Title of Invention	"PROCESS FOR PREPARING OXYCODONE HYDROCHLORIDE COMPOSITION HAVING LESS THAN 25 PPM 14-HYDROXYCODEINONE"
Abstract	A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone, which process comprises the steps of firstly providing an oxycodone base composition, said oxycodone base composition comprising an amount of 8a,14-dihydroxy-7,8-dihydrocodeinone, secondly reacting said oxycodone base composition with an acid under conditions suitable to convert the oxycodone base composition to an oxycodone hydrochloride composition and to promote an acid catalyzed dehydration of 8a,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone; and finally reducing an amount of 14-hydroxycodeinone in the oxycodone hydrochloride composition formed in the second step to produce an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.

Title of Invention

"PROCESS FOR PREPARING OXYCODONE HYDROCHLORIDE COMPOSITION HAVING LESS THAN 25 PPM 14-HYDROXYCODEINONE"

Abstract

A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone, which process comprises the steps of firstly providing an oxycodone base composition, said oxycodone base composition comprising an amount of 8a,14-dihydroxy-7,8-dihydrocodeinone, secondly reacting said oxycodone base composition with an acid under conditions suitable to convert the oxycodone base composition to an oxycodone hydrochloride composition and to promote an acid catalyzed dehydration of 8a,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone; and finally reducing an amount of 14-hydroxycodeinone in the oxycodone hydrochloride composition formed in the second step to produce an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.

Full Text	A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone, which process comprises the steps of (a) providing an oxycodone base composition, said oxycodone base composition comprising an amount of 8a,14-dihydroxy-7,8-dihydrocodeinone, (b) reacting said oxycodone base composition with an acid under conditions suitable to convert the oxycodone base composition to an oxycodone salt composition and to promote an acid catalyzed dehydration of 8α,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone; and (c) reducing an amount of 14-hydroxycodeinone in the oxycodone salt composition formed in step (b) to produce an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone. We Claim: 1. A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone, which process comprises the steps of: (a) providing an oxycodone base composition, said oxycodone base composition comprising an amount of 8α,14-dihydroxy-7,8-dihydrocodeinone, (b) reacting said oxycodone base composition with an acid under conditions suitable to convert the oxycodone base composition to an oxycodone hydrochloride composition and to promote an acid catalyzed dehydration of 8α,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone; and (c) reducing an amount of 14-hydroxycodeinone in the oxycodone hydrochloride composition formed in step (b) to produce an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. 2. The process as claimed in claim 1, comprising a step of removing 8α,14-dihydroxy-7,8-dihydrocodeinone from the oxycodone base composition before step (b). 3. The process as claimed in claim 1, or 2, wherein the reacting in step (b) is carried out in a solvent. 4. The process as claimed in any one of claims 1 to 3 wherein the oxycodone salt composition formed in step (b) has less than about 15 ppm 14-hydroxycodeinone. 5. The process as claimed in any one of claims 1 to 3 wherein the oxycodone salt composition formed in step (b) has less than about 10 ppm 14-hydroxycodeinone. 6. The process as claimed in any one of claims 1 to 3 wherein the oxycodone salt composition formed in step (b) has less than about 5 ppm 14-hydroxycodeinone. 7. The process as claimed in any one of claims 1 to 6, comprising the step of hydrogenating the oxycodone hydrochloride composition formed in step (b). 8. The process as claimed in claim 7, comprising a pH adjustment step which is performed after said hydrogenation step. 9. The process as claimed in claim 8, wherein the pH is adjusted from about 1.5 to about 2.5. 10. The process as claimed in any one of claims 1 to 9, comprising a step of recovering the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. 11. The process as claimed in claim 10, wherein the reacting in step (b) is carried out in a solvent, and the recovery step comprises crystallizing the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone and filtering the crystallized composition from the solvent. 12. The process as claimed in any one of claims 1 to 11, wherein in step (b), the acid is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone. 13. The process as claimed in claim 12, wherein the acid is present in an amount greater than about 1.2 molar equivalents compared to the amount of oxycodone. 14. The process as claimed in claim 12, wherein the acid is present in an amount greater than about 1.4 molar equivalents compared to the amount of oxycodone. 15. The process as claimed in claim 12, wherein the acid is present in an amount greater than about 1.5 molar equivalents compared to the amount of oxycodone. 16. A process for preparing an oxycodone salt composition as claimed in any one of claims 1 to 15 wherein the 14-hydroxycodeinone is removed by hydrogenation with hydrogenation reagents and under conditions sufficient for conversion of 14-hydroxycodeinone to oxycodone salt. 17. The process as claimed in claim 16, wherein the hydrogenation reagents comprise a catalyst. 18. The process as claimed in claim 16, wherein the hydrogenation reagents are a catalyst and a hydrogen donor. 19. The process as claimed in claim 17 or 18, wherein the catalyst is palladium on carbon. 20. The process as claimed in claim 18, 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. 21. The process as claimed in any one of claims 7 and 16-20 wherein the hydrogenation is carried out at a temperature of from about 20°C to about 100°C. 22. The process as claimed in claim 21, wherein the hydrogenation is carried out at a temperature of from about 40°C to about 85°C. 23. The process as claimed in any one of claims 7 or 16-22, wherein the hydrogenation is carried out at a pH of less than 5 or less than 3. 24. The process as claimed in any one of claims 7 or 16 to 23, wherein the hydrogenation is carried out at a pH of less than 1. 25. The process as claimed in any one of claim 7 or claims 16-24, wherein step (c) comprises hydrogenating the oxycodone hydrochloride composition formed in step (b) and wherein said oxycodone hydrochloride composition formed in step (b) has at least 100 ppm 14-hydroxycodeinone. 26. The process as claimed in claim 25, wherein said hydrogenation is performed under reflux. 27. The process as claimed in any one of claims 7 or 16-24, wherein the hydrogenation produces an oxycodone hydrochloride composition having between 15 ppm and 25 ppm 14-hydroxycodeinone, and the oxycodone salt composition having between 15 ppm and 25 ppm 14-hydroxycodeinone is further hydrogenated to produce an oxycodone hydrochloride composition having less than 10 ppm 14-hydroxycodeinone. 28. The process as claimed in any one of claims 7 or 16-24, wherein the hydrogenation produces an oxycodone salt composition having a 14-hydroxycodeinone level of between 10 ppm and 25 ppm, and the oxycodone salt composition having between 10 ppm and 25 ppm 14-hydroxycodeinone is further hydrogenated to produce an oxycodone hydrochloride composition having less than 5 ppm 14-hydroxycodeinone. 29. The process as claimed in any one of claims 21 to 28, wherein the hydrogenation is performed without a hydrogen gas feed. 30. The process as claimed in any one of claims 7 or 16 to 29, wherein the hydrogenation time is from about 10 min to about 36 hours. 31. The process as claimed in any one of claims 7 or 16 to 30, wherein the hydrogenation is carried out in a solvent. 32. The process as claimed in claim 31, wherein the solvent is an alcohol. 33. The process as claimed in claim 32, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol. 34. The process as claimed in claim 31, wherein the solvent is a combination of isopropanol and water. 35. The process as claimed in any one of claims 31 to 34, comprising increasing the pH of the solution with a basic agent after the hydrogenation. 36. The process as claimed in claim 35, wherein the basic agent is sodium hydroxide. 37. The process as claimed in claim 35 or 36, wherein the pH of the solution is less than 1.0 and is adjusted to a pH of about 1.5 to about 2.5. 38. A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone as claimed in any of claims 1 to 15, wherein step (c) is performed by contacting the oxycodone hydrochloride composition formed in step (b) with a substance that preferentially removes 14-hydroxycodeinone as compared to the oxycodone hydrochloride. 39. A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 to 15, comprising contacting the oxycodone base composition of step (a) with a substance that preferentially removes 8α,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting the oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone after said contacting. 40. The process as claimed in claims 38 and 39, wherein said contacting comprises passing a solution comprising said oxycodone hydrochloride composition through said substance. 41. The process as claimed in claims 38 and 39, wherein said substance is a gel. 42. The process as claimed in claim 41, wherein said contacting comprises forming a slurry with said oxycodone hydrochloride composition and said gel. 43. A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 to 15, wherein step (b) is performed by titrating the oxycodone base composition of step (a) with the acid. 44. A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 to 15, comprising subjecting the oxycodone base composition of step (a) to chromatographic separation to preferentially remove 8α,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and, subsequently, converting said oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. 45. The process as claimed in claim 44, wherein said chromatographic separation is a simulated moving bed. 46. A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 and 2 to 15, comprising: performing step (b) by reacting the oxycodone base composition with an acid having a higher pH than hydrochloric acid to form a corresponding acid addition salt of oxycodone, and 56. The oxycodone salt composition as claimed in any one of claims 51, 52 or 53, having less than about 5 ppm 14-hydroxycodeinone. 57. The oxycodone salt composition as claimed in any one of claims 51 to 55, having a lower limit of 14-hydroxycodeinone of 5 ppm. 58. The oxycodone salt composition as claimed in any one of claims 51 to 57, having a lower limit of 14-hydroxycodeinone of 0.25 ppm, 0.5 ppm, 1 ppm or 2 ppm. 59. A pharmaceutically acceptable package containing at least 1 kg of the oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 51 to 58.

Full Text

A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone, which process comprises the steps of (a) providing an oxycodone base composition, said oxycodone base composition comprising an amount of 8a,14-dihydroxy-7,8-dihydrocodeinone, (b) reacting said oxycodone base composition with an acid under conditions suitable to convert the oxycodone base composition to an oxycodone salt composition and to promote an acid catalyzed dehydration of 8α,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone; and (c) reducing an amount of 14-hydroxycodeinone in the oxycodone salt composition formed in step (b) to produce an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone.

We Claim:
1. A process for preparing an oxycodone hydrochloride composition having less than
25 ppm 14-hydroxycodeinone, which process comprises the steps of:
(a) providing an oxycodone base composition, said oxycodone base composition
comprising an amount of 8α,14-dihydroxy-7,8-dihydrocodeinone,
(b) reacting said oxycodone base composition with an acid under conditions
suitable to convert the oxycodone base composition to an oxycodone
hydrochloride composition and to promote an acid catalyzed dehydration of
8α,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone; and
(c) reducing an amount of 14-hydroxycodeinone in the oxycodone hydrochloride
composition formed in step (b) to produce an oxycodone hydrochloride
composition having less than 25 ppm 14-hydroxycodeinone.
2. The process as claimed in claim 1, comprising a step of
removing 8α,14-dihydroxy-7,8-dihydrocodeinone from the oxycodone base composition before step (b).
3. The process as claimed in claim 1, or 2, wherein the reacting in step (b) is carried out in a solvent.
4. The process as claimed in any one of claims 1 to 3 wherein the oxycodone salt composition formed in step (b) has less than about 15 ppm 14-hydroxycodeinone.
5. The process as claimed in any one of claims 1 to 3 wherein the oxycodone salt composition formed in step (b) has less than about 10 ppm 14-hydroxycodeinone.
6. The process as claimed in any one of claims 1 to 3 wherein the oxycodone salt composition formed in step (b) has less than about 5 ppm 14-hydroxycodeinone.
7. The process as claimed in any one of claims 1 to 6, comprising the step of hydrogenating the oxycodone hydrochloride composition formed in step (b).
8. The process as claimed in claim 7, comprising a pH adjustment step which is performed after said hydrogenation step.
9. The process as claimed in claim 8, wherein the pH is adjusted from about 1.5 to about 2.5.
10. The process as claimed in any one of claims 1 to 9, comprising a step of recovering the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.
11. The process as claimed in claim 10, wherein the reacting in step (b) is carried out in a solvent, and the recovery step comprises crystallizing the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone and filtering the crystallized composition from the solvent.
12. The process as claimed in any one of claims 1 to 11, wherein in step (b), the acid is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone.
13. The process as claimed in claim 12, wherein the acid is present in an amount greater than about 1.2 molar equivalents compared to the amount of oxycodone.
14. The process as claimed in claim 12, wherein the acid is present in an amount greater than about 1.4 molar equivalents compared to the amount of oxycodone.
15. The process as claimed in claim 12, wherein the acid is present in an amount greater than about 1.5 molar equivalents compared to the amount of oxycodone.
16. A process for preparing an oxycodone salt composition as claimed in any one of claims 1 to 15 wherein the 14-hydroxycodeinone is removed by hydrogenation
with hydrogenation reagents and under conditions sufficient for conversion of 14-hydroxycodeinone to oxycodone salt.
17. The process as claimed in claim 16, wherein the hydrogenation reagents comprise a catalyst.
18. The process as claimed in claim 16, wherein the hydrogenation reagents are a catalyst and a hydrogen donor.
19. The process as claimed in claim 17 or 18, wherein the catalyst is palladium on carbon.
20. The process as claimed in claim 18, 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.
21. The process as claimed in any one of claims 7 and 16-20 wherein the hydrogenation is carried out at a temperature of from about 20°C to about 100°C.
22. The process as claimed in claim 21, wherein the hydrogenation is carried out at a temperature of from about 40°C to about 85°C.
23. The process as claimed in any one of claims 7 or 16-22, wherein the hydrogenation is carried out at a pH of less than 5 or less than 3.
24. The process as claimed in any one of claims 7 or 16 to 23, wherein the hydrogenation is carried out at a pH of less than 1.
25. The process as claimed in any one of claim 7 or claims 16-24, wherein step (c) comprises hydrogenating the oxycodone hydrochloride composition formed in
step (b) and wherein said oxycodone hydrochloride composition formed in step (b) has at least 100 ppm 14-hydroxycodeinone.
26. The process as claimed in claim 25, wherein said hydrogenation is performed under reflux.
27. The process as claimed in any one of claims 7 or 16-24, wherein the hydrogenation produces an oxycodone hydrochloride composition having between 15 ppm and 25 ppm 14-hydroxycodeinone, and the oxycodone salt composition having between 15 ppm and 25 ppm 14-hydroxycodeinone is further hydrogenated to produce an oxycodone hydrochloride composition having less than 10 ppm 14-hydroxycodeinone.
28. The process as claimed in any one of claims 7 or 16-24, wherein the hydrogenation produces an oxycodone salt composition having a 14-hydroxycodeinone level of between 10 ppm and 25 ppm, and the oxycodone salt composition having between 10 ppm and 25 ppm 14-hydroxycodeinone is further hydrogenated to produce an oxycodone hydrochloride composition having less than 5 ppm 14-hydroxycodeinone.
29. The process as claimed in any one of claims 21 to 28, wherein the hydrogenation is performed without a hydrogen gas feed.
30. The process as claimed in any one of claims 7 or 16 to 29, wherein the hydrogenation time is from about 10 min to about 36 hours.
31. The process as claimed in any one of claims 7 or 16 to 30, wherein the hydrogenation is carried out in a solvent.
32. The process as claimed in claim 31, wherein the solvent is an alcohol.
33. The process as claimed in claim 32, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.
34. The process as claimed in claim 31, wherein the solvent is a combination of isopropanol and water.
35. The process as claimed in any one of claims 31 to 34, comprising increasing the pH of the solution with a basic agent after the hydrogenation.
36. The process as claimed in claim 35, wherein the basic agent is sodium hydroxide.
37. The process as claimed in claim 35 or 36, wherein the pH of the solution is less than 1.0 and is adjusted to a pH of about 1.5 to about 2.5.
38. A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone as claimed in any of claims 1 to 15, wherein step (c) is performed by contacting the oxycodone hydrochloride composition formed in step (b) with a substance that preferentially removes 14-hydroxycodeinone as compared to the oxycodone hydrochloride.
39. A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 to 15, comprising
contacting the oxycodone base composition of step (a) with a substance that preferentially removes 8α,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and
converting the oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone after said contacting.
40. The process as claimed in claims 38 and 39, wherein said contacting comprises passing a solution comprising said oxycodone hydrochloride composition through said substance.
41. The process as claimed in claims 38 and 39, wherein said substance is a gel.
42. The process as claimed in claim 41, wherein said contacting comprises forming a slurry with said oxycodone hydrochloride composition and said gel.
43. A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 to 15,
wherein step (b) is performed by titrating the oxycodone base composition of step (a) with the acid.
44. A process for preparing an oxycodone salt composition having less than 25 ppm
14-hydroxycodeinone as claimed in any one of claims 1 to 15, comprising
subjecting the oxycodone base composition of step (a) to chromatographic separation to preferentially remove 8α,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and, subsequently,
converting said oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.
45. The process as claimed in claim 44, wherein said chromatographic separation is a simulated moving bed.
46. A process for preparing an oxycodone salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of claims 1 and 2 to 15, comprising:
performing step (b) by reacting the oxycodone base composition with an acid having a higher pH than hydrochloric acid to form a corresponding acid addition salt of oxycodone, and
56. The oxycodone salt composition as claimed in any one of claims 51, 52 or 53, having less than about 5 ppm 14-hydroxycodeinone.
57. The oxycodone salt composition as claimed in any one of claims 51 to 55, having a lower limit of 14-hydroxycodeinone of 5 ppm.
58. The oxycodone salt composition as claimed in any one of claims 51 to 57, having a lower limit of 14-hydroxycodeinone of 0.25 ppm, 0.5 ppm, 1 ppm or 2 ppm.
59. A pharmaceutically acceptable package containing at least 1 kg of the oxycodone
salt composition having less than 25 ppm 14-hydroxycodeinone as claimed in any one of
claims 51 to 58.

"PROCESS FOR PREPARING OXYCODONE HYDROCHLORIDE COMPOSITION HAVING LESS THAN 25 PPM 14-HYDROXYCODEINONE"

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