Novel process for the manufacture of pharmaceutical preparations

Abstract

The present invention is related to an improved method for the manufacture of Micro-precipitated Bulk Powder (MBP) containing the active pharmaceutical ingredient Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3- b ]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS). The invention is further directed to pharmaceutical compositions containing said MBP, as well as its use in the manufacture of medicaments for the treatment of cancer.

1 . A method for manufacturing a solid dispersion containing the amorphous form of the compound of formula 1 
       
         
           
           
               
               
           
         
       
       and HPMCAS, comprising the following steps:
 (a) dissolving the compound of formula 1 and HPMCAS in the same organic solvent to give one single organic phase; 
 (b) continuously adding the organic phase obtained under (a) into an aqueous phase which is present in a mixing chamber, said mixing chamber being equipped with a high shear mixing unit and two additional openings which connect said mixing chamber to a closed loop wherein said aqueous phase is circulated and passes through the mixing chamber; 
 (c) precipitating a mixture consisting of the amorphous form of the compound of formula 1 and HPMCAS out of the aqueous phase mentioned under (b), while the high shear mixer is operating and said aqueous phase is passed through the mixing chamber in a closed loop, resulting in the formation of an aqueous suspension of the precipitate; 
 (d) continuously circulating the aqueous suspension through the mixing chamber while the high shear mixing unit is operating and after the organic solution prepared under (a) has been completely added to the aqueous phase until a defined particle size and/or particle size distribution is obtained; 
 (e) isolating the solid phase from the suspension; 
 (f) washing of the isolated solid phase with 0.01 N HCl and/or water; and 
 (g) delumping and drying the solid phase. 
 
     
     
         2 . The method according to  claim 1 , wherein
 the organic phase in (a) is a 10 to 40% solution of the compound of formula 1 and HPMCAS in DMA, the ratio of said compound to HPMCAS being from about 10 to 90% (w/w) to about 60 to 40% (w/w); and   the continuous adding in step (b) is achieved via an injector nozzle which is oriented in an angle between 40 and 50° to the longitudinal axis of the high shear mixer and has a distance of about 1 to about 10 mm from the rotor of said high shear mixer which is operating with a tip speed of about 15 to about 25 m/sec.   
     
     
         3 . The method according to  claim 2 , wherein the organic phase in (a) is a 35% solution of the compound of formula 1 and HPMCAS in DMA, the ratio of said compound to HPMCAS being 30% to 70% (w/w). 
     
     
         4 . The method according to  claim 1 , wherein the organic phase in (a) comprises DMA, the compound of formula 1 and HPMCAS-L, and step (b) comprises adding said organic phase into aqueous (0.01 N) HCl at a mass flow ratio in the range of about 80/1 to 200/1 (aqueous phase/organic phase) while said aqueous HCl is kept at a temperature of about 2-8° C. 
     
     
         5 . The solid dispersion produced by the method according to  claim 1 . 
     
     
         6 . The solid dispersion according to  claim 5 , characterized in that it is a microprecipitated bulk powder (MBP) wherein the compound of formula 1 is predominantly present in its amorphous form. 
     
     
         7 . A pharmaceutical preparation containing the solid dispersion as obtainable according to the method of  claim 1 , optionally together with additional pharmaceutically acceptable adjuvants.