Stable crystalline salts of tetrahydrofolate acid (options), the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to new stable crystalline calcium or magnesium salts of (6R,S),(6S) - or (6R)-tetrahydrofolate acid, method for their production and pharmaceutical compositions based on them. These salts can be used as a means of regulating metabolic processes in the body, as antagonists of known anticancer drugs, such as methotrexate, as an antidote to enhance the portability of folic acid antagonists, for the treatment of megaloblastic palaeosalinity anemia and autoimmune diseases, to enhance the portability of a number of anti-parasitic substances, and to reduce the toxicity of dideuteroindole chemotherapy. The method of obtaining these salts is that the corresponding salt of tetrahydrofolate acid is crystallized from the polar medium at pH 7 to 10, mainly at high temperatures and/or from dilute solutions, in particular water or its mixture with mixing with the water solvent, such as acetic acid or lower organic alcohol. The invention also relates to pharmaceutical compositions, soteria-amino-l, 4, 5, 6, 7, 8-hexahydro-4-oxo-(6S)-, -(6R)- and(6R,S)-pteridinyl)methyl]amino] benzoyl] -L-glutamic acid (called in the following salts of tetrahydrofolate acid), for their use, as well as the way they are received.

Derivatives tetrahydrofolate acids contain two asymmetric center. In the synthesis of these derivatives of folic acid, N-(pteroyl)-L-glutamic acid contained in the residue glutamic acid optically active s-atom is represented in an L-shape, while usually formed by hydrogenation of the double bond in position 5,6 Teroldego balance optically active C-atom in position 6 presents in racemic, (6R, S)-form. In accordance with this synthetic derivatives of tetrahydrofolate acids consist of a mixture of two diastereomers in a ratio of 1:1.

As medicines tetrahydrofolate used primarily in the form of the calcium salt of 5-formyl-5,6,7,8-tetrahydrofolate acid (leucovorin) or 5-methyl-5,6,7,8-tetrahydrofolate acid for the treatment of megaloblastic palaeosalinity anemia, as an antidote to enhance the portability of folic acid antagonists, primarily aminopterin and methotrexate in the treatment of p is olivani, such as psoriasis and rheumatoid arthritis, to enhance the portability of certain anti-parasitic substances, in particular trimethoprim-sulfamethoxazole, and also to reduce the toxicity of dideuteroindole chemotherapy. In the body of the individual derivatives of tetrahydrofolate acid can vzaimotruschiesya (folate cycles). Tetrahydrofolate acid plays a major role. Similarly, tetrahydrofolate acid serves as the main substance for various derivatives of tetrahydrofolate acid.

Direct application of the salts tetrahydrofolate acid in the quality of medicines, as as the primary substance to obtain various derivatives of tetrahydrofolate acid, to date, been unsuccessful for two reasons. First, because of the difficulty of obtaining the salts tetrahydrofolate acid with acceptable pharmaceutical active substance degree of purity and, secondly, because of the instability of tetrahydrofolate acid, manifested primarily in the susceptibility to oxidation [see also A. L. Fitzhugh, Pteridines 4(4), 187-191 (1993)]. It should be noted that while most common in the pharmaceutical industry parentline pH of the injected solution. Therefore, the salt tetrahydrofolate acid in this application, most preferably correspond in shape to the specified condition. To eliminate the instability of tetrahydrofolate acid used various methods, such in particular as the maximum possible exception of oxygen or supplementation agents that protect against oxidation, such as ascorbic acid. However, the complete exclusion of oxygen in pharmaceutical use is hardly feasible, and if it can be implemented, it is associated with very high costs, and the addition of agents that protect against oxidation, when the pharmaceutical use is also not always possible. For these reasons, up to the present time could not be found technically acceptable method that would be suitable for obtaining the salts tetrahydrofolate acid with high purity, sufficient stability and which thereby would provide the opportunity for pharmaceutical application of salts of tetrahydrofolate acid.

Unexpectedly it was found that the salt of (6S)-, (6R)- or (6R,S)-tetrahydrofolate acid can be obtained with high purity and very good stability by crystallization of the corresponding salt of choice for the acid. Thus obtained crystalline salt of (6S)-, (6R)and/or (6R.S)-tetrahydrofolate acid in an appropriate form at room temperature differ practically unlimited stability. They are suitable for use as a component or as a starting material for the manufacture of various forms of drugs, respectively, as starting material to obtain industrially other derivatives of tetrahydrofolate acid with a high degree of purity.

The subject of the invention in accordance with this are crystalline salts of (6R,S)-, (6S)- and (6R)-tetrahydrofolate acid. For crystallization as the salts tetrahydrofolate acid is preferably used salts of alkaline earth metals, especially magnesium or calcium salt.

Another object of the invention is a method of obtaining a crystalline salts of (6R, S)-, (6S)- and (6R)-tetrahydrofolate acid, characterized in that the corresponding salt of tetrahydrofolate acid crystallized. Crystallization of the salts tetrahydrofolate acid is carried out at this preferably from polar environment when the pH value from 7 to 10.

As polar environment prigodin the action alcohols, for example, methanol, ethanol, n-propanol, isopropanol, ethylene glycol, water-soluble lower aliphatic carboxylic acid, such as, for example, formic acid, acetic acid, lactic acid, or water-soluble inorganic salts, such as, for example, formamide, dimethylformamide, dimethylacetamide, 1-organic, 2-organic, 2-piperidine. Regarding the type of solvent and the ratio of components in the mixture, there are no special restrictions as crystalline salts of tetrahydrofolate acids differ in the principle of better solubility than the corresponding amorphous forms.

The crystallization is preferably carried out at elevated temperature, more specifically in the range from 50 to 90oWith, or from diluted solutions, more specifically from 1 to 10% comments.

Crystallization of salts (6S)-, (6R)- and (6R,S)-tetrahydrofolate acid occurs spontaneously or by priming the corresponding crystalline salt of tetrahydrofolate acid.

As the source material of suitable crystallization is preferably amorphous or crystalline, pure (6S)- or (6R)-tetrahydrofolate acid, but it can and is folievaya acid. As the source material is suitable as the selected solids, such as (6R, S)-tetrahydrofolate acid, (6S)-tetrahydrofolate acid , sulfuric acid and additive salts of sulfonic acid, obtained according to European patent EP-495204 and obtained in situ by catalytic hydrogenation or by grafting using borohydride of folic acid tetrahydrofolate acid.

Thanks to the use of amorphous or partially crystalline optically pure tetrahydrofolate acid or its salts as starting material for crystallization using the above method are crystalline salts of tetrahydrofolate acid with a degree of purity (>98%) and such stability, to achieve which up to this time was not possible.

The invention relates also to the use of crystalline salts of (6S)-, (6R)and/or (6R,S)-tetrahydrofolate acid as components for the manufacture of medicines or for other derivatives of tetrahydrofolate acid as a crystalline salt of (6S)-, (6R)- and (6R,S)-tetrahydrofolate acid due to their excellent stability in solid form retain practically not limited to the Kim songs containing crystalline salt of (6S)-, (6R) and/or (6R,S)-tetrahydrofolate acid. The process of obtaining these pharmaceutical compositions is carried out using known methods, such as lyophilization. The solubility of crystalline salts of tetrahydrofolate acid in water at 20oWith less than 1 mg/ml Application carried out analogous to the use of known substances belonging to the group of tetrahydrofolate, such as 5-formyl-5,6,7,8-tetrahydrofolate acid.

The invention relates further to a method of separating the magnesium salt of (6R, S)-tetrahydrofolate acid on both diastereoisomer, i.e., the magnesium salt of (6S)- and (6R)-tetrahydrofolate acid, carried out by fractionated crystallization. This method is simple and productive. Already at the first stage of crystallization of the crude racemic magnesium salt of (6R, S)-tetrahydrofolate acid get crystalline magnesium salt of (6R)-tetrahydrofolate acid with a share of (6R)-diastereoisomer more than 95% when the output of the enantiomers of over 50%. During the subsequent crystallization carried out in similar conditions, can be obtained crystalline magnesium salt of (6S)- and (6R)-tetrahydrofolate acid with a higher the P>Examples

Specified in the examples, the amount of salt tetrahydrofolate acid and the content of the isomers were determined respectively using ghvd.

Example 1. Stability

To determine the stability of the crystalline salt of (6S)- and (6R)-tetrahydrofolate acid test substance together with samples for comparison were kept at 25oC and humidity 60% in nitrogen atmosphere, respectively, at 4oWith in the air. Through discrete time intervals was determined remaining amount of salt tetrahydrofolate acid and pointed it in comparison with the original measure (see table).

Crystalline salts of tetrahydrofolate acid even after storage for a long time was still very bright. In contrast, amorphous samples change color quickly and very strongly. The content of amorphous calcium salt of (6R,S)-tetrahydrofolate acid after storage for one month at 4oWith in the air is reduced in comparison with the crystalline calcium salt of (6R,S)-tetrahydrofolate acid 8%.

Example 2. Powder x-ray

To characterize the structural properties (crystallinity) of the crystalline salts tet is their substances (diffraction spectra).

Crystalline salt of (6S)-, (6R)- and (6R,S)-tetrahydrofolate acid find spectra with good resolution, with clear bands and low background. The spectra confirm the high crystallinity.

Example 3

of 8.2 g of (6R,S)-tetrahydrofolate acid are suspended in atmopshere nitrogen in 100 ml of water containing 1 g of diglycerin, with 30% caustic soda set at pH 3.3 and mixed with a solution of 3.8 g of calcium chloride in 4 g of water. The resulting solution has a pH value of 9.3. After stirring for 20 h at room temperature the resulting suspension having a pH value of 10.0, filtered by suction and the residue washed with a small amount of water. After drying, the gain of 7.7 g of a slightly coloured in reddish crystalline calcium salt of (6R,S)-tetrahydrofolate acid content (6S)-isomer of 51.1% and the integrated peak area of 96%. The solubility of the resulting product is less than 1 mg/ml of water (25oC).

Example 4

28.6 g (6R,S)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen in 114 ml of water, with 30% caustic soda set at pH 7.5 and mixed with a solution of 48.5 g of calcium chloride in 500 ml of water. Formed retinopathy mass is heated to 90ois anii filtered by suction and washed with a small amount of water. After drying obtain 17.3 g of crystalline calcium salt of (6R,S)-tetrahydrofolate acid beige color with a content of (6S)-isomer of 50.9% and the integral area of the peak of 94%.

Example 5

4.0 g of (6R,S)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen at 40 ml of water containing 0.4 g of diglycerin, with 30% caustic soda set at pH 8.5 and 50oWith mixed with 2.0 g of calcium acetate. Slowly crystallized from the resulting solution of the product of beige color filter on the suction and washed with water. After drying receive of 3.64 g of crystalline calcium salt of (6R, S)-tetrahydrofolate acid content (6S)-isomer 50.5% integrated peak area of 94.6% (in the form of a salt, in terms of dry substance). The proportion of calcium is 1.12 equivalent.

Example 6

12.0 g (6S)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen at 60 ml of water containing 0.6 g of diglycerin, using 50% caustic soda set at pH 7.5 and at 85oWith mixed with a solution of 22.5 g of calcium chloride in 20 ml of water. After stirring for 2 h at 85oWith phase crystals, the product is filtered by suction and washed with water. After drying, the gain of 12.9 g of crystalline calcium salt (obtained by such product in water at 50oC and a pH value of 6 is 0.12%.

Example 7

When using 12.0 g (6R)-tetrahydrofolate acid after treatment, similar to that described in example 6, to obtain 13.8 g of crystalline calcium salt of (6R)-tetrahydrofolate acid content of (6R) isomer 99% and the integral area of the peak of 93%. The solubility of the thus obtained product in water at 50oC and a pH value of 6 is 0.07 per cent.

Example 8

40,0 g (6S)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen in 160 ml of water at 0-5oWith c using 25% ammonia set at a pH of 9.8. To the resulting solution was added 34 g of magnesium chloride in 34 ml of water. After setting the pH to 7.0 and add 200 ml ethanol precipitated in the form of crystals product beige color filter on the suction and washed with a mixture of ethanol/water. After drying receive 37,0 g of crystalline magnesium salt of (6S)-tetrahydrofolate acid content (6S)-isomer of 99.4% and the integrated peak area of 91.7%.

Example 9

40,0 g (6R)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen, 400 ml of water containing 4.0 g of diglycerin, and mixed with 6.0 g of magnesium hydroxide and 60.0 g of magnesium acetate. Using 25% ammonia establish the pH value UP>oWith in a liquid suspension. This suspension is filtered at 35oWith the suction and washed with water. After drying obtain 18.0 g of crystalline magnesium salt of (6R)-tetrahydrofolate acid content of (6R)-isomer of 99.4% and the integrated peak area 92,0%.

Example 10

to 20.0 g of (6R,S)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen in 200 ml of water containing 2 g of diglycerin, mixed with 2.7 g of magnesium hydroxide and heated to 50oC. After adding 30 g of magnesium acetate pH value with 25% aqueous ammonia establish 7.3, the solution is cooled to 20oC and stirred overnight. The resulting suspension is filtered by suction and washed with water. After drying receive 5.0 g of crystalline magnesium salt of (6R)-tetrahydrofolate acid content of (6R)-isomer of 94.8% and the integrated peak area to 97.1%.

Example 11

of 28.0 g of (6R,S)-tetrahydrofolate acid are suspended in 110 ml of water and 75 ml of methanol content 18 g diglycerin, then mixed with 9.5 g of magnesium hydroxide and 50oWith c using 25% ammonia establish a pH value of 9.3. Formed after cooling to -5oWith highly dispersed suspension is filtered by suction and washed with a mixture of methanol/water. After drying receive 10,th peak area 95,9%.

Example 12

4.0 g of (6R,S)-tetrahydrofolate acid are suspended in the atmosphere of nitrogen in 16 ml of water, with 25% aqueous ammonia establish a pH value of 9.7 and mixed with a solution of 3.2 g of magnesium chloride in 3.2 ml of water. The resulting clear solution is introduced into 200 ml of ethanol. The obtained light yellow suspension after stirring for 2 h, filtered at 5oWith the suction and washed with a cold mixture of ethanol/water. After drying obtain 4.5 g of crystalline magnesium salt of (6R, S)-tetrahydrofolate acid with 30 content (6S)-isomer of 49.3% and the integrated peak area of 90.3%.

In the European patent 0600460 described and patented the method of separation of racemic (6R, S)-tetrahydrofolate acid by selective crystallization of (6S)-tetrahydrofolate acid at pH values between 4.8 and the 5.3, preferably at pH 4,9-5,2, in particular at pH 5.0 (paragraph 5). On the contrary, in the present application is described and patented crystalline calcium and magnesium salt of (6R,S)-, (6S)and (6R)-tetrahydrofolate acid, as well as the method of obtaining these salts by crystallization at pH values between 7 and 10.

The obtained product/crystalline state

In EP 0600460 in any of the sections of the description of the invention not preporucena by the claimed method. The only reference to the selected salt tetrahydrofolate acid in the cited EP can be found on page 3. If this describes a common way of separating solids from the solution by concentration to drop from a solution of the desired product. Thus obtained product does not have crystalline properties.

On the contrary, the present invention describes a crystalline product and how to obtain it.

The obtained product/optical division

In the EP in all sections of the description is always described a higher content of (6S)-product origin. The selection of crystal, racemic products, such as, for example, calcium salt of (6R. S)-tetrahydrofolate acid, as described in primeras 3,4 and 5, or magnesium salt of (6R,S)-tetrahydrofolate acid as described in examples 11 and 12 of the present invention, in the cited EP impossible. Therefore, the method and result of these products of different ways.

Key process parameter/pH

In EP 0 600 460 described and patented method, which results in pH values between 4.8 and the 5.3, preferably between 4.9 and 5.2 to, especially when 5,0. Data are based on the description of E, the higher the pH value, the higher the yield of crystallization.

Such prior art is unlikely to force specialist search conditions of crystallization of the salts tetrahydrofolate acid beyond these narrow areas pH, for example at pH values between 7 and 10. Specialist working in the field of tetrahydrofolate acid, is also unlikely to become search terms crystallization at pH values higher than indicated in the EP, because of the data tables in this patent, page 3, lines 12-33 can be concluded that a slight increase of the pH during crystallization from 4.5 to 5.0 causes a significant reduction in output from 68 to 48% (at 45oC).

The specialist in this area are also unlikely to crystallization at higher pH values due to the known high volatility of tetrahydrofolate acid, and also due to the fact that in the literature as the optimal conditions for the stability of the solutions tetrahydrofolate acids are pH values between 5 and 6 (see, for example, B. R. G. Kallen, Methods of Enzymology, 18B, 1971, 705-716, in particular p. 706, the second Chapter).

To prove the novelty of the crystalline calcium salt of (6R)-tetrahydrofolate acid compared with EP 600 460 applicant describes the experiment, including the conditions is oliebol acid are added to a solution of 0.2 g EDTA in 75 ml of water. By dispensing drops of 20% caustic soda get a clear solution with a pH of 6.5. With the help of 18% hydrochloric acid the pH of the solution was adjusted to 4.8 and the solution is heated to 45oC. the thus Obtained suspension is filtered, the solid washed with water and dried in vacuum.

Get 6,87 g tetrahydrofolate acid. To the mother liquor from the above filter add 2.0 g of dihydrate of calcium chloride and add another 2 N. caustic soda to a pH of 6.0. The obtained clear solution was concentrated in vacuo to approximately 50 ml Thin slurry was filtered, the resulting solid is washed with water and dried in vacuum. Obtain 0.31 g of a solid substance (internal reference number Am 1007/b) with the content of tetrahydrofolate acid 33,6%, calcium 6,0% sodium 1% (all analyses were performed by the method IHVR). The mother liquor is cooled tooC for 12 h in This way can be obtained an additional amount of solid substances. After washing with water and drying in a vacuum get 2,40 g solids (internal reference number Am s) with the content of tetrahydrofolate acid and 39.9%, calcium 7.6% and sodium 9,7% (all analyses were performed by the method IHVR).

Crystal The Wolf 2). As a control sample of the crystalline substance in the measurement used crystalline calcium salt of (6R)-tetrahydrofolate acid obtained according to example 7 of the present application (internal reference number Am 602/a).

The result of x-ray analysis is illustrated on the attached copies of the strips of film. While the narrow lines indicate the crystalline state products. (see Appendix). These results show that neither the first fraction solids, selected according to EP 600 460 (Am 1007/a) or the second fraction (Am 1007/s) does not exhibit the properties of crystalline substances. The narrow lines in the spectrum of the Am 1007/s due only salt component of this fraction and are not associated with the crystalline state of tetrahydrofolate acid. In contrast, the control sample (Am 602/a) is the spectrum of the clear lines that indicate high crystallinity of the product, which represents the calcium salt of (6R)-tetrahydrofolate acid.

So based on the above data we can conclude that according to the method described in EP-A-0 600 460, page 3, lines 36-45, it is impossible to obtain a crystalline calcium salt of (6R)-tetrahydrofolate acid.

Protugese. In particular, folinate calcium or calcium salt of 5-formyltetrahydrofolate acid, as in racemic (6R, S)-form, known as leucovorin, and pure (6S)-form (called levofolinate) for many years successfully present on the world market. In particular, calcium folinate is used as an antagonist side effects known anticancer drug methotrexate.

From the available literature it is possible to cite, for example, a well-known reference books, such as M. D. Mashkovsky "Drugs", so 2, pages 87, 88, Kharkov, 1998; drugs of foreign firms in Russia", Moscow, 1993

You can use as an antidote to enhance the portability of folic acid antagonists, for the treatment of megaloblastic palaeosalinity anemia and autoimmune diseases, to enhance the portability of a number of anti-parasitic substances, and to reduce the toxicity of dideuteroindole chemotherapy.

1. Crystalline calcium salt of (6R,S),(6S) - or (6R)-tetrahydrofolate acid.

2. Crystalline magnesium salt of (6R,S),(6S) - or (6R)-tetrahydrofolate acid.

3. The method of obtaining crystalline calcium is tetrahydrofolate acid is crystallized from the polar medium at pH values from 7 to 10.

4. The method according to p. 3, characterized in that the crystallization is carried out at elevated temperature and/or diluted solutions.

5. The method according to p. 4, characterized in that the crystallization is carried out in water or in a mixture of water with miscible with water and organic solvent.

6. The method according to p. 5, characterized in that as miscible with water, the organic solvent used acetic acid or lower organic alcohol.

7. Pharmaceutical composition comprising crystalline calcium or magnesium salt of (6R,S),(6S) - or (6R)-tetrahydrofolate acid.

 

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