Process for the preparation of a stable polymorphic form of atovaguone

Abstract

The present invention provides a process for the preparation of a stable polymorph III of Atovaquone exhibiting characteristic peaks (expressed in degrees 2θ±0.2°θ) at about 6.9, 9.6, 14.1, 14.7, 17.0, 18.5, 19.1, 19.9, 20.3, 22.0, 22.6, 23.2, 24.2, 26.8, and 28.5, which comprises: (a) providing a sample of Atovaquone particles; (b) heating the sample of Atovaquone particles at a minimal temperature of between 140° C. to 160° C. depending on the particle size of the sample; and (c) cooling the sample to obtain the stable polymorphic form of Atovaquone.

1 . A process for the preparation of a stable polymorph III of Atovaquone which comprises:
 (a) providing a sample of Atovaquone particles;   (b) heating the sample of Atovaquone particles of step (a) at a temperature of at least about 160′C for a time sufficient of at least about one hour to obtain a stable polymorphic faun of Atovaquone, having characteristic peaks (expressed in degrees 20±0.2°θ) at approximately one or more of the positions: about 6.9, 9.6, 14.1, 14.7, 17.0, 18.5, 19.1, 19.9, 20.3, 22.0, 22.6, 23.2, 24.2, 26.8, and 28.5; and   (c) cooling the sample of step (b).   
     
     
         2 . A process for the preparation of a stable polymorph III of Atovaquone which comprises:
 (a) providing a sample of Atovaquone particles wherein at least about 90% of the Atovaquone particles have a volume diameter of equal or less than about 40μ;   (b) heating the sample of Atovaquone particles of step (a) at a temperature of at least about 140′C for a time sufficient to obtain a stable polymorphic form of Atovaquone, having characteristic peaks (expressed in degrees 20±0.2°θ) at approximately one or more of the positions: about 6.9, 9.6, 14.1, 14.7, 17.0, 18.5, 19.1, 19.9, 20.3, 22.0, 22.6, 23.2, 24.2, 26.8, and 28.5; and   (c) cooling the sample of step (b).   
     
     
         3 . The process of  claim 1 , wherein the Atovaquone particles of step (c) are further micronized if non-micronized particles are used in step (a), to obtain Atovaquone particles having particle volume diameter suitable for the preparation of pharmaceutical compositions of Atovaquone. 
     
     
         4 . The process of  claim 3 , wherein at least about 90% of the Atovaquone particles have a volume diameter of equal or less than about 10μ following micronization. 
     
     
         5 . The process of  claim 4 , wherein at least about 90% of the Atovaquone particles have a volume diameter in the range of between 4μ to 10μ. 
     
     
         6 . The process of  claim 5 , wherein at least about 90% of the Atovaquone particles have a volume diameter in the range of between 8μ to 10μ or between 4μ to 6μ. 
     
     
         7 . The process of  claim 1 , wherein the heating time sufficient to obtain the stable polymorphic form of Atovaquone is between about 1 hour to about 24 hours. 
     
     
         8 . The process of  claim 1 , wherein the sample is cooled to a temperature of between about 20° C. to about 40° C. 
     
     
         9 . The process of  claim 1  or  2 , wherein the stable polymorph III of Atovaquone has a chemical purity of at least about 99.5 percent. 
     
     
         10 . The process of  claim 9 , wherein the stable polymorph III of Atovaquone has a chemical purity of at least about 99.9 percent. 
     
     
         11 . The process of  claim 1 , wherein the stable polymorph III of Atovaquone has total chemical impurities of not more than about 0.5 area percent. 
     
     
         12 . A process for the preparation of a stable polymorph III of Atovaquone which comprises:
 (a) providing a sample of Atovaquone particles wherein at least about 90% of the Atovaquone particles have a volume diameter of equal or less than about 10μ;   (b) heating the sample of Atovaquone particles of step (a) at a temperature of at least about 140° C. for a time sufficient to obtain a stable polymorphic form of Atovaquone, having characteristic peaks (expressed in degrees 20±0.2°0) at approximately one or more of the positions:   about 6.9, 9.6, 14.1, 14.7, 17.0, 18.5, 19.1, 19.9, 20.3, 22.0, 22.6, 23.2, 24.2, 26.8, and 28.5; and   (c) cooling the sample of step (b).   
     
     
         13 . The process of  claim 12 , wherein at least about 90% of the Atovaquone particles of step (a) have a volume diameter in the range of between 4μ to 10μ. 
     
     
         14 . The process of  claim 13 , wherein at least about 90% of the Atovaquone particles of step (a) have a volume diameter in the range of between 8μ to 10μ or between 4μ to 6μ. 
     
     
         15 . The process of  claim 12 , wherein the heating time sufficient to obtain the stable polymorphic form of Atovaquone is between about 1 hour to about 24 hours. 
     
     
         16 . The process of  claim 15 , wherein the heating time sufficient to obtain the stable polymorphic form of Atovaquone is between about 1 hour to about 3 hours. 
     
     
         17 . The process of  claim 16 , wherein the heating time sufficient to obtain the stable polymorphic form of Atovaquone is about 2 hours. 
     
     
         18 . The process of  claim 12 , wherein the sample is cooled to a temperature of between about 20′C. to about 40′C. 
     
     
         19 . The process of  claim 12 , wherein the stable polymorph III of Atovaquone has a chemical purity of at least about 99.5 percent. 
     
     
         20 . The process of  claim 19 , wherein the stable polymorph III of Atovaquone has a chemical purity of at least about 99.9 percent. 
     
     
         21 . The process of  claim 12 , wherein the stable polymorph III of Atovaquone has total chemical impurities of not more than about 0.5 area percent.