Conversion of oxycodone base to oxycodone hydrochloride
Synthetic methods are provided for preparation of oxycodone and salts thereof with an improved impurity profile. Thebaine is converted to 14-hydroxycodeinone sulfate intermediate to minimize a 7,8-dihydro-8,14-dihydroxycodeinone impurity. Efficient methods for conversion of oxycodone base to oxycodone hydrochloride are provided to minimize 14-hydroxycodeinone impurity in the final product.
1. A method for preparation of oxycodone hydrochloride from oxycodone base comprising:
dissolving oxycodone base in an aqueous organic acid solution comprised of water and an organic carboxylic acid, wherein the organic carboxylic acid is acetic acid, to form an oxycodone organic acid salt,
wherein the dissolving is performed at a temperature within a range of from 0° C. to 50° C.; and
adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone hydrochloride.
2. The method of claim 1 , wherein the dissolving comprises complete or partial dissolution of the oxycodone base in the aqueous organic acid solution.
3. The method of claim 1 further comprising
crystallizing the oxycodone hydrochloride by adding water and/or one or more water miscible organic solvents to the oxycodone hydrochloride to form purified oxycodone hydrochloride.
4. The method of claim 1 , wherein any 8,14-dihydroxy-7,8-dihydrocodeinone impurity present in the oxycodone base is not converted to 14-hydroxycodeinone.
5. The method of claim 3 , wherein the crystallizing is performed at a temperature within a range of from 0° C. to 35° C.
6. The method of claim 3 , wherein the crystallizing is performed at a temperature within a range of from 5° C. to 30° C.
7. The method of claim 3 , wherein the one or more water miscible organic solvents is/are selected from the group consisting of isopropyl alcohol, ethanol, methanol, methyl ethyl ketone and acetone.
8. The method of claim 3 , wherein the purified oxycodone hydrochloride has not more than 0.001% 14-hydroxycodeinone.
9. The method of claim 3 , wherein the purified oxycodone hydrochloride has no more than 0.0005% 14-hydroxycodeinone.
10. The method of claim 1 , wherein the dissolving step is performed at a temperature within a range of from 10° C. to 40° C.
11. The method of claim 10 , wherein the dissolving step is performed at ambient temperature.
12. The method of claim 3 , wherein the crystallizing step is performed at a temperature within a range of 0° C. to 30° C.
13. The method of claim 12 , wherein the crystallizing is performed at a temperature within a range of from 5° C. to 15° C.
14. The method of claim 1 , wherein the oxycodone organic acid salt is oxycodone acetate.
15. The method of claim 3 , wherein the purified oxycodone hydrochloride has not more than 0.25% 6-α oxycodol impurity.
16. The method of claim 3 , wherein the purified oxycodone hydrochloride has not more than 0.05% of a 8,14-dihydroxy-7,8-dihydrocodeinone impurity.
17. The method of claim 14 , comprising
dissolving oxycodone base in an aqueous organic carboxylic acid solution comprised of water and acetic acid to form the oxycodone acetate salt; and
adding hydrochloric acid or ammonium chloride to the oxycodone acetate salt to form oxycodone hydrochloride.
18. The method of claim 17 , wherein the adding comprises exposing the oxycodone acetate salt to hydrochloric acid at ambient temperature to form oxycodone hydrochloride.
19. The method of claim 2 , wherein the aqueous organic acid is added in about 1 molar equivalent or less compared to moles of oxycodone base.
20. The method of claim 19 , wherein the aqueous organic acid is added in about 0.9 molar equivalents or less compared to moles of oxycodone base.
21. The method of claim 1 , wherein the dissolving the oxycodone base in the organic acid and water is performed without heating prior to introduction of hydrochloric acid.
22. The method of claim 1 , wherein the oxycodone base is dissolved without heating in acetic acid and water.
23. The method of claim 1 , comprising
at least partially dissolving oxycodone base in acetic acid and water at a temperature within a range of from 10° C. to 40° C.;
adding hydrochloric acid at ambient temperature to convert to oxycodone hydrochloride, and
adding isopropyl alcohol to precipitate the oxycodone hydrochloride, wherein the precipitated oxycodone hydrochloride has not more than 10 ppm 14-hydroxycodeinone.
24. The method of claim 23 , wherein the precipitated oxycodone hydrochloride has not more than 5 ppm 14-hydroxycodeinone.