Stable crystalline salts of 5-methyltetrahydrofolic acid

• US 6,441,168 B1
• Filed: 04/17/2000
• Issued: 08/27/2002
• Est. Priority Date: 04/15/1999
• Status: Expired due to Term

• Current Assignee: Merck & Cie (Merck & Co., Inc.)
• Original Assignee: Eprova AG
• Inventors: Egger, Thomas, Müller, Rudolf, Moser, Rudolf
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): McKenzie, Thomas C
• Application Number:
  US09/551,405
• Time in Patent Office: 862 Days
• Field of Search: 544/258
• US Class Current: 544/258
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 475/04 with a nitrogen atom directly attached in position 2

Abstract

This invention relates to stable crystalline salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid, to methods of producing these salts and to the use thereof use as a constituent for the production of drugs or as a food additive, and to preparations containing these salts.

Claims

1. A crystalline salt of 5-methyl-(6R,S)-, -(6S)- or -(6R)-tetrahydrofolic acid said crystalline salt having a water of crystallization of at least one equivalent per equivalent of 5-methyltetrahydrofolic acid.

2. A crystalline salt according to claim 1, of 5-methyl-(6S)- or -(6R)-tetrahydrofolic acid.

3. A crystalline calcium salt according to claim 1, of 5-methyl-(6S)- and -(6R)-tetrahydrofolic acid having ≧

3 equivalents of water.

5. A crystalline calcium salt according to claim 1, of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 5.3, 6.9, 18.7 and 21.1 (Type II).

6. A crystalline calcium salt according to claim 1, of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.8, 10.2, 15.4 and 22.5 (Type III).

7. A crystalline calcium salt according to claim 1, of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.6, 15.9, 20.2 and 22.5(Type IV).

4. A crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.5, 13.3, 16.8 and 20.1 (Type I) said crystalline salt having a water of crystallization of at least one equivalent per equivalent of 5-methyltetrahydrofolic acid.

8. A method of producing crystalline salts of 5-methyl-(6R,S)-, -(6S)- and 5-methyl-(6R)-tetrahydrofolic acid, comprising subjecting a salt of 5-methyl-(6R,S)-, -(6S)- or -(6R)-tetrahydrofolic acid in a polar medium to a thermal treatment, at a temperature above 60°

C., and thereafter crystallizing said salt from the resultant heated solution.

9. A method according to claim 8, wherein the crystallisation is effected after thermal treatment at a temperature above 85°

C.

10. A method according to claim 8, wherein the crystallisation is effected from a solution.

11. A method according to claim 8, wherein the crystallisation is effected from a suspension.

12. A method according to claim 10, characterised in that crystallisation is effected from water or from a mixture of water and an organic solvent which is miscible with water.

13. A method according to claim 8, wherein said salt is an alkaline earth salt.

14. A method according to claim 8, wherein said salt is calcium.

15. A method of producing 5-methyl-(6S)-tetrahydrofolic acids with 2 theta values of 5.3, 6.9, 18.7 and 21.1 (Type II) comprising drying sufficiently 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.5, 13.3, 16.8 and 20.1 (Type I).

16. A method of producing 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.8, 10.2, 15.4 and 22.5 (Type III) comprising subjecting to sufficient thermal treatment at above 90°

C., a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.5, 13.3, 16.8 and 20.1 (Type I).

17. A method of producing 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.6, 15.9, 20.2, 22.5 (Type IV) comprising subjecting to sufficient thermal treatment at above 95 °

C., a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.5, 13.3, 16.8 and 20.1 (Type I).