Preparation of oxycodone

Abstract

A process for preparing oxycodone or an oxycodone salt, wherein the oxycodone or oxycodone salt has low levels of impurities (especially 14-hydroxycodeinone) is disclosed. The process comprises the steps of: a) preparing a mixture comprising oxycodone and a solvent and adjusting the pH of the mixture to less than 6; and subsequently b) exposing the mixture to hydrogenation reagents for a period of at least 1 hour. This process provides oxycodone with very low levels of α,β-unsaturated ketone impurities. Oxycodone or an oxycodone salt produced according to the process of the invention has low levels of α,β-unsaturated ketones and is advantageously incorporated into pharmaceutical products.

1 . A composition comprising oxycodone or an oxycodone salt, said oxycodone or oxycodone salt containing less than 15 ppm of 14-hydroxycodeinone.  
   
   
       2 . The composition of  claim 1 , wherein the oxycodone or oxycodone salt contains less than 10 ppm of 14-hydroxycodeinone.  
   
   
       3 . The composition of  claim 1 , wherein the oxycodone or oxycodone salt contains less than 5 ppm of 14-hydroxycodeinone.  
   
   
       4 . The composition of  claim 1 , wherein the oxycodone or oxycodone salt contains less than 2 ppm of 14-hydroxycodeinone.  
   
   
       5 . The composition of  claim 1 , wherein the oxycodone or oxycodone salt contains about 0 ppm of 14-hydroxycodeinone.  
   
   
       6 . The composition of  claim 1 , having less than 20 ppm of heavy metal content.  
   
   
       7 . The composition of  claim 1 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride.  
   
   
       8 . The composition according to  claim 1 , said oxycodone or oxycodone salt being a purified oxycodone or salt thereof prepared by a process comprising the steps of: 
 a) preparing a solution comprising oxycodone or a salt thereof in a solvent, said solution having a pH less than 6;    b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and    c) contacting the solution with hydrogenation reagents for a period of at least 1 hour;    wherein the step of maintaining is performed in the absence of hydrogenation reagents.    
   
   
       9 . The composition of  claim 8 , wherein the oxycodone or salt thereof comprises oxycodone hydrochloride.  
   
   
       10 . The composition of  claim 8 , wherein the pH is less than 5.  
   
   
       11 . The composition of  claim 8 , wherein the pH is less than 3.  
   
   
       12 . The composition of  claim 8 , wherein the temperature is at least 60° C.  
   
   
       13 . The composition of  claim 8 , wherein the temperature is from about 70° C. to 75° C.  
   
   
       14 . The composition of  claim 8 , wherein the period is at least 3 hours.  
   
   
       15 . The composition of  claim 8 , wherein the period is at least 5 hours.  
   
   
       16 . The composition of  claim 8 , wherein the period is from 5 to 10 hours.  
   
   
       17 . The composition of  claim 8 , wherein the process further comprises after step (c) the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.    
   
   
       18 . The composition of  claim 17 , wherein the oxycodone or salt thereof is oxycodone hydrochloride.  
   
   
       19 . The composition of  claim 17 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.  
   
   
       20 . The composition of  claim 8 , wherein the pH is less than or about 1.  
   
   
       21 . The composition of  claim 17 , wherein the pH is less than or about 1.  
   
   
       22 . The composition of  claim 8 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.  
   
   
       23 . The composition of  claim 8 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.  
   
   
       24 . The composition of  claim 23 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.  
   
   
       25 . The composition of  claim 24 , wherein the process further comprises, after step (c), the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof; 
 wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.  
   
   
   
       26 . The composition of  claim 25 , wherein step (c) is carried out for about 6 hours at a temperature from about 45° C. to 55° C.  
   
   
       27 . The composition of  claim 25 , wherein step (b) is carried out for about 10 hours at a temperature of about 75° C.  
   
   
       28 . The composition of  claim 19 , further comprising, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).  
   
   
       29 . The composition of  claim 8 , wherein the process further comprises, after step (c), the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof; 
 wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.  
   
   
   
       30 . The composition of  claim 29 , wherein step (c) is carried out for about 6 hours at a temperature from about 45° C. to 55° C.  
   
   
       31 . The composition of  claim 29 , wherein step (b) is carried out for about 10 hours at a temperature of about 75° C.  
   
   
       32 . The composition according to  claim 1 , said oxycodone or oxycodone salt being prepared by a process comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of at least 55° C. for at least 1 hour, said solution having a pH less than 6; and    b) subsequently exposing the solution to hydrogenation reagents for a period of at least 1 hour.    
   
   
       33 . The composition of  claim 32 , wherein the solution comprises, after the maintaining step but before the exposing step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.  
   
   
       34 . The composition of  claim 32 , wherein the pH is less than 5.  
   
   
       35 . The composition of  claim 32 , wherein the pH is less than 3.  
   
   
       36 . The composition of  claim 32 , wherein the pH is less than or about 1.  
   
   
       37 . The composition of  claim 32 , wherein the temperature is at least 60° C.  
   
   
       38 . The composition of  claim 32 , wherein the temperature is about 70-75° C.  
   
   
       39 . The composition of  claim 32 , wherein in step a) the period is at least 3 hours.  
   
   
       40 . The composition of  claim 32 , wherein in step a) the period is 5-10 hours.  
   
   
       41 . The composition of claims  32 , wherein step b) is carried out at or above about 40° C.  
   
   
       42 . The composition of  claim 32 , wherein step b) is carried out at a temperature between 40° C. and 70° C.  
   
   
       43 . The composition of  claim 32 , wherein in step b) the period is at least 2 hours.  
   
   
       44 . The composition of  claim 32 , wherein in step b) the period is about 6 hours.  
   
   
       45 . The composition of  claim 32 , wherein in step b) the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.  
   
   
       46 . The composition of  claim 32 , wherein the process further comprises in sequence the subsequent steps of c) stirring the solution in contact with charcoal at a temperature of approximately 60-65° C. for 5-10 hours, d) filtering the solution to remove the charcoal, and e) cooling the solution.  
   
   
       47 . The composition according to  claim 1 , said oxycodone or oxycodone salt being prepared by a process comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of about 75° C. for about 10 hours, said solution having a pH less than 6; and    b) subsequently exposing the solution to hydrogenation reagents at or above about 40° C. for about 6.5 hours.    
   
   
       48 . The composition of  claim 47 , wherein the process further comprises, after step b), a step c) of filtering the solution at a temperature of about 56° C.  
   
   
       49 . The composition of  claim 47 , wherein the pH is less than 5.  
   
   
       50 . The composition of  claim 47 , wherein the pH is less than 3.  
   
   
       51 . The composition of  claim 47 , wherein the pH is less than or about 1.  
   
   
       52 . The composition according to  claim 1 , said oxycodone or oxycodone salt being prepared by a process comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of about 75° C. for about 5 hours, said solution having a pH of about 1; and    b) subsequently exposing the solution to hydrogenation reagents at about 65° C. for about 6 hours.    
   
   
       53 . The composition of  claim 32 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.  
   
   
       54 . The composition of  claim 47 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.  
   
   
       55 . The composition of  claim 52 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.  
   
   
       56 . The composition of  claim 32 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.  
   
   
       57 . The composition of  claim 32 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.  
   
   
       58 . The composition of  claim 57 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.  
   
   
       59 . The composition of  claim 47 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.  
   
   
       60 . The composition of  claim 47 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.  
   
   
       61 . The composition of  claim 60 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.  
   
   
       62 . The composition of  claim 52 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.  
   
   
       63 . The composition of  claim 52 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.  
   
   
       64 . The composition of  claim 63 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.  
   
   
       65 . The composition of  claim 57 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride, the pH is less than or about 1, and the maintaining is performed for at least 5 hours at a temperature from about 70° C. to 75° C.  
   
   
       66 . The composition of  claim 65 , wherein step (b) is performed for about 6 hours from about 45° C. to 55° C.  
   
   
       67 . The composition of  claim 65 , wherein the maintaining is performed for about 10 hours at a temperature of about 75° C.  
   
   
       68 . The composition of  claim 32 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride, the pH is less than or about 1, and the maintaining is performed for at least 5 hours at a temperature from about 70° C. to 75° C.  
   
   
       69 . The composition of  claim 68 , wherein step (b) is performed for about 6 hours from about 45° C. to 55° C.  
   
   
       70 . The composition of  claim 68 , wherein the maintaining is performed for about 10 hours at a temperature of about 75° C.  
   
   
       71 . The composition according to  claim 1 , said oxycodone or oxycodone salt being a purified oxycodone or oxyxodone salt prepared by a process comprising the steps of: 
 a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6;    b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and    c) contacting the solution with hydrogenation reagents for a period of at least 1 hour; and    wherein the solution comprises, after the maintaining step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.    
   
   
       72 . The composition of  claim 71 , wherein the oxycodone or salt thereof comprises oxycodone hydrochloride.  
   
   
       73 . The composition of  claim 71 , wherein the pH is less than 5.  
   
   
       74 . The composition of  claim 71 , wherein the pH is less than 3.  
   
   
       75 . The composition of  claim 71 , wherein the temperature is at least 60° C.  
   
   
       76 . The composition of  claim 71 , wherein the temperature is from about 70° C. to 75° C.  
   
   
       77 . The composition of  claim 71 , wherein the period is at least 5 hours.  
   
   
       78 . The composition of  claim 71 , wherein the period is from 5 to 10 hours.  
   
   
       79 . The composition of  claim 71 , wherein the step of maintaining is performed in the absence of hydrogenation reagents.  
   
   
       80 . The composition of  claim 71 , wherein the process further comprises after step (c) the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.    
   
   
       81 . The composition of  claim 80 , wherein the oxycodone or salt thereof is oxycodone hydrochloride.  
   
   
       82 . The composition of  claim 80 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.  
   
   
       83 . The composition of  claim 80 , wherein the pH is less than or about 1.  
   
   
       84 . The composition of  claim 71 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.  
   
   
       85 . The composition of  claim 71 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.  
   
   
       86 . The composition of  claim 85 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.  
   
   
       87 . The composition of  claim 85 , wherein the process further comprises, after step (c), the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;    wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.    
   
   
       88 . The composition of  claim 87 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.  
   
   
       89 . The composition of  claim 87 , wherein step (b) is performed at about 75° C. for about 10 hours.  
   
   
       90 . The composition of  claim 71 , wherein the process further comprises, after step (c), the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;    wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.    
   
   
       91 . The composition of  claim 90 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.  
   
   
       92 . The composition of  claim 90 , wherein step (b) is performed at about 75° C. for about 10 hours.  
   
   
       93 . The composition of  claim 80 , further comprising, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).  
   
   
       94 . A pharmaceutical product comprising a composition comprising oxycodone or an oxycodone salt, said oxycodone or oxycodone salt containing less than 15 ppm of 14-hydroxycodeinone.  
   
   
       95 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt contains less than 10 ppm of 14-hydroxycodeinone.  
   
   
       96 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt contains less than 5 ppm of 14-hydroxycodeinone.  
   
   
       97 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt contains less than 2 ppm of 14-hydroxycodeinone.  
   
   
       98 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt contains about 0 ppm of 14-hydroxycodeinone.  
   
   
       99 . The pharmaceutical product of  claim 94 , having less than 20 ppm of heavy metal content.  
   
   
       100 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride.  
   
   
       101 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt is prepared by a process comprising the steps of: 
 a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6;    b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and    c) contacting the solution with hydrogenation reagents for a period of at least 1 hour;    wherein the step of maintaining is performed in the absence of hydrogenation reagents.    
   
   
       102 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt is prepared by a process comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of at least 55° C. for at least 1 hour, said solution having a pH less than 6; and    b) subsequently exposing the solution to hydrogenation reagents for a period of at least 1 hour.    
   
   
       103 . The pharmaceutical product of  claim 94 , wherein the oxycodone or oxycodone salt is a purified oxycodone or oxycodone salt prepared by a process comprising the steps of: 
 a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6;    b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and    c) contacting the solution with hydrogenation reagents for a period of at least 1 hour;    wherein the solution comprises, after the maintaining step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.    
   
   
       104 . The pharmaceutical product of  claim 103 , wherein the process further comprises after step (c) the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.    
   
   
       105 . The pharmaceutical product of  claim 104 , wherein the oxycodone or salt thereof is oxycodone hydrochloride.  
   
   
       106 . The pharmaceutical product of  claim 104 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.  
   
   
       107 . The pharmaceutical product of  claim 104 , wherein the pH is less than or about 1.  
   
   
       108 . The pharmaceutical product of  claim 103 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.  
   
   
       109 . The pharmaceutical product of  claim 103 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.  
   
   
       110 . The pharmaceutical product of  claim 109 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.  
   
   
       111 . The pharmaceutical product of  claim 109 , wherein the process further comprises after step (c) the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;    wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.    
   
   
       112 . The pharmaceutical product of  claim 111 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.  
   
   
       113 . The pharmaceutical product of  claim 111 , wherein step (b) is performed at about 75° C. for about 10 hours.  
   
   
       114 . The pharmaceutical product of  claim 103 , wherein the process further comprises after step (c) the step of: 
 d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;    wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.    
   
   
       115 . The pharmaceutical product of  claim 114 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.  
   
   
       116 . The pharmaceutical product of  claim 114 , wherein step (b) is performed at about 75° C. for about 10 hours.  
   
   
       117 . The pharmaceutical product of  claim 114 , wherein the process further comprises, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).