Acetate salt of buprenorphine and methods for preparing buprenorphine

Abstract

The present disclosure provides acetate salts of buprenorphine, and its anhydrates, solvates, hydrates, and crystalline forms thereof, where the acetate salts of buprenorphine are essentially free of impurities. The disclosure further provides method of preparing the acetate salts, buprenorphine free base prepared from the acetate salts, other salts prepared from the free base, and pharmaceutical compositions thereof essentially free of impurities.

What is claimed: 
     
         1 . An acetate salt of buprenorphine. 
     
     
         2 . The acetate salt of buprenorphine of  claim 1 , comprising a hydrate. 
     
     
         3 . The acetate salt of buprenorphine of  claim 2 , wherein the hydrate comprises from 1 to 6 water molecules per molecule of the acetate salt of buprenorphine. 
     
     
         4 . The acetate salt of buprenorphine of  claim 3 , wherein the hydrate is a tetrahydrate. 
     
     
         5 . A purified acetate salt of buprenorphine of any one of  claims 1  to  4 . 
     
     
         6 . The purified acetate salt of buprenorphine of  claim 5 , which is an essentially pure acetate salt of buprenorphine. 
     
     
         7 . A crystalline form of the acetate salt of buprenorphine of any one of  claims 1  to  6 . 
     
     
         8 . A crystalline form of the acetate salt of buprenorphine of  claim 4 . 
     
     
         9 . The crystalline form of  claim 8 , characterized by an X-ray powder diffraction pattern obtained by exposure to CuKα radiation comprising peaks at 2θ angles substantially equivalent to at least the peaks at 16.21 and 18.70, and having at least one additional peak at a 2θ angle substantially equivalent to at least one of the peaks at 8.77, 10.31, or 18.47. 
     
     
         10 . The crystalline form of  claim 8 , characterized by an X-ray powder diffraction pattern obtained by exposure to CuKα radiation comprising peaks at 2θ angles substantially equivalent to at least the peaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and having at least one additional peak at a 2θ angle substantially equivalent to at least one of the peaks at 6.38, 11.93, or 19.40. 
     
     
         11 . The crystalline form of  claim 8 , characterized by an X-ray powder diffraction pattern obtained by exposure to CuKα radiation comprising peaks at diffraction angles substantially equivalent to at least the peaks at those in the following table: 
       
         
           
                 
               
                     
                 
                   Position [°2Theta] 
                 
                     
                 
                    6.38 
                 
                    8.77 
                 
                   10.31 
                 
                   11.93 
                 
                   16.21 
                 
                   18.47 
                 
                   18.70 
                 
                   19.40 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . The crystalline form of  claim 8 , which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in  FIG. 4  when measuring using CuKα radiation. 
     
     
         13 . The crystalline form of any one of  claims 8  to  12 , wherein the crystalline form exhibits a first transition region with at least one peak position at from about 50° C. to about 140° C. as measured by a heat flow differential scanning calorimeter at a heating rate of about 10° C. per minute. 
     
     
         14 . The crystalline form of any one of  claims 8  to  13 , wherein the crystalline form exhibits a second transition region having a peak position at from about 217° C. to about 225° C. as measured by a heat flow differential scanning calorimeter at a heating rate of about 10° C. per minute. 
     
     
         15 . The crystalline form of  claim 14 , which exhibits an integral ratio of from about 7 to about 8 for the first transition region at from about 50° C. to about 140° C. relative to the second transition region at from about 217° C. to about 225° C., wherein the integrals are determined over the temperature ranges of from about 35° C. to about 180° C. and from about 203° C. to about 233° C., respectively. 
     
     
         16 . The crystalline form of  claim 15 , wherein the crystalline form exhibits an integral ratio of from about 7.1 to about 7.8. 
     
     
         17 . The crystalline form of any one of  claims 8  to  16 , characterized in that it is a monoclinic crystal. 
     
     
         18 . The crystalline form of  claim 17 , wherein the unit cell parameters are a=10.5±0.5 Å, b=10.9±0.5 Å, and c=14.4±0.5 Å. 
     
     
         19 . The crystalline form of  claim 17 , wherein the unit cell parameters are a=10.52±0.05 Å, b=10.92±0.05 Å, and c=14.44±0.05 Å. 
     
     
         20 . The crystalline form of any one of  claims 17  to  19 , wherein the space group is P2 1 . 
     
     
         21 . A pharmaceutical composition comprising the acetate salt of buprenorphine of any one of  claims 1  to  6  or the crystalline form of any of  claims 7  to  20 , and a pharmaceutically acceptable carrier. 
     
     
         22 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the acetate salt of buprenorphine of any one of  claims 1  to  6 , the crystalline form of any of  claims 7  to  20  or a pharmaceutical composition of  claim 21 . 
     
     
         23 . A method for preparing an acetate salt of buprenorphine, comprising the steps of:
 (a) contacting buprenorphine free base with a solution comprising acetic acid in a dissolution vessel to form an admixture, wherein the admixture is at a temperature of from about 40° C. to about 80° C.;   (b) optionally filtering the admixture of step (a);   (c) adding an agent to the admixture produced in step (a) or (b) to precipitate the acetate salt of buprenorphine; and   (d) isolating the acetate salt of buprenorphine precipitated in step (c).   
     
     
         24 . The method of  claim 23 , wherein in step (a) the buprenorphine free base is contacted with from about 2 mass equivalents to about 6 mass equivalents of the solution comprising acetic acid relative to the starting mass of the free base. 
     
     
         25 . The method of  claim 23 , wherein the buprenorphine free base is contacted with from about 3 mass equivalents to about 5 mass equivalents of the solution comprising acetic acid relative to the starting mass of the free base. 
     
     
         26 . The method of any one of  claims 23  to  25 , wherein the solution comprising acetic acid is an aqueous solution. 
     
     
         27 . The method of  claim 26 , wherein the aqueous solution has from about 40 wt % to about 70 wt % acetic acid relative to the weight of the aqueous solution. 
     
     
         28 . The method of  claim 26 , wherein the aqueous solution has from about 45 wt % to about 60 wt % acetic acid relative to the weight of the aqueous solution. 
     
     
         29 . The method of any one of  claims 23  to  28 , wherein in step (a) the admixture is at a temperature of from about 40° C. to about 80° C. for a period of time such that a substantial portion of the buprenorphine free base has dissolved. 
     
     
         30 . The method of  claim 29 , wherein in step (a) the admixture is at a temperature of from about 45° C. to about 75° C. for a period of time such that a substantial portion of the buprenorphine free base has dissolved. 
     
     
         31 . The method of  claim 29 , wherein in step (a) the admixture is at a temperature of from about 50° C. to about 70° C. for a period of time such that a substantial portion of the buprenorphine free base has dissolved. 
     
     
         32 . The method of any one of  claims 23  to  31 , wherein in step (a) the admixture is agitated to accelerate dissolution of the buprenorphine free base. 
     
     
         33 . The method of  claim 23 , wherein the admixture of step (a) is filtered in step (b) in a filtration apparatus. 
     
     
         34 . The method of  claim 33 , wherein in step (b), the admixture of step (a) added to the filtration apparatus is at a temperature of from about 40° C. to about 80° C. 
     
     
         35 . The method of  claim 33 , wherein in step (b), the admixture of step (a) added to the filtration apparatus is at a temperature of from about 45° C. to about 75° C. 
     
     
         36 . The method of any one of  claims 33  to  35 , wherein an additional volume of a solution comprising acetic acid is used to rinse the dissolution vessel, the filtration apparatus or the dissolution vessel and the filtration apparatus. 
     
     
         37 . The method of  claim 36 , wherein the additional volume of the solution comprising acetic acid is from about 0.1 mass equivalents to about 2.0 mass equivalents relative to the starting mass of the buprenorphine free base in step (a). 
     
     
         38 . The method of  claim 36 , wherein the additional volume of the solution comprising acetic acid is from about 0.3 mass equivalents to about 0.5 mass equivalents relative to the starting mass of the buprenorphine free base in step (a). 
     
     
         39 . The method of any one of  claims 36  to  38 , wherein the additional volume of the solution is acetic acid in an aqueous solution. 
     
     
         40 . The method of  claim 39 , wherein the additional volume of the solution comprising acidic acid is an aqueous solution comprising acetic acid present at from about 40 wt % to about 70 wt % relative to the weight of the solution. 
     
     
         41 . The method of any one of  claims 23  to  40 , wherein in step (c) the agent is selected from an anti-solvent, a seed crystal, and combinations thereof. 
     
     
         42 . The method of  claim 41 , wherein the agent comprises an anti-solvent. 
     
     
         43 . The method of  claim 42 , wherein the anti-solvent comprises water. 
     
     
         44 . The method of  claim 42  or  43 , wherein from about 0.2 mass equivalents to about 8.0 mass equivalents of anti-solvent relative to the starting mass of free base in step (a) are added to the admixture of step (a) or (b). 
     
     
         45 . The method of any one of  claims 42  to  44 , wherein the anti-solvent is added at within about 10° C. of the temperature of the admixture of step (a) or step (b). 
     
     
         46 . The method of  claim 45 , wherein the anti-solvent is added at a temperature within about 5° C. of the temperature of the admixture of step (a) or step (b). 
     
     
         47 . The method of  claim 41 , wherein the agent comprises a seed crystal. 
     
     
         48 . The method of  claim 47 , wherein the seed crystal comprises an acetate salt of buprenorphine. 
     
     
         49 . The method of  claim 48 , wherein from about 0.1 wt % to about 5.0 wt % of seed crystal is added to the admixture of step (a) or (b) relative to the starting mass of the buprenorphine free base in step (a). 
     
     
         50 . The method of any one of  claims 47  to  49 , wherein the admixture of step (a) or (b) is at a temperature of from about 40° C. to about 80° C. when the seed crystal is added. 
     
     
         51 . The method of  claim 50 , wherein the admixture of step (a) or (b) is at a temperature of from about 55° C. to about 65° C. when the seed crystal is added. 
     
     
         52 . The method of  claim 41 , wherein a first amount of the anti-solvent is added followed by addition of the seed crystal. 
     
     
         53 . The method of  claim 52 , wherein the addition of the seed crystal is followed by the addition of a second amount of the anti-solvent. 
     
     
         54 . The method of  claim 52  or  53 , wherein the first amount of the anti-solvent is from about 0.2 mass equivalents to about 2.0 mass equivalents relative to the starting mass of the buprenorphine free base in step (a). 
     
     
         55 . The method of any one of  claims 52  to  54 , wherein from about 0.1 wt % to about 5.0 wt % of the seed crystal is added relative to the starting mass of the buprenorphine free base in step (a). 
     
     
         56 . The method of any one of  claims 53  to  55 , wherein the second amount of anti-solvent is from about 1.0 mass equivalent to about 6.5 mass equivalents relative to the starting mass of the buprenorphine free base in step (a). 
     
     
         57 . The method of any one of  claims 23  to  56 , further comprising cooling the admixture to a temperature of about 30° C. or lower following addition of the agent and prior to isolating the acetate salt of buprenorphine in step (d). 
     
     
         58 . The method of any one of  claims 23  to  56 , further comprising adding a co-solvent to the admixture following the precipitation of step (c) and prior to the isolating of the acetate salt of buprenorphine in step (d). 
     
     
         59 . The method of  claim 58 , wherein the co-solvent is selected from methanol, ethanol, isopropyl alcohol, and combinations thereof. 
     
     
         60 . The method of  claim 58 , wherein the co-solvent is isopropyl alcohol. 
     
     
         61 . The method of any one of  claims 58  to  60 , further comprising cooling the admixture to a temperature of about 30° C. or lower following addition of the co-solvent and prior to the isolating of the acetate salt of buprenorphine in step (d). 
     
     
         62 . The method of any one of  claims 23  to  61 , wherein the isolation in step (d) is accomplished by filtration. 
     
     
         63 . The method of any one of  claims 23  to  62 , further comprising slurrying the acetate salt of buprenorphine obtained from the isolation of step (d) with a slurrying solution comprising water and an alcohol, and filtering the acetate salt therefrom. 
     
     
         64 . A buprenorphine acetate salt product obtained from the method of any one of  claims 23  to  63 . 
     
     
         65 . The product of  claim 64 , wherein the product comprises about 0.10 wt % or less of a compound of formula (10): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         66 . The product of  claim 64  or  65 , wherein the product comprises about 0.10 wt % or less of a compound of formula (11): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         67 . The product of any one of  claims 64  to  66 , wherein the product comprises about 0.10 wt % or less of a compound of formula (12): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         68 . The product of  claim 67 , wherein the product comprises about 0.08 wt % or less of the impurity represented by the Compound of formula (12) or a salt thereof. 
     
     
         69 . The product of any one of  claims 64  to  68 , wherein the product comprises about 0.10 wt % or less of a compound of formula (14): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         70 . The product of any one of  claims 64  to  69 , wherein the product comprises about 0.10 wt % or less of a compound of formula (13): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         71 . The product of any one of  claims 64  to  70 , wherein the product comprises about 0.10 wt % or less of a compound of formula (15): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         72 . A pharmaceutical composition comprising the product of any one of  claims 64  to  71  and a pharmaceutically acceptable carrier. 
     
     
         73 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the product of any one of  claims 64  to  71 . 
     
     
         74 . A method for preparing buprenorphine free base comprising the steps of:
 (a) contacting an acetate salt of buprenorphine with a solution and a basic material to form an admixture;   (b) agitating the admixture of step (a) at a temperature of from about 20° C. to about 90° C. to provide buprenorphine free base;   (c) isolating the buprenorphine free base of step (b); and   (d) optionally repeating steps (a) through (c) one or more times.   
     
     
         75 . The method of  claim 74 , wherein in step (a), the acetate salt of buprenorphine is contacted with at least about 1 mass equivalent of the solution relative to the starting mass of the acetate salt in step (a). 
     
     
         76 . The method of  claim 74  or  75 , wherein the solution of step (a) comprises water and an alcohol. 
     
     
         77 . The method of  claim 76 , wherein the solution comprises from about 30 wt % to about 70 wt % alcohol in water. 
     
     
         78 . The method of  claim 76 , wherein the solution comprises from about 40 wt % to about 60 wt % alcohol in water. 
     
     
         79 . The method of any one of  claims 76  to  78 , wherein the alcohol is selected from methanol, ethanol, isopropyl alcohol, and combinations thereof. 
     
     
         80 . The method of  claim 79 , wherein the alcohol is isopropyl alcohol. 
     
     
         81 . The method of  claim 74 , wherein the basic material is selected from a hydroxide, carbonate, alkoxide, hydride, phosphate, borate, oxide, cyanide, silicate, amine, and combinations thereof. 
     
     
         82 . The method of  claim 74 , wherein the acetate salt of buprenorphine is contacted with from about 0.5 molar equivalents to about 20 molar equivalents of basic material relative to starting moles of the acetate salt of buprenorphine in step (a). 
     
     
         83 . The method of  claim 82 , wherein the acetate salt of buprenorphine is contacted with from about 1 molar equivalent to about 10 molar equivalents of basic material relative to the starting moles of acetate salt of buprenorphine in step (a). 
     
     
         84 . The method of any one of  claims 74  to  83 , wherein the admixture of step (a) is agitated in step (b) for from about 1 hour to about 36 hours. 
     
     
         85 . The method of  claim 84 , wherein agitating step (b) takes from about 2 hours to about 8 hours. 
     
     
         86 . The method of  claim 84  or  85 , wherein in step (b) the admixture is agitated at a temperature of from about 25° C. to about 90° C. 
     
     
         87 . The method of  claim 86 , wherein in step (b) the admixture is agitated at a temperature of from about 30° C. to about 45° C. 
     
     
         88 . The method of any one of  claims 74  to  87 , wherein the isolating in step (c) is accomplished by filtration. 
     
     
         89 . The method of any one of  claims 74  to  88 , further comprising a step of slurrying the buprenorphine free base of step (c) with a slurrying solution comprising water and an alcohol, and filtering the free base therefrom. 
     
     
         90 . A buprenorphine free base product obtained from the method of any one of  claims 74  to  89 . 
     
     
         91 . The product of  claim 90 , wherein the product comprises about 0.10 wt % or less of a compound of formula (10): 
       
         
           
           
               
               
           
         
       
     
     
         92 . The product of  claim 90  or  91 , wherein the product comprises about 0.10 wt % or less of a compound of formula (11): 
       
         
           
           
               
               
           
         
       
     
     
         93 . The product of any one of  claims 90  to  92 , wherein the product comprises about 0.10 wt % or less of a compound of formula (12): 
       
         
           
           
               
               
           
         
       
     
     
         94 . The product of  claim 93 , wherein the product comprises about 0.08 wt % or less of the impurity represented by the compound of formula (12). 
     
     
         95 . The product of any one of  claims 90  to  94 , wherein the product comprises about 0.10 wt % or less of a compound of formula (14): 
       
         
           
           
               
               
           
         
       
     
     
         96 . The product of any one of  claims 90  to  95 , wherein the product comprises about 0.10 wt % or less of a compound of formula (13): 
       
         
           
           
               
               
           
         
       
     
     
         97 . The product of any one of  claims 90  to  96 , wherein the product comprises about 0.10 wt % or less of a compound of formula (15): 
       
         
           
           
               
               
           
         
       
     
     
         98 . A pharmaceutical composition comprising the product of any one of  claims 90  to  97  and a pharmaceutically acceptable carrier. 
     
     
         99 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the product of any one of  claims 90  to  97  or a pharmaceutical composition of  claim 98 . 
     
     
         100 . A method for preparing buprenorphine free base, comprising treating an acetate salt of buprenorphine at a pressure, temperature and for a time sufficient to remove the acetic acid. 
     
     
         101 . The method of  claim 100 , wherein the pressure is a sub-atmospheric pressure of from about 100 Torr to about 200 Torr. 
     
     
         102 . The method of  claim 101 , wherein the temperature is at least about 30° C. and the time is at least about 1 hour. 
     
     
         103 . The method of  claim 102 , wherein the temperature is at least about 50° C. 
     
     
         104 . The method of  claim 102 , wherein the temperature is at least about 65° C. 
     
     
         105 . The method of any one of  claims 100  to  104 , wherein the treatment lasts at least about 5 hours. 
     
     
         106 . The method of  claim 105 , wherein the treatment lasts at least about 10 hours. 
     
     
         107 . The method of any one of  claims 100  to  106 , further comprising slurrying the buprenorphine free base with a slurrying solution comprising water and an alcohol, and filtering the free base therefrom. 
     
     
         108 . The method of  claim 100 , wherein the pressure is an atmospheric pressure of from about 620 Torr to about 780 Torr. 
     
     
         109 . The method of  claim 108 , wherein the temperature is from about 65° C. to about 100° C. 
     
     
         110 . The method of  claim 108  or  109 , wherein the treatment lasts at least about 7 hours. 
     
     
         111 . The method of any one of  claims 108  to  110 , wherein the treatment lasts long enough to form essentially pure buprenorphine free base. 
     
     
         112 . The method of any one of  claims 100  to  111 , wherein acetic acid in the final buprenorphine free base product is present at less than about 0.5 wt %. 
     
     
         113 . A buprenorphine free base product obtained from the method of any one of  claims 100  to  112 . 
     
     
         114 . A pharmaceutical composition comprising the product of  claim 113  and a pharmaceutically acceptable carrier. 
     
     
         115 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the product of  claim 113 . 
     
     
         116 . A method for preparing buprenorphine free base, comprising the steps of:
 (a) dissolving an acetate salt of buprenorphine in a solution to form an admixture;   (b) optionally filtering the admixture of step (a);   (c) adding a basic material to the admixture in step (a) or (b) to form a second admixture;   (d) adding an anti-solvent to the second admixture produced in step (c) to form a precipitate of the buprenorphine free base; and   (e) isolating the precipitate from step (d).   
     
     
         117 . The method of  claim 116 , wherein the solution of step (a) comprises an organic solvent. 
     
     
         118 . The method of  claim 117 , wherein the organic solvent comprises an alcohol. 
     
     
         119 . The method of  claim 118 , wherein the organic solvent comprises an alcohol selected from the group consisting of methanol, ethanol, and isopropyl alcohol. 
     
     
         120 . The method of any one of  claims 116  to  119 , wherein the anti-solvent of step (d) comprises an aqueous solution. 
     
     
         121 . The method of any one of  claims 116  to  120 , wherein the acetate salt of buprenorphine is contacted with at least about 3 mass equivalents of the solution relative to the starting mass of the acetate salt of buprenorphine in step (a). 
     
     
         122 . The method of any one of  claims 116  to  121 , further comprising mixing the admixture of step (a) at a temperature of about 20° C. to about 90° C. such that substantially all the acetate salt of buprenorphine is dissolved. 
     
     
         123 . The method of  claim 122 , wherein in step (a) the admixture is at a temperature of at least about 40° C. 
     
     
         124 . The method of  claim 122 , wherein in step (a) the admixture is at a temperature of at least about 50° C. 
     
     
         125 . The method of any one of  claims 116  to  124 , wherein the admixture of step (a) is filtered in step (b). 
     
     
         126 . The method of any one of  claims 116  to  125 , wherein in step (c), from about 1.0 molar equivalent to about 20 molar equivalents of basic material relative to the starting number of moles of acetate salt of buprenorphine in step (a) are added to the admixture produced in step (a) or (b). 
     
     
         127 . The method of any one of  claims 116  to  126 , wherein in step (d), at least about 3 mass equivalents of the anti-solvent relative to the starting mass of the acetate salt of buprenorphine in step (a) are added to the second admixture produced in step (c). 
     
     
         128 . The method of any one of  claims 116  to  127 , wherein the isolating in step (e) is accomplished by filtration. 
     
     
         129 . The method of any one of  claims 116  to  128 , further comprising slurrying the free base obtained from the isolation of step (c) with a slurrying solution comprising water and an alcohol, and filtering the free base therefrom. 
     
     
         130 . A buprenorphine free base product obtained from the method of any one of  claims 116  to  129 . 
     
     
         131 . The product of  claim 130 , wherein the product comprises about 0.10 wt % or less of a compound of formula (10): 
       
         
           
           
               
               
           
         
       
     
     
         132 . The product of  claim 130  or  131 , wherein the product comprises about 0.10 wt % or less of a compound of formula (11): 
       
         
           
           
               
               
           
         
       
     
     
         133 . The product of any one of  claims 130  to  132 , wherein the product comprises about 0.10 wt % or less of a compound of formula (12): 
       
         
           
           
               
               
           
         
       
     
     
         134 . The product of  claim 133 , wherein the product comprises about 0.08 wt % or less of the compound of formula (12). 
     
     
         135 . The product of any one of  claims 130  to  134 , wherein the product comprises about 0.10 wt % or less of a compound of formula (14): 
       
         
           
           
               
               
           
         
       
     
     
         136 . The product of any one of  claims 130  to  135 , wherein the product comprises about 0.10 wt % or less of a compound of formula (13): 
       
         
           
           
               
               
           
         
       
     
     
         137 . The product of any one of  claims 130  to  136 , wherein the product comprises about 0.10 wt % or less of a compound of formula (15): 
       
         
           
           
               
               
           
         
       
     
     
         138 . A pharmaceutical composition comprising the product of any one of  claims 130  to  137  and a pharmaceutically acceptable carrier. 
     
     
         139 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the product of any one of  claims 130  to  137 . 
     
     
         140 . A method for preparing buprenorphine free base comprising:
 (a) heating an admixture of an acetate salt of buprenorphine and an aqueous solution to provide precipitated buprenorphine free base; and   (b) filtering the admixture of step (a).   
     
     
         141 . The method of  claim 140 , wherein the aqueous solution consists essentially of water. 
     
     
         142 . The method of  claim 140 , wherein the aqueous solution comprises a mixture of water and an alcohol. 
     
     
         143 . The method of  claim 142 , wherein the alcohol is isopropyl alcohol. 
     
     
         144 . The method of any one of  claims 140  to  143 , wherein the heating is to a temperature of from about 70° C. to about 90° C. 
     
     
         145 . The method of  claim 140  or  141 , further comprising washing the solid filtered product of step (b) with a second aqueous solution. 
     
     
         146 . The method of any one of  claims 140  to  145 , further comprising the step of drying the solid filtered product of step (b). 
     
     
         147 . A buprenorphine free base product obtained from the method of any one of  claims 140  to  146 . 
     
     
         148 . A pharmaceutical composition comprising the product of  claim 147  and a pharmaceutically acceptable carrier. 
     
     
         149 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the product of  claim 147 . 
     
     
         150 . A method for preparing buprenorphine free base: comprising:
 (a) mixing an acetate salt of buprenorphine in a solvent to form an admixture;   (b) refluxing the admixture at a reflux temperature and removing the acetate as acetic acid in the vapor phase;   (c) cooling the admixture to provide precipitated buprenorphine free base; and   (d) isolating the buprenorphine free base.   
     
     
         151 . The method of  claim 150 , wherein the isolating of step (d) comprises filtering the precipitated buprenorphine free base of step (c). 
     
     
         152 . The method of  claim 150  or  151 , wherein the solvent comprises an organic solvent. 
     
     
         153 . The method of  claim 152 , wherein the organic solvent comprises heptane. 
     
     
         154 . A buprenorphine free base product obtained from the method of any one of  claims 150  to  153 . 
     
     
         155 . A pharmaceutical composition comprising the product of  claim 154  and a pharmaceutically acceptable carrier. 
     
     
         156 . A method for treating pain comprising administering to an animal in need thereof an effective amount of the product of  claim 154 . 
     
     
         157 . Use of a product of any one of  claims 64  to  71 ,  90  to  97 ,  113 ,  130  to  137 ,  147  and  154  or the pharmaceutical composition of any one of  claims 72 ,  98 ,  114 ,  138 ,  148  and  155  in the manufacture of a medicament for the treatment of pain. 
     
     
         158 . Product of any one of  claims 64  to  71 ,  90  to  97 ,  113 ,  130  to  137 , and  154  or the pharmaceutical composition of any one of  claims 72 ,  98 ,  114 ,  138  and  155  for use in the treatment of pain. 
     
     
         159 . Use of an acetate salt of buprenorphine of any one of  claim 1  to  6  or the crystalline form of an acetate salt of buprenorphine of any one of  claims 7  to  20  in the manufacture of a medicament for the treatment of pain. 
     
     
         160 . An acetate salt of buprenorphine of any one of  claim 1  to  6  or the crystalline form of an acetate salt of buprenorphine of any one of  claims 7  to  20  for use in the treatment of pain.