Folate salts

Abstract

To provide folate salts that are chemically bonded to a further active compound, and exhibit superior stability and superior solubility in both water and apolar solvents.SOLUTION: The invention relates to a crystalline folate salt. The folate salt consists of a folate anion and an organic cation. The folate anion is 5-methyl-(6S)-tetrahydrofolic acid, and the organic cation is an organic compound which is an alkanolamine selected from the group consisting of choline, N-methylaminoethanol, 2-amino-2-methylpropanol, and 2-dimethylaminoethanol.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to folates, folate preparations and compositions comprising folate. [Background technology]

[0002] Depression and other psychiatric disorders such as dementia, autism, attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease, as well as chronic non-communicable diseases (NCDs) such as type 1 and type 2 diabetes, vascular disorders and cancer, are an increasing burden for patients and healthcare systems, especially in view of the ageing population. Although these diseases have various distinct causes, a common risk factor has been found to be suboptimal systemic folate status or folate status in specific tissues.

[0003] It is well known that B complex vitamins are involved in many of the body's metabolic processes, such as converting carbohydrates into glucose, which is metabolized to produce energy. These vitamins are also essential for the breakdown of fats and proteins, and play an important role in maintaining muscle tone along the lining of the digestive tract and promoting the health of the nervous system, including the health of the eyes, skin, hair, liver and kidneys.

[0004] In addition, folate is known to be essential for the production and maintenance of new cells, especially during periods of rapid cell division and proliferation, such as in infancy and pregnancy. Folate is required for DNA replication. Thus, folate deficiency impairs DNA synthesis and cell division, most clinically affecting the bone marrow, the site of rapid cell turnover. Because RNA and protein synthesis are not impeded, large red blood cells, i.e. megaloblasts, are produced, resulting in macrocytic anemias, such as megaloblastic anemia, as seen in celiac disease and nutritional anemia, i.e., during pregnancy, infancy, or childhood. Thus, adults, especially the elderly, and children require folate to produce normal red blood cells and prevent anemia. Folate also helps prevent DNA changes that may lead to cancer.

[0005] Folic acid derivatives, such as various tetrahydrofolic acid derivatives, can also be used as a base material for making drugs or other derivatives. Moreover, tetrahydrofolic acid and its derivatives are known to have extreme instability, especially due to their susceptibility to oxidation. In particular, 5-formyltetrahydrofolic acid (folinic acid, leucovorin) and its physiologically active 5-formyl-(6S) form are important mainly as oncological drug components, in combination therapy with methotrexate and 5-fluorouracil, in the treatment of folate deficiency anemia associated with pregnancy, in antibiotic therapy, etc. Among folic acid and reduced folates, the calcium salts thereof can be said to be the relatively most stable derivatives. That is, US Pat. No. 5,817,659 and US Pat. No. 6,441,168 disclose crystalline salts, preferably calcium salts, of 5-methyl-(6R,S)-, (6S)- or (6R)-tetrahydrofolic acid, having at least one equivalent of water of crystallization per equivalent of the acid. 5-Methyltetrahydrofolic acid is the only commercially available folic acid derivative that can directly penetrate the blood-brain barrier without further metabolism. Naturally occurring 5-methyltetrahydrofolic acid is exclusively in the 6S form. Its 6R form is considered biochemically inactive and is excreted through the kidney. Furthermore, several compositions for humans and animals containing various forms of folic acid and / or reduced folic acid, in various forms and with vitamins, arginine, lysine, thiamine and / or other active ingredients, have been published as dietary supplements or for the treatment and prevention of various diseases, such as neurological diseases, pathophysiological diseases, cardiovascular diseases, arthritis and inflammatory conditions.

[0006] Various folates are known. In general, these salts contain folic acid and inorganic cations such as calcium and magnesium. These alkaline earth metal cations are inert insofar as they have no pharmacological effect in humans. The poor solubility of such salts in aqueous solutions has been widely documented. Hydrous compositions with improved solubility and stability of folic acid are disclosed, for example, in US 9,301,922 and US 9,642,853.

[0007] US 5,382,581 discloses the diastereomeric separation of 5-methyl-tetrahydrofolic acid using ammonium salts. WO 2018 / 178142 describes binary salts of 5-methyl-tetrahydrofolic acid with sodium and an organic base. US 2016 / 0207925 discloses salts of L-methyl-folic acid containing amino acids such as L-arginine and L-asparagine. The salts are freeze-dried and appear amorphous. US 5,710,271 describes a process for the production, separation and purification of the (6S) and (6R) diastereomers of folic acid. Furthermore, WO 2009 / 103334 discloses freeze-dried or spray-dried glucosamine and galactosamine salts of L-methyl-tetrahydrofolic acid. WO2009 / 103333 describes a process for the separation of the (6R) and (6S) diastereomers of 5-methyl-tetrahydrofolic acid using an organic base in the form of a phenylethyl-amine or naphthylethyl-amine compound to obtain pure and stable diastereomers. CN107304212 discloses a process for producing amorphous L-methyl-tetrahydrofolic acid amino acid salts. WO93 / 17022 discloses a process for the separation of the stereoisomers of folinic acid. The separation is carried out by salifying (R / S) folinic acid with a diamine or polyamine, followed by the addition of the amine to the (R / S) folinic acid. This is achieved by selectively crystallizing the (6S) diastereomer of folinic acid.

[0008] Furthermore, a large number of folate compounds have been described that contain folic acid and additional compounds such as vitamins, lysine, thiamine, and other active ingredients, but a stable salt of folic acid with good solubility in both water and organic solvents would provide broader applications in pharmaceutical compositions. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US5,817,659 [Patent Document 2] US6,441,168 [Patent Document 3] US9,301,922 [Patent Document 4] US9,642,859 [Patent Document 5] US5,382,581 [Patent Document 6] WO2018 / 178142 [Patent Document 7] US2016 / 0207925 [Patent Document 8] US5,710,271 [Patent Document 9] WO2009 / 103334 [Patent Document 10] WO2009 / 103333 [Patent Document 11] CN107304212 [Patent Document 12] WO93 / 17022 Summary of the Invention [Problem to be solved by the invention]

[0010] It is an object of the present invention to provide folates that are chemically bound to additional active compounds and that exhibit good stability and good solubility in both water and non-polar solvents. [Means for solving the problem]

[0011] This object is achieved by the folate according to the invention as defined in claim 1. Further preferred embodiments are according to the dependent claims.

[0012] A particular folate is considered highly soluble in a non-polar solvent if its solubility in that particular organic or non-polar solvent is greater than 2 weight percent (w / w) of the total weight of the solution. The solubility is measured at 20° C. Non-polar solvents or mixtures thereof are, for example, glycerol, methanol, ethanol, 1-propanol, 2-propanol and dimethylsulfoxide (DMSO). A non-polar solvent is understood to be a dry solvent that does not contain any water. A non-polar solvent can be a pure solvent comprising a single type of non-polar solvent or a mixture of at least two of said non-polar solvents. The polarity is compared to the polarity of water.

[0013] High crystallinity means that the crystalline content of the folate is greater than 40% of the total amount of folate. Thus, crystalline folate is understood to be a folate that contains more than 40% crystalline matter. The crystallinity is determined by X-ray diffraction analysis (XRD).

[0014] The folates of the present invention comprise a tetrahydrofolate anion and an organic cation, the anion being a folate, preferably 5-methyl-(6S)-tetrahydrofolate, and the cation being an organic compound, the organic compound being an alkanolamine selected from the group consisting of choline, N-methylaminoethanol, 2-amino-2-methylpropanol, or 2-dimethyl-aminoethanol.

[0015] The folate of the crystalline folate according to claim 1 has a high solubility in organic solvents. High solubility in organic solvents is understood as a solubility of more than 2 weight percent of the total weight of the solution.

[0016] In a further embodiment, the anion of the folate may also be 5-formyl-(6S)-tetrahydrofolate. The viable organic cations are selected from the same group, i.e., choline, N-methyl-aminoethanol, 2-dimethyl-aminoethanol, and 2-amino-2-methyl-propanol. Effect of the Invention

[0017] The crystalline folates according to the invention exhibit high stability and also high solubility in water and in non-polar solvents.

[0018] The further counterion of the folate anion, 5-formyl-(6S)-tetrahydrofolic acid or 5-methyl-(6S)-tetrahydrofolic acid, can be the organic cation arginine.

[0019] In a preferred embodiment, the crystalline folate salt comprises a tetrahydrofolate anion and an organic cation. The anion is 5-methyl-(6S)-tetrahydrofolate. The cation is di-choline.

[0020] In another embodiment, the crystalline folate salt comprises a tetrahydrofolate anion and an organic cation, the anion being 5-methyl-(6S)-tetrahydrofolic acid and the cation being mono-2-dimethylaminoethanol.

[0021] In another embodiment, the crystalline folate salt comprises a tetrahydrofolate anion and an organic cation, the anion being 5-methyl-(6S)-tetrahydrofolic acid and the cation being N-methylaminoethanol.

[0022] In yet another embodiment, the crystalline folate salt comprises a tetrahydrofolate anion and an organic cation, the anion being 5-methyl-(6S)-tetrahydrofolic acid and the cation being 2-amino-2-methylpropanol.

[0023] In yet another embodiment, the crystalline folate salt comprises a tetrahydrofolate anion and an organic cation, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolic acid and the organic cation is di-choline, wherein the H-NMR shifts in deuterium oxide are as set forth in Table 1.

[0024] [Table 1]

[0025] In yet another embodiment, the crystalline tetrahydrofolate salt comprises a tetrahydrofolate anion and an organic cation, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolic acid and the organic cation is di-2-dimethylaminoethanol, wherein the H-NMR shifts in deuterium oxide are as set forth in Table 2.

[0026] [Table 2]

[0027] In yet another embodiment, the crystalline tetrahydrofolate salt comprises a tetrahydrofolate anion and an organic cation, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolic acid and the organic cation is mono-2-dimethylaminoethanol, wherein the H-NMR shifts in deuterium oxide are as set forth in Table 3.

[0028] [Table 3]

[0029] In yet another embodiment, the crystalline tetrahydrofolate salt comprises a tetrahydrofolate anion and an organic cation, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolic acid and the organic cation is di-N-methylaminoethanol, wherein the H-NMR shifts in deuterium oxide are as set forth in Table 4.

[0030] [Table 4]

[0031] In yet another embodiment, the crystalline tetrahydrofolate comprises a tetrahydrofolate anion and an organic cation, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolate and the organic cation is di 2-amino-2-methylpropanol, wherein the H-NMR shifts in deuterium oxide are as set forth in Table 5.

[0032] [Table 5]

[0033] In a further preferred embodiment, the pharmaceutical composition comprises at least one folate according to the invention as the main active compound. The composition further comprises at least one pharmacologically acceptable excipient. The composition can, for example, contain a buffer compound. Suitable and preferred buffer compounds are trometamol and HEPES. Furthermore, an antioxidant compound can be present in the composition. Preferred antioxidant compounds are thioglycerol, dithiothreitol (DTT) and cysteine.

[0034] Furthermore, at least one folate according to the invention as described above can be used to produce a medicament, food additive or dietary supplement for the prevention and / or treatment of deficiencies or disorders that are favorably affected by the administration of folate. There are many pathological conditions that are favorably affected by compositions containing folate. Such diseases are, for example, pathophysiological diseases, neurological diseases and inflammatory diseases.

[0035] Further, the method of the present invention for producing crystalline folates and tetrahydrofolates consisting of folate anions and organic cations comprises the step of adding oxalic acid, or alternatively a fluoride salt, or directly from the free compound, to an aqueous composition of alkaline earth metal folate or free folic acid.

[0036] Surprisingly, crystallization was achieved from organic solvents such as 1-propanol, which contain limited amounts of water, e.g. less than 12% by weight, preferably less than 10% by weight. The weight percent of water is based on the total weight of the organic solvent and water. The minimum amount of water corresponds to 0.2% by weight of water in the organic solvent. This corresponds to 1 to 170 equivalents of crystal water based on the molar amount of folic acid. 1.5 to 2 waters of crystallization have been detected in the isolated folate. The organic solvent or non-polar solvent is understood to be dry, i.e. anhydrous. Without adding water to the organic solvent in the various amounts mentioned above, all the folate precipitates in amorphous form.

[0037] The crystalline folates according to the present invention are further illustrated in the figures. [Brief description of the drawings]

[0038] [Figure 1] FIG. 1 shows an X-ray diffractogram of the 5-methyl-(6S)-tetrahydrofolic acid dicholine salt of Example 1. [Diagram 2] FIG. 2 shows an X-ray diffractogram of 5-methyl-(6S)-tetrahydrofolic acid mono 2-dimethylaminoethanol salt of Example 3. [Diagram 3] FIG. 3 shows an X-ray diffractogram of 5-methyl-(6S)-tetrahydrofolic acid di-2-dimethylaminoethanol salt of Example 4. [Figure 4] FIG. 4 shows an X-ray diffractogram of 5-methyl-(6S)-tetrahydrofolic acid di-N-methylaminoethanol salt of Example 5. [Diagram 5] FIG. 5 shows an X-ray diffractogram of 5-methyl-(6S)-tetrahydrofolic acid di 2-amino-2-methylpropanol salt of Example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0039] Preparation of 5-methyl-(6S)-tetrahydrofolic acid dicholine salt

[0040] Under argon, 7.00 g (15.23 mmol) of levomefolic acid was suspended in 70 ml of 1-propanol and refluxed. Then, 7.71 ml (31.99 mmol) of 47% aqueous choline hydroxide was added and stirred under reflux until a clear solution was obtained. An additional 80 ml of 1-propanol was added to obtain a water concentration of 3.2% w / w in 1-propanol, and the solution was seeded with a crystalline sample of the product. After crystallization began at 65°C, the suspension was slowly cooled down from 65°C to 2-8°C. The suspension was slowly stirred for another 2 hours at 2-8°C. The granular crystals were aspirated, washed with chilled 1-propanol, and dried to give 7.29 g of the white crystalline crude title compound. Recrystallization of 7.29 g of the crude title compound under argon was carried out by dissolving in about 130 ml of methanol at 60° C. and evaporating under vacuum at 60° C. The residue was taken up in about 60 ml of 1-propanol, dissolved at 60° C. and concentrated to a final mass of 40 g of solution. In an oil bath at 70° C., the solution was diluted with a mixture of 1-propanol and water (20:2% v / v) (about 4.0% water in 1-propanol) at 70° C. under argon, while crystallization was initiated from the pale yellow solution after seed formation. The temperature of the suspension was gradually reduced to 20° C. and crystallization was completed by slow stirring at 2-8° C. The separated crystals were dried at 60° C. / <1 mbar, yielding 5.76 g of MTHF di-choline. Analytical data are as follows:

[0041] [Table 6]

[0042] The angle of rotation is α20D+33.6° (c=1 H2O). The water of crystallization in MTHF dicholine was calculated to be 1.6 by water analysis and microanalysis by Karl Fischer (KF). The melting point was determined to be 232-233° C. by differential scanning calorimetry (DSC). The X-ray diffraction analysis is shown in Table 7.

[0043] [Table 7]

[0044] The solubilities are as shown in Table 8.

[0045] [Table 8]

[0046] The solubility of crystalline dicholine folate in organic solvents is highly variable and appears to depend on the degree of crystallinity. When dicholine folate is highly crystallized, in other words when the crystalline content is high, the solubility of dicholine folate in ethanol is low, 0.3% by weight of the total solution weight. When the amorphous content is high, the solubility of dicholine folate in ethanol is very high (38.8% by weight). Furthermore, in mixtures of organic solvents, for example in methanol at 5% by weight of the total solution weight or in mixtures of glycerol and ethanol, the solubility of highly crystallized dicholine folate is enhanced, reaching 25% by weight (of the total solution weight). High crystallinity means that the crystalline content of the folate is more than 40% by weight of the total folate. High solubility in the solvent means that the folate can be dissolved in more than 2% by weight of the total solution weight. EXAMPLES

[0047] Preparation of 5-methyl-(6S)-tetrahydrofolic acid dicholine salt

[0048] 13.72 g (28.9 mmol) of levomefolic acid was suspended in 70 ml of methanol at 20-22° C. under argon. Then, 160 ml (57.6 mmol, 0.360 mol / l in 1-propanol) of choline hydroxide solution was added at 20-22° C. for about 3 minutes, rinsed with 4 ml of 1-propanol, and stirred at 20-22° C. until a clear solution was obtained. Then, an additional 13.5 ml of 1-propanol was added and the reaction mixture was evaporated at 50° C. / 50 mbar, then coevaporated twice with 11 ml of 1-propanol, yielding a residue of 43.6 g. This residue was diluted with 140 ml of 1-propanol under argon and heated to an external temperature of 65° C. Seed crystals were added and 5.25 ml of water was added slowly at 65° C. until crystallization started while turbidity remained (approximately 3.7% w / w water). The mixture was stirred and the temperature was reduced to 50° C. over 20 min, then allowed to cool to 30° C., and the thick suspension thus formed was stirred at 2-8° C. for 70 min. The crystals were isolated, washed with a mixture of 4 ml of 1-propanol / water 31:1 (v / v) and 24 ml of 1-propanol, and dried at 45-60° C. / 50-5 mbar to give 16.1 g of L-MTHF di-choline. Analytical data are as follows:

[0049] [Table 9]

[0050] The water of crystallization in L-MTHF dicholine was calculated to be 2.0 by (KF and microanalysis). The melting point was determined to be 232-233° C. by DSC. EXAMPLES

[0051] Preparation of 5-methyl-(6S)-tetrahydrofolic acid mono 2-dimethylaminoethanol salt

[0052] 2.00 g (4.353 mmol) of levomefolic acid was placed in 20 ml of water under argon with a small amount of cysteine ​​and heated to 70° C. The suspension was then treated with 876 μl (8.706 mmol, 2 eq.) of 2-dimethylaminoethanol and stirred at 70° C. until a clear solution was obtained. Isopropanol was then added slowly at 70° C. to a total of 150 ml. When turbidity was reached, another 70 ml of 2-propanol was added and the mixture was treated with seed crystals at about 60° C. to initiate crystallization (about 10.4% water in 2-propanol). The mixture was then slowly and gradually cooled down from 60° C. to 2-8° C. The crystals were aspirated, washed with chilled 2-propanol and dried under vacuum at 50° C. to give 1.96 g of the title compound as white crystals. The analytical data are as follows:

[0053] [Table 10]

[0054] The optical rotation was α20D+11.0° (c=1 H2O). The water of crystallization in L-MTHF monodimethylaminoethanol (L-MTHF monodeanol) was 1.5 by thermogravimetry (TG), KF and microanalysis. The melting point was determined to be 194°C by (DSC). The X-ray diffraction analysis is shown in Table 11.

[0055] [Table 11]

[0056] The solubilities are as shown in Table 12.

[0057] [Table 12] EXAMPLES

[0058] Preparation of 5-methyl-(6S)-tetrahydrofolic acid di-2-dimethylaminoethanol salt

[0059] 2.00 g (4.353 mmol) of levomefolic acid was placed in 20 ml of 1-propanol under argon and heated to reflux while adding 800 μl of water. The suspension was then treated with 876 μl (8.706 mmol, 2 equiv.) of 2-dimethylaminoethanol, diluted with 3.2 ml of water, and stirred at 100° C. until a clear solution was obtained. 1-propanol (7 ml) was then added and the solvent was evaporated in vacuum at 40° C. The residue (3.68 g) was dissolved in 30 ml of 2-propanol / 10 ml of water and concentrated by distilling off the solvent in vacuum at 40° C. until crystallization began. These crystals were sonicated in 1-propanol for 5 min at 20-25° C., suction filtered, washed three times with 1-propanol, and dried at 60° C. / <1 mbar to give 2.34 g of the title compound as white crystals with the following analytical data:

[0060] [Table 13]

[0061] The optical rotation was α20D+31.6° (c=1 H2O). The melting point was determined to be 157° C. by (DSC). The X-ray diffraction analysis is as follows:

[0062] [Table 14] EXAMPLES

[0063] Preparation of 5-methyl-(6S)-tetrahydrofolic acid di-N-methylaminoethanol salt

[0064] 3.00 g (5.30 mmol) of levomefolinate calcium was placed in 45 ml of water with a small amount of cysteine ​​under argon and heated to 70° C. The resulting suspension was then treated with 848 μl (10.60 mmol) of N-methylaminoethanol and 668 mg (5.30 mmol) of oxalic acid dissolved in 5 ml of water. The dilute suspension was further stirred at 70° C. for 5 min, then cooled to 0° C. and stirred for 50 min. The reaction mixture was filtered and the clear solution was stabilized with a small amount of cysteine ​​and concentrated at 45° C. / <200 mbar. The residue was seeded and the product slowly started to crystallize, which was completed at 2-8° C. The crystals were dried at 50° C. / <1 mbar to give 3.08 g of crude product. The crude product was dissolved in 25 ml of methanol, 1.21 ml (3 eq.) of N-methylaminoethanol and 5 ml of 1-propanol. The cloudy solution was filtered, washed with 10 ml of methanol and the clear filtrate was heated to 60° C. Then, 65 ml of 1-propanol, 150 μl of water and 1 eq. of N-methylaminoethanol were added to the solution. The mixture was treated with seed crystals at 60° C. to initiate crystallization and then slowly and gradually cooled down from 60° C. to 0° C. The crystals were aspirated and washed with 1-propanol / methanol 2:1, then with 1-propanol and ether. The isolated crystals were dried at 50° C. / <1 mbar to give 2.60 g of the title compound as off-white crystals. Analytical data are as follows:

[0065] [Table 15]

[0066] The optical rotation was α20D+41.2° (c=1 H2O). The water of crystallization in L-MTHF di N-methylaminoethanol (L-MTHF di NMAE) was 1.5 by KF and microanalysis. The melting point was determined to be 199° C. by (DSC). The X-ray diffraction analysis is shown in Table 16.

[0067] [Table 16]

[0068] The solubilities are as shown in Table 17.

[0069] [Table 17] EXAMPLES

[0070] Preparation of 5-methyl-(6S)-tetrahydrofolic acid di-2-amino-2-methylpropanol salt

[0071] 3.00 g (5.30 mmol) of levomefolinate calcium was placed in 45 ml of water with a small amount of cysteine ​​under argon and heated to 70° C. The suspension was then treated with 1012 μl (10.60 mmol) of 2-amino-2-methylpropanol and 668 mg (5.30 mmol) of oxalic acid dissolved in 5 ml of water. The dilute suspension was stirred at 70° C. for 5 min and then cooled to 0° C. The dilute suspension was filtered, the solution stabilized with cysteine ​​and concentrated at 45° C. / <200 mbar. The residue was treated with seed crystals and the crystallization was completed at 2-8° C. overnight. The crystals were dried at 50° C. / 1 mbar. The crude product was dissolved in 6.5 ml of water and heated to 70° C. The solution was diluted with 70 ml of 1-propanol (10.4% water in 1-propanol), treated with seed crystals and slowly cooled gradually to 20-23° C. The crystals were isolated, washed with 1-propanol / water 20:1 (v / v), 1-propanol and ether and dried at 50° C. / <1 mbar to give 2.79 g of the title compound as off-white crystals. Analytical data:

[0072] [Table 18]

[0073] The optical rotation was α20D+34.6° (c=1 H2O). The water of crystallization in L-MTHF di 2-amino-2-methylpropanol was 1.5 by (KF and microanalysis). X-ray diffraction analysis is given in Table 19.

[0074] [Table 19]

[0075] The solubility is as shown in Table 20.

[0076] [Table 20] EXAMPLES

[0077] Preparation of Choline Hydroxide Solution Used in Example 2

[0078] 10.39 g (74.42 mmol) of choline chloride was placed in a solution of 110 ml of 1-propanol and 3.02 g (74.42 mmol) of sodium hydroxide under argon at 20-25°C. The mixture was heated to 70-72°C for approximately 70 minutes and then heated to 70°C. The suspension was then cooled to 0-5°C for 45 minutes. The white suspension was filtered through a silica bed and the filtrate was filled up to 200 ml with 1-propanol in a volumetric flask. The concentration of the choline hydroxide was 0.36 mol / l (measured by titration).

[0079] This solution was used as a stock form of choline used to produce a high purity choline salt of folic acid.

Claims

1. A crystalline folate comprising a tetrahydrofolate anion and an organic cation, wherein the anion is 5-methyl-(6S)-tetrahydrofolic acid, and the cation is an organic compound, the organic compound being an alkanolamine selected from the group consisting of choline, 2-dimethylaminoethanol, N-methylaminoethanol, and 2-amino-2-methylpropanol.

2. 2. The crystalline folate of claim 1, wherein the folate has high solubility in an organic solvent.

3. 3. The crystalline folate according to claim 1 or 2, wherein the organic compound is di-choline.

4. 3. The crystalline folate according to claim 1 or 2, wherein the organic compound is mono-2-dimethylaminoethanol.

5. 3. The crystalline folate according to claim 1 or 2, wherein the organic compound is di-2-dimethylaminoethanol.

6. 3. The crystalline folate according to claim 1 or 2, wherein the organic compound is di-N-methylaminoethanol.

7. 3. The crystalline folate according to claim 1 or 2, wherein the organic compound is di-2-amino-2-methylpropanol.

8. 3. The crystalline folate according to claim 1 or 2, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolic acid and the organic cation is di-choline.

9. 3. The crystalline folate according to claim 1 or 2, wherein the tetrahydrofolate anion is 5-methyl-(6S)-tetrahydrofolic acid and the organic cation is mono-2-dimethylaminoethanol.

10. 10. A pharmaceutical composition comprising as the main active compound at least one folate as defined in any one of claims 1 to 9 and at least one pharma-ceutically acceptable excipient.

11. 10. A folate according to any one of claims 1 to 9, which is a folate for use as a drug, food additive or dietary supplement and for the prevention and / or treatment of deficiencies and disorders that are beneficially affected by the administration of tetrahydrofolic acid.

12. A method for producing a crystalline folate salt as described in any one of claims 1 to 9, which is composed of a tetrahydrofolate anion and an organic cation, comprising the step of crystallizing the folate salt from an organic solvent containing water in the range of 0.2 to 12 weight percent of the total weight of the mixture of organic solvent and water.

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