Process for preparing a crystalline form of halobetasol propionate

Abstract

The present invention provides a process for preparing a crystalline form of halobetasol propionate, comprising the step of crystallizing halobetasol propionate from absolute ethanol or a mixture of ethanol and water, wherein the crystalline form of halobetasol propionate is characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.

1 . A process for preparing a crystalline form of halobetasol propionate, comprising the step of crystallizing halobetasol propionate from absolute ethanol or a mixture of ethanol and water, wherein the crystalline form of halobetasol propionate is characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.  
   
   
       2 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate is further characterized by an infrared spectrum having absorption peaks at 1741, 1709, 1665, 1627, and 1611±4 cm −1 .  
   
   
       3 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate is further characterized by a melting point of about 220° C. to about 221° C.  
   
   
       4 . The process of  claim 1 , wherein the ethanol and water is present in the mixture at a vol/vol ratio of about 50:50 to about 100:0.  
   
   
       5 . The process of  claim 1 , wherein the ethanol and water is present in the mixture at a vol/vol ratio of about 50:50 to about 67:33.  
   
   
       6 . The process of  claim 1 , wherein the ethanol and water is present in the mixture at a vol/vol ratio of about 50:50.  
   
   
       7 . The process of  claim 1 , wherein the crystallizing step is performed by a process comprising the steps of: 
 (a) preparing a solution of halobetasol propionate in absolute ethanol or a mixture of ethanol and water; and    (b) inducing precipitation of a crystalline form of halobetasol propionate.    
   
   
       8 . The process of  claim 7 , wherein step (a) is performed by heating the solution of halobetasol propionate to an elevated temperature.  
   
   
       9 . The process of  claim 8 , wherein the elevated temperature is between about 60° C. to about 80° C.  
   
   
       10 . The process of  claim 7 , wherein step (b) is performed by cooling the prepared solution.  
   
   
       11 . The process of  claim 7 , wherein step (b) is performed by cooling the prepared solution to a temperature of about 0° C. to about 25° C.  
   
   
       12 . The process of  claim 7 , wherein step (b) is performed by adding water to the prepared solution.  
   
   
       13 . The process of  claim 7 , wherein step (b) is performed by adding water to the prepared solution over the course of about 30 minutes to about 90 minutes.  
   
   
       14 . The process of  claim 1 , further comprising the step of isolating the crystallized halobetasol propionate from the mixture of ethanol and water.  
   
   
       15 . The process of  claim 14 , wherein the isolating step is performed by filtration.  
   
   
       16 . The process of  claim 1 , wherein the crystallizing step is repeated at least once.  
   
   
       17 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate has a purity of at least about 99.0% (w/w).  
   
   
       18 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate has a purity of at least about 99.8% (w/w).  
   
   
       19 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate contains about 0.1% (w/w) or less of each individual impurity.  
   
   
       20 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate contains about 0.02% (w/w) or less of diflorasone.  
   
   
       21 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate contains about 0.02% (w/w) or less of halobetasol.  
   
   
       22 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate contains about 0.03% (w/w) or less of diflorasone 21-propionate.  
   
   
       23 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate contains about 0.03% (w/w) or less of diflorasone 17-propionate 21-mesylate.  
   
   
       24 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate contains about 0.05% (w/w) or less of 6α,9α-difluoro-10-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].  
   
   
       25 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate is prepared as a single batch of at least about 100 grams.  
   
   
       26 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate is prepared as a single batch of at least about 500 grams.  
   
   
       27 . The process of  claim 1 , wherein the crystalline form of halobetasol propionate is prepared as a single batch of at least about one kilogram.  
   
   
       28 . A process for preparing a crystalline form of halobetasol propionate, comprising the steps of: 
 (a) crystallizing halobetasol propionate from a first ethanol;    (b) isolating the crystallized halobetasol propionate from the first ethanol;    (c) crystallizing the isolated halobetasol propionate from a second ethanol; and    (d) isolating the crystallized halobetasol propionate from the second ethanol, wherein the crystalline form of halobetasol propionate is characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.    
   
   
       29 . The process of  claim 28 , wherein the first ethanol further comprises water.  
   
   
       30 . The process of  claim 29 , wherein the first ethanol and water is present at a vol/vol ratio of about 1:1  
   
   
       31 . The process of  claim 28 , wherein the second ethanol further comprises water.  
   
   
       32 . The process of  claim 31 , wherein the second ethanol and water is present at a vol/vol ratio of about 2:1.  
   
   
       33 . The process of  claim 28 , wherein the crystalline form of halobetasol propionate has a purity of at least about 99.0% (w/w).  
   
   
       34 . The process of  claim 28 , wherein the crystalline form of halobetasol propionate has a purity of at least about 99.8% (w/w).  
   
   
       35 . The process of  claim 28 , wherein the crystalline form of halobetasol propionate contains about 0.1% (w/w) or less of each individual impurity.  
   
   
       36 . A commercial scale composition of a crystalline form of halobetasol propionate prepared by the process of  claim 1 .  
   
   
       37 . A commercial scale composition of a crystalline form of halobetasol propionate characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ, wherein the composition contains about 0.1% or less of each of diflorasone, diflorasone 17-propionate, halobetasol, diflorasone 21-propionate, diflorasone 17-propionate 21-mesylate, and 6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].  
   
   
       38 . The commercial scale composition of  claim 37 , wherein the composition contains about 0.1% (w/w) or less of each impurity present in the composition.  
   
   
       39 . The commercial scale composition of  claim 37 , wherein the composition contains about 0.05% (w/w) or less of each of diflorasone, halobetasol, diflorasone 21-propionate, diflorasone 17-propionate 21-mesylate, and 6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].  
   
   
       40 . The commercial scale composition of  claim 37 , wherein the composition contains about 0.03% (w/w) or less of each of diflorasone, halobetasol, diflorasone 21-propionate, and diflorasone 17-propionate 21-mesylate.  
   
   
       41 . The commercial scale composition of  claim 37 , wherein the composition contains about 0.02% (w/w) or less of each of diflorasone and halobetasol.  
   
   
       42 . The commercial scale composition of  claim 37 , wherein the commercial scale composition has a purity of at least about 99.5% (w/w).  
   
   
       43 . The commercial scale composition of  claim 42 , wherein the commercial scale composition has a purity of at least about 99.8% (w/w).  
   
   
       44 . The commercial scale composition of  claim 37 , wherein the composition is produced as a single batch of at least about 500 grams.  
   
   
       45 . The commercial scale composition of  claim 44 , wherein the composition is produced as a single batch of at least about one kilogram.