Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone

• US 7,674,800 B2
• Filed: 03/29/2007
• Issued: 03/09/2010
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Hong, Qi, Kyle, Donald, Chapman, Robert, Kupper, Robert, Rider, Lonn S.
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US11/729,741
• Publication Number:
  US 20070179169A1
• Time in Patent Office: 1,076 Days
• Field of Search: 514/282, 546/45, 546/44
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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: C07D 489/02 with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
• CPC Class Codes: C07D 489/04 Salts; Organic complexes
• CPC Class Codes: C07D 489/08 Oxygen atom

Abstract

In certain embodiments the invention is directed to a process for preparing an oxycodone hydrochloride composition having less than 25 ppm of 14-hydroxycodeinone.

Claims

1. A process for preparing an oxycodone salt substantially free of 14-hydroxycodeinone, which process comprises steps of:

(a) preparing a mixture of oxycodone free base, solvent and an acid, the oxycodone free base having an 8α

,14-dihydroxy-7,8-dihydrocodeinone component;

(b) incubating the mixture under conditions suitable to convert the oxycodone free base to an oxycodone salt, wherein said conditions promote an acid catalyzed dehydration consisting of conversion of the 8α

,14-dihydroxy-7,8-dihydrocodeinone component to 14-hydroxycodeinone; and

(c) preferentially removing the 14-hydroxycodeinone from the oxycodone salt.

2. The process according to claim 1, wherein in step (b) the mixture is heated to a temperature of about 75°

C.

3. The process according to claim 1, wherein the mixture has a pH of about 2.5 or less.

4. The process according to claim 3, wherein the mixture has a pH of about 1.8 or less.

5. The process according to claim 4, wherein the mixture has a pH of about 1.5 or less.

6. The process according to claim 5, wherein the mixture has a pH of about 1 or less.

7. The process according to claim 1, wherein the 14-hydroxycodeinone is preferentially removed by subjecting the oxycodone salt to chromatographic separation.

8. The process according to claim 1, wherein step (b) is carried out at a temperature of about 20°

C.

9. The process according to claim 1, wherein step (b) is carried out at a temperature between about 40°

C. to about 85°

C.

10. The process according to claim 9, wherein in step (c) the mixture is exposed to hydrogenation reagents for at least about 4 hours.

11. The process according to claim 10, wherein in step (c) the mixture is exposed to the hydrogenation reagents for at least about 5 hours.

12. The process according to claim 11, wherein in step (c) the mixture is exposed to the hydrogenation reagents for about 21 hours.

13. The process according to claim 1, wherein the acid in said mixture is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone.

14. The process according to claim 1, wherein the acid is hydrochloric acid.

15. The process according to claim 14, wherein the hydrochloric acid is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone.

16. The process according to claim 15, wherein the hydrochloric acid is present in an amount greater than about 1.2 molar equivalents compared to the amount of oxycodone.

17. The process according to claim 16, wherein the hydrochloric acid is present in an amount greater than about 1.4 molar equivalents compared to the amount of oxycodone.

18. The process according to claim 17, wherein the hydrochloric acid is present in an amount greater than about 1.5 molar equivalents compared to the amount of oxycodone.

19. The process according to claim 1, wherein the resultant oxycodone salt contains less than about 25 ppm 14-hydroxycodeinone.

20. The process according to claim 19, wherein the resultant oxycodone salt contains less than about 15 ppm 14-hydroxycodeinone.

21. The process according to claim 20, wherein the resultant oxycodone salt contains less than about 10 ppm 14-hydroxycodeinone.

22. The process according to claim 21, wherein the resultant oxycodone salt contains less than about 5 ppm 14-hydroxycodeinone.

23. The process according to claim 1, wherein the 14-hydroxycodeinone is preferentially removed by exposing the oxycodone salt to hydrogenation reagents under conditions sufficient for conversion of the 14-hydroxycodeinone to oxycodone salt.

24. The process according to claim 23, wherein the hydrogenation reagents are a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.

25. The process according to claim 1, wherein in step (c) the mixture is exposed to hydrogenation reagents for between about 10 minutes to about 36 hours.

26. The process according to claim 1, wherein the 14-hydroxycodeinone is preferentially removed by exposing the oxycodone salt to a substance that preferentially removes the 14-hydroxycodeinone compared to the oxycodone salt.

27. The process according to claim 26, wherein the substance is a gel.

28. The process according to claim 26, wherein the oxycodone salt is passed through the substance that preferentially removes the 14-hydroxycodeinone.

29. The process according to claim 26, wherein a slurry is formed with the oxycodone salt and the substance that preferentially removes the 14-hydroxycodeinone.

30. Oxycodone salt prepared according to the process of claim 1.

31. Oxycodone salt according to claim 30, wherein the oxycodone salt is oxycodone hydrochloride.

32. Oxycodone salt according to claim 31 having less than about 25 ppm 14-hydroxycodeinone.

33. Oxycodone salt according to claim 32 having less than about 15 ppm 14-hydroxycodeinone.

34. Oxycodone salt according to claim 33 having less than about 10 ppm 14-hydroxycodeinone.

35. Oxycodone salt according to claim 34 having less than about 5 ppm 14-hydroxycodeinone.

36. Oxycodone salt according to claim 32, wherein the 14-hydroxycodeinone is derived solely from 8α

,14-dihydroxy-7,8-dihydrocodeinone.

37. Oxycodone salt according to claim 33, wherein the 14-hydroxycodeinone is derived solely from 8α

,14-dihydroxy-7,8-dihydrocodeinone.

38. An oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone, the composition prepared by a process comprising:

preparing a mixture of oxycodone free base, solvent and hydrochloric acid, the oxycodone free base having an 8α

,14-dihydroxy-7,8-dihydrocodeinone component,

incubating the mixture under conditions suitable to convert the oxycodone free base to an oxycodone hydrochloride having more than 100 ppm 14-hydroxycodeinone, wherein said conditions promote an acid catalyzed dehydration of the 8α

,14-dihydroxy-7,8-dihydrocodeinone component to 14-hydroxycodeinone, and

hydrogenating the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone until the oxycodone hydrochloride composition contains less than 25 ppm 14-hydroxycodeinone,

wherein at least a portion of the 14-hydroxycodeinone in the composition having more than 100 ppm 14-hydroxycodeinone was derived from the 8α

,14-dihydroxy-7,8-dihydrocodeinone component during the conversion of the oxycodone free base to the oxycodone salt.

39. The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed with a hydrogen donor and a catalyst.

40. The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed under reflux.

41. The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed in a solvent comprising an alcohol.

42. The oxycodone hydrochloride composition of claim 41, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.

43. The oxycodone hydrochloride composition of claim 41, wherein the process further comprises recovering the oxycodone hydrochloride composition having less than 25 ppm from the solvent.

44. The oxycodone hydrochloride composition of claim 43, wherein the recovering comprises crystallizing the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone and filtering the crystallized composition from the solvent.

45. The oxycodone hydrochloride composition of claim 43, wherein the process comprises after said recovering further hydrogenating the recovered oxycodone hydrochloride composition.

46. The oxycodone hydrochloride composition of claim 38 having less than 15 ppm 14-hydroxycodeinone.

47. The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed with a hydrogen donor.

48. The oxycodone hydrochloride composition of claim 47, wherein the hydrogen donor is selected from the group consisting of hydrogen gas, formic acid, indoline, cyclohexene, sodium borohydride, tetrahydroquinoline, 2,5-dihydrofuran, phosphoric acid, and combinations thereof.

49. The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed with a catalyst.

50. The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 15 ppm 14-hydroxycodeinone.

51. The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 10 ppm 14-hydroxycodeinone.

52. The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 5 ppm 14-hydroxycodeinone.

53. The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 15 ppm 14-hydroxycodeinone, and the process further comprises additional hydrogenation until the oxycodone hydrochloride composition contains less than 10 ppm 14-hydroxycodeinone.

54. The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains between 10 ppm and 15 ppm 14-hydroxycodeinone, and the process further comprises additional hydrogenation until the oxycodone hydrochloride composition contains less than 5 ppm 14-hydroxycodeinone.

55. The composition of claim 38, having a lower limit of the 14-hydroxycodeinone of 0.25 ppm, 0.5 ppm, 1 ppm, 2 ppm or 5 ppm.

56. The composition of claim 38, which is suitable for use in a commercial oxycodone product.

81. The composition of claim 55 having a lower limit of the 14-hydroxycodeinone of 2 ppm or 5 ppm.

57. A process for preparing an oxycodone salt substantially free of 14-hydroxycodeinone, which process comprises steps of:

(a) preparing a mixture of oxycodone free base, solvent and an acid, the oxycodone free base having an 8α

,14-dihydroxy-7,8-dihydrocodeinone component;

(b) incubating the mixture under conditions suitable to convert the oxycodone free base to an oxycodone salt, wherein said conditions promote an acid catalyzed dehydration whereby the 8α

,14-dihydroxy-7,8-dihydrocodeinone component is converted to 14-hydroxycodeinone; and

(c) reducing an amount of 14-hydroxycodeinone in the oxycodone salt formed in step (b) to produce an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone.

58. The process according to claim 57, wherein the acid is hydrochloric acid.

59. The process according to claim 58, wherein the hydrochloric acid is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone free base.

60. The process according to claim 59, wherein the hydrochloric acid is present in an amount greater than about 1.2 molar equivalents compared to the amount of oxycodone free base.

61. The process according to claim 57, wherein the mixture has a pH of about 2.5 or less.

62. The process according to claim 61, wherein the mixture has a pH of about 1.8 or less.

63. The process according to claim 62, wherein the mixture has a pH of about 1.5 or less.

64. The process according to claim 63, wherein the mixture has a pH of about 1 or less.

65. The process according to claim 57, wherein step (b) is carried out at a temperature between about 40°

C. to about 85°

C.

66. The process according to claim 57, wherein the amount of 14-hydroxycodeinone is reduced by subjecting the oxycodone salt to chromatographic separation.

67. The process according to claim 57, wherein the amount of 14-hydroxycodeinone is reduced by exposing the oxycodone salt to hydrogenation reagents under conditions sufficient for conversion of the 14-hydroxycodeinone to oxycodone salt.

68. The process according to claim 67, wherein the hydrogenation reagents are a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.

69. The process according to claim 68, wherein in step (c) the mixture is exposed to the hydrogenation reagents for between about 10 minutes to about 36 hours.

70. The process according to claim 57, wherein the amount of 14-hydroxycodeinone is reduced by exposing the oxycodone salt to a substance that preferentially removes the 14-hydroxycodeinone compared to the oxycodone salt.

71. The process according to claim 70, wherein the substance is a gel.

72. The process according to claim 71, wherein the oxycodone salt is passed through the substance that preferentially removes the 14-hydroxycodeinone.

73. The process according to claim 57, wherein the resultant oxycodone salt contains less than about 25 ppm 14-hydroxycodeinone.

74. The process according to claim 73, wherein the resultant oxycodone salt contains less than about 10 ppm 14-hydroxycodeinone.

75. The process according to claim 74, wherein the resultant oxycodone salt contains less than about 5 ppm 14-hydroxycodeinone.

76. Oxycodone salt prepared according to the process of claim 57.

77. Oxycodone salt according to claim 76, wherein the oxycodone salt is oxycodone hydrochloride.

78. Oxycodone salt according to claim 77 having less than about 25 ppm 14-hydroxycodeinone.

79. Oxycodone salt according to claim 78 having less than about 15 ppm 14-hydroxycodeinone.

80. Oxycodone salt according to claim 57 having between 0.5 ppm and 25 ppm 14-hydroxycodeinone.