Process for the preparation of stable, amorphous calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid

1. A calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V

prepared by:

(a) adding to an aqueous solution of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula III

having a content of the corresponding (6R)-diastereoisomer of ≦2% by weight either acetic acid or a sulfonic acid in such an amount, until a pH-value of 5.5 is obtained;

(b) warming the resulting solution to a temperature from 44° C. to 46° C.;

(c) adding to the warmed solution either acetic acid or a sulfonic acid in such an amount, until a pH-value in the range from 4.3 to 4.4 is obtained, whereby the crystallization of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV

begins, and whereby during this crystallization the pH-value is maintained in the range from 4.3 to 4.4 by continuous addition of either acetic acid or of a sulfonic acid;

(d) filtering off crystalline (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV at a temperature in the range from 44° C. to 46° C.;

(e) isolating (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV;

(f) suspending the (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (e) in water at a temperature from 35° C. to 41° C.;

(g) continuously adding a sodium hydroxide solution to the aqueous suspension containing (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (f) to adjust the pH to a range from 6.7 to 6.9;

(h) adding 0.90 equivalents of calcium chloride to the solution of step (g) with respect to each equivalent of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV;

(i) adjusting the concentration of the compound of Formula IV in the resulting mixture of step (h) to a value in the range from 14% by weight to 16% by weight by the addition or by removal of water;

(j) starting the precipitation of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (i) by the addition of a small amount of previously prepared compound of Formula V;

(k) maintaining the mixture of step (j) at a temperature of 40° C. for one hour;

(l) lowering the temperature of the mixture of step (k) from 40° C. to a temperature of 23° C. over two hours;

(m) maintaining the mixture of step (l) at 23° C. for a period of 16 hours to 18 hours; and

(n) isolating the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (m),

and having:

(i) the differential scanning calorimetric profile of FIG. 4 a,

(ii) the thermogravimetric profile of FIG. 4 b,

(iii) the X-ray powder diffraction diagram of FIG. 5 , and

(iv) the Raman spectrum of FIG. 6 .

2. A process for the preparation of the stable, amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of Formula V,

comprising:

(a) adding to an aqueous solution of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula III

having a content of the corresponding (6R)-diastereoisomer of ≦2% by weight either acetic acid or a sulfonic acid in such an amount, until a pH-value of 5.5 is obtained;

(b) warming the resulting solution to a temperature from 44° C. to 46° C.;

(c) adding to the warmed solution either acetic acid or a sulfonic acid in such an amount, until a pH-value in the range from 4.3 to 4.4 is obtained, whereby the crystallization of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV

begins, and whereby during this crystallization the pH-value is maintained in the range from 4.3 to 4.4 by continuous addition of either acetic acid or of a sulfonic acid;

(d) filtering off crystalline (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV at a temperature in the range from 44° C. to 46° C.;

(e) isolating (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV;

(f) suspending the (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (e) in water at a temperature from 35° C. to 41° C.;

(g) continuously adding a sodium hydroxide solution to the aqueous suspension containing (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (f) to adjust the pH to a range from 6.7 to 6.9;

(h) adding 0.90 equivalents of calcium chloride to the solution of step (g) with respect to each equivalent of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV;

(i) adjusting the concentration of the compound of Formula IV in the resulting mixture of step (h) to a value in the range from 14% by weight to 16% by weight by the addition or by removal of water;

(j) starting the precipitation of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (i) by the addition of a small amount of previously prepared compound of Formula V;

(k) maintaining the mixture of step (j) at a temperature of 40° C. for one hour;

(l) lowering the temperature of the mixture of step (k) from 40° C. to a temperature of 23° C. over two hours;

(m) maintaining the mixture of step (l) at 23° C. for a period of 16 hours to 18 hours; and

(n) isolating the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (m).

3. The process of claim 2 , further comprising the steps of:

(o) rinsing the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V, obtained in step (n), with water having a temperature of 10° C.;

(p) suspending the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V of step (o) in 94% v/v EtOH:H 2 O at room temperature; and

(q) filtering off the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the suspension of step (p).

4. A process for the preparation of the stable, amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of Formula V,

comprising:

(a) adding to an aqueous solution of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula III

having a content of the corresponding (6R)-diastereoisomer of ≦2% by weight either acetic acid or a sulfonic acid in such an amount, until a pH-value of 5.5 is obtained;

(b) warming the resulting solution to a temperature from 44° C. to 46° C.;

(c) adding to the warmed solution either acetic acid or a sulfonic acid in such an amount, until a pH-value in the range from 4.3 to 4.4 is obtained, whereby the crystallization of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV

begins, and whereby during this crystallization the pH-value is maintained in the range from 4.3 to 4.4 by continuous addition of either acetic acid or of a sulfonic acid;

(d) filtering off crystalline (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV at a temperature in the range from 44° C. to 46° C.;

(e) isolating (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV;

(f) suspending the (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (e) in water at a temperature from 35° C. to 41° C.;

(g) continuously adding a sodium hydroxide solution to the aqueous suspension containing (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (f) to adjust the pH to a range from 6.7 to 6.9;

(h) adding 0.90 equivalents of calcium chloride to the solution of step (g) with respect to each equivalent of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV;

(i) adjusting the concentration of the compound of Formula IV in the resulting mixture of step (h) to a value in the range from 14% by weight to 16% by weight by the addition or by removal of water;

(j) starting the precipitation of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (i) by the addition of a small amount of previously prepared compound of Formula V;

(k) maintaining the mixture of step (j) at a temperature of 40° C. for one hour;

(l) lowering the temperature of the mixture of step (k) from 40° C. to a temperature of 23° C. over two hours;

(m) maintaining the mixture of step (l) at 23° C. for a period of 16 hours to 18 hours; and

(n) isolating the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (m),

wherein the calcium chloride is added as a solid or an aqueous solution.