5-methyltetrahydrofolic acid crystalline alkaline-earth salts (variants), method for their preparing and composition for pharmaceutical agents and nutrition supplements

FIELD: vitamins, chemical technology, food industry, pharmacy.

SUBSTANCE: invention relates to crystalline alkaline-earth salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid with the content of at least one equivalent of crystallizing water per equivalent of 5-methyltetrahydrofolic acid, in particular, 5-methyl-(6R)-tetrahydrofolic acid crystalline calcium salt or to different types of 5-methyl(6S)-tetrahydrofolic acid crystalline calcium salts. These salts can be used in preparing medicinal agents or as a nutrition supplement for treatment or prophylaxis of folic acid-mediated diseases. Also, invention relates to a method for preparing crystalline salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid by crystallization of the corresponding salt of 5-methyl-(6R,S)-, -(6S)- or -(6R)-tetrahydrofolic acid from a polar medium by using heat treatment at temperature above 60°C followed, if necessary, by drying the prepared product. Also, invention relates to a composition for pharmaceutical agents or nutrition supplements.

EFFECT: improved preparing method, valuable properties of salts and composition.

13 cl, 5 dwg, 4 tbl, 11 ex

 

The present invention relates to crystalline salts of N-[4-[[2-amino-1,4,5,6,7,8-hexahydro-4-oxo-5-methyl-(6S)-, -(6R)- and -(6R,S)-pteridinyl) methyl] amino] benzoyl] -L-glutamic acid (hereafter referred to as salts of 5-methyltetrahydrofolate acid)containing water of crystallization, for their use, as well as the way they are received.

Tetrahydrofolate is used primarily in the form of 5-formyltetrahydrofolate acid and its salts (leucovorin) or in the form of 5-methyltetrahydrofolate acid and its salts for the treatment of mediated folic acid megaloblastic anemia, as safener (antidote) to improve portability of folic acid antagonists, in particular of aminopterin and methotrexate in therapy of cancer ("antifolate salvation"), to enhance therapeutic effect of fluorinated pyrimidines for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis, to improve portability of certain anti-parasitic substances, such as trimethoprimsulfamethoxazole, and to reduce the toxicity of dideuteroindole chemotherapy. 5-Methyltetrahydrofolate acid is used primarily as a medicine and as a dietary Supplement, a vitamin preparation, to prevent damage to the neural tube, for the treatment of depressive h the problems and to influence the level of homocysteine.

5-Methyltetrahydrofolate acid and its salts are extremely unstable, with their characteristic feature is the high oxidation [see A.L. Fitzhugh, Pteridines 4(4), 187-191 (1993)] and consequently, they are difficult to distinguish acceptable for pharmaceutical or food additives purity.

To overcome the difficulties associated with the instability of 5-methyltetrahydrofolate acid, use a variety of methods, such as possible the complete elimination of oxygen or the addition of substances that protect against oxidation (antioxidants, such as ascorbic acid or restored L-glutathione. However, to completely eliminate the access of oxygen is almost impossible, and if it turns out to be possible only at very high cost, with the addition of substances that protect against oxidation, is also not always possible. As a consequence, up to the present time was not developed acceptable from a technical point of view the method is suitable to obtain a sufficiently stable salts 5-methyltetrahydrofolate acid with a high degree of purity.

With the invention it has been unexpectedly found that salts of 5-methyltetrahydrofolate acid having a high degree of chemical purity and very high stability, can be obtained by crystallization according to the corresponding salt of the polar environment after heat treatment of the solution at a temperature above 60° C. Obtained in this way vysokobaricheskie salt 5-methyltetrahydrofolate acids have at room temperature practically unlimited stability. They are suitable as an ingredient or source of the product for the preparation of drugs or as a nutritional Supplement.

Thus, the object of the present invention are crystalline salts of 5-methyltetrahydrofolate acid. To obtain crystalline salts of 5-methyltetrahydrofolate acid is preferably used salts of alkaline earth metals, in particular a salt of calcium. Crystalline salts of 5-methyltetrahydrofolate acids have unattainable still purity, component >98%, along with unattainable up to the present time stability, component >98% relative to the original value that was estimated by the results of storage for 6 months in air at 25°C and 60%relative humidity. Crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid can be represented in four different crystalline modifications (type I, type II, type III and type IV) and are characterized by sharp peaks according to x-ray diffraction analysis of the powder (see figure 1-4 and table 1-4). The most characteristic peaks in different crystalline modifications occur in the following is meant is I 2θ : 6,5, 13,3, 16,8 and 20.1 (type I), respectively, 5,3, 6,9, and 18,7 21,1 (type II), respectively, 6,8, 10,2, 15,4 and 22.5 (type III), 6,6, 15,9, 20,2 and 22.5 (type IV). The content of water of crystallization in the crystalline calcium salt of 5-methyltetrahydrofolate acid is at least 1 equivalent of water per 1 equivalent of 5-methyltetrahydrofolate acid. Thus, modification of type I, as a rule, contains ≥3 equivalents of water, modification of type II, as a rule, contains ≤2 equivalents of water, and modification of type III and IV, as a rule, contain ≤3 water equivalent.

Salts of 5-methyl-(6R)-tetrahydrofolate acid and salts of 5-methyl-(6R,S)-tetrahydrofolate acid can also be obtained in vysokomaslichnoy form.

Another object of the invention is a method for vysokokritichnyh salts 5-methyltetrahydrofolate acid, characterized in that the corresponding salt of 5-methyltetrahydrofolate acid is obtained by crystallization. According to this method, the crystallization of salt 5-methyltetrahydrofolate acid is carried out polar environment after heat treatment at temperatures above 60°C, in particular above 85°C.

As polar environment suitable primarily water or a mixture of water and miscible with water, an organic solvent selected from the group comprising water-soluble alcohols, for example methanol, ethanol, n-disappear to the ol, isopropanol, ethylene glycol, water-soluble lower aliphatic carboxylic acids, for example formic acid, acetic acid, lactic acid, or water-soluble amides, such as formamide, dimethylformamide, dimethylacetamide, 1-organic, 2-organic, 2-piperidine. On the type of solvent and the ratio in the mixture is not imposed no particular restriction as crystalline salts of 5-methyltetrahydrofolate acids in General have a higher solubility than the corresponding amorphous form.

The crystallization is preferably carried out from solutions. However, it is also possible crystallization of the suspension.

By additional heat treatment at temperatures above 60°in conditions of controlled humidity of various crystalline modifications can be transformed into each other. Thus, modification of type I, obtained by crystallization from a polar environment after heat treatment at temperatures above 60°With, can be converted by drying in vacuum at 70°With the modification of type II, by heat treatment at temperatures above 90° - modification of type III, and by heat treatment at temperatures above 95° - modification of type IV. Modification of type II water treatment in a humid chamber at 90°can be re-pravarasena modification type I.

Crystallization of salt 5-methyltetrahydrofolate acid may occur spontaneously or be triggered by priming with the corresponding crystalline salts of 5-methyltetrahydrofolate acid.

As the initial product for crystallization is preferable to use amorphous or crystalline pure 5-methyl-(6S)- or 5-methyl-(6R) - tetrahydrofolic acid, but can also be used racemic 5-methyl-(6R,S)-tetrahydrofolic acid or enriched 5-methyl-(6S)-, -(6R)- or(6R,S)-tetrahydrofolic acid.

When using as starting product for the crystallization of amorphous or partially crystalline optically pure 5-methyltetrahydrofolate acid or its salts in the implementation of the described method are almost pure crystalline salt of 5-methyltetrahydrofolate acid, characterized previously unattainable purity and stability.

The invention also relates to the use of vysokokritichnyh salts 5-methyltetrahydrofolate acid as a component for the preparation of drugs or as a food additive or for other derivatives of tetrahydrofolate acid as crystalline salts of 5-methyltetrahydrofolate acid due to their very high stability in hard four the e remain almost indefinitely consistently very high quality. The invention also relates to compositions comprising vysokobaricheskie salt 5-methyltetrahydrofolate acid. The compositions are prepared by known techniques. Application exercise analogous to the use of known substances from the class of tetrahydrofolate, such as, for example, 5-formyltetrahydrofolate acid (leucovorin).

The description of the present invention enables the specialist in the art to implement the invention in practice in full. Therefore, the following examples are presented only to illustrate possible embodiments of the invention and in no way should be construed as limiting its scope.

All temperatures given in the examples presented here, indicated in degrees Celsius. Unless otherwise noted, the quantitative data of the components are given as wt.%.

Examples illustrating the invention

Specified in the examples, the salt content of 5-methyltetrahydrofolate acid in each case were determined using liquid chromatography high resolution (IHVR) and was calculated in % of the surface area under the peak corresponding to the diagram, the water content was determined by Karl-Fischer.

Example 1 [stability Indicators]

To assess the stability of the crystalline salts of 5-methyltetra is kopolevoy acid test substance together with the control samples were stored in air at 25° C and 60%relative humidity. After a certain period of time measured remaining amount of salt 5-methyltetrahydrofolate acid and was expressed in % relative to its original value.

The test period in months
036121888
crystalline calcium salt of 5-methyl-(6S) -tetrahydrofolate acid100%98,6%98,7%99,1%99,0%of 97.8%
amorphous calcium salt of 5-methyl-(6S)-tetrahydrofolate acid100%84,2%

Crystalline salts of 5-methyltetrahydrofolate acid after a long period of testing was still very bright. In contrast, the coloration of amorphous samples in a short period of time was very much changed.

Example 2 [X-rays obtained powder]

For characterization of structural features (crystalline modifications) crystalline salts of 5-methyltetrahydrofolate acid, these substances were subjected to x-ray diffraction analysis of the powder is e with the corresponding x-ray (diffraction spectra).

Crystalline salts of 5-methyltetrahydrofolate acid are well soluble spectra with sharp peaks and low background level. These spectra indicate the presence of vysokomaslichnoy component parts.

Examples of the spectra shown in figure 1 (type I), 2 (type II), 3 (type III) and 4 (type IV), respectively, and in table 1 (type I), table 2 (type II), table 3 (type III) and table 4 (type IV). For comparison, in similar conditions was obtained spectrogram for the amorphous sample, presented in figure 5 (Amorin.).

Below are the typical values of 2θ for different crystalline modifications of crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid:

TypeThe typical values of 2θ
type I6,5, 13,3, 16,8 and 20.1
type II5,3, 6,9, and 18,7 21,1
type III6,8, 10,2, 15,4 and 22.5
type IV6,6, 15,9, 20,2 and 22.5

Example 3 [Figures solubility]

Data on the solubility of the crystalline calcium salt of 5-methyl-(6S) tetrahydrofolate acid shown in the following table:

TypeSolubility at 20° In
0,9%NaClwater
type I1,6%1,1%
type II5,8%3,8%
type III1,5%1,0%

Example 4 [Amorphous calcium salt of 5-methyl-(6S)-tetrahydrofolate acid]

7.5 g of 5-methyl-(6S)-tetrahydrofolate acid at room temperature was added in an atmosphere of N2to 75 ml of water and the pH value was brought to 12 with 30%caustic soda. The pH value thus obtained transparent solution was brought to pH 7.5 with 37%hydrochloric acid and to this solution was added a solution containing 7,15 g CaCl2·6N2About 11.7 ml of water. The resulting white suspension after peremeshivanija for 5 h at room temperature, filtered through a nutsche filter, washed with water and dried in vacuum at 45°C. the result obtained 5.8 g of a white amorphous calcium salt of 5-methyl-(6S)-tetrahydrofolate acid with purity 98,0% and the content of the 6S-isomer 99,6%.

After processing of the substance in a humid chamber at 60°found no crystalline component or through a polarizing microscope or x-ray diffraction analysis.

Example 5 [Crystalline calcium salt of 5-methyl-(6R,S)-tetrahydrofolate acid]

70 g of 5-methyl-(6S)-tetrahydrofolate is islote was added to 780 ml of water and the pH was brought to 7.5 with the help of 45.2 g of 30%NaOH solution. To clear slightly reddish solution was added a solution containing 62,7 g CaCl2·6N2About 140 ml of water, was filtered and washed with a small amount of water. Thus obtained crude product is suspended in water and kept for 24 h in a humid chamber at 90°C. the result was of 74.0 g of white crystalline salts of 5-methyl-(6R,S)-tetrahydrofolate acid with a purity of 99.1%.

Example 6 [Crystalline calcium salt of 5-methyl-(6R)-tetrahydrofolate acid]

16.5 g of 5-methyl-(6R-tetrahydrofolate acid was dissolved in 100 ml of water at 92°and added 50 g of CaCl2·6N2O. Transparent slightly yellow suspension was stirred for 10 min at 91°C, filtered, washed with a small amount of water and dried in vacuum at 35°C. as a result got to 15.4 g of a light beige crystalline calcium salt of 5-methyl-(6R)-tetrahydrofolate acid with a purity of 97.9% of and with a water content of 7.8%.

Example 7 [Type I]

To 130 kg of water was added to 12.8 kg 5-methyl-(6S)-tetrahydrofolate acid. The pH value was brought about to 11.6 with approximately 9.1 kg 30%NaOH, and then to 7.6 with approximately 1.9 kg of 37%hydrochloric acid. To the clear solution was added a suspension containing 0.3 kg of coal and 0.3 kg of cellulose fibre was filtered and washed with 13 l of water. To filter the ATU was mixed into the solution, containing 8.3 kg CaCl2·2H2O was heated to 90°and was stirred for 30 minutes the Product was filtered while hot and washed with 2x20 kg of water. Thus obtained wet crude product is suspended in 115 liters of water, heated to 90°With, then immediately filtered while hot, washed with 2x20 kg of water and dried in vacuum at 40°C. the result was 11.6 kg white crystalline salts of 5-methyl-(6S)-tetrahydrofolate acid (type I) with a purity rate of 99.0% and a water content of 14.5%.

Example 8 [Type I]

To 1600 ml of water was added 194 g of 5-methyl-(6S)-tetrahydrofolate acid. The pH was brought to 7.0 with approximately 80 ml of 30%NaOH. To the clear solution was added a suspension containing 20 g of coal and 20 g of cellulose fibers in 190 ml of water, filtered and washed with water. To the filtrate was mixed into 950 ml of 5,5M solution of calcium chloride, was heated to 90°and was stirred for 60 minutes, the Product was filtered while hot, washed with water and dried in vacuum at 45°C. the result was 156,2 g of crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid (type I) white with purity of 99.7%, and the content 6S-isomer of 99.9%.

Example 9 [Type I into type II]

To 554 g of water was added to 53.1 g of 5-methyl-(6S) -tetrahydrofolate acid. The pH was brought to 7.5 with 30%rest the RA NaOH. To the clear solution was added 1.3 g of coal, 1.3 g of cellulose fibre and 19.5 g of water. The suspension was filtered and washed with 55 ml of water. To the filtrate was mixed into a solution containing 52,0 g CaCl2·6N2In 84,6 g of water, was heated to 90°and made a seed crystal in the form of 100 mg of crystalline calcium salt of 5-methyltetrahydrofolate acid. After crystallization, the product was filtered in hot condition at 90°and washed h g of water. The resulting moist crude product is suspended in 480 ml of water, was heated to 90°With, then immediately was filtered while hot, washed as described above and dried in vacuum at 45°C. the result is received and 47.5 g of crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid (type I) white with purity 98,8% and a water content of 12.2%.

By drying in vacuum for 30 min at 70°With this modification of type I can be converted into a modification of type II, the water content of which is 5.0%.

Example 10 [Type III]

to 15.8 g of the calcium salt of 5-methyl-(6S)-tetrahydrofolate acid was heated to 95°With 140 ml of water in the atmosphere N2after exposure for 30 min at 95°With the white suspension was filtered while hot through a nutsche filter, washed with water and dried in vacuum at 35°C. the result obtained 14.0 g of crystalline calcium is Oli 5-methyl-(6S)-tetrahydrofolate acid (type III) white color with a purity of 98.9 per cent and content 6S-isomer of 99.9%.

Example 11 [Type IV]

to 20.0 g of the calcium salt of 5-methyl-(6S)-tetrahydrofolate acid was heated to 100°With 180 ml of water in the atmosphere N2after exposure for 30 min at 100°With the white suspension was filtered while hot through a nutsche filter, washed with water and dried in vacuum at 25°C. In the received 16.9 g of crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid (type IV) white with a purity of 98.3% and a water content of 9.9%.

By drying in vacuum at 65°With the water content of this product may be reduced to 5.5%, while not turning into another crystal modification.

1. Crystalline alkaline-earth salt of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolate acid c content of water of crystallization from at least one equivalent per equivalent of 5-methyltetrahydrofolate acid.

2. Crystalline alkaline-earth salt of 5-methyl-(6S)- and -(6R) -tetrahydrofolate acid.

3. Crystalline calcium salt of 5-methyl-(6S)- and -(6R)-tetrahydrofolate acid.

4. Crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid, characterized by values of 2θ, 6.5, 13,3, 16,8 and 20.1(Type I).

5. Crystallize the Kai calcium salt of 5-methyl-(6S)-tetrahydrofolate acid, characterized by values of 2θ, 5.3, 6,9, and 18,7 21,1(Type II).

6. Crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid, characterized by values of 2θequal to 6.8, 10,2, 15,4 and 22.5(Type III).

7. Crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolate acid, characterized by values of 2θequal to 6.6, 15,9, 20,2 and 22.5(Type IV).

8. The method of obtaining crystalline salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolate acid according to any one of claims 1 to 7, characterized in that the corresponding salt of 5-methyl -(6R,S)-, -(6S)- or(6R)-tetrahydrofolate acid is crystallized from the polar environment, using a heat treatment at a temperature above 60aboutWith, followed, if necessary, drying the obtained product.

9. The method according to claim 8, characterized in that the crystallization is carried out using heat treatment at temperatures above 85°C.

10. The method according to claim 8, characterized in that the crystallization is carried out from a solution.

11. The method according to claim 8, characterized in that the crystallization is carried out suspension.

12. The method according to PP or 11, characterized in that the crystallization is carried out from the water or from a mixture of water with miscible with water and organic solvent.

13. Composition for pharmaceutical or dietary supplements for treating or preventing oposreduemyh Foley is howling acid diseases, including crystalline alkaline-earth salt of 5-methyl-(6S)- or(6R)-tetrahydrofolate acid according to any one of claims 1 to 7.



 

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