Method for preparing tungsten(VI) salt hydrate

Abstract

The present invention provides a method for preparing a tungsten(VI) salt hydrate, comprising the steps of: (a) preparing a tungsten(VI) salt in an alkaline aqueous solution; (b) filtering the aqueous solution at a temperature at which the tungsten(VI) salt remains dissolved; (c) precipitating a tungsten(VI) salt hydrate from the filtrate obtained from step (b); (d) filtering; (e) washing the obtained filter cake with a water-miscible solvent; and (f) drying the washed cake under conditions capable of removing the water-miscible solvent. The obtained salt exhibits very low levels of impurities and solvents, making it suitable for pharmaceutical, veterinary, and dietary applications.

Description

[Technical Field]

[0001] The present invention relates to the field of chemistry, in particular to the synthesis of hydrated compounds. The present invention specifically relates to a method for preparing tungsten salt hydrates. [Background technology]

[0002] It is known that solutions of alkaline (especially sodium) or ammonium tungstate or molybdate formed during alkalinization of tungsten- and / or molybdenum-containing materials are contaminated with various hydrolysis ions (silicon, phosphorus, arsenic, etc.). These solutions must be purified before further processing. According to a known purification method, an alkaline solution (pH 13), e.g., Na2WO4, is acidified (e.g., to pH 9) with some acid (e.g., H2SO4, HCl), followed by the addition of aluminum ions. The resulting large-area Al(OH)3 precipitate binds the impurities in the solution.

[0003] The precipitate can be removed by filtration. The remaining pure solution can then be used to produce W acid by any method. Tungstic acid can be advantageously produced from the purified alkali or ammonium tungstate solution by cation exchange electrodialysis, and the digestion liquid can also be recovered.

[0004] This known method has several disadvantageous properties: on the one hand, there is an economic disadvantage since pure acid is required for acidification, which increases the cost of the process, and on the other hand, there is an additional source of contamination since sulfate or chloride ions are introduced into the solution. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, despite previous efforts, there is a need to provide a method for obtaining tungsten salts that comply with quality standards in accordance with Good Manufacturing Practices (GMP) in the pharmaceutical, veterinary and nutritional supplement fields. [Means for solving the problem]

[0006] The object of the present invention is to develop a process that is efficient in eliminating impurities incorporated into the starting tungsten-containing compound, and that allows for obtaining an active pharmaceutical ingredient (API) that complies with GMP standards.

[0007] However, in developing this method, the inventors identified a further problem: when metal tungstates are obtained in the form of hydrates, the water molecules coordinating with the metal salts are highly unstable. As shown below, it was found that approximately 94% of the starting Na2WO4·2H2O loses water molecules when vacuum dried at a mild temperature of approximately 50°C.

[0008] Therefore, in view of the above, the problem to be solved by the present invention was not only to provide a process by which tungstate hydrates suitable for use in any of the abovementioned fields of pharmaceutical, veterinary or dietetics can be obtained, but also to ensure that the final active product retains a water molecule at the end of the process.

[0009] The present invention provides a method for obtaining tungsten(VI) salt hydrate, comprising the steps of: (a) preparing a tungsten(VI) salt in an alkaline aqueous solution; (b) filtering the aqueous solution at a temperature at which the tungsten(VI) salt remains dissolved; (c) precipitating tungsten(VI) salt hydrate from the filtrate obtained from step (b) at a temperature below 100°C, in particular below 50°C; (d) filtering, preferably at a temperature below 50°C, more preferably at a temperature between 15°C and 25°C; (e) washing the resulting filter cake with a water-miscible solvent; (f) drying the washed cake under conditions sufficient to remove the water-miscible solvent; The above identified problems are solved by the methods of the present invention, including a method comprising:

[0010] Steps (a) and (b) ensure a reduction in impurities within GMP quality standards suitable for use in areas of interest related to humans and non-human animals.

[0011] Steps (d) and (e) ensure that the final product after drying is stable and retains water molecules.

[0012] The process of the present invention makes it possible to obtain sodium tungstate dihydrate having a significantly low content of water and residual water-miscible solvents.

[0013] Indeed, the salts obtained from this method exhibit remarkable stability on storage.

[0014] Thus, in a second aspect, the present invention provides sodium tungstate dihydrate obtainable by the process of the first aspect of the invention.

[0015] The resulting sodium tungstate dihydrate of the present invention is characterized by having a water content of less than 15% (w / w) based on the total weight of the salt, and by having impurities and residual solvents at safe levels, making it suitable for use in the fields of medicine and dietetics.

[0016] Therefore, in a third aspect, the present invention provides sodium tungstate dihydrate for pharmaceutical, veterinary or dietary use, which has a residual content of water of up to 15% by weight, in particular a content of 10% to 15% by weight, relative to the total weight of the salt.

[0017] In a fourth aspect, the present invention provides a pharmaceutical, veterinary, or dietary composition comprising a therapeutically effective amount of sodium tungstate dihydrate of the second and third aspects together with one or more pharmaceutically, veterinarily, or dietarily acceptable excipients.

[0018] In a fourth aspect, the present invention provides sodium tungstate dihydrate as defined in the second or third aspect for use in therapy.

[0019] Sodium tungstate dihydrate compounds have already been reported in female infertility, such as in WO 2016012632 or Ballester, 2007 (see J. Ballester et al., "Tungstate administration improves the sexual and reproductive function in female rats with streptozotocin-induced diabetes", Human Reproduction, 2007, vol. 22, pp. 2128-2135). Due to such low levels of water and solvents, the dihydrate compounds of the present invention are believed to be suitable for the specific treatment of female infertility.

[0020] Thus, in a fifth aspect, the present invention provides sodium tungstate dihydrate as defined in the second or third aspect for treating female infertility, particularly non-diabetic female infertility. This aspect can alternatively be expressed as use of the sodium tungstate dihydrate salt provided by the present invention in the manufacture of a medicament for treating female infertility, particularly non-diabetic female infertility. This aspect can alternatively be expressed as a method for treating female infertility, particularly non-diabetic female infertility, comprising administering a therapeutically effective amount of the sodium tungstate dihydrate salt provided by the present invention. [Brief explanation of the drawings]

[0021] [Figure 1] Figure 1 shows the IR spectra of Na2WO4·2H2O obtained according to the method of the invention starting from two different batches of APT and WO3. The IR is identical in all four cases, and two peaks associated with two water molecules are identified (at 3266 cm-1 and 1676 cm-1). [Figure 2]1A and 1B show IR spectra of sodium tungstate after drying at 50° C. and 100° C. (A and B, respectively). IR spectra of sodium tungstate according to the method of the present invention. It can be seen that at 50° C. and 100° C., no water molecules are present, but under the conditions of the method of the present invention, both molecules are identified (positions 3266 cm-1 and 1676 cm-1). DETAILED DESCRIPTION OF THE INVENTION

[0022] All terms used herein in this application are to be understood in their ordinary meaning as known in the art unless otherwise specified. Other, more specific definitions for certain terms used herein are set forth below and are intended to be applied uniformly throughout the specification and claims unless another explicitly stated definition gives a broader definition.

[0023] So long as the objectives of the invention are met, any given range will include both the lower and upper endpoints of the range.

[0024] As used herein, the meaning of the term "comprising" encompasses three options: "comprising," "consisting of," and "consisting essentially of."

[0025] The present invention provides a method for preparing tungsten(VI) salt hydrates suitable for use in the pharmaceutical, veterinary and dietary fields.

[0026] In one embodiment, optionally in combination with any of the embodiments provided above or below, the tungsten(VI) salt hydrate comprises one anion selected from the group consisting of tungstate and isopolytungstate. In another embodiment, optionally in combination with any of the embodiments provided above or below, the anion is tungstate.

[0027] In one embodiment, optionally in combination with any of the embodiments provided above or below, the tungsten(VI) salt hydrate includes one cation moiety selected from the group of alkali metal or alkaline earth metal cations, such as sodium, potassium, magnesium, and calcium, as well as other cations, such as ammonium, copper, zinc, and silver. In another embodiment, optionally in combination with any of the embodiments provided above or below, the cation is sodium.

[0028] In one embodiment, optionally in combination with any of the above or below provided embodiments, the tungsten (VI) salt hydrate is sodium tungstate dihydrate.

[0029] According to the method of the present invention, the first step involves solubilizing a tungsten-containing compound in an alkaline aqueous solution.

[0030] In one embodiment, optionally in combination with any of the embodiments provided above or below, the tungsten-containing compound is selected from WO, paratungstate, and tungstic acid. Illustrative, non-limiting examples of paratungstate are ammonium paratungstate (APT), sodium, calcium, or potassium paratungstate, among others. In one particular embodiment, optionally in combination with any of the embodiments provided above or below, the tungsten-containing compound is WO.

[0031] In the context of the present invention, the term "aqueous alkaline solution" may be any that is already known to a person skilled in the art. In the context of the present invention, an alkaline solution is any that results in a pH value greater than 7. In one embodiment of the present invention, optionally in combination with any of the embodiments provided above or below, the aqueous alkaline solution results in a pH greater than 8, greater than 9, or greater than 10. Illustrative, non-limiting examples of "alkaline solutions" include, inter alia, carbonates, hydroxides, phosphates, bicarbonates, phenolates, or hydrogen phosphates. In one embodiment, optionally in combination with any of the embodiments provided above or below, the aqueous alkaline solution is an aqueous hydroxide solution.

[0032] In one embodiment, optionally in combination with any of the embodiments provided above or below, solubilization is carried out using an alkaline aqueous solution that already contains the cations intended to form the desired tungstate. Thus, in one embodiment, optionally in combination with any of the embodiments provided above or below, the alkaline solution contains cations selected from alkali metal or alkaline earth metal cations such as sodium, potassium, magnesium, and calcium, as well as other cations such as ammonium, copper, zinc, and silver. In one embodiment, optionally in combination with any of the embodiments provided above or below, the alkaline aqueous solution contains sodium cations.

[0033] In an alternative embodiment, optionally in combination with any of the embodiments provided above or below, solubilization is carried out using an aqueous alkaline solution containing cations other than those intended to form the desired tungstate. In this embodiment, additional solution of the intended cation is added to the already formed tungstate. For example, sodium salt / MeOH can provide the desired tungstate.

[0034] In one embodiment, optionally in combination with any of the above or below provided embodiments, the tungsten(VI) salt hydrate is Na2WO4·2H2O and the alkaline aqueous solution is aqueous sodium hydroxide.

[0035] If solubilization is performed, the solution can be heated below the reflux temperature to facilitate or accelerate solubilization of the tungsten-containing compound. In one embodiment, optionally in combination with any of the embodiments provided above or below, step (a) is carried out at a temperature from 30°C to the reflux temperature.

[0036] In one embodiment, optionally in combination with any of the embodiments provided above or below, step (a) is carried out by solubilizing WO in aqueous NaOH, particularly at a temperature of 80° C. to 95° C., particularly 85° C. to 95° C., and especially 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., 91° C., 92° C., 93° C., 94° C. or 95° C. In this embodiment, NaOH is in molar excess relative to the tungsten-containing compound.

[0037] In an alternative embodiment, optionally in combination with any of the embodiments provided above or below, step (a) is carried out by solubilizing a paratungstate, such as ammonium paratungstate (APT), in an aqueous NaOH solution, particularly at a temperature of 50° C. to 70° C., particularly 55° C., 56° C., 57° C., 58° C., 59° C. or 60° C. In this embodiment, the NaOH is in molar excess relative to the tungsten-containing compound.

[0038] In an alternative embodiment, optionally in combination with any of the embodiments provided above or below, step (a) is carried out by solubilizing HWO in aqueous NaOH, particularly at a temperature between 30° C. and 50° C., particularly at 30° C., 31° C., 32° C., 33° C., 34° C., 35° C., 36° C., 37° C., 38° C., 39° C., 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C. or 50° C. In this embodiment, NaOH is in molar excess relative to the tungsten-containing compound.

[0039] After step (a) is completed and the tungsten-containing compound is solubilized in the aqueous alkaline solution, the resulting solution is filtered to remove impurities, and for that purpose, the filtration is carried out at a temperature that ensures that the tungstate already formed in step (a) remains solubilized.

[0040] Those skilled in the art can, according to general knowledge, optimize the T for filtration based on, for example, the concentration of the tungstate solution obtained from step (a). For a highly concentrated solution (e.g., close to salt saturation), a higher temperature is required than for a less concentrated solution. The appropriate T can also be easily optimized to ensure that the tungstate dissolves. If an undesired precipitate is detected in the solution by those skilled in the art, this means that filtration should be performed at a higher T.

[0041] In one embodiment of the present invention, the filtration in step (b) is carried out at a temperature above 30° C. and below the reflux temperature.

[0042] Filtration can be performed using any of the known techniques and commercially available filters. Illustrative, non-limiting examples include filters, precoat filters, Cuno filters, and sintered glass filters, among others. In the case of precoat filters, a layer of filtration media, such as cellulose, perlite, or diatomaceous earth, is deposited on the surface of a filter element, for example, in an auto-jet pressure leaf filter, according to the manufacturer's instructions. During filtration, the precoat layer serves to retain particles as small as 0.5 microns in size. Celite is one commercially available material for making these precoat filters, but other suitable materials, such as sand or activated carbon, can also be used in the context of the present invention.

[0043] After the filtration step is completed, the filtrate is subjected to a precipitation step.

[0044] The precipitation step can be carried out by any suitable technique, such as adding a countersolvent, cooling below the saturation point (which reduces the solubility of the salt), adding a highly soluble salt containing the same metal as that already forming the tungstate (inducing precipitation by the common ion effect), or a combination thereof.

[0045] In the context of the present invention, the precipitation step is carried out under conditions that do not promote the loss of coordinated water molecules. To that end, precipitation of the salt from the aqueous solution is carried out at a temperature below 100°C, in particular below 50°C, in particular between 17°C and 35°C, in particular between 17°C and 25°C.

[0046] In one embodiment, optionally in combination with any of the embodiments provided above or below, the precipitation step is carried out by cooling below the saturation point and / or by adding a water-miscible solvent.

[0047] In one embodiment, optionally in combination with any of the embodiments provided above or below, the precipitation step is carried out by adding a water-miscible solvent having a boiling temperature below 100°C, in particular below 50°C, at a T comprised between 17°C and 35°C, in particular between 17°C and 25°C.

[0048] In the context of the present invention, a "water-miscible solvent" refers to a solvent that has a boiling temperature below 100°C, is miscible with water, and provides a homogeneous solution at a temperature of 25°C in solvent / water ratios ranging from 1:100 to a maximum of 100:1 (v / v), 1:20 to a maximum of 20:1 (v / v), or 1:2 to 2:1 (v / v). The water-miscible solvent is not particularly limited, but it is preferred that the water-miscible solvent is pharmaceutically / dietarily / veterinarily acceptable. The solvent may be a protic or aprotic solvent. Suitable protic solvents include primary, secondary, and tertiary alcohols with linear or branched, cyclic or acyclic alkyl chains having 1 to 6 carbon atoms, carbon acids, and primary or secondary amines with linear or branched, cyclic or acyclic alkyl chains having 1 to 6 carbon atoms. Preferred protic solvents include primary, secondary and tertiary alcohols with a linear or branched acyclic alkyl chain having 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, such as methanol, ethanol, propan-2-ol, acetic acid or propylamine.

[0049] In the context of the present invention, the term "water-miscible solvent comprises" includes solvents that incorporate some content of water. Thus, a water-miscible solvent comprising an alkanol also includes any solvent that contains an alkanol plus water.

[0050] In another embodiment, optionally in combination with any of the embodiments provided above or below, the water-miscible solvent comprises or consists solely of a (C1-C8) alkanol, a ketone, a nitrile, a sulfoxide, an amine, an amine, or a mixture thereof. In another embodiment, optionally in combination with any of the embodiments provided above or below, the water-miscible solvent further comprises water. In one embodiment, optionally in combination with any of the embodiments provided above or below, crystallization is carried out by adding a mixture of water and a (C1-C8) alkanol, particularly a mixture of water and a (C1-C8) alkanol. In an alternative embodiment, optionally in combination with any of the embodiments provided above or below, the crystallization step is carried out by adding a water-miscible solvent consisting solely of a (C1-C8) alkanol, particularly a (C1-C4) alkanol, such as, in particular, methanol, ethanol, or isopropanol.

[0051] After the precipitation process is complete, the solids are filtered, illustrative non-limiting examples of which are a centrifuge or a Nutsche filter according to the manufacturer's instructions.

[0052] After filtration is complete, the resulting cake is washed with a water-miscible solvent. This step is essential because its purpose is to reduce the amount of water required to wet the solids, thereby minimizing the requirements for the subsequent drying step. To that end, the wet cake is washed with a water-miscible solvent, such as a solvent suitable for salt precipitation in step (c). The washing step can be repeated as many times as deemed appropriate to minimize the amount of wet water. The less wet water used, the lower the drying temperature. Several washes can be performed using the same water-miscible solvent, or using different solvents each time.

[0053] In one embodiment, optionally in combination with any of the embodiments provided above or below, washing is carried out in two sub-steps: a first sub-step with a solvent comprising water+(C1-C8) alkanol, and a second sub-step with only (C1-C8) alkanol, in particular (C1-C4) alkanol, to release as much water as possible from the cake and soak it in this volatile alcohol.

[0054] After the washing step is completed, a drying step is carried out. This step is carried out under conditions that allow the removal of the water-miscible solvent. Those skilled in the art can routinely determine the most appropriate conditions, particularly temperature, time, or pressure, to achieve solvent removal. The term "removal" should be understood as the elimination of solvent at a level (residual amount) that makes the salt acceptable for human or veterinary medicine or dietary use. Knowing the appropriate level of solvent in the final product is part of the general knowledge of those skilled in the art. Those skilled in the art can also use supporting guidelines such as ICH Q3C (R8) Residual Solvents, available on the EMEA webpage. As a result of the washing step, the drying step can be carried out efficiently at room temperature in a very short time (as shown below). A vacuum can be used to accelerate the drying process. In the example shown below, the product was efficiently dried under vacuum in 1 hour. Another exemplary, but non-limiting, suitable alternative to vacuum is countercurrent airflow with stirring. The required time varies depending on the batch size and the equipment used to dry the product. For example, drying a large batch in a drying oven takes much longer than drying a small batch in a Nutsche filter equipped with agitators and heaters, but in both cases the drying is carried out at milder temperatures so that the hydrate molecules are retained in the final product.

[0055] In one embodiment, optionally in combination with any of the embodiments provided above or below, the step is carried out at a temperature below 50°C, below 49°C, below 48°C, below 47°C, below 46°C, below 45°C, below 44°C, below 43°C, below 42°C, below 41°C, below 40°C, below 39°C, below 38°C, below 37°C, below 36°C, below 35°C, below 34°C, below 33°C, below 32°C, below 31°C, below 30°C, below 29°C, below 28°C, below 27°C, below 26°C, below 25°C, below 24°C, below 23°C, below 22°C, below 21°C or below 20°C, particularly at a T comprised between 17°C and 35°C, particularly between 17°C and 25°C.

[0056] In one embodiment, optionally in combination with any of the embodiments provided above or below, the present invention provides a method for obtaining Na2WO4·2H2O, comprising the steps of: (i) preparing a tungsten (VI) salt in an alkaline aqueous solution by dissolving a tungsten-containing compound selected from WO, paratungstate, or tungstic acid in a sodium alkaline aqueous solution at a temperature of 30°C to 95°C; (ii) filtering the aqueous solution at a temperature of 30°C to 60°C, particularly 40°C to 50°C; (iii) precipitating tungsten(VI) salt dihydrate from the filtrate obtained from step (b1) by adding a water-miscible solvent comprising or consisting of a (C1-C8) alkanol; (iv) filtering at room temperature (15°C to 25°C); (v) washing the resulting filter cake with a water-miscible solvent comprising or consisting solely of a (C1-C8) alkanol; (vi) drying at a temperature below 50°C, below 49°C, below 48°C, below 47°C, below 46°C, below 45°C, below 44°C, below 43°C, below 42°C, below 41°C, below 40°C, below 39°C, below 38°C, below 37°C, below 36°C, below 35°C, below 34°C, below 33°C, below 32°C, below 31°C, below 30°C, below 29°C, below 28°C, below 27°C, below 26°C, below 25°C, below 24°C, below 23°C, below 22°C, below 21°C or below 20°C, in particular between 18°C ​​and 22°C; The present invention provides a method comprising:

[0057] In another embodiment, optionally in combination with any of the embodiments provided above or below, the present invention provides a method for obtaining Na2WO4·2H2O, comprising the steps of: (a1) preparing a tungsten(VI) salt in an alkaline aqueous solution by dissolving WO3 in a sodium alkaline aqueous solution at a temperature of 80°C to 95°C; (b1) filtering the aqueous solution at a temperature of 30°C to 60°C, particularly 40°C to 50°C; (c1) precipitating tungsten(VI) salt dihydrate from the filtrate obtained from step (b1) by adding a water-miscible solvent comprising or consisting of a (C1-C8) alkanol; (d1) filtering at room temperature (15°C to 25°C); (e1) washing the resulting filter cake with a water-miscible solvent comprising or consisting solely of a (C1-C8) alkanol; (f1) drying at a temperature below 50°C, below 49°C, below 48°C, below 47°C, below 46°C, below 45°C, below 44°C, below 43°C, below 42°C, below 41°C, below 40°C, below 39°C, below 38°C, below 37°C, below 36°C, below 35°C, below 34°C, below 33°C, below 32°C, below 31°C, below 30°C, below 29°C, below 28°C, below 27°C, below 26°C, below 25°C, below 24°C, below 23°C, below 22°C, below 21°C or below 20°C, in particular at a temperature between 18°C ​​and 22°C; The present invention provides a method comprising:

[0058] In another embodiment, optionally in combination with any of the embodiments provided above or below, the present invention provides a method for obtaining Na2WO4·2H2O, comprising the steps of: (a2) preparing a tungsten(VI) salt in an alkaline aqueous solution by dissolving APT in an alkaline aqueous solution of sodium at a temperature of 50-70°C; (b2) filtering the aqueous solution at a temperature of 35°C to 60°C, particularly 40°C to 50°C, particularly 45°C; (c2) precipitating tungsten(VI) salt dihydrate from the filtrate obtained from step (b2) by adding a water-miscible solvent comprising or consisting of a (C1-C8) alkanol; (d2) filtering at room temperature (15°C to 25°C); (e2) washing the resulting filter cake with a water-miscible solvent comprising or consisting solely of a (C1-C8) alkanol; (f2) drying at a temperature below 50°C, below 49°C, below 48°C, below 47°C, below 46°C, below 45°C, below 44°C, below 43°C, below 42°C, below 41°C, below 40°C, below 39°C, below 38°C, below 37°C, below 36°C, below 35°C, below 34°C, below 33°C, below 32°C, below 31°C, below 30°C, below 29°C, below 28°C, below 27°C, below 26°C, below 25°C, below 24°C, below 23°C, below 22°C, below 21°C or below 20°C, in particular between 18°C ​​and 22°C; The present invention provides a method comprising:

[0059] In another embodiment, optionally in combination with any of the embodiments provided above or below, the present invention provides a method for obtaining Na2WO4·2H2O, comprising the steps of: (a3) preparing a tungsten (VI) salt in an alkaline aqueous solution by dissolving H2WO4 in an aqueous sodium alkaline solution at a temperature below 40°C; (b3) filtering the aqueous solution at a temperature of 30°C to 60°C, particularly 35°C to 45°C, particularly 35°C; (c3) precipitating tungsten(VI) salt dihydrate from the filtrate obtained from step (b3) by adding a water-miscible solvent comprising or consisting of a (C1-C8) alkanol; (d3) filtering at room temperature (15°C to 25°C); (e3) washing the resulting filter cake with a water-miscible solvent comprising or consisting solely of a (C1-C8) alkanol; (f3) drying at a temperature below 50°C, below 49°C, below 48°C, below 47°C, below 46°C, below 45°C, below 44°C, below 43°C, below 42°C, below 41°C, below 40°C, below 39°C, below 38°C, below 37°C, below 36°C, below 35°C, below 34°C, below 33°C, below 32°C, below 31°C, below 30°C, below 29°C, below 28°C, below 27°C, below 26°C, below 25°C, below 24°C, below 23°C, below 22°C, below 21°C or below 20°C, in particular at a temperature of 18°C ​​to 22°C; The present invention provides a method comprising:

[0060] Advantageously, as discussed extensively throughout this document, the methods of the present invention can result in tungsten salts with reduced amounts of impurities and residual solvents, making these salts suitable for pharmaceutical, veterinary, and dietary applications.

[0061] As shown by way of example below, the resulting sodium tungstate dihydrate obtained according to the method of the present invention had a residual MeOH content of less than 3000 ppm, a level recognized as safe by ICH Q3C (R8)-Residual solvents (EMA / CHMP / ICH / 82260 / 2006), available on the EMEA webpage.

[0062] TIFF2025542091000001.tif134170

[0063] In further aspects, the present invention provides pharmaceutical, veterinary and food compositions and therapeutic uses based on the novel sodium tungstate salts of the present invention.

[0064] In one embodiment of the present invention, the treated subject is a human. In one embodiment, the tungsten(VI) salts of the present invention are useful for preparing a medicament for treating female infertility caused by alterations in the hypothalamic-pituitary axis. Diseases or conditions caused by alterations in the hypothalamic-pituitary axis include, in particular, polycystic ovary syndrome, metabolic syndrome, hyperprolactinemia, endometriosis, eating disorders, obesity, hypothyroidism, multiple sclerosis, rheumatoid arthritis, lupus erythematosus, cirrhosis of the liver, celiac disease, chronic renal failure, and idiopathic causes.

[0065] In another embodiment, the tungsten (VI) salt of the present invention is useful for preparing a medicament for treating female idiopathic infertility. The terms "idiopathic infertility" or "infertility without a clear cause" or "unexplained infertility" have the same meaning and are used interchangeably. These terms refer to cases of infertility where the reason for the inability to conceive has not been discovered through standard infertility testing.

[0066] In another embodiment, the tungsten(VI) salts of the present invention are useful in the preparation of a medicament for the treatment of female infertility due to eating disorders, including, in particular, anorexia nervosa and bulimia, which are associated with alterations in the hypothalamic-pituitary axis.

[0067] In another embodiment, the treatment of infertility comprises restoring ovulation. The term "ovulation" is understood as the process by which a woman releases oocytes into the uterus, and the term "restoring ovulation" is understood as the process of re-establishing the menstrual cycle, i.e., the regular release of oocytes into the uterus in women who have not ovulated (anovulation) or have had irregular ovulation (oligoovulation).

[0068] In another embodiment, treating infertility involves increasing the number of oocytes that implant in the uterine wall or improving the chances of a successful pregnancy without increasing the risk of multiple pregnancies. The term "increasing the implantation of a fertilized egg" is understood as the process of increasing the efficiency of oocyte implantation in the uterus.

[0069] One embodiment of the present invention, a pharmaceutical, veterinary or food composition, is a composition for oral administration. Of particular interest are solid oral compositions such as tablets and capsules, and liquid oral compositions such as oral solutions or suspensions.

[0070] The phrase "pharmaceutically or veterinarily or dietarily acceptable excipient or carrier" refers to an excipient or carrier suitable for use in pharmaceutical, veterinary, or dietary technology for the preparation of a medicinal composition. These components, excipients, and carriers must be compatible with the other ingredients of the composition and suitable for use in contact with human or animal tissues or organs without undue toxicity, irritation, allergic response, or other immunogenic problems or complications, at a reasonable risk / benefit ratio.

[0071] As used herein, the term "therapeutically effective amount" refers to an amount of tungsten(VI) salt sufficient to treat female infertility as defined herein upon administration. The specific dosage of the tungsten(VI) salt according to the present invention will be determined by the specific circumstances surrounding the case, including, for example, the salt administered, the route of administration, the pharmaceutical, veterinary, or food composition administered, and the characteristics of the patient, particularly height, weight, and age, as well as the nature and stage of the disease. For example, an amount of the tungsten(VI) salt defined above ranging from 50 mg / kg / day to 500 mg / kg / day can be used.

[0072] The following examples are presented to give those skilled in the art a sufficiently clear and complete description of the present invention, but should not be construed as limiting the essential aspects of the subject matter described hereinabove. [Example]

[0073] Example 1: Synthesis and isolation of Na2WO4·2H2O starting from APT 2.0 equivalents of NaOH(s) were added to an APT suspension containing 1.52 volumes of water.

[0074] This resulted in a suspension of the same starting product in water, which in the case of the APT experiments only occurred when the mixture was heated to 55 °C. The need to heat the initial mixture is due to the low solubility of APT in water.

[0075] After the sodium tungstate solution was obtained, it was filtered through a Celite precoat to remove insoluble impurities. To obtain higher recovery, these filtrations were performed at elevated temperatures (45°C) to avoid retaining part of the desired product, since the salt concentration in the crude material was close to its saturation point at room temperature.

[0076] After filtering the solution, MeOH was added in a proportion equivalent to 1.27 times the amount of water in the filtrate, resulting in a mobile white suspension that could be filtered through a sintered glass funnel without the need for recirculation.

[0077] The solid was washed with the same MeOH / HO ratio (14:11) as the crude reaction material, plus a final wash with MeOH to release as much water as possible and allow the solid to soak in this volatile alcohol. After the water had been fully drained, a vacuum was applied to the plate itself and an airflow was applied for 1 hour.

[0078] To determine whether entrainment with MeOH or entrainment with air also leads to undesired dehydration of the Na2WO4·2H2O salt, 5.6131 g of each of the solids obtained from two similar batches was dried in a vacuum oven at 105 °C for 15 h.

[0079] The weight loss was approximately equivalent to two parts water weight, with a final weight of 5.000 g expected.

[0080] The weights obtained were 5.0092 g and 5.0099 g for two similar batches of solids.

[0081] The results showed, on the one hand, that the drying process conditions of the present invention were efficient, and, on the other hand, that the initial solid obtained was a dihydrate. The presence of water molecules in the solid dried at room temperature was also evidenced by recording an IR spectrum (Perkin Elmer "Spectrum Two", 120100), which showed the same bands as the standard compound Na2WO4·2H2O (Figure 1).

[0082] In terms of yield, the APT-based experiments reached 81%.

[0083] Example 2: Synthesis and isolation of Na2WO4·2H2O starting from WO3 Starting with a WO suspension in 3.07 volumes of HO, the same procedure as in Example 1 was followed with the following slight modifications in the solubilization step: for the WO suspension, 4.0 equivalents of NaOH were added and the resulting suspension was heated to 90 °C.

[0084] Again, the dehydration of the Na2WO4·2H2O salt was determined by drying 5.6131 g of the solid from two similar batches in a vacuum oven at 105 °C for 15 h.

[0085] The weight loss was approximately equivalent to two parts water weight, with a final weight of 5.000 g expected.

[0086] The weights obtained were 5.0086 g and 5.0103 g for two similar batches of solids.

[0087] The results again showed that the drying conditions of the present invention were efficient, while the initial solid obtained was a dihydrate. The presence of water molecules in the non-temperature dried solid was also evidenced by recording an IR spectrum that showed the same bands as the standard compound Na2WO4 2H2O (Figure 1).

[0088] In terms of yield, 95% and 96% were achieved in two runs of the experiment based on WO3.

[0089] The higher performance of the experiments starting from WO3 is due to the higher salt loading of each crude material, which required the addition of twice the amount of NaOH equivalents to generate the sodium salt, allowing a higher proportion of salt to precipitate than the crude material starting from APT.

[0090] Example 3: Synthesis and isolation of Na2WO4·2H2O starting from H2WO4 The same process as presented in Example 1 was followed, with some modifications.

[0091] The solubilization step was carried out by slowly adding 2.0 equivalents of NaOH to a cold suspension of the acid in 2.1 volumes of water. To achieve higher recovery, the initial amount of water was adjusted to the amount necessary to dissolve the resulting salt at rt.

[0092] The resulting solution was heated at 40°C and then filtered through Celite to retain insoluble impurities to obtain a Na2WO4(aq) solution, from which the final sodium tungstate was isolated by precipitation under the same conditions as those mentioned in Example 1.

[0093] In this case, precipitation was performed by adding 2.0 volumes of either MeOH, EtOH, acetone, or IPA at room temperature. After stirring overnight at room temperature, the suspension was filtered at room temperature, and the cake was washed by percolation with 0.4 volumes of HO / solvent (1:1) and 0.4 volumes of the corresponding solvent. The final wet cake was dried overnight at 100°C.

[0094] The chemical yields achieved using each solvent were 85% for MeOH, 80% for EtOH, 50% for IPA, and 69% for acetone. The yields using EtOH were similar to those for MeOH, but the latter was chosen due to its lower cost, availability, and lower boiling point, which facilitates drying of the final product.

[0095] This point proved to be of utmost importance, since the Na2WO4·2H2O hydration water was found to be extremely unstable. Indeed, the dehydration process of tungsten salts was detected during various drying processes at 100-110 °C of these and other synthesized solids. This phenomenon was observed when IR spectra were recorded of the synthesized and dried products, as none of them showed the stretching and bending bands typical of water molecules (Figure 2).

[0096] The same process was repeated, but the final cake was dried at room temperature (rt), thus preventing the loss of water of crystallization in the final product. The product was dried at room temperature in an open container without forced air. The weight after 2 days at room temperature is the same as after 4 days under the same conditions. It is necessary to determine whether the process can be accelerated by forcing air through the solid, and what the maximum temperature is that does not cause dehydration of the solid.

[0097] The synthesis yield of the final acid product step was 70%-72%.

[0098] Example 4: Analytical testing Two direct synthesis scale-ups of Na2WO4·2H2O from WO3 were analyzed by ICP-MS (ICP-MS VARIAN 820) because they were assumed to be the highest purity candidates based on previous analyses.

[0099] As far as metal impurities are concerned, both products comply with the specifications. The sodium and tungsten contents were also analyzed (Table 1).

[0100] TIFF2025542091000002.tif136170

[0101] The amount of MeOH in the final product was determined according to the protocol below.

[0102] i. Preparation of solutions: Blank solvent: 250 mg of sodium chloride and 1.0 mL of water are introduced into a 10 mL headspace vial. Standard solution: Prepare in duplicate. Accurately weigh 150 mg of methanol standard into a 10.0 mL volumetric flask with 5 mL of water. Dissolve and bring to volume with water. Homogenize the solution. Add 1.0 mL of the previous solution to a 50.0 mL volumetric flask. Make to volume with water and homogenize the solution. Introduce 250 mg of sodium chloride and 1.0 mL of the previous standard solution into a 10 mL headspace vial. Test solution: Prepare in duplicate: 250 mg of sodium chloride, 100 mg of sample and 1.0 mL of water are introduced into a 10 mL headspace vial.

[0103] ii. Chromatography conditions: Equipment: Gas chromatograph equipped with FID detector and headspace sampler (HSS). Column: Agilent BPX-VOL, 30 m x 0.25 mm ID, 1.4 μm (or equivalent). GC parameters: Injector: Temperature: 180℃ Oven temperature gradient:

[0104] TIFF2025542091000003.tif43170

[0105] Carrier gas: He, constant flow mode 1.4 mL / min Split mode, split ratio 25, split flow rate 35 mL / min Detector: Temperature: 270℃ H2 flow rate: 35mL / min Air flow rate: 350 mL / min Additional gas flow rate (N2): 40 mL / min Analysis time: 10.0 minutes Post run: 1.0 min

[0106] HS parameters: Oven temperature: 80℃ Loop temperature: 90℃ Transfer line temperature: 100℃ Vial equilibration: 40 minutes Infusion time: 0.20 minutes GC cycle time: 20 min Approximate retention time (RT) of methanol: 1.74 min

[0107] Passing criteria: 1. Standard solution A: The coefficient of variation of the response factor (n=6) should be d 10.0%.

[0108] For the time being, it can be concluded that the product obtained by direct reaction from WO3 results in sodium tungstate dihydrate that meets the impurity specifications.

[0109] 2. Standard solution B: The ratio of STDA-STDB (initial) response factors must be within 90% to 110%. The ratio of STDB(initial)-STDB(final) response factor must be within 90% to 110%.

[0110] Result: The area of ​​the MeOH peak in the test solution is not larger than the area of ​​the MeOH peak in the standard solution, and the test complies with the specification (d 3000 ppm).

[0111] Example 5: Stability testing The inventors have confirmed the stability of the hydrate obtained from the method of the present invention and determined the loss on drying over time.

[0112] To that end, a thoroughly mixed sample of sodium tungstate hydrate obtained from Example 2 was subjected to the following protocol: A dry, clean, shallow weighing bottle with a glass stopper is dried under the same conditions as those used for the determination. Cool to room temperature in a desiccator and weigh accurately ((W1) g). 1 g of sample is transferred to the bottle, the cap is put on and the bottle and contents are weighed accurately ((W2) g). The filled bottle is placed in a drying chamber (oven), the stopper is removed and it also remains in the chamber. The sample is dried to constant mass (105°C) for the specified time and temperature. After drying is complete, the drying chamber is opened and the bottle is quickly closed and cooled to room temperature (if applicable) in a desiccator before being weighed. The bottle and contents are weighed ((W3) g).

[0113] Calculation: Loss on drying % = (W2-W3) x 100 / (W2-W1)

[0114] Loss on drying should be less than 15% (w / w).

[0115] It was found that the hydrate obtained from the method of the present invention exhibited a loss on drying of less than 15%, and this loss was maintained over an 18-month test at 25°C / 60% HR and a 6-month test at 40°C / 75% HR.

Claims

1. 1. A method for obtaining a tungsten (VI) salt hydrate, comprising the steps of: (a) preparing a tungsten (VI) salt in an alkaline aqueous solution; (b) filtering the aqueous solution at a temperature at which the tungsten (VI) salt remains dissolved; (c) precipitating tungsten(VI) salt hydrate from the filtrate obtained from step (b) at a temperature below 100°C, in particular below 50°C; (d) filtering the precipitated salts; (e) washing the resulting filter cake with a water-miscible solvent; (f) drying the washed cake under conditions sufficient to remove the water-miscible solvent; A method comprising:

2. 2. The method of claim 1, wherein the tungsten (VI) salt hydrate comprises one anion selected from the group consisting of tungstate and isopolytungstate, in particular the anion is tungstate.

3. 3. The method of claim 1 or 2, wherein the tungsten (VI) salt hydrate comprises a cationic moiety selected from the group of cations: sodium, ammonium, potassium, magnesium and calcium, zinc, copper and silver.

4. 4. The method of claim 1, wherein the tungsten (VI) salt hydrate is sodium tungstate dihydrate.

5. Step (a) ３ The method according to any one of claims 1 to 4, wherein the method is carried out by dissolving a tungsten-containing compound selected from the group consisting of paratungstate and tungstic acid in an alkaline aqueous solution.

6. 6. The method of any one of claims 1 to 5, wherein the alkaline aqueous solution further comprises one cationic moiety selected from sodium, ammonium, copper, potassium, magnesium and calcium, zinc and silver.

7. 7. The method of claim 5 or 6, wherein the alkaline aqueous solution is added in molar excess relative to the tungsten-containing compound.

8. 8. The process of any one of claims 1 to 7, wherein step (a) is carried out by heating to a temperature below reflux.

9. 9. The process according to any one of claims 1 to 8, wherein the filtration step (b) is carried out at a temperature of at least 30°C but below the reflux temperature.

10. The process of any one of claims 1 to 9, wherein step (c) is carried out by cooling or by adding a water-miscible solvent.

11. The water-miscible solvent used in step (c) and step (e) is １ ~C ８ 11. The method according to any one of claims 1 to 10, comprising or consisting solely of an alkanol.

12. The method of any one of claims 1 to 11, wherein step (e) is repeated.

13. Na ２ WO ４ ・2H ２ To obtain O, (i) WO ３ preparing a tungsten (VI) salt in an alkaline aqueous solution by dissolving a tungsten-containing compound selected from the group consisting of tungsten, paratungstate, and tungstic acid in an alkaline aqueous solution at a temperature of 30°C to 95°C; (ii) filtering the aqueous solution at a temperature of 30°C to 60°C; (iii) (C １ ~C ８ ) precipitating tungsten(VI) salt dihydrate from the filtrate obtained from step (b1) by adding a water-miscible solvent comprising or consisting solely of an alkanol; (iv) filtering the precipitated salts; (v) The resulting filter cake is treated with (C １ ~C ８ ) washing with a water-miscible solvent comprising or consisting solely of an alkanol; (vi) drying at a temperature below 50°C, in particular between 15°C and 25°C, in particular between 18°C ​​and 22°C; or alternatively, (a1) WO ３ in an aqueous sodium alkaline solution at a temperature of 80°C to 95°C to prepare a tungsten (VI) salt in an aqueous alkaline solution; (b1) filtering the aqueous solution at a temperature of 50°C to 90°C; (c1) (C １ ~C ８ ) precipitating tungsten(VI) salt dihydrate from the filtrate obtained from step (b1) by adding a water-miscible solvent comprising or consisting solely of an alkanol; (d1) filtering the precipitated salt; (e1) The obtained filter cake is subjected to (C １ ~C ８ ) washing with a water-miscible solvent comprising or consisting solely of an alkanol; (f1) drying at a temperature of 18°C ​​to 22°C; or alternatively, (a2) preparing a tungsten (VI) salt in an alkaline aqueous solution by dissolving APT in an aqueous sodium alkaline solution at a temperature of 50°C to 70°C; (b2) filtering the aqueous solution at a temperature of 35°C to 60°C; (c2) (C １ ~C ８ a) precipitating a tungsten(VI) salt dihydrate from the filtrate obtained from step (b2) by adding a water-miscible solvent comprising or consisting solely of an alkanol; (d2) filtering the precipitated salt; (e2) The obtained filter cake is treated with (C １ ~C ８ ) washing with a water-miscible solvent comprising or consisting solely of an alkanol; (f2) drying at a temperature of 18°C ​​to 22°C; or alternatively, (a3) H ２ WO ４ in an aqueous sodium alkaline solution at a temperature below 40°C to prepare a tungsten (VI) salt; (b3) filtering the aqueous solution at a temperature of 30°C to 60°C, particularly 35°C to 45°C, particularly 35°C; (c3) (C １ ~C ８ a) precipitating a tungsten(VI) salt dihydrate from the filtrate obtained from step (b3) by adding a water-miscible solvent comprising or consisting solely of an alkanol; (d3) filtering the precipitated salt; (e3) The obtained filter cake is treated with (C １ ~C ８ ) washing with a water-miscible solvent comprising or consisting solely of an alkanol; (f3) drying at a temperature below 50°C, below 49°C, below 48°C, below 47°C, below 46°C, below 45°C, below 44°C, below 43°C, below 42°C, below 41°C, below 40°C, below 39°C, below 38°C, below 37°C, below 36°C, below 35°C, below 34°C, below 33°C, below 32°C, below 31°C, below 30°C, below 29°C, below 28°C, below 27°C, below 26°C, below 25°C, below 24°C, below 23°C, below 22°C, below 21°C or below 20°C, in particular at a temperature of 18°C ​​to 22°C; The method according to any one of claims 1 to 12, comprising:

14. Sodium tungstate dihydrate for pharmaceutical, veterinary or dietary use, with a residual content of water of at most 15% by weight, in particular a content of 10% to 15% by weight, relative to the total weight of the salt.

15. Sodium tungstate obtainable by the method according to any one of claims 1 to 13.

16. 16. A pharmaceutical or veterinary or food composition comprising a therapeutically effective amount of the sodium tungstate dihydrate of claim 14 or 15 together with one or more pharmaceutically, veterinarily or dietarily acceptable excipients or carriers.

17. 16. Sodium tungstate dihydrate according to claim 14 or 15 for therapeutic use.

18. 16. Sodium tungstate dihydrate according to claim 14 or 15 for the treatment of female infertility.

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