Method for the enrichment of buprenorphine using chromatographic techniques

1. A method for enriching buprenorphine relative to 2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol and 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol in a buprenorphine product, the method comprising:

a. forming a first feed solution by dissolving a crude buprenorphine composition comprising buprenorphine, 2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol, and 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol in a solvent mixture comprising an acid, a first organic polar solvent, and water;

b. contacting the first feed solution with a stationary phase;

c. introducing into the stationary phase a first mobile phase comprising a second organic solvent and water, wherein the amount of the second organic solvent is at least 85% (V/V) of the mobile phase; and,

d. eluting from the stationary phase a first product fraction comprising between about 80% and 100% of the amount of buprenorphine contained in the crude buprenorphine composition.

2. The method of claim 1 , wherein the acid is chosen from acetic acid, malic acid, tartaric acid, sulfuric acid, formic acid, oxalic acid, lactic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phosphorous acid, nitric acid and combinations thereof; the first organic polar solvent is chosen from ethanol, methanol, propanol, isopropanol, butanol, t-butanol, acetonitrile and combinations thereof; and the second organic polar solvent is chosen from ethanol, methanol, propanol, isopropanol, butanol, t-butanol, acetonitrile and combinations thereof.

3. The method of claim 1 , wherein the acid is acetic acid; the amount of acetic acid ranges between about 0.1 and about 10 mL of pure acetic acid per gram of the crude buprenorphine composition; the first organic polar solvent is methanol; and the second organic polar solvent is methanol.

4. The method of claim 1 , wherein the mass of the stationary phase ranges between about 50 and about 250 times the mass of crude buprenorphine composition dissolved in the first feed solution; and the ratio of the mass of buprenorphine in the product fraction and the combined mass of 2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol, and 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol in the first product fraction is at least 200:1.

5. The method of claim 1 , wherein the stationary phase comprises a plurality of particles with attached ligands, wherein the particles comprise a material chosen from silica, polymers, zirconium oxide, and titanium, and wherein the ligands are chosen from octadecyl ligands, octyl ligands, butyl ligands, tricosane ligands, cyano ligands, phenyl ligands, and combinations thereof; and the size of the particles range between about 15 and about 50 microns in diameter.

6. The method of claim 1 , further comprising forming a first buprenorphine base solid by evaporating the first product fraction to form a first slurry and increasing the pH of the first slurry to about 9 by adding an amount of a first proton-acceptor.

7. The method of claim 6 , further comprising forming a first buprenorphine salt and a first mother liquor by contacting the first buprenorphine base solid with a third organic solvent and a first salt-forming agent, wherein the first mother liquor comprises buprenorphine, the third organic polar solvent, and the first salt-forming agent.

8. The method of claim 7 , wherein the third organic polar solvent is chosen from ethanol, methanol, propanol, isopropanol, butanol, t-butanol, acetonitrile and combinations thereof; the third organic polar solvent is isopropanol; and the first salt-forming agent is chosen from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, methyl fluoride, methyl chloride, methyl bromide, and methyl iodide.

9. The method of claim 1 , further comprising eluting from the stationary phase a first recycle fraction prior to eluting the first product phase, wherein the first recycle fraction comprises between about 1% and about 20% of the amount of buprenorphine contained in the crude buprenorphine composition.

10. The method of claim 9 , further comprising eluting from the stationary phase a second recycle fraction after eluting the first product phase, wherein the second recycle fraction comprises between about 1% and about 20% of the amount of buprenorphine contained in the crude buprenorphine composition.

11. The method of claim 10 , further comprising:

a. forming a second feed solution by evaporating at least one of the first recycle fraction, the second recycle fraction, the first mother liquor, and combinations thereof;

b. contacting the second feed solution with the stationary phase;

c. introducing into the stationary phase a second mobile phase comprising a fourth organic polar solvent and water, wherein the amount of the fourth organic polar solvent is at least 85% (V/V) of the second mobile phase; and,

d. eluting from the stationary phase a second product fraction comprising between about 80% and 100% of the amount of buprenorphine contained in the second feed solution.

12. The method of claim 11 , wherein the fourth organic polar solvent is chosen from ethanol, methanol, propanol, isopropanol, butanol, t-butanol, acetonitrile and combinations thereof.

13. The method of claim 11 , further comprising forming an additional amount of buprenorphine base solid by evaporating the second product fraction to form a second slurry and increasing the pH of the second slurry to about 9 by adding an amount of a second proton-acceptor.

14. The method of claim 13 , further comprising forming an additional amount of buprenorphine salt by contacting the additional amount of buprenorphine base solid with a fifth organic polar solvent and a second salt-forming agent.

15. The method of claim 14 , wherein the fifth organic polar solvent is chosen from ethanol, methanol, propanol, isopropanol, butanol, t-butanol, acetonitrile and combinations thereof; and the second salt-forming agent is chosen from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, methyl fluoride, methyl chloride, methyl bromide, and methyl iodide.

16. The method claim 1 , wherein the additional amount of buprenorphine salt comprises less than about 0.1% by weight of combined 2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol and 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol.

17. The method of claim 1 , wherein the buprenorphine salt comprises less than about 0.05% by weight of combined 2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol and 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol.

18. The method of claim 1 , wherein the buprenorphine salt comprises less than about 0.01% by weight of combined 2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol and 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol.

19. The method of claim 1 , wherein color is removed from the buprenorphine.

20. The method of claim 1 , wherein any adsorbed color is removed from the stationary phase with a mobile phase consisting of an organic solvent and an organic acid.