12+8+2+1、12+8+3+1、12+8+4+、 1、12+8+5+1、12+8+5+2+1、12+8+5+3+1、12+9+1、12+9+2+1、12+9+3+1、12+9+4+1、12+9+5+1、12+9+5+2+1、12+9+5+3+1、13+1、13+2+1、13+3+1、13+4+1、13+5+1、13+5+2+1、13+5+3+1、13+6+1、13+6+2+1、13+6+3+1、13+6+4+1、13+6+5+1、13+6+5+2+1、13+6+5+3+1、13+7+1、13+7+2+1、13+7+3+1、13+7+4+1、13+7+5+1、13+7+5+2+1、13+7+5+3+1、13+8+1、13+8+2+1、13+8+3+1、13+8+4+1、13+8+5+1、13+8+5+2+1、13+8+5+3+1、13+9+1、13+9+2+1、13+9+3+1、13+9+4+1、13+9+5+1、13+9+5+2+1、13+9+5+3+1、 14+1、14+2+1、14+3+1、14+4+1、14+5+1、14+5+2+1、14+5+3+1、14+6+1、14+6+2+1、14+6+3+1、14+6+4+1、14+6+5+1、14+6+5+2+1、14+6+5+3+1、14+7+1、14+7+2+1、14+7+3+1、14+7+4+1、14+7+5+1、14+7+5+2+1、14+7+5+3+1、14+8+1、14+8+2+1、14+8+3+1、14+8+4+1、14+8+5+1、14+8+5+2+1、14+8+5+3+1、14+9+1、14+9+2+1、14+9+3+1、14+9+4+1、14+9+5+1、14+9+5+2+1、14+9+5+3+1、15+1、15+2+1、15+3+1、15+4+1、15+5+1、15+5+2+1、15+5+3+1、15+6+1、15+6+2+1、15+6+3+1、15+6+4+1、15+6+5+1、15+6+5+2+1、15+6+5+3+1、15+7+1、15+7+2+1、15+7+3+1、15+7+4+1、15+7+5+1、15+7+5+2+1、15+7+5+3+1、15+8+1、15+8+2+1、15+8+3+1、15+8+4+1、15+8+5+1、15+8+5+2+1、15+8+5+3+1、15+9+1、15+9+2+1、15+9+3+1、15+9+4+1、15+9+5+1、15+9+5+2+1、15+9+5+3+1、18+1、18+2+1、18+3+1、18+4+1、18+5+1、18+5+2+1、18+5+3+1、18+6+1、18+6+2+1、18+6+3+1、18+6+4+1、18+6+5+1、18+6+5+2+1、18+6+5+3+1、18+7+1、18+7+2+1、18+7+3+1、18+7+4+1、18+7+5+1、18+7+5+2+1、18+7+5+3+1、18+8+1、18+8+2+1、18+8+3+1、18+8+4+1、18+8+5+1、18+8+5+2+1、18+8+5+3+1、18+9+1、18+9+2+1、18+9+3+1、18+9+4+1、18+9+5+1、18+9+5+2+1、18+9+5+3+1、19+1、19+2+1、19+3+1、19+4+1、19+5+1、19+5+2+1、19+5+3+1、19+6+1、19+6+2+1、19+6+3+1、19+6+4+1、19+6+5+1、19+6+5+2+1、19+6+5+3+1、19+7+1、19+7+2+1、19+7+3+1、19+7+4+1、19+7+5+1、19+7+5+2+1、19+7+5+3+1、19+8+1、19+8+2+1、19+8+3+1、19+8+4+1、19+8+5+1、19+8+5+2+1、19+8+5+3+1、19+9+1、19+9+2+1、19+9+3+1、19+9+4+1、19+9+5+1、19+9+5+2+1、19+9+5+3+1、20+1、20+2+1、20+3+1、20+4+1、20+5+1、20+5+2+1、20+5+3+1、20+6+1、20+6+2+1、20+6+3+1、20+6+4+1、20+6+5+1、20+6+5+2+1、20+6+5+3+1、20+7+1、20+7+2+1、20+7+3+1、20+7+4+1、20+7+5+1、20+7+5+2+1、20+7+5+3+1、20+8+1、20+8+2+1、20+8+3+1、20+8+4+1、20+8+5+1、20+8+5+2+1、20+8+5+3+1、20+9+1、20+9+2+1、20+9+3+1、20+9+4+1、20+9+5+1、20+9+5+2+1、20+9+5+3+1、21+1、 21+2+1、21+3+1、21+4+1、21+5+1、21+5+2+1、21+5+3+1、21+6+1、21+6+2+1、21+6+3+1、21+6+4+1、21+6+5+1、21+6+5+2+1、21+6+5+3+1、21+7+1、21+7+2+1、21+7+3+1、21+7+4+1、21+7+5+1、21+7+5+2+1、21+7+5+3+1、21+8+1、21+8+2+1、21+8+3+1、21+8+4+1、21+8+5+1、21+8+5+2+1、21+8+5+3+1、21+9+1、21+9+2+1、21+9+3+1、21+9+4+1、21+9+5+1、21+9+5+2+1、21+9+5+3+1、 22+1、22+2+1、22+3+1、22+4+1、22+5+1、22+5+2+1、22+5+3+1、22+6+1、22+6+2+1、22+6+3+1、22+6+4+1、22+6+5+1、22+6+5+2+1、22+6+5+3+1、22+7+1、22+7+2+1、22+7+3+1、22+7+4+1、22+7+5+1、22+7+5+2+1、22+7+5+3+1、22+8+1、22+8+2+1、22+8+3+1、22+8+4+1、22+8+5+1、22+8+5+2+1、22+8+5+3+1、22+9+1、22+9+2+1、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 or 27+9+5+3+1.

[0067] In the list above, the numbers represent the corresponding aspects, and the "+" indicates a subordinate relationship from other aspects. The various aspects are separated individually by commas. In other words, for example, "5+2+1" means aspect 5) which is subordinate to aspect 2) which is subordinate to aspect 1), that is, aspect "5+2+1" corresponds to aspect 5) which is further characterized by the features of aspects 2) and 1).

[0068] Abbreviations (used above or below): EtOH Ethanol eq. equivalent weight GVS Gravimetric Vapor Adsorption Analysis h time kV (kilovolt) mA (milliampere) mbar (millibar) MeOH methanol mg milligrams min mL (milliliter) mm (millimeters) nm (nanometer) n / a Not applicable NaOMe Sodium Methoxy ppm parts per million RH (Relative Humidity) rt room temperature rpm (revolutions per minute) s seconds TGA XRPD (Powder X-ray Diffraction) wt. weight w / w weight per unit weight

[0069] Experiment section All temperatures should be expressed in degrees Celsius (°C).

[0070] Powder X-ray diffraction (XRPD) X-ray diffractograms were measured on a Bruker D8 Advance diffractometer equipped with a FlipStick® sample stage, Cu Kα irradiation (40kV, 40mA), and a 1D-linear LynxEye® detector. Samples were prepared on a silicon single-crystal sample holder with a cavity of 25mm in diameter and 0.1 or 0.5mm in depth. The powder was spread on a microscope slide and the surface was flattened. Difractograms were collected in reflection mode with a bond θ / 2θ angle in the range of 3–50°, an increase of 0.02° per step, and an accumulation time of 0.4s or 1.6s. Divergence and anti-scatter slits were used. The antiscatter slit was set to 0.3°. The sample was continuously rotated at 30 rpm during the measurement. The 2θ value of the peak position is recorded with an accuracy of + / -0.2°.

[0071] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed using a Mettler Toledo® TGA / SDTA851e module coupled with a Pfeiffer ThermoStar® quadrupole mass spectrometer. Approximately 5 mg of the sample was weighed into an aluminum pan and heated in a nitrogen stream from room temperature to 250°C or 350°C at a constant rate of 10°C / min. In some cases, off-gases were analyzed by mass spectrometry for specific volatile substances that were expected to be present.

[0072] Gravimetric vapor adsorption (GVS) analysis Gravimetric vapor adsorption (GVS) analysis of crystalline form C was performed using a Hiden Isochema IGAsorp® Model HAS-036-080. Approximately 20 mg of the sample was placed in a stainless steel mesh sample holder without any pretreatment. The measurement was performed at 25°C, varying the humidity in 5% RH steps in the order of 40%-95%-0%-40% RH, with a maximum equilibrium time of 24 hours for each step. Gravimetric vapor adsorption experiments for all other hydrates disclosed herein were performed using a ProUmid GmbH&Co.KG SPS100n instrument. Typically, 10-20 mg of the substance was placed in a tare-weighed aluminum pan without any pretreatment. The measurement was again performed at 25°C, varying the humidity in 5% steps in the order of 20%-90%-0%-25% RH, with a maximum equilibrium time of 24 hours for each step. When plotting the data (see the corresponding figure), the change in weight of one equivalent of water is shown by a horizontal dotted line.

[0073] The "compound" may be synthesized by procedures known in the art, such as those described in EP0979822.

[0074] Example 1 - Preparation of the "compound" in solid form B (tri-methanol solvate) A suspension of 209 mg of the compound in 1 mL of MeOH was stirred at room temperature for 1 month. The solid was isolated by filtration. The total gas loss (TGA) showed a 13.8% weight loss between 55°C and 160°C. The release of MeOH and water was detected by off-gas mass spectrometry. Assuming that the weight loss process is mainly related to MeOH, it corresponds to 3 equivalents of MeOH. Further weight loss below 55°C is attributed to surface-adsorbed solvent. The XRPD of this sample (Figure 1) shows a pattern characteristic of crystalline form B.

[0075] Example 2 - Preparation of the "compound" in solid form B1 (di-ethanol solvate) A suspension of 513 mg of the compound in 4 mL of EtOH was stirred at room temperature for 2 days. The solid was isolated by filtration. The total gas absorption (TGA) showed a broad weight loss of 13.7% between 80 and 230°C. The release of EtOH was confirmed by off-gas mass spectrometry. The weight loss corresponds to 2 equivalents of EtOH. The XRPD of this sample (Figure 2) shows a pattern characteristic of crystalline form B1.

[0076] Example 3 - Preparation of a "compound" in solid form C (pentahydrate) 1 g of the dried "compound" was dissolved in 2 mL of water under heating. Upon cooling, the solution became slightly cloudy. 20 mL of 2-propanol was added dropwise while stirring, and after adding approximately half the volume of 2-propanol, a large precipitate formed. After stirring continued at rt for 2 weeks, the solid was filtered. The sample was left uncovered for 1 day under ambient conditions, and then stored at 85% RH for 10 days. 1.04 g of a white, fluid powder was obtained. The TGA of the "compound" in solid form C showed a weight loss step in the range of approximately 50°C to 150°C, with the amount being approximately 12.2% relative to the water content (Figure 16), which corresponds to 4.8 equivalents of water. GVS analysis (Figure 10) The water content of the sample was stable, increasing slightly between 5% and 95% RH at 25°C and decreasing dramatically below 5% RH. Assuming all water is removed at 0% RH, the water content of solid form C ranges from 13% to 14.5% relative to the dry weight, corresponding to 4.5–5.0 equivalents of water. The starting water content at 40% RH is 14% (based on dry weight), which is in good agreement with the weight loss observed in TGA (based on 12.2% water content). The XRPD of this sample (Figure 3) shows a pattern characteristic of crystalline form C.

[0077] Example 4 - Preparation of the "compound" in solid form E (monohydrate) A 290 mg sample (solid form B1) of the diethanol solvate of the compound was stored uncovered for 7 days under ambient conditions. The TGA showed a broad weight loss step between rt and 180°C, which was attributed to water by off-gas mass spectrometry. The weight loss corresponds to 1.8 equivalents of water. According to the GVS scan (Figure 11), the water content at equilibrium is 3% or approximately 1 equivalent. The XRPD of this sample (Figure 4) shows a pattern characteristic of crystalline form E.

[0078] Example 5 - Preparation of the "compound" in solid form L (trihydrate) The solid form C sample of the compound was first dried at 0% relative humidity (RH), and then re-humidified at 40% RH in a GVS apparatus. The TGA of the product showed a two-step weight loss in the temperature range of approximately 50°C to 210°C. The total weight loss of 9.4% corresponds to 3.6 equivalents of water. According to the GVS experiment (Figure 12), the final water content was approximately 8%, which corresponds to 3 equivalents of water. The XRPD of this sample (Figure 5) shows a pattern characteristic of crystalline form L.

[0079] Example 6 - Preparation of the "compound" in solid form M (trihydrate) A suspension of 97 mg of the compound in 1 mL of 2-propanol containing 1.3 wt.% water was stirred at ambient temperature for 2 days. The solid was isolated by centrifugal filtration. The TGA showed a weight loss of 9.0%, which occurred mainly between 150 and 240°C. Assuming that the small amount of early weight loss in the TGA analysis can be attributed to excess water, the water content of this substance is 3 equivalents. According to GVS (Figure 13), the water content is also best described by the trihydrate structure. The XRPD of this sample (Figure 6) shows a pattern characteristic of crystalline form M.

[0080] Example 7 - Production of a "compound" of solid-state nitrogen (tetrahydrate) A suspension of 116 mg of the compound in 1 mL of 2-propanol containing 3.8% w / w water was stirred at ambient temperature for 2 days. The solid was isolated by centrifugal filtration. TGA showed a weight loss of 11.3% over a wide temperature range of approximately 50°C to 230°C, corresponding to slightly more than 4 equivalents of water. According to GVS behavior (Figure 14), this substance can be attributed to a tetrahydrate, and significant adsorption of excess water occurs at high relative humidity. The XRPD of this sample (Figure 7) shows a pattern characteristic of crystalline form N.

[0081] Example 8 - Preparation of a "compound" of solid form P (trihydrate) A solid sample of a "compound" derived from the drying of a solvated structure similar to crystalline form B1 was exposed to 25°C at 63% relative humidity for 15 hours. Based on water uptake in a GVS experiment starting from the same substance (Figure 15), this polymorph can be attributed to the trihydrate. The XRPD of this sample (Figure 8) shows a pattern characteristic of crystalline form P.

[0082] Preparation of the "compound" in Example 9 of Reference Example 1-EP0979822 2 g (3.5 mmol) of 5-methylpyridine-2-sulfonic acid {6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]pyrimidine-4-yl}amide was suspended in 10 mL of MeOH, and then 1.3 mL (7 mmol) of freshly prepared 5.4 N NaOMe solution was added. This solution was heated under reflux for 3 hours, first to room temperature within about 25 minutes, and then further cooled to 0°C until a solid substance was formed. The solid was then separated by filtration. The material was washed with 3 mL of ice-cold methanol and dried overnight at 70°C under vacuum (10 mbar). The XRPD of the obtained solid material is shown in Figure 9. Figure 9 shows the broad-spectrum halo characteristic of amorphous solid materials.

Claims

1. A crystalline hydrate of 5-methylpyridine-2-sulfonic acid N-{6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazole-5-yl)-pyrimidine-4-yl]pyrimidine-4-yl}amide disodium salt, the hydrate characterized by the presence of peaks at the following refraction angles 2θ: 7.6°, 10.6°, 18.5°, 24.3° and 25.0° in a powder X-ray diffractogram.

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

3. A method for producing a crystalline hydrate according to claim 1 or 2, the method comprising the step of precipitating 5-methylpyridine-2-sulfonic acid N-{6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl}amide disodium salt from an aqueous solution by adding at least one water-miscible organic solvent to an aqueous solution such that the water activity of the mixture of water and the water-miscible organic solvent is at least 0.

2.

4. A pharmaceutical composition comprising a crystalline hydrate according to claim 1 or 2 and at least one pharmaceutically acceptable carrier material.

5. Use of the crystalline hydrate according to claim 1 or 2 in the production of an aqueous pharmaceutical composition.

6. A method for producing an aqueous pharmaceutical composition, comprising the step of dissolving the crystalline hydrate described in claim 1 or 2.

7. A crystalline hydrate according to claim 1 or 2, for use as a pharmaceutical.

8. A crystalline hydrate according to claim 1 or 2 for use in the manufacture of an aqueous pharmaceutical composition, wherein the pharmaceutical composition is used for the prevention and / or treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) and its subsequent ischemic effects and / or symptoms.

9. A pharmaceutical product for the prevention and / or treatment of a disease or disorder involving endothelin receptors, wherein the pharmaceutical product contains, as an active ingredient, an effective amount of the crystalline hydrate of 5-methylpyridine-2-sulfonic acid N-{6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl}amide disodium salt as described in claim 1 or 2.

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