Crystallization of amino acids using ultrasonic agitation

• US 20030166726A1
• Filed: 01/07/2003
• Published: 09/04/2003
• Est. Priority Date: 01/07/2002
• Status: Active Grant

• Current Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Inventors: Rauls, Matthias, Simpson, Seth C., Bechtel, Siegfried, Gelder, Richard Van
• Granted Patent: US 6,992,216 B2
• Time in Patent Office: Days
• US Class Current: 514/567
• CPC Class Codes: C07C 227/42 Crystallisation
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Abstract

A method for reducing the particle size of amino acid crystals using ultrasound is discussed.

Claims

1. A process for crystallizing an amino acid, comprising subjecting a solution of said amino acid to ultrasonic agitation at a temperature and for a period of time sufficient to produce a crystalline form of said amino acid having a reduced particle size as compared to a particle size of a crystalline form of said amino acid obtained without ultrasonic agitation.

2. The process of claim 1, wherein said amino acid is a tyrosine derivative.

3. The process of claim 2, wherein said amino acid is an aryl tyrosine derivative.

4. The process of claim 3, wherein said aryl tyrosine derivative is L-thyroxine or a salt thereof.

5. The process of claim 4, wherein said aryl tyrosine derivative is a sodium salt of L-thyroxine.

6. The process of claims 1, wherein said solution of said amino acid is subjected to ultrasonic agitation while being cooled.

7. The process of claims 1, wherein said solution of said amino acid is subjected to ultrasonic agitation for a period of time sufficient to reduce a metastable zone of said solution by about 1°

C. to about 5°

C.

8. The process of claims 1, wherein the mean reduced particle size of said amino acid is less than about 18 microns.

9. The process of claim 8, wherein said mean reduced particle size of said amino acid is less than about 12 microns.

10. The process of claim 9, wherein said mean reduced particle size of said amino acid is less than about 10 microns.

11. The process of claim 10, wherein said mean reduced particle size of said amino acid is less than about 7 microns.

12. The process of claims 1, wherein the mean reduced particle size of said amino acid is between about 5 and about 18 microns.

13. The process of claim 12, wherein said mean reduced particle size of said amino acid is between about 6 and about 12 microns.

14. The process of claim 13, wherein said mean reduced particle size of said amino acid is between about 6.1 and about 8 microns.

15. The process of claim 4, wherein said solution comprises crystals of L-thyroxine.

16. The process of claim 15, wherein said solution comprises about 2 to about 6% L-thyroxine.

17. The process of claim 4, wherein said solution comprises about 11 to about 17% n-propanol.

18. The process of claim 4, wherein said solution comprises about 2 to about 4% sodium carbonate.

19. The process of claim 4, wherein said solution comprises an aqueous mother liquor.

20. The process of claims 1, wherein said ultrasonic agitation is applied in periodic pulses.

21. The process of claims 1, wherein said ultrasonic agitation is applied continuously.

22. The process of claims 1, wherein said ultrasonic agitation is at a frequency of about 20 to about 50 kHz.

23. The process of claims 1, wherein said ultrasonic agitation is at an intensity ranging from about 0.01 W/cm² to about 0.3 W/cm².

24. The process of claims 1, wherein the source of said ultrasonic agitation is a transducer.

25. The process of claims 1, wherein the ultrasonic agitation is applied at a power of between about 5 and about 50 watts.

26. The process of claim 5, wherein said ultrasonic agitation is applied while said solution is cooled from above the nucleation temperature of said amino acid to below the nucleation temperature of said amino acid.

27. The process of claim 26, wherein said nucleation temperature ranges from about 32 to about 42°

C.

28. The process of claim 5, wherein said solution is cooled a rate of greater than about 0.1°

C. per minute.

29. The process of claim 5, wherein the solution is cooled at a rate of greater than about 0.4°

C. per minute.

30. The process of claims 1, wherein said ultrasonic agitation is applied for at least about 2 hours.

31. The process of claim 3, wherein said ultrasonic agitation is applied while said solution is cooled from about 40 to about 50°

C. down to below the nucleation temperature.

32. The process of claim 5, wherein said ultrasonic agitation is applied while said solution is cooled from about 40 to about 50°

C. down to about 30 to about 35°

C.

33. The process of claim 5, wherein said ultrasonic agitation is applied while the solution is cooled from about 40 to about 50°

C. down to about 10 to about 20°

C.

34. The process of claims 1, further comprising stirring the solution.

35. The process of claims 1, wherein the solution is stirred with stirrer having an energy greater than a 5 watt/kg.

38. The process of claims 1, wherein the amino acid having a reduced particle size, as compared to a particle size of a crystalline form of the amino acid obtained without ultrasonic agitation, possesses enhanced properties as compared to the properties a crystalline form of the amino acid obtained without ultrasonic agitation.

39. The process of claim 38, wherein the enhanced properties result in dosage forms of the amino acid with improved dissolution or content uniformity or both.

36. A process for crystallizing sodium L-thyroxine, comprising subjecting an aqueous solution of sodium L-thyroxine to ultrasonic agitation while the solution is cooled to a temperature and for a period of time sufficient to produce a crystalline form of the sodium L-thyroxine having a particle size less than about 18 microns.

37. A crystalline salt of L-thyroxine having a particle size less than about 18 microns, wherein said crystalline salt is prepared by a process comprising subjecting an aqueous solution of an L-thyroxine salt to ultrasonic agitation while the solution is cooled to a temperature and for a period of time sufficient to produce a crystalline form of said L-thyroxine salt having a particle size less than about 18 microns.