Process for formulation of antibiotic compounds

• US 20020002160A1
• Filed: 04/27/2001
• Published: 01/03/2002
• Est. Priority Date: 10/29/1999
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Reynolds, Scott D., Kanike, Anand, Hunke, William A., Tsinontides, Stelios C., Patel, Hiren S., Al-Dehneh, Anthony S., Illig, Kathleen J.
• Granted Patent: US 6,486,150 B2
• Time in Patent Office: Days
• US Class Current: 514/210.13
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 477/02 Preparation by microbiological processes C12P17/18
• CPC Class Codes: C07D 477/20 Sulfur atoms

Abstract

The present invention involves a process for preparing a stable final formulation product of a compound of formula I,

or its pharmaceutically acceptable salt, hydrate or solvate by incorporating a suitable carbon dioxide source to an unstable monosodium adduct of carbapenem antibiotic compound.

Claims

1. A process for preparing a final formulation product of a compound of formula I,

2. The process of claim 1, wherein the carbon dioxide source is selected from the group consisting of carbon dioxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, and a mixture thereof.

3. The process of claim 2, wherein the carbon dioxide source is sodium bicarbonate.

4. The process of claim 3, wherein the carbon dioxide source in Step (1) is present in an amount relative to the amount of active ingredient, wherein a mole ratio of carbon dioxide source to the active ingredient is about 0.5 to about 1.5.

5. The process of claim 4, wherein the carbon dioxide source in Step (1) is present in an amount relative to the amount of active ingredient, wherein a mole ratio of carbon dioxide source to the active ingredient is about 0.8 to about 1.2.

6. The process of claim 5, wherein the pH range in Step (1) is about 7.0 to about 9.0.

7. The process of claim 6, wherein a temperature range in Step (1) is about −

3°

C. to about 15°

C.

8. The process of claim 7, where the active ingredient is a compound of formula (a),

9. The process of claim 8, wherein the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide.

10. The process of claim 9, wherein the base is sodium hydroxide at a concentration range of about 1N to about 3N.

11. The process of claim 10, wherein the effective amount of a mole ratio of a base to an active ingredient in Step (2) is about 0.7 to about 1.0.

12. The process of claim 11, wherein the mole ratio of a base to an active ingredient in Step (2) is about 0.8 to about 0.9.

13. The process of claim 12, wherein the pH range in Step (2) is about 7.0 to about 8.0.

14. The process of claim 13, wherein the temperature range in Step (2) is about −

1°

C. to about 5°

C.

15. The process of claim 14, wherein the base is added followed by the addition of the active ingredient in Step (2).

16. The process of claim 15, wherein the temperature range in Step (2) is about −

1°

C. to about 5°

C.

17. The process of claim 16, wherein the Step (2) further comprises a titration of the solution using a titrating agent to maintain the pH of the solution at a range of about 6.5 to about 8.5.

18. The process of claim 17, wherein the titrating agent is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide.

19. The process of claim 18, wherein the moisture content of the final formulation product is less than about 5%.

20. The process of claim 1, wherein the step (3) initially further comprises the following steps of:

(a) filtering the final formulation product into a receiving vessel using a sterilizing filter;

(b) aseptically filling the filtered final formulation product into a sterile vial; and

(c) placing a lyophilization stopper on the filled sterile vial containing the final formulation product.

21. A process for preparing a final formulation product of a compound of Formula Ia,

22. The process of claim 21, wherein the carbon dioxide source is selected from the group consisting of carbon dioxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, and a mixture thereof.

23. The process of claim 22, wherein the carbon dioxide source is sodium bicarbonate.

24. The process of claim 23, wherein the carbon dioxide source in Step (1) is present in an amount relative to the amount of active ingredient, wherein a mole ratio of carbon dioxide source to the active ingredient is about 0.5 to about 1.5.

25. The process of claim 24, wherein the carbon dioxide source in Step (1) is present in an amount relative to the amount of active ingredient, wherein a mole ratio of carbon dioxide source to the active ingredient is about 0.8 to about 1.2.

26. The process of claim 25, wherein the pH range in Step (1) is about 7.0 to about 9.0.

27. The process of claim 26, wherein a temperature range in Step (1) is about −

3°

C. to about 15°

C.

28. The process of claim 27, where the active ingredient is a compound of formula (a)′

,

29. The process of claim 28, wherein the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert- butoxide.

30. The process of claim 29, wherein the base is sodium hydroxide at a concentration range of about 1N to about 3N.

31. The process of claim 30, wherein the effective amount of a mole ratio of a base to an active ingredient in Step (2) is about 0.7 to about 1.0.

32. The process of claim 31, wherein the mole ratio of a base to an active ingredient in Step (2) is about 0.8 to about 0.9.

33. The process of claim 32, wherein the pH range in Step (2) is about 7.0 to about 8.0.

34. The process of claim 33, wherein the temperature range in Step (2) is about −

1°

C. to about 5°

C.

35. The process of claim 34, wherein the base is added followed by the addition of the active ingredient in Step (2).

36. The process of claim 35, wherein the temperature range in Step (2) is about −

1°

C. to about 5°

C.

37. The process of claim 36, wherein the Step (2) further comprises a titration of the solution using a titrating agent to maintain the pH of the solution at a range of about 6.5 to about 8.5.

38. The process of claim 37, wherein the titrating agent is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert- butoxide.

39. The process of claim 38, wherein the moisture content of the final formulation product is less than about 5%.

40. The process of claim 21, wherein the step (3) initially further comprises the following steps of:

(a) filtering the final formulation product into a receiving vessel using a sterilizing filter;

(b) aseptically filling the filtered final formulation product into a sterile vial; and

(c) placing a lyophilization stopper on the filled sterile vial containing the final formulation product.