Novel crystalline forms of the anti-cancer compound zd1839

Abstract

The invention concerns certain crystalline solvates and hydrates of the compound of the Formula I which is known inter alia by way of the code number ZD1839. In particular, the invention concerns a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD1839 trihydrate. The invention further concerns processes for the preparation of these solvates and the trihydrate and for their conversion back to the compound ZD1839, pharmaceutical compositions containing them and their use in the manufacture of medicaments for use the production of an anti-proliferative effect in a warm-blooded animal such as man.

1 - 9 . (canceled) 
   
   
       10 . A crystalline form of the compound of the Formula I 
     
       
         
         
             
             
         
       
     
     substantially in the form of Form 2 ZD1839 MeOH solvate. 
   
   
       11 . The solvate according to  claim 10  characterised by an X-ray diffraction pattern having characterising peaks at about 6.5, 10.0 and 13.2° on the 2θ scale. 
   
   
       12 . The solvate according to  claim 10  characterised by an X-ray diffraction pattern substantially as shown in  FIG. 4 . 
   
   
       13 . The solvate according to  claim 10  characterised by a desolvation point in the range of about 125° C. to 130° C. 
   
   
       14 . The solvate according to  claim 10  characterised by one or both of the Differential Scanning Calorimetry thermogram and Thermal Gravimetric Analysis trace substantially as shown in  FIG. 5 . 
   
   
       15 . The solvate according to  claim 10  characterised by a Diffuse Reflectance Infrared Fourier Transform spectrum with distinguishing peaks at about 3380, 1650, 1530, 1450, 1235, 870 and 570 cm −1 . 
   
   
       16 . The solvate according to  claim 10  characterised by a Diffuse Reflectance Infrared Fourier Transform spectrum substantially as shown in  FIG. 6 . 
   
   
       17 . A crystalline form of the compound of the Formula I substantially in the form of Form 2 ZD1839 MeOH solvate according to  claim 10  which is substantially free of any other ZD1839 solvate or any Form 1 ZD1839 polymorph. 
   
   
       18 . A process for preparing a crystalline form of the compound of the Formula I substantially in the form of Form 2 ZD1839 MeOH solvate according to  claim 10  which comprises:
 (a) heating a mixture of the compound 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline in methanol or a solvent mixture containing methanol and a co-solvent until dissolution has occurred;   (b) reducing the temperature of the solvent system to induce nucleation;   (c) maintaining the mixture at a temperature below that at which nucleation has commenced; and   (d) isolating the crystalline solid so deposited.   
   
   
       19 . (canceled) 
   
   
       20 . A process for the preparation of the compound of Formula I 
     
       
         
         
             
             
         
       
     
     substantially in the form of Form 1 ZD1839 polymorph which comprises:
 (a) washing Form 2 ZD1839 MeOH solvate according to  claim 10  with a solvent or solvent mixture substantially to remove methanol; and 
 (b) isolating the Form 1 ZD1839 polymorph so formed. 
 
   
   
       21 . A compound of the Formula I 
     
       
         
         
             
             
         
       
     
     substantially in the form of Form 5 ZD1839 trihydrate. 
   
   
       22 . The Form 5 ZD1839 trihydrate according to  claim 21  characterised by an X-ray diffraction pattern having characterising peaks at about 6.1, 7.1 and 25.7° on the 2θ scale. 
   
   
       23 . The Form 5 ZD1839 trihydrate according to  claim 21  characterised by an X-ray diffraction pattern having characterising peaks at about 6.1, 7.1, 9.3, 14.2, 18.5, 18.8, 19.8, 22.3, 23.3, 24.7 and 25.7° on the 2θ scale. 
   
   
       24 . The Form 5 ZD1839 trihydrate according to  claim 21  characterised by an X-ray diffraction pattern substantially as shown in  FIG. 10 . 
   
   
       25 . The Form 5 ZD1839 trihydrate according to  claim 21  characterised by a Differential Scanning Calorimetry thermogram having a first endotherm with a peak at approximately 100° C. and a second endotherm with a peak at approximately 194° C. to 198° C. 
   
   
       26 . The Form 5 ZD1839 trihydrate according to  claim 21  characterised by one or both of the Differential Scanning Calorimetry thermogram and Thermal Gravimetric Analysis trace substantially as shown in  FIG. 11 . 
   
   
       27 . The Form 5 ZD1839 trihydrate according to  claim 21  which is substantially free of any other ZD1839 solvate or any other crystalline Form of ZD1839. 
   
   
       28 . The Form 5 ZD1839 trihydrate according to  claim 21  which is highly crystalline. 
   
   
       29 . A process for preparing a compound of the Formula I substantially in the form of Form 5 ZD1839 trihydrate according to  claim 21  which comprises:
 (a) contacting 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline with water for a sufficient time to convert the 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline to the Form 5 trihydrate; and   (b) isolating the Form 5 ZD1839 trihydrate.   
   
   
       30 . A process for crystallising a compound of the Formula I substantially in the form of Form 5 ZD1839 trihydrate according to  claim 21  which comprises the steps:
 (a) dissolving the compound 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline in a solvent system comprising water and an organic solvent;   (b) reducing the temperature of the solvent system to induce nucleation;   (c) maintaining the mixture at a temperature below that at which nucleation has commenced; and   (d) isolating the crystalline Form 5 ZD1839 trihydrate.   
   
   
       31 . A process for the preparation of a compound of Formula I 
     
       
         
         
             
             
         
       
     
     substantially in the form of Form 1 ZD1839 polymorph which comprises:
 (a) washing a compound of Formula I substantially in the form of Form 5 ZD1839 trihydrate as defined in  claim 21  with a solvent or solvent mixture substantially to remove water; and 
 (b) isolating the Form 1 ZD1839 polymorph so formed. 
 
   
   
       32 . A process for the preparation of the compound of Formula I 
     
       
         
         
             
             
         
       
     
     substantially in the form of Form 1 ZD1839 polymorph which comprises heating a compound of Formula I substantially in the form of Form 5 ZD1839 trihydrate for a sufficient time and at sufficient temperature to drive off water and effect transformation to Form 1 ZD1839 polymorph. 
   
   
       33 . A pharmaceutical composition which comprises the crystalline form of the compound of the Formula I according to  claim 21  and a pharmaceutically-acceptable diluent or carrier. 
   
   
       34 . A pharmaceutical composition according to  claim 33  that is adapted for oral administration. 
   
   
       35 . A pharmaceutical composition according to  claim 33  which comprises a suspension of a compound of Formula I substantially in the form of Form 5 ZD1839 trihydrate in an aqueous medium. 
   
   
       36 . A pharmaceutical composition which comprises the crystalline form of the compound of the Formula I according to  claim 10  and a pharmaceutically-acceptable diluent or carrier. 
   
   
       37 . A pharmaceutical composition according to  claim 36  that is adapted for oral administration.