# US 2018/0022754 A1 · Process for preparing oxycodone compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2018/0022754 A1 - Document ID: US20180022754A1 - Status: Published application - Kind: A1 - Application number: 15/721,167 - Filed: 2017-09-29 - Published: 2018-01-25 - Earliest claimed: 2005-03-30 - Assignees: Purdue Pharma L.P.; The P.F. Laboratories, Inc.; Purdue Pharmaceuticals L.P.; Rhodes Technologies - Applicants: Purdue Pharma L.P.; The P.F. Laboratories, Inc.; Purdue Pharmaceuticals L.P.; Rhodes Technologies - Inventors: Robert CHAPMAN; Lonn S. RIDER; Qi HONG; Donald KYLE; Robert KUPPER - Web page: https://patentgrep.com/patent/US20180022754A1 ## CPC - C07D 489/08: Oxygen atom - 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)} - A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} - A61K 9/2095: {Tabletting processes} - A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)} - A61K 9/4833: {Encapsulating processes; Filling of capsules (mechanical aspects A61J3/07)} - A61K 31/485: Morphinan derivatives, e.g. morphine, codeine - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - C07D 489/02: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone - C07D 489/04: Salts; Organic complexes - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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 ### Claim 1 A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising hydrogenating an oxycodone hydrochloride composition having at least 100 ppm 14-hydroxycodeinone in a suitable solvent to produce an oxycodone composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 2 (depends on 1) The process of claim 1, wherein said hydrogenation is performed with a hydrogen donor and a catalyst. ### Claim 3 (depends on 1) The process of claim 1 wherein said hydrogenation is performed under reflux. ### Claim 4 (depends on 1) The process of claim 1, wherein the solvent is an alcohol. ### Claim 5 (depends on 4) The process of claim 4, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol. ### Claim 6 (depends on 1) The process of claim 1, further comprising recovering the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone from the solvent. ### Claim 7 (depends on 6) The process of claim 6, wherein the recovery step comprises crystallizing the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone and filtering the crystallized composition from the solvent. ### Claim 8 (depends on 6) The process of claim 6, comprising further hydrogenating the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 9 (depends on 6) The process of claim 6, wherein the oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than 15 ppm. ### Claim 10 (depends on 2) The process of claim 2, wherein the hydrogenation is performed with a hydrogen donor. ### Claim 11 (depends on 10) The process of claim 10, wherein the hydrogenation is further performed with a catalyst. ### Claim 12 (depends on 10) The process of claim 10, 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. ### Claim 13 A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising reacting hydrochloric acid with an oxycodone free base composition in a solvent under conditions to form oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm. ### Claim 14 (depends on 13) The process of claim 13, wherein the oxycodone hydrochloride has a 14-hydroxycodeinone level of less than 15 ppm. ### Claim 15 (depends on 13) The process of claim 13, wherein the hydrochloric acid is present in an amount of more than 1 molar equivalents to the oxycodone free base composition. ### Claim 16 (depends on 13) The process of claim 13, wherein the hydrochloric acid is present in an amount of more than about 1.2 molar equivalents. ### Claim 17 (depends on 13) The process of claim 13, wherein the hydrochloric acid is present in an amount of more than about 1.5 molar equivalents. ### Claim 18 (depends on 13) The process of claim 13, further comprising increasing the pH of the solution with a basic agent. ### Claim 19 (depends on 18) The process of claim 18, wherein the pH of the solution is less than 1.0 and is adjusted to a pH of about 1.5 to about 2.0. ### Claim 20 (depends on 18) The process of claim 18, wherein the basic agent is sodium hydroxide. ### Claim 21 (depends on 1) The process of claim 1, wherein the hydrogenation produces an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 15 ppm. ### Claim 22 (depends on 1) The process of claim 1, wherein the hydrogenation produces an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 10 ppm. ### Claim 23 (depends on 1) The process of claim 1, wherein the hydrogenation produces an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 5 ppm. ### Claim 24 (depends on 13) The process of claim 13, wherein the oxycodone hydrochloride composition has a 14-hydroxycodeinone level of about 15 ppm. ### Claim 25 (depends on 13) The process of claim 13, wherein the oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than 10 ppm. ### Claim 26 (depends on 13) The process of claim 13, wherein the oxycodone hydrochloride composition has a 14-hydroxycodeinone level of about 5 ppm. ### Claim 27 (depends on 1) The process of claim 1, wherein the hydrogenation produces an oxycodone composition having a 14-hydroxycodeinone level of between 15 ppm and 25 ppm, further comprising additional hydrogenation to produce an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount less than 10 ppm. ### Claim 28 (depends on 1) The process of claim 1, wherein the hydrogenation produces an oxycodone composition having a 14-hydroxycodeinone level of between 10 ppm and 25 ppm, further comprising additional hydrogenation to produce an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount less than 5 ppm. ### Claim 29 (depends on 13) The process of claim 13, wherein the hydrogenation produces an oxycodone composition having a 14-hydroxycodeinone level of between 15 ppm and 25 ppm, further comprising additional hydrogenation to produce an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount less than 10 ppm. ### Claim 30 (depends on 13) The process of claim 13, wherein the hydrogenation produces an oxycodone composition having a 14-hydroxycodeinone level of between 10 ppm and 25 ppm, further comprising additional hydrogenation to produce an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount less than 5 ppm. ### Claim 31 (depends on 13) The process of claim 13, wherein the hydrogenation produces an oxycodone composition having a 14-hydroxycodeinone level of between 10 ppm and 25 ppm, further comprising additional hydrogenation to produce an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount less than 5 ppm. ### Claim 32 (depends on 1) The process of claim 1, wherein the hydrogenation step is performed without a hydrogen gas feed. ### Claim 33 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising reacting in a suitable solvent an oxycodone base composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone; with hydrochloric acid in an amount greater than 1.0 molar equivalent as compared to the oxycodone base composition to promote the dehydration of the 8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone to form an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm; the reacting step being performed under reducing conditions to promote the conversion of 14-hydroxycodeinone to oxycodone. ### Claim 34 (depends on 33) The process of claim 33, further comprising recovering the oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm. ### Claim 35 (depends on 33) The process of claim 33, wherein the recovery step comprises crystallizing the oxycodone composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm and filtering the crystallized composition from the solvent. ### Claim 36 (depends on 33) The process of claim 33 comprising increasing the pH of the solution with a basic agent. ### Claim 37 (depends on 33) The process of claim 33, wherein the pH of the solution is less than 1.0 and is adjusted to a pH of about 1.5 to about 2.0. ### Claim 38 (depends on 33) The process of claim 33, comprising hydrogenating the resultant oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm. ### Claim 39 (depends on 38) The process of claim 38, wherein the pH is not adjusted with an acid during the hydrogenation step. ### Claim 40 (depends on 38) The process of claim 38, wherein the pH is greater than 2. ### Claim 41 A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising titrating an oxycodone base composition comprising an amount of 8,14-dihydroxy-7,8-dihydrocodeinone with hydrochloric acid in order to reduce the amount of excess hydrochloric acid and minimize the dehydration of 8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone during formation of the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 42 (depends on 33, 41) The process of claims 33 and 41, wherein the oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than 15 ppm. ### Claim 43 (depends on 33, 41) The process of claims 33 and 41, wherein the oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than 10 ppm. ### Claim 44 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising reacting in a suitable solvent an oxycodone base composition with hydrochloric acid in an amount greater than 1.0 molar equivalent as compared to the oxycodone base composition, the reacting step being performed under reducing conditions, to form an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm. ### Claim 45 A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising hydrogenating a 14-hydroxycodeinone composition to obtain an oxycodone free base composition; converting the oxycodone free base composition to oxycodone hydrochloride; and hydrogenating the oxycodone hydrochloride to obtain an oxycodone composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 46 A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising hydrogenating a 14-hydroxycodeinone composition to obtain an oxycodone free base composition; converting the oxycodone free base composition to oxycodone hydrochloride; isolating the oxycodone hydrochloride; and hydrogenating the oxycodone hydrochloride to obtain an oxycodone composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 47 A process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising oxidizing a thebaine composition to form 14-hydroxycodeinone composition, said oxidizing being performed at a suitable pH to minimize or eliminate the production of 8,14-dihydroxy-7,8-dihydrocodeinone in said 14-hydroxycodeinone composition; hydrogenating said 14-hydroxycodeinone composition to form an oxycodone base composition; and converting said oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 48 A process for preparing 14-hydroxycodeinone comprising oxidizing a thebaine composition to form 14-hydroxycodeinone composition, said oxidizing being performed at a suitable pH to minimize or eliminate the production of 8,14-dihydroxy-7,8-dihydrocodeinone in said 14-hydroxycodeinone composition; ### Claim 49 A process for preparing an oxycodone hydrochloride composition comprising reacting an oxycodone base composition with an acid having a higher pH than hydrochloric acid to form a corresponding acid addition salt of oxycodone, and converting said acid addition salt of oxycodone to oxycodone hydrochloride. ### Claim 50 (depends on 49) The process of claim 49, wherein said oxycodone hydrochloride composition has less than 25 ppm 14-hydroxycodeinone. ### Claim 51 (depends on 49) The process of claim 49, wherein said acid is selected from the group consisting of tartaric acid, oxalic acid, fumaric acid, phosphoric acid, sulfuric acid and mixtures thereof. ### Claim 52 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising contacting an oxycodone base composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone with a substance that preferentially removes the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting said oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 53 (depends on 52) The process of claim 52, wherein said substance is a gel. ### Claim 54 (depends on 52) The process of claim 52, wherein said contacting comprises passing a solution comprising said oxycodone base composition through said substance. ### Claim 55 (depends on 53) The process of claim 53, wherein said contacting comprises forming a slurry with said oxycodone base composition and said gel. ### Claim 56 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising subjecting an oxycodone base composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone to chromatographic separation to preferentially removes the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting said oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 57 (depends on 56) The process of claim 56, wherein said chromatographic separation is a simulated moving bed. ### Claim 58 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising contacting an oxycodone hydrochloride composition having an amount of 14-hydroxycodeinone with a substance that preferentially removes the 14-hydroxycodeinone as compared to the oxycodone hydrochloride; and recovering an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 59 (depends on 58) The process of claim 58, wherein said substance is a gel. ### Claim 60 (depends on 58) The process of claim 58, wherein said contacting comprises passing a solution comprising said oxycodone hydrochloride composition through said substance. ### Claim 61 (depends on 59) The process of claim 59, wherein said contacting comprises forming a slurry with said oxycodone hydrochloride composition and said gel. ### Claim 62 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising subjecting an oxycodone hydrochloride composition having an amount of 14-hydroxycodeinone to chromatographic separation to preferentially removes the 14-hydroxycodeinone as compared to the oxycodone hydrochloride; and recovering oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 63 (depends on 62) The process of claim 62, wherein said chromatographic separation is a simulated moving bed. ### Claim 64 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising reacting in a suitable solvent an oxycodone base composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone, with boronated polystyrene resin; and converting said oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone. ### Claim 65 A process for preparing an oxycodone hydrochloride composition comprising reacting in a suitable solvent an oxycodone base composition with boronated polystyrene resin; and converting said oxycodone base composition to an oxycodone hydrochloride composition. ### Claim 66 (depends on 64, 65) The process of claims 64-65, wherein said reacting is performed at a temperature below about 20 degrees C. ### Claim 67 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising combining hydrochloric acid and an oxycodone base composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; and spray drying said solution to generate oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm. ### Claim 68 A process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising combining hydrochloric acid and an oxycodone base composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; and lyophilizing said solution to generate oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm. ### Claim 69 A process for preparing an oxycodone hydrochloride composition comprising combining hydrochloric acid and an oxycodone base composition in a solvent to form a solution; and spray drying said solution to generate oxycodone hydrochloride. ### Claim 70 A process for preparing an oxycodone hydrochloride composition comprising combining hydrochloric acid and an oxycodone base composition in a solvent to form a solution; and lyophilizing said solution to generate oxycodone hydrochloride.