Crystalline forms of olaparib and manufacturing processes therefor

Abstract

In certain aspects, the invention provides crystalline forms of olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one). In related aspects, the invention provides processes for preparing the crystalline forms of olaparib. The processes include: forming a solution comprising crude olaparib and an organic solvent; adding an anti-solvent to the solution to form a slurry comprising a precipitate; isolating the precipitate; and drying the precipitate to obtain a crystalline form I of olaparib or a crystalline form II of olaparib.

1 . Crystalline form I of olaparib, characterized by an X-ray powder diffraction pattern comprising peaks at 6.4, 12.7, 15.1, 19.7, 22.0, and 23.0 degrees 2θ (±0.2 degrees 2θ). 
     
     
         2 . The crystalline form I of olaparib according to  claim 1 , wherein the X-ray powder diffraction pattern further comprises peaks at 6.9, 8.3, 15.9, 17.9, 20.8, 26.2, and 29.1 degrees 2θ (±0.2 degrees 2θ). 
     
     
         3 . The crystalline form I of olaparib according to  claim 1 , wherein the X-ray powder diffraction pattern further comprises peaks at 7.5, 13.7, 16.4, 18.7, 24.0, and 30.4 degrees 2θ (±0.2 degrees 2θ). 
     
     
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         11 . The crystalline form I of olaparib, according to  claim 1 , characterized by an X-ray powder diffraction pattern substantially in accordance with  FIG. 1 . 
     
     
         12 . The crystalline form I of olaparib according to  claim 1 , further characterized by a weight loss ranging from about 3.5% to about 4.5% upon heating to around 150° C., as measured by thermal gravimetric analysis. 
     
     
         13 . The crystalline form I of olaparib according to  claim 1 , further characterized by a differential scanning calorimetry thermogram comprising endothermic peaks at around 62.9, 138.7, and 210.2° C. 
     
     
         14 . The crystalline form I of olaparib according to  claim 13 , wherein the differential scanning calorimetry thermogram is substantially in accordance with  FIG. 3 . 
     
     
         15 . The crystalline form I of olaparib according to  claim 1 , wherein the crystalline form I of olaparib is a hydrated form. 
     
     
         16 . A process for preparing the crystalline form I of olaparib of  claim 1 , the process comprising:
 a) forming a solution comprising crude olaparib and an organic solvent;   b) adding an anti-solvent to the solution to form a slurry comprising a precipitate;   c) isolating the precipitate; and   d) drying the precipitate to obtain the crystalline form I of olaparib.   
     
     
         17 . The process of  claim 16 , wherein forming the solution comprises heating the solution. 
     
     
         18 . The process of  claim 17 , wherein the solution is heated to a temperature of at least about 50° C. 
     
     
         19 . The process of  claim 17 , wherein the solution is heated to a temperature ranging from about 55° C. to about 65° C. 
     
     
         20 . The process of  claim 17 , further comprising cooling the slurry prior to isolating the precipitate. 
     
     
         21 . The process of  claim 20 , wherein the slurry is cooled to a temperature lower than about 30° C. 
     
     
         22 . The process of  claim 17 , wherein the organic solvent is selected from the group consisting of methanol; acetic acid; N,N-dimethylacetamide; dimethyl sulfoxide; and combinations thereof. 
     
     
         23 . The process of  claim 17 , wherein the organic solvent is methanol. 
     
     
         24 . The process of  claim 17 , wherein the anti-solvent is water. 
     
     
         25 . The process of  claim 17 , wherein the solution comprises the crude olaparib in an amount ranging from about 5% (w/w) to about 30% (w/w). 
     
     
         26 . The process of  claim 17 , wherein the slurry comprises the anti-solvent in an amount ranging from about 60% (w/w) to about 95% (w/w). 
     
     
         27 . The process of  claim 17 , wherein drying the precipitate comprises heating the precipitate to a temperature ranging from about 30° C. to about 80° C. 
     
     
         28 . The process of  claim 17 , further comprising washing the precipitate prior to drying the precipitate. 
     
     
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