Crystalline forms of dimethoxy docetaxel and methods for preparing the same

Abstract

The invention relates to anhydrides, solvates and ethanol hetero-solvates and hydrates of dimethoxy docetaxel or (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-tax-11-ene-13α-yle, and to the preparation thereof.

What is claimed is:  
     
         1 . Crystalline forms of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, with the exception of the acetonate form. 
     
     
         2 . Forms according to  claim 1 , characterized in that they are anhydrous forms of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 
     
     
         3 . Anhydrous form B of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 2 , characterized by a PXRD diagram exhibiting characteristic lines located at 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and 15.9±0.2 degrees 2-theta. 
     
     
         4 . Anhydrous form C of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 2 , characterized by a PXRD diagram exhibiting characteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1±0.2 degrees 2-theta. 
     
     
         5 . Anhydrous form D of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 2 , characterized by a PXRD diagram exhibiting characteristic lines located at 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6, 10.8, 11.1 and 12.3±0.2 degrees 2-theta. 
     
     
         6 . Anhydrous form E of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 2 , characterized by a PXRD diagram exhibiting characteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7, 13.2, 13.4 and 13.9±0.2 degrees 2-theta. 
     
     
         7 . Anhydrous form F of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 2 , characterized by a PXRD diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3±0.2 degrees 2-theta. 
     
     
         8 . Forms according to  claim 1 , characterized in that they are ethanolic solvate or heterosolvate forms of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 
     
     
         9 . Ethanolate form B of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 8 , characterized by a PXRD diagram exhibiting characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9, 13.4, 14.2, 14.7 and 15.1±0.2 degrees 2-theta. 
     
     
         10 . Ethanolate form D of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 8 , characterized by a PXRD diagram exhibiting characteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9±0.2 degrees 2-theta. 
     
     
         11 . Ethanolate form E of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 8 , characterized by a PXRD diagram exhibiting characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2, 13.4, 13.9 and 14.2±0.2 degrees 2-theta. 
     
     
         12 . Ethanol/water heterosolvate form F of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate according to  claim 8 , characterized by a PXRD diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2±0.2 degrees 2-theta. 
     
     
         13 . Forms according to  claim 1 , characterized in that they are hydrate forms of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 
     
     
         14 . Monohydrate form C of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 13 , characterized by a PXRD diagram exhibiting characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3±0.2 degrees 2-theta. 
     
     
         15 . Dihydrate form C of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate according to  claim 13 , characterized by a PXRD diagram exhibiting characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2±0.2 degrees 2-theta. 
     
     
         16 . Method for preparing the anhydrous form B according to  claim 3 , which consists in heating the acetone solvate form A between 100 and 110° C. under vacuum or nitrogen sweeping, preferably for at least 9 hours, and then returning to ambient temperature. 
     
     
         17 . Method for preparing the anhydrous form C according to  claim 4 , by maturation of the acetone solvate form A, or of the anhydrous form B, in water, followed by drying up to approximately 50° C. and then maintaining at ambient temperature at a relative humidity of less than 5%. 
     
     
         18 . Method for preparing the anhydrous form D according to  claim 5 , by maturation, at ambient temperature, of the acetone solvate form A in ethanol and drying under nitrogen or under vacuum. 
     
     
         19 . Method for preparing the anhydrous form D according to  claim 5 , by crystallization, at ambient temperature, of the acetone solvate form A from an oil, followed by rinsing with an alkane. 
     
     
         20 . Method for preparing the anhydrous form D according to  claim 5 , by crystallization of a solution of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in a mixture of Polysorbate 80, pH 3.5, ethanol and water (preferably, a 25/25/50 mixture) for approximately 48 hours at ambient temperature. 
     
     
         21 . Method for preparing the anhydrous form E according to  claim 6 , by maturation of the acetone solvate form A in ethanol so as to intermediately form an ethanolic form which is subsequently desolvated under nitrogen sweeping or by heating at approximately 100° C. for 2 hours and then returning to ambient temperature. 
     
     
         22 . Method for preparing the anhydrous form F according to  claim 7 , by desolvating the ethanol/water heterosolvate at 120° C. under a nitrogen atmosphere for 24 hours and then maintaining at a relative humidity of 0% at ambient temperature.