Process for the preparation of fluticasone propionate form i

Abstract

The invention relates to a novel crystallisation process for preparing fluticasone propionate as crystalline form 1 polymorph with controlled particle size and suitable for micronisation. Said process comprises the step of dissolving fluticasone propionate in acetone or in a mixture of acetone and water and then adding this solution to water or to a mixture of water 10 and acetone, thereby causing fluticasone propionate to crystallise out of the solution as crystalline form.

1 . A process for preparing fluticasone propionate as crystalline polymorphic form 1, the process comprising: dissolving fluticasone propionate in a solvent to form a solution, and then adding the solution to a non-solvent, thereby causing fluticasone propionate to crystallise out of the solution as crystalline form 1;
 wherein the solvent comprises acetone and from 0% to 10% water, based on the volume of the solvent; and   wherein the non-solvent comprises water and from 0% to 35% acetone, based on the volume of the non-solvent.   
     
     
         2 . A process according to  claim 1 , wherein fluticasone propionate is dissolved in the solvent in an amount between 30 and 50 grams per litre of solvent. 
     
     
         3 . A process according to  claim 1 , wherein fluticasone propionate is dissolved in a first defined volume of the solvent to form a solution, and the solution is then added to a second defined volume of the non-solvent;
 a ratio of the first defined volume to the second defined volume being between 1:0.65 and 1:1.35.   
     
     
         4 . A process according to  claim 2 , wherein fluticasone propionate is dissolved in a first defined volume of the solvent to form a solution, and the solution is then added to a second defined volume of the non-solvent;
 a ratio of the first defined volume to the second defined volume being between 1:0.65 and 1:1.35.   
     
     
         5 . A process according to  claim 1 , wherein said adding the solution takes place at a temperature between about 10° C. and about 40° C. 
     
     
         6 . A process according to  claim 1 , wherein said adding the solution takes place over a period of between about 10 minutes and about 6 hours. 
     
     
         7 . A process according to  claim 5 , wherein said adding the solution takes place over a period of between about 10 minutes and about 6 hours. 
     
     
         8 . A process according to  claim 1 , wherein said adding the solution occurs via a pump in the form of pulsed aliquots. 
     
     
         9 . A process according to  claim 1 , wherein said adding the solution occurs over a period of between about 10 minutes and about 6 hours via a pump in the form of pulsed aliquots. 
     
     
         10 . A process according to  claim 1 , wherein once the step of adding the solution to the non-solvent is completed, a slurry forms and the slurry is stirred over a period of between 0 and about 12 hours, followed by filtration of the slurry to recover fluticasone propionate as crystalline form 1 and drying of the recovered fluticasone propionate. 
     
     
         11 . A process according to  claim 5 , wherein once the step of adding the solution to the non-solvent is completed, a slurry forms and the slurry is stirred over a period of between 0 and about 12 hours, followed by filtration of the slurry to recover fluticasone propionate as crystalline form 1 and drying of the recovered fluticasone propionate. 
     
     
         12 . A process according to  claim 7 , wherein once the step of adding the solution to the non-solvent is completed, a slurry forms and the slurry is stirred over a period of between 0 and about 12 hours, followed by filtration of the slurry to recover fluticasone propionate as crystalline form 1 and drying of the recovered fluticasone propionate. 
     
     
         13 . A process according to  claim 8 , wherein once the step of adding the solution to the non-solvent is completed, a slurry forms and the slurry is stirred over a period of between 0 and about 12 hours, followed by filtration of the slurry to recover fluticasone propionate as crystalline form 1 and drying of the recovered fluticasone propionate. 
     
     
         14 . Fluticasone propionate form 1, wherein said fluticasone propionate form 1 is obtained by a process according to according to  claim 1 ,
 wherein said fluticasone propionate form 1 has a median particle size of between 5 microns and 35 microns.   
     
     
         15 . Fluticasone propionate form 1, wherein said fluticasone propionate form 1 is obtained in the form of particles by a process according to according to  claim 1 ,
 wherein said particles do not exhibit agglomeration.   
     
     
         16 . Fluticasone propionate form 1, wherein said fluticasone propionate form 1 is obtained in the form of particles by a process according to according to  claim 1 ,
 wherein said particles are between 5 and 200 microns in length, and have a width of between 3 and 30 microns.