Hydromorphone and hydrocodone compositions and methods for their synthesis

• US 6,589,960 B2
• Filed: 09/27/2002
• Issued: 07/08/2003
• Est. Priority Date: 11/09/1999
• Status: Expired due to Term

• Current Assignee: Rhodes Pharmaceuticals LP (Purdue Pharma L.P.)
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Sandison, Mark D., Gault, Robert, Harclerode, William H.
• Primary Examiner(s): Aulakh, Charanjit S.
• Application Number:
  US10/256,996
• Publication Number:
  US 20030045720A1
• Time in Patent Office: 284 Days
• Field of Search: 514/282, 546/45
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: C07D 489/02 with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Abstract

A method for the preparation of a ketone from a narcotic alkaloid having an allyl alcohol moiety is disclosed. The method includes mixing the narcotic alkaloid with an acid in the presence of a catalyst wherein the method is carried out in the substantial absence of hydrogen gas. The method is useful for preparing hydromorphone and hydrocodone compositions having novel impurity profiles. Compositions comprising hydromorphone and hydrocodone are also disclosed.

Claims

1. A composition comprising hydromorphone and:

a) from about 0.05% up to about 1.0% dihydromorphine;

b) up to about 0.1% morphine;

c) up to about 0.8% 8-hydroxy hydromorphone;

d) up to about 0.5% bis-hydromorphone; and

e) up to about 0.2% other impurities.

2. The composition of claim 1, comprising from about 0.05% up to about 0.5% dihydromorphine.

3. The composition of claim 1, comprising from about 0.0% up to about 0.05% morphine.

4. The composition of claim 1, comprising from about 0.0% up to about 0.5% 8-hydroxy hydromorphone.

5. The composition of claim 1, comprising from about 0.0% up to about 0.05% bis-hydromorphone.

6. The composition of claim 1, comprising from about 0.0% up to about 0.1 % other impurities.

9. The composition of any one of claims 1, 7, or 8, wherein said composition is prepared by a process comprising mixing morphine with an acid in the presence of a catalyst wherein said process is carried out in the substantial absence of hydrogen gas.

10. The composition of claim 9, wherein said process further comprises heating said mixture for a period of time sufficient to yield a hydromorphone composition comprising less than about 1.0% 8-hydroxy hydromorphone.

11. The composition of claim 10, wherein said period of time is sufficient to yield a hydromorphone composition comprising less than or equal to 2.0% dihydromorphone.

12. The composition of claim 10, wherein said time is greater than about thirty minutes.

13. The composition of claim 10, wherein said time is greater than or equal to about five hours.

14. The composition of claim 9, wherein said acid is hydrochloric acid and said catalyst is non-supported palladium.

7. A composition comprising hydromorphone and:

a) from about 0.22% up to about 0.29% dihydromorphine;

b) up to about 0.02% morphine;

c) from about 0.04% up to about 0.05% 8-hydroxy hydromorphone;

d) up to about 0.02% bis-hydromorphone; and

e) up to about 0.06% other impurities.

8. A composition comprising hydromorphone and about 0.26% dihydromorphine;

about 0.01% morphine;

about 0.04% 8-hydroxy hydromorphone;

about 0.02% bis-hydromorphone; and

about 0.06% other impurities.

15. A composition comprising hydromorphone, from about 0.05% up to about 1.0% of dihydromorphine, and one or more compounds selected from the group consisting of morphine, 8-hydroxy hydromorphone, bis-hydromorphone, and other impurities.

16. A hydromorphone composition which is substantially free of impurities.

17. The composition of claim 16, which comprises:

a) from about 0.05% up to about 1.0% dihydromorphine;

b) up to about 0.1% morphine;

c) up to about 0.8% 8-hydroxy hydromorphone;

d) up to about 0.5% bis-hydromorphone; and

e) up to about 0.2% other impurities.

27. The composition of claim 16, wherein said composition is prepared by a process comprising heating an aqueous mixture of hydromorphone salt, 8-hydroxy hydromorphone and dihydromorphone for a time sufficient to reduce the concentration of 8-hydroxy hydromorphone to less than about 1.0%.

28. The composition of claim 27, comprising hydromorphone and:

a) from about 0.05% up to about 1.0% dihydromorphine;

b) up to about 0.1% morphine;

c) up to about 0.8% 8-hydroxy hydromorphone;

d) up to about 0.5% bis-hydromorphone; and

e) up to about 0.2% other impurities.

29. The composition of claim 27, wherein said acid is hydrochloric acid and said catalyst is non-supported palladium.

18. A method of forming a pharmaceutical composition comprising a hydromorphone salt, 8-hydroxy hydromorphone and dihydromorphone by heating an aqueous mixture of said salt, 8-hydroxy hydromorphone and dihydromorphone for a time sufficient to reduce the concentration of 8-hydroxy hydromorphone to less than about 1.0%.

19. The method of claim 18, wherein said time is sufficient to reduce the concentration of dihydromorphine to less than or equal to about 2.0%.

20. The method of claim 18, wherein said aqueous mixture is obtained by mixing morphine or a salt thereof with an acid in the presence of a catalyst in the substantial absence of hydrogen gas.

21. The method of claim 20, wherein said catalyst comprises non-supported palladium.

22. The method of claim 20, wherein said acid is hydrochloric acid.

23. The method of claims 18, wherein the time is greater than about thirty minutes.

24. The method of claim 23, wherein the time is greater than or equal to about five hours.

25. The method of claim 18, wherein said salt is bisulfite.

26. The method of claim 18, wherein said pharmaceutical composition comprises hydromorphone and:

a) from about 0.05% up to about 1.0% dihydromorphine;

b) up to about 0.1% morphine;

c) up to about 0.8% 8-hydroxy hydromorphone;

d) up to about 0.5% bis-hydromorphone; and

e) up to about 0.2% other impurities.