Folate

Abstract

It is an object of the present invention to provide folates chemically bound to additional active compounds, which exhibit good stability and good solubility in both water and non-polar solvents. The present invention relates to a crystalline folate salt, which is composed of a folate anion and an organic cation, the folate anion being 5-methyl-(6S)-tetrahydrofolic acid, and the organic cation being an alkanolamine selected from the group consisting of choline, N-methylaminoethanol, 2-amino-2-methylpropanol, and 2-dimethylaminoethanol.

Description

[Technical Field]

[0001] The present invention relates to folates, folate preparations and compositions containing 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, represent 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 the folate status of 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] Furthermore, 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 necessary for DNA replication. Therefore, folate deficiency interferes with DNA synthesis and cell division, most clinically affecting the bone marrow, the site of rapid cell turnover. Because RNA and protein synthesis are unimpeded, large red blood cells, or megaloblasts, are produced, resulting in macrocytic anemias, such as megaloblastic anemia, seen in celiac disease and nutritional anemias, i.e., those seen during pregnancy, infancy, or childhood. Therefore, 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 base materials for preparing drugs or other derivatives. Furthermore, tetrahydrofolic acid and its derivatives are known to be extremely unstable, particularly due to their susceptibility to oxidation. In particular, 5-formyltetrahydrofolic acid (folinic acid, leucovorin) and its physiologically active 5-formyl-(6S) form are important as pharmaceutical components, primarily in oncological combination therapy with methotrexate and 5-fluorouracil, as well as in the treatment of folate deficiency anemia associated with pregnancy and antibiotic therapy. Among folic acid and reduced folates, calcium salts are relatively the most stable derivatives. Specifically, US Pat. Nos. 5,817,659 and 6,441,168 disclose crystalline salts, preferably calcium salts, of 5-methyl-(6R,S)-, (6S)-, or (6R)-tetrahydrofolic acid, each 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. The 6R form is considered biochemically inactive and is excreted through the kidneys. Furthermore, several compositions for humans and animals containing various forms of folic acid and / or reduced folic acid, in various forms and together 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 disorders, pathophysiological disorders, cardiovascular disorders, arthritis, and inflammatory conditions.

[0006] Various folates are known. Generally, these salts contain folic acid and inorganic cations such as calcium and magnesium. These alkaline earth metal cations are inert insofar as they themselves have no pharmacological effect on 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 U.S. Pat. Nos. 9,301,922 and 9,642,853.

[0007] US 5,382,581 discloses the diastereomeric separation of 5-methyl-tetrahydrofolic acid using an ammonium salt. WO 2018 / 178142 describes binary salts of 5-methyl-tetrahydrofolic acid containing 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 lyophilized 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 separating 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 stereoisomers of folinic acid. This separation involves salifying (R / S) folinic acid with a diamine or polyamine, followed by the addition of this This is achieved by selectively crystallizing the (6S) diastereomer of folinic acid.

[0008] Furthermore, numerous folate compounds have been described that contain folic acid and additional compounds such as vitamins, lysine, thiamine, and other active ingredients. However, stable salts of folic acid that have good solubility in both water and organic solvents would offer 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] US$9,301,922 [Patent Document 4] US$9,642,859 [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 chemically bound to additional active compounds, which 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 salt 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 nonpolar solvent if its solubility in that organic or nonpolar solvent is greater than 2 weight percent (w / w) of the total weight of the solution. Solubility is measured at 20°C. Nonpolar solvents or mixtures thereof are, for example, glycerol, methanol, ethanol, 1-propanol, 2-propanol, and dimethyl sulfoxide (DMSO). A nonpolar solvent is understood to be a dry solvent that does not contain any water. A nonpolar solvent can be a pure solvent containing a single type of nonpolar solvent, or a mixture of at least two of the nonpolar solvents. 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 containing more than 40% crystalline. 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 salt, preferably 5-methyl-(6S)-tetrahydrofolate, and the cation being an organic compound, which is an alkanolamine selected from the group consisting of choline, N-methylaminoethanol, 2-amino-2-methylpropanol, or 2-dimethylaminoethanol.

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

[0016] In a further embodiment, the folate anion may also be 5-formyl-(6S)-tetrahydrofolate, and 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. [Effects of the Invention]

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

[0018] The additional counterion of the folate anion, 5-formyl-(6S)-tetrahydrofolate or 5-methyl-(6S)-tetrahydrofolate, 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 being 5-methyl-(6S)-tetrahydrofolate, and the cation being di-choline.

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

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

[0022] In yet another embodiment, the crystalline folate salt comprises a tetrahydrofolate anion and an organic cation, wherein the anion is 5-methyl-(6S)-tetrahydrofolic acid and the cation is 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, and 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, and wherein the H-NMR shifts in deuterated water 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, and wherein the H-NMR shifts in deuterated water 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, and wherein the H-NMR shifts in deuterated water are as set forth in Table 4.

[0030] [Table 4]

[0031] In yet another embodiment, the crystalline tetrahydrofolate salt 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, and wherein the H-NMR shifts in deuterated water are as set forth in Table 5.

[0032] [Table 5]

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

[0034] Furthermore, the at least one folate salt according to the present invention as described above can be used to produce a medicament, food additive or dietary supplement for the prevention and / or treatment of deficiency 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, neurological and inflammatory diseases.

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

[0036] Surprisingly, crystallization was achieved from an organic solvent, such as 1-propanol, containing a limited amount 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 is 0.2% by weight of water in the organic solvent. This corresponds to 1 to 170 equivalents of crystallization water based on the molar amount of folic acid. 1.5 to 2 waters of crystallization were detected in the isolated folate. The organic solvent or nonpolar solvent is understood to be dry, i.e., anhydrous. Without adding water to the organic solvent in the various amounts mentioned above, all of the folate precipitates in an amorphous form.

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

[0038] [Figure 1] FIG. 1 shows the X-ray diffractogram of 5-methyl-(6S)-tetrahydrofolic acid dicholine salt of Example 1. [Figure 2] FIG. 2 shows an X-ray diffractogram of 5-methyl-(6S)-tetrahydrofolic acid mono 2-dimethylaminoethanol salt of Example 3. [Figure 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. [Figure 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 INVENTION [Example]

[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. 7.71 mL (31.99 mmol) of a 47% aqueous solution of choline hydroxide was then added and stirred under reflux until a clear solution was obtained. An additional 80 mL of 1-propanol was then added to achieve a water concentration of 3.2% w / w in the 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 from 65°C to 2-8°C. The suspension was slowly stirred for an additional 2 hours at 2-8°C. The granular crystals were aspirated, washed with chilled 1-propanol, and dried to yield 7.29 g of the crude white crystalline title compound. Recrystallization of 7.29 g of the crude title compound under argon was carried out by dissolving it in approximately 130 ml of methanol at 60°C and evaporating it under vacuum at 60°C. The residue was taken up in approximately 60 ml of 1-propanol, dissolved at 60°C, and concentrated to a final mass of 40 g. In an oil bath at 70°C, the solution was diluted with a mixture of 1-propanol and water (20:2% v / v) (approximately 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 lowered to 20°C, and crystallization was completed by slow stirring at 2-8°C. The isolated crystals were dried at 60°C / <1 mbar to yield 5.76 g of MTHF-di-choline. Analytical data are as follows:

[0041] [Table 6]

[0042] The optical 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 varies widely and appears to depend on the degree of crystallinity. When dicholine folate is highly crystalline, i.e., when the crystalline content is high, the solubility of dicholine folate in ethanol is low, at 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 a mixture of organic solvents, for example, in a mixture of methanol or glycerol and ethanol at 5% by weight of the total solution weight, the solubility of highly crystalline dicholine folate is enhanced, reaching 25% by weight (of the total solution weight). A high degree of crystallinity means that the crystalline content of the folate is greater than 40% of the total weight of the folate. A high solubility in a solvent means that the folate can dissolve at more than 2% by weight of the total solution weight. [Example]

[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. Next, 160 ml (57.6 mmol, 0.360 mol / L in 1-propanol) of choline hydroxide solution was added at 20-22°C for approximately 3 minutes, rinsed with 4 ml of 1-propanol, and stirred at 20-22°C until a clear solution was obtained. Next, an additional 13.5 ml of 1-propanol was added, and the reaction mixture was evaporated at 50°C / 50 mbar, followed by two coevaporations with 11 ml of 1-propanol, yielding 43.6 g of residue. 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 slowly added at 65°C until crystallization began while turbidity persisted (approximately 3.7% w / w water). The mixture was stirred, and the temperature was reduced to 50°C over 20 minutes. It was then allowed to cool to 30°C, and the thick suspension thus formed was stirred at 2-8°C for 70 minutes. 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 yield 16.1 g of L-MTHF di-choline. Analytical data were 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. [Example]

[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 equiv.) 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, an additional 70 mL of 2-propanol was added, and the mixture was seeded at approximately 60°C to initiate crystallization (approximately 10.4% water in 2-propanol). The mixture was then slowly and gradually cooled from 60°C to 2-8°C. The crystals were aspirated, washed with chilled 2-propanol, and dried under vacuum at 50°C to yield 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 determined to be 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] [Example]

[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 800 μL of water was added. This 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 vacuo 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 vacuo at 40°C until crystallization began. These crystals were sonicated in 1-propanol for 5 minutes at 20-25°C, filtered under suction, 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. Analytical data are as follows:

[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] [Example]

[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 minutes, then cooled to 0°C and stirred for 50 minutes. 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 began to crystallize, completing at 2-8°C. These crystals were dried at 50°C / <1 mbar to yield 3.08 g of crude product. The crude product was dissolved in 25 ml of methanol, 1.21 ml (3 equivalents) 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. Next, 65 ml of 1-propanol, 150 μl of water, and 1 equivalent 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 from 60°C to 0°C. The crystals were aspirated and washed with 2:1 1-propanol / methanol, followed by 1-propanol and ether. The isolated crystals were dried at 50°C / <1 mbar to yield 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] [Example]

[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. This 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 minutes and then cooled to 0°C. The dilute suspension was filtered, and the solution was stabilized with cysteine ​​and concentrated at 45°C / <200 mbar. The residue was treated with seed crystals, and crystallization was completed overnight at 2-8°C. The crystals were then 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 to 20-23°C. These crystals were separated, 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 are as follows:

[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). The X-ray diffraction analysis is shown in Table 19.

[0074] [Table 19]

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

[0076] [Table 20] [Example]

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

[0078] Under argon, 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 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 to 200 ml with 1-propanol in a volumetric flask. The concentration of the choline hydroxide was 0.36 mol / L (determined by titration).

[0079] This solution was used as a stock form of choline 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 organic solvents.

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

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

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

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

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

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

9. 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 according to any one of claims 1 to 9 and at least one pharmaceutically 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 deficiency diseases and disorders that are beneficially affected by the administration of tetrahydrofolic acid.

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

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