Crystallization of amino acids using ultrasonic agitation

• US 6,992,216 B2
• Filed: 01/07/2003
• Issued: 01/31/2006
• Est. Priority Date: 01/07/2002
• Status: Expired due to Fees

• Current Assignee: Abbott GmbH & Company KG (Abbott Laboratories)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories)
• Inventors: Rauls, Matthias, Simpson, Seth C., Bechtel, Siegfried, Gelder, Richard Van
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/337,692
• Publication Number:
  US 20030166726A1
• Time in Patent Office: 1,120 Days
• Field of Search: 232/95.R, 562/445, 562/447, 562/554
• US Class Current: 562/447
• 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 of crystallizing L-thyroxine comprising subjecting a solution of L-thyroxine or a salt thereof to ultrasonic agitation at a temperature and for a period of time sufficient to produce a crystalline form of said L-thyroxine.

2. The process of claim 1, wherein said L-thyroxine is a sodium salt of L-thyroxine.

3. The process of claim 1, wherein said solution of said L-thyroxine is subjected to ultrasonic agitation while being cooled.

4. The process of claim 1, wherein said solution of said L-thyroxine 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.

5. The process of claim 1, wherein the mean particle size of said L-thyroxine is less than about 18 microns.

6. The process of claim 5, wherein said mean particle size of said L-thyroxine is less than about 12 microns.

7. The process of claim 6, wherein said mean particle size of said L-thyroxine is less than about 10 microns.

8. The process of claim 7, wherein said mean particle size of said L-thyroxine is less than about 7 microns.

9. The process of claim 1, wherein the mean particle size of said L-thyroxine is between about 5 and about 18 microns.

10. The process of claim 9, wherein said mean particle size of said L-thyroxine is between about 6 and about 12 microns.

11. The process of claim 10, wherein said mean particle size of said L-thyroxine is between about 6.1 and about 8 microns.

12. The process of claim 1, wherein said solution comprises crystals of L-thyroxine.

13. The process of claim 12, wherein said solution comprises about 2 to about 6% L-thyroxine.

14. The process of claim 1, wherein said solution comprises about 11 to about 17% n-propanol.

15. The process of claim 1, wherein said solution comprises about 2 to about 4% sodium carbonate.

16. The process of claim 1, wherein said solution comprises an aqueous mother liquor.

17. The process of claim 1, wherein said ultrasonic agitation is applied in periodic pulses.

18. The process of claim 1, wherein said ultrasonic agitation is applied continuously.

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

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

21. The process of claim 1, wherein the source of said ultrasonic agitation is a transducer.

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

23. The process of claim 2, 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.

24. The process of claim 23, wherein said nucleation temperature ranges from about 32 to about 42°

C.

25. The process of claim 2, wherein said solution is cooled a rate of greater than about 0.1°

C. per minute.

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

27. The process of claim 1, wherein said ultrasonic agitation is applied while said solution is cooled from about 40 to about 50°

C. down to below the nucleation temperature.

28. The process of claim 2, 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.

29. The process of claim 2, 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.

30. The process of claim 1, further comprising stirring the solution.

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

33. The process of claim 1, wherein the process results in dosage forms of the amino acid with improved dissolution or content uniformity or both.

32. 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.