Stable crystalline 6(s) or 6(r)-tetrahydrofolate acid, processes for their preparation and pharmaceutical composition

 

(57) Abstract:

The invention relates to crystalline forms of 6(R) or 6(S)-tetrahydrofolate acid, method for their production and pharmaceutical compositions. The method of crystallization of 6(R), 6(S) -, or 6(RS)-tetrahydrofolate acid in the environment of the polar solvent. At pH 3.5 in receive 6(S)- isomer, and at pH 2 get 6(R)isomer. The method is simple to implement. The obtained crystalline compounds have a high degree of purity and high stability to the effects of air and elevated temperatures without additional additives. Crystalline products can be used for the manufacture of medicaments and for other derivatives of tetrahydrofolate acid. The proposed pharmaceutical composition containing the resulting crystalline products. 6 C. and 7 C.p. f-crystals, 7 tab., 1 Il.

The invention relates to crystalline N-[4-[[(2-amino - 1,4,5,6,7,8-hexahydro-4-oxo-(6S)- or(6R)- pteridinyl)methyl]amino]benzoyl]-L-glutamic acid (referred to in subsequent crystalline (6S) -, (6R)- tetrahydrofolate acid), as well as to its preparation and pharmaceutical compositions.

Proizvodnyh of folic acid, N-(pteroyl)-L - glutamic acid contained in the residue glutamic acid optically active C-atom has the L-configuration, whereas the optically active C-atom, formed usually as a result of hydrogenation of the double bond in position 5,6 marolboro residue is at position 6 in racemic (6R,S)-form. Accordingly, the synthetic derivatives tetrahydrofolate acids consist of a mixture of two diastereomers in a ratio of 1:1.

As medicines tetrahydrofolate used primarily in the form of salts of calcium 5-formyl-5,6,7,8-tetrahydrofolate acid (leucovorin) or 5-methyl-5,6,7,8-tetrahydrofolate acid for the treatment of megaloblastic anemia, as an antidote to improve the compatibility of folic acid antagonists, in particular of aminopterin and methotrexate, in the treatment of cancer ("Antifolate rescue"), to enhance therapeutic effect of fluorinated pyrimidines in the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis, to enhance compatibility with certain antiparasitic funds, as trimethoprim-sulfamethoxazole, and to reduce the toxicity of ideatorealization in chemotherapie. Tetrahydrofolate kislota.

Direct application of tetrahydrofolate acid as a drug, as well as as the primary substance to obtain various derivatives of tetrahydrofolate acid did not give up to the present time, positive results because of the difficulties associated with obtaining tetrahydrofolate acid can be applied to the pharmaceutical active substance degree of purity and extreme instability of tetrahydrofolate acid, and in the first place is noted for her high oxidizability [see also A. L. Fitzhugh, Pteridines4(4), 187-191 (1993)]. To correct this instability, various techniques have been developed, and in connection with the present invention it is necessary to specially mention lined with the application of Germany 2323124. Among the ways to get tetrahydrofolate acid and in connection with the present invention it is also worth mentioning the European application EP-600460. However, to date, has not been offered no technically satisfactory way by which you could get tetrahydrofolic acid with high purity and sufficiently stable and which thereby would provide an opportunity for pharmaceutical applications tetragidrofolievoy acid with a high degree of chemical and optical purity and good stability, namely, that optically pure (6S)- or optically pure (6R) - enriched (6S) or enriched (6R) - or (6R, S)-tetrahydrofolic acid is crystallized. Thus obtained crystalline (6S)- and/or (6R)-tetrahydrofolate acid for the first time gives the possibility of its application as a drug or as a source material for technical other derivatives of tetrahydrofolate acid with a high degree of purity.

Thus, the invention relates to crystalline (6S)-tetrahydrofolate acid or crystalline (6R)-tetrahydrofolate acid.

The invention also relates to a method of obtaining crystalline (6S)- and/or (6R)-tetrahydrofolate acid by crystallization of (6S)- or (6R)-tetrahydrofolate acid in the range of pH values at which crystallization starts isomer in the polar environment.

Crystallization of (6S)-tetrahydrofolate acid is usually carried out in a polar environment when the value of pH3,5, crystallization of (6R)-tetrahydrofolate acid is usually carried out in a polar environment when the value of pH2.

As polar environment can be used primarily water or a mixture of water and the mixture is, canal, n-propanol, isopropanol, ethylene glycol, water-soluble lower aliphatic carboxylic acids, such as formic, acetic, lactic acid, or water soluble amides, such as, for example, formamide, dimethylformamide, dimethylacetamide, 1-organic, 2-organic, 2-piperidine. In principle there is no restriction on the type of solvent and the ratio in the mixture as a crystalline (6S)-tetrahydrofolate acid and crystalline (6R)-tetrahydrofolate acid differ substantially better solubility than the corresponding amorphous forms. Crystallization was carried out from a solution or suspension.

For the initial stage of crystallization (6S)-tetrahydrofolate acid should choose the pH value is preferably in the range from 3.5 to 6.5. For the initial stage of crystallization (6R)-tetrahydrofolate acid, the preferred pH value should be in the range of from 2 to 5.5. The choice of the optimal pH value for the onset of crystallization depends on the materials used and the objectives and can be determined by simple experiments. The basic principle is the following: the higher the salt content and the lower the pH, required for the onset of crystallization, the slower should be the crystallization, as otherwise, when the pH values of about 3 is the deposition of the amorphous tetrahydrofolate acid. For the direct crystallization of (6S)-tetrahydrofolate acid from the reaction solution obtained by reduction of borohydride folic acid is required, for example, pH4,8, since only under this condition can begin crystallization. After making the initial stage of crystallization pH value can be changed.

During crystallization (6S)-tetrahydrofolate acid, as well as during the crystallization of (6R)-tetrahydrofolate acid pH value is increased or it can be kept constant by the additives of any acid or buffer. For crystallization (6S)-tetrahydrofolate acid, if the purpose of such crystallization is an optical enrichment of these acids, it is necessary that the pH during crystallization was preferably in the range from 4.5 to 5.5, if the purpose of crystallization is obtaining a stable crystalline (6S)-tetrahydrofolate acid, the pH value should be selected preferably in the range from 3.5 to 4.5. D is during crystallization from 3.5 to 4.5. The crystallization can be performed respectively at room temperature, at elevated temperature and at low temperature.

The crystallization process can last from several minutes to several days. With a longer crystallization time get generally, products with higher purity and better stability.

Crystallization of (6S)- and (6R)-tetrahydrofolate acid occurs spontaneously due to the slow setting of the pH value or based on the value of pH that is less than required for the onset of crystallization of the corresponding isomer, or preferably from a higher pH. Crystallization can be called with the appropriate seed crystal tetrahydrofolate acid in the range of pH values at which crystallization starts the corresponding isomer.

(6S)-Tetrahydrofolic acid are preferably separated by fractional crystallization from the remaining mother liquor allocate (6R)-tetrahydrofolic acid.

As starting material for crystallization can be used as racemic (6R,S)-tetrahydrofolate acid enriched (6S)- or (6R) is DNAME for this purpose are highlighted in solid form, for example, (6R,S)-tetrahydrofolate acid, (6S)-tetrahydrofolate acid - sulfuric acid and additive salts of sulfonic acids obtained according to the European application EP-495204 and tetrahydrofolate acid produced in situ by catalytic hydrogenation or restore borohydride of folic acid.

Crystallization of (6R)-tetrahydrofolate acid can be made directly from the mother liquor, obtained by crystallization of (6S)-tetrahydrofolate acid. The crystallization of both isomers can be carried out both from the solution obtained, for example, by setting the values of pH > 7 or < 2, and suspension.

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 tetrahydrofolic acid with a degree of purity (> 98%) and of such stability so far I couldn't get.

Crystalline (6S)- and/or (6R)-tetrahydrofolate acid can be used as an ingredient for a pharmaceutical composition or to obtain Dragonara its excellent stability in solid form retains virtually no limited time, constant, very good quality.

The invention relates also to pharmaceutical compositions containing crystalline (6S)- and/or (6R)-tetrahydrofolic acid. The manufacture of pharmaceutical compositions is carried out using known methods, such as lyophilization. Application carried out in the same way as it is carried out using known substances related to the number of tetrahydrofolate, as, for example, 5-formyl-5,6,7,8-tetrahydrofolate acid.

Separation of (6R,S)-tetrahydrofolate acid on both diastereoisomer: (6S)- and (6R)-tetrahydrofolic acid is carried out by fractional crystallization. This method is very simple and productive. Already at the first stage of crystallization of the crude racemic (6R,S)-tetrahydrofolate acid get crystalline (6S)-tetrahydrofolic acid of component (6S) more than 75% and over 70% crystalline (6R)-tetrahydrofolic acid of component (6R) more than 80% and more than 50%. Subsequent crystallization under similar conditions allows to obtain a crystalline (6S)- and (6R)-tetrahydrofolic acid with a degree of purity of the isomers of over 95%.

(6S)- or (6R)-tetrahydrofolate acid may COI is you. So, for example, with addition of formaldehyde to a solution of (6R)-tetrahydrofolate acid in a simple way you can get enriched 5,10-methylene-(6S)- tetrahydrofolic acid.

The examples of the invention

All the examples the data on the content of tetrahydrofolate acid and isomeric components were determined respectively using ghvd. All data on the content of tetrahydrofolate acid is specified relative to the anhydrous basis.

Example 1 (Stability)

To determine the stability of the crystalline (6S)- and (6R)-tetrahydrofolate acid substances are kept together with the samples for comparison in stressful conditions at a temperature of 60oWith air (see tab. 1). After a certain period of time measured remaining amount of tetrahydrofolate acid and compared it to the original value.

Crystalline (6S)- and (6R)-tetrahydrofolate acid even after prolonged heating at a temperature of 60oC in the air is very light, almost white. In contrast to the above-mentioned acids other products that are used as comparative, change color quickly and very strongly.

Use hydrofolate acid according to example 6 of the present application;

crystalline (6R)-tetrahydrofolic acid according to example 9 of the present application;

crystalline (6R, S)-tetrahydrofolic acid according to Yamanouchi" according to the posted application Germany 2323124, example 3;

amorphous (6S)-tetrahydrofolic acid in the following way: (6S)-tetrahydrofolic acid dissolved in acetic acid and precipitated with simple diethyl ether;

amorphous (6R)-tetrahydrofolic acid in the following way: (6R)-tetrahydrofolic acid dissolved in acetic acid and precipitated with simple diethyl ether;

amorphous (6R, S)-tetrahydrofolic acid in the following way: (6R,S)- tetrahydrofolic acid dissolved in acetic acid and precipitated with simple diethyl ether.

Example 2 (Powder roentgenogram)

To characterize the structural properties (crystallinity) of crystalline (6S)- and crystalline (6R)-tetrahydrofolate acid was removed under the same conditions powder roentgenogram (diffraction spectra) of these substances together with the samples for comparison.

Both acid as crystalline (6S) - and crystalline (6R)-tetrahydrofolate acid are different, with good is In contrast spectrum of crystalline (6R, S)-tetrahydrofolate acid according to Yamanouchi" is a bad resolution, fuzzy stripes (diffuse maxima) and high background. This range indicates the presence of a predominantly amorphous (6R,S)-tetrahydrofolate acid with only a small percentage of crystallinity.

Used to produce powder roentgenogram substance was prepared as follows:

crystalline (6S)-tetrahydrofolic acid according to example 6 of the present application (Annex 1);

crystalline (6R)-tetrahydrofolic acid according to example 9 of the present application;

"crystalline (6R, S)-tetrahydrofolic acid according to Yamanouchi" according to the posted application Germany 2323124, example 3.

Example 3 (table. 2-5)

a) 4 g of (6R,S)-tetrahydrofolate acid are suspended in 16 ml of water and with 25% aqueous ammonia set at pH 9. The resulting solution at a temperature of 50oC set first with hydrochloric acid to pH 5, and then with caustic soda slowly to the desired pH value. Upon reaching the specified pH value of the sample, respectively 2 ml, which is filtered by suction and washed with a small amount of water.

b) 4 g of (6R,S)-tetrahydrofolate giclee 50oC set first with hydrochloric acid to pH 5, and then with caustic soda slowly to the desired pH value. Upon reaching the specified pH value of the sample, respectively 2 ml, which is filtered by suction and washed with a small amount of water.

b) 4 g of (6R,S)-tetrahydrofolate acid are suspended in 16 ml of water and with 25% aqueous ammonia set at pH 9. The resulting solution at a temperature of 50oC set first with hydrochloric acid to pH 5, and then with caustic soda slowly to the desired pH value. Upon reaching the specified pH value of the sample, respectively 2 ml, which is filtered by suction and washed with a small amount of water.

g) 10 g of (6R,S)-tetrahydrofolate acid are suspended in 80 ml of water and with 1 N. hydrochloric acid set at a pH of 1.3. The resulting solution at room temperature using a 1.8 N. ammonia solution slowly set to the desired pH value. Upon reaching the specified pH value of the sample, respectively 2 ml, which is filtered by suction and washed with a small amount of water.

Are given in table. 2-5 values do not correspond to the optimal parameters of the method, as all former is nl. 6)

According to 5 g of (6R,S)-tetrahydrofolate acid are suspended in 50 ml of water and allow to settle for 5 days at room temperature, respectively, at 40oC. After filtering off by suction (the temperature of the filter is identical to the temperature of crystallization and washing get:

1)the pH value with suspendirovanie (6R,S)-tetrahydrofolate acid without amendment, similarly laid out the application Germany 2323124, example 3;

2)installed using sodium hydroxide to the desired pH value.

Shown in the table values do not correspond to the optimal parameters of the method, since all the experiments were carried out similarly with the aim of obtaining the best opportunity for comparison.

Example 5

40 g of (6R, S)-tetrahydrofolate acid are suspended in 160 ml of water and set with 25% aqueous ammonia at a pH of 9.3. The resulting solution at a temperature of 50oC with hydrochloric acid slowly set at pH 5.1 and during the subsequent crystallization of the pH value is maintained within the range from 5.1 to 5.2. After crystallization is cooled to 0-5oC, filtered under pressure and washed with water. This way obtain 19 g of crystalline (6S)-tetrahydrofolate acid with ethanol obtain 1.1 g of enriched amorphous (6R)-tetrahydrofolate acid with the chemical content of 63,3% and the content of (6R) 75,9%, the other half of the mother liquor at a rapid settlement pH 3.5 with hydrochloric acid to obtain 6.3 g of enriched amorphous (6R)-tetrahydrofolate acid with the chemical content of 84.8% and a content of (6R) 75,9%.

Example 6

60 g of the additive salt of (6S)-tetrahydrofolate acid - benzosulfimide content (6S) 99,9% (obtaining, according to the European application 495204) are suspended in 240 ml of water and with 63 ml of 1.8 n solution of ammonia or of 55.2 ml of 2n. caustic soda set at pH 5.5. The pH value of the support is equal to 5.5. Then thick white suspension with 30% caustic soda set at pH 9.3 and the obtained clear solution is heated to 50oC.

Then after the slow setting of the pH with hydrochloric acid to pH 5.2 and after the seed crystalline (6S)-tetrahydrofolate acid get to 43.0 g of crystalline (6S)-tetrahydrofolate acid with the chemical content of 96.8 per cent and the content of (6S) of 99.9%.

After dissolving 40 g of the obtained crystalline (6S)-tetrahydrofolate acid in 160 ml of water at pH 9 and subsequent slow setting pH using hydrochloric acid 4.2 and after the seed crystalline (6S)-tetrahydrofolic is the content of (6S) 100%.

By subsequent recrystallization at pH 4.2 to obtain crystalline (6S)-tetrahydrofolic acid with the chemical content of > 99% and a content of (6S) 100%.

The solubility of the thus obtained crystalline (6S)-tetrahydrofolate acid at room temperature in water is 0,0022%.

Example 7

40 g of (6R,S)-tetrahydrofolate acid are suspended in 160 ml of water and 40 ml of methanol and using 25% ammonia set at a pH of 9.1. The resulting solution with hydrochloric acid at a temperature of 50oC slowly set at pH 5.1 and during subsequent crystallization of the pH value is maintained within the range from 5.1 to 5.2. After completion of the crystallization process at a temperature of 50oC filter on the suction of the sample 20 ml) and washed with water/methanol. The result of 1.3 g of crystalline (6S)-tetrahydrofolate acid with the chemical content of 96.1 per cent and the content of (6S) 83,0%.

The basic amount of the above solution is cooled to 0-5oC, filtered under pressure and washed with water/methanol. In this way gain of 18.6 g of crystalline (6S)-tetrahydrofolate acid with the chemical content of 90.9% content (6S) of 67.1%.

Example 8

60 g of folic acid WM who are using 30 g of sodium borohydride in 120 ml of water and 12 g of 30% aqueous caustic soda at a temperature of 70oC. after Approximately 5 h, during which the reaction proceeds, the reaction mixture was diluted with 180 ml of water and hydrochloric acid slowly set at pH 4.5. During the subsequent crystallization of the pH value increases to approximately 5.5. The suspension is filtered under pressure at a temperature of 0-5oC and washed with a small amount of water.

In this way gain of 25.5 g of crystalline (6S)-tetrahydrofolate acid with the chemical content of 94,4% and the content of (6S) 82.7 per cent. The water content after drying is 4.0%.

After dissolving 20 g of the obtained crystalline (6S)-tetrahydrofolate acid in 80 ml of water at pH 9 and subsequent slow setting pH using hydrochloric acid 5.1 and after the seed crystalline (6S)-tetrahydrofolate acid to obtain 4.5 g of crystalline (6S)-tetrahydrofolate acid with the chemical content 94,0% and the content of (6S) to 94.7%. The water content after drying is 1.8%.

Example 9

50 g of amorphous (6R)-tetrahydrofolate acid content of (6R) 99,4% are suspended in 600 ml of water and with 25% aqueous ammonia set at a pH of 9.0. The obtained clear solution is heated to a temperature of 50oC.

Then after slow the gain of 42.0 g of crystalline (6R)-tetrahydrofolate acid with the chemical content of 96.2% and a content of (6R) of 99.5%.

The solubility of the thus obtained crystalline (6R)-tetrahydrofolate acid in water at room temperature is of 0.014%.

By subsequent recrystallization at pH 4,4 get crystalline (6R)-tetrahydrofolic acid with the chemical content of > 98,0% and the content of (6R) > 99.5% pure.

Example 10

40 g of (6R, S)-tetrahydrofolate acid are suspended in 160 ml of water and with 25% aqueous ammonia set at a pH of 9.3. The resulting solution at a temperature of 50oC with hydrochloric acid slowly set at pH 5.1 and during subsequent crystallization of the pH value is maintained within the range from 5.1 to 5.2. After completion of the crystallization process is cooled to room temperature, filtered under pressure and washed with water.

In this way gain of 18.2 g of crystalline (6S)-tetrahydrofolate acid with the chemical content 94,0% and the content of (6S) 77,8%.

The mother liquor from which was led (6S)-tetrahydrofolic acid, re-heated to 50oC, then with hydrochloric acid slowly establish on pH of 4.4 and a subsequent crystallizatio (6R)-tetrahydrofolate acids maintain the pH in the range from 4.0 to 4.5. After completing the P CLASS="ptx2">

The result is 12 g of crystalline (6R)-tetrahydrofolate acid with the chemical content of 78.0% and with a content of (6R) 74,8%.

Example 11 (PL.7)

(6R, S)-tetrahydrofolic acid are suspended in water and immediately added dropwise a 20% aqueous solution of caustic soda to obtain a homogeneous solution with a pH of 6.5.

Adding dropwise an 18% aqueous solution of hydrochloric acid to bring the pH to 5.2 and supports the constant. The temperature is set 45oC. the Precipitated substance is separated and determine its chemical and optical 5 cleanliness. This process is repeated and record the total output to achieve the necessary degree of purification.

As clearly seen from the data through repeated implementation of the method described above can, apparently, to improve the content of (6S) in the final product, however, must cope with a decrease in the content of the product, due to the repeated carrying out of the way. For this reason, obtaining a product with purity of more than 98% even after repeated implementation of this method impossible.

Example 12

Tablet containing 1 mg of (6S)-tetrahydrofolate acid

A mixture of 10 g of (6S)-tetrahydrofolate sour is each tablet contains 1 mg of (6S)-tetrahydrofolate acid.

Tablets can be used as tablets, coated, or can be crushed and placed in capsules.

Example 13

Candles containing 60 mg of (6S)- tetrahydrofolate acid

A mixture of 500 g of (6S)-tetrahydrofolate acid, 50 hydroxypropylcellulose and 2 kg of semi-synthetic glycerides alloys in the form of suppositories so that each candle contains 500 mg of (6S)-tetrahydrofolate acid.

Example 14

The solution for injection containing 0.5 mg of (6S)-tetrahydrofolate acid

0.5 g of (6S)-tetrahydrofolate acid, 10 g of glutathione, 30 g of citric acid, 160 g mannitol, 1 g methyl para-hydroxybenzoic acid, and 17.7 g of sodium hydroxide (or the number needed to establish in solution pH of 7.3 to 7.8) dissolved in 3 l of water for injection and poured into vials so that each vial contains 0.5 mg of (6S)-tetrahydrofolate acid.

Example 15

The dry preparation (freeze-dried) for injection containing 1 mg of (6S)-tetrahydrofolate acid

A solution of 1 g of (6S)-tetrahydrofolate acid (as sodium salt) in 1000 ml of double-distilled water is sterilized in ampoules and freeze-dried so that each ampoule contains 1 mg of (6S)-tetrahydrofolate it is to work in an anoxic environment. It may be necessary to add antioxidants, such as ascorbic acid.

1. Crystalline (6S)-tetrahydrofolate acid.

2. Crystalline (6R)-tetrahydrofolate acid.

3. The method of obtaining crystalline (6S)- and/or (6R)-tetrahydrofolate acid, characterized in that the crystallization of (6S)- or (6R)-tetrahydrofolate acid is carried out in the range of pH values at which crystallization starts isomer in the polar environment.

4. The method according to p. 3, characterized in that the (6S) tetrahydrofolic acid is crystallized at pH values of 3.5.

5. The method according to p. 3, characterized in that the (6R)-tetrahydrofolic acid is crystallized at pH values 2.

6. The method according to one of paragraphs.3 to 5, characterized in that as the polar environment apply water or a mixture of water and water soluble organic polar solvent and the crystallization is carried out from a solution or suspension.

7. The method according to p. 4 or 6, characterized in that for the implementation of the initial stage of crystallization (6S)-tetrahydrofolate acid establish a pH value of 3.5 to 6.5.

8. The method according to p. 5 or 6, characterized in that for the implementation of the initial stage Krist - 8, characterized in that the pH in the crystallization process support permanent.

10. The method according to one of paragraphs.3 to 9, characterized in that the (6S)-tetrahydrofolic acid is separated by fractionated crystallization and from the remaining mother liquor allocate (6R)-tetrahydrofolic acid.

11. Crystalline (6S)- and/or (6R)-tetrahydrofolate acid as a component for the manufacture of medicaments and for other derivatives of tetrahydrofolate acid.

12. Crystalline (6S)- and/or (6R)-tetrahydrofolate acid obtained in one of the paragraphs. 3 - 10, as a component for the manufacture of medicines for other derivatives of tetrahydrofolate acid.

13. The pharmaceutical composition containing the active ingredient in the form of tetrahydrofolate acid, characterized in that as the active ingredient it contains crystalline (6S)- and/or (6R)-tetrahydrofolic acid.

 

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