Solid forms of ortataxel

Abstract

The present invention relates to solid forms of 13-(N-Boc-β-isobutylserinyl)-14-β-hydroxybaccatin III 1,14-carbonate (Ortataxel). Amorphous Form A, crystalline Form B, mixtures thereof and processes for preparing them are disclosed. Amorphous Form A is prepared by fast precipitation of Ortataxel from a mixture of acetone and water. Form A transforms in Form B when suspended and stirred in a mixture of ethanol and water for 4-8 hours. If the suspension is stirred for less than 4 hours, mixtures of Form B and Form A are obtained. Form B or mixtures of Forms A and B can also be obtained dissolving Ortataxel in a protic organic solvent, followed by addition of water.

1 . Ortataxel [13-(N-Boc-β-isobutylserinyl)-14-β-hydroxybaccatin III 1,14-carbonate] (1) 
       
         
           
           
               
               
           
         
       
       amorphous Form A. 
     
     
         2 . Process for preparing amorphous Form A of  claim 1 , which comprises dissolving Ortataxel in a ketone or in an aprotic dipolar organic solvent, followed by addition of water containing 0.001-0.003% w/v of an organic acid. 
     
     
         3 . The process according to  claim 2  wherein the solvent is acetone or dimethylsulfoxide. 
     
     
         4 . The process according to  claim 2  or  3  wherein the organic acid is citric or ascorbic acid. 
     
     
         5 . The process according to  claim 3  wherein the organic acid is citric acid. 
     
     
         6 . Ortataxel [13-(N-Boc-β-isobutylserinyl)-14-β-hydroxybaccatin III 1,14-carbonate] (1) 
       
         
           
           
               
               
           
         
       
       crystalline Form B of having the XRPD characterized by the following peaks 3.5, 6.8, 9.9, 10.1, 10.7, 12.1, 13.1, 14.8, 18.2, 19.7, 21.3, 29.3 deg 2-theta. 
     
     
         7 . A process for the preparation of Ortataxel Form B of  claim 6 , which comprises dissolving Ortataxel in ethanol containing traces of an organic acidic, followed by addition of water and stirring at a temperature ranging from 0 to 60° C. for a time ranging from 4 to 8 hours. 
     
     
         8 . The process of  claim 7  wherein the Ortataxel dissolved in ethanol is Ortataxel acetone solvate or Ortataxel form A as defined in  claim 1 . 
     
     
         9 . The process according to  claim 7  or  8  wherein the temperature is 40° C. 
     
     
         10 . The process according to  claim 9  wherein stirring is carried out for 6 hours. 
     
     
         11 . The process according to any one of  claims 8  to  10  wherein the organic acid is citric acid. 
     
     
         12 . Mixtures of Ortataxel Form A as defined in  claim 1  and Form B as defined in  claim 6 . 
     
     
         13 . A mixture as defined in  claim 12  wherein the amount of Form B is about 75% by weight. 
     
     
         14 . A process for the preparation of the mixtures of Form A and Form B as defined in  claim 12  or  13 , which comprises suspending Ortataxel in a mixture of ethanol and water containing an organic acid and stirring for less than 4 hours and at a temperature ranging from 0 to 60° C. 
     
     
         15 . The process according to  claim 14  wherein the Ortataxel suspended in the mixture of ethanol and water is Ortataxel acetone solvate or Ortataxel Form A. 
     
     
         16 . The process according to  claim 15  wherein ethanol and water are in a 0.5-0.7 ratio. 
     
     
         17 . The process according to  claim 16  wherein the temperature is 40° C. 
     
     
         18 . The process according to any one of  claims 15 - 17  wherein the organic acid is citric acid or ascorbic acid. 
     
     
         19 . The process according to  claim 18  wherein the organic acid is citric acid. 
     
     
         20 . Pharmaceutical compositions containing Ortataxel amorphous form A as defined in  claim 1  or Ortataxel crystalline form B as defined in  claim 5  or mixtures thereof as defined in  claim 12  or  13  in admixture with suitable excipients and/or carriers. 
     
     
         21 . Use of Ortataxel amorphous form A as defined in  claim 1  or of Ortataxel crystalline form B as defined in  claim 6  or of mixtures thereof as defined in  claim 12  or  13  for the preparation of pharmaceutical compositions for the treatment of cancer.