Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
In certain embodiments the invention is directed to a process for preparing an oxycodone hydrochloride composition having less than 25 ppm of 14-hydroxycodeinone.
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.
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.
81. The composition of claim 55 having a lower limit of the 14-hydroxycodeinone of 2 ppm or 5 ppm.