Patent Abstract:
The present invention relates to novel crystalline forms of (S)-citalopram oxalate, to processes for their preparation and to pharmaceutical compositions containing them.

Full Description:
FIELD OF THE INVENTION  
       [0001]     The present invention relates to novel crystalline forms of (S)-citalopram oxalate, to processes for their preparation and to pharmaceutical compositions containing them.  
       BACKGROUND OF THE INVENTION  
       [0002]     (S)-Citalopram of formula (1):  
                         
 
 or 1(S)-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile as well as acid addition salts thereof are valuable antidepressants. EP 0347066 disclosed the therapeutic uses of (S)-citalopram and its salts. In the prior art literature no crystalline forms of (S)-citalopram oxalate were reported 
 
         [0003]     We have discovered two novel crystalline forms of (S)-citalopram oxalate. The novel forms have been found to be stable and reproducible and suitable for pharmaceutical preparations.  
         [0004]     Thus the object of the present invention is to provide stable novel crystalline forms of (S)-citalopram oxalate, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.  
       DESCRIPTION OF THE INVENTION  
       [0005]     According to one aspect of the present invention, there is provided a novel crystalline form of (S)-citalopram oxalate, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 6.9, 8.9, 10.8, 13.4, 14.0, 16.3, 17.6, 18.6, 19.1, 19.5, 21.2, 22.8, 23.1, 24.2, 24.5, 25.3, 27.3 degrees.  FIG. 1  shows typical Form I x-ray powder diffraction pattern.  
         [0006]     According to another aspect of the present invention, there is provided a process for preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram oxalate is mixed with a suitable solvent. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, dioxane and acetonitrile. (S)-Citalopram oxalate prepared by the process described in, for example, EP 0347066 or Form II of (S)-citalopram oxalate (prepared by the process described below) may be used. The contents may be heated to reflux. The Form I of (S)-citalopram oxalate is separated by filtration.  
         [0007]     According to another aspect of the present invention, there is provided an alternative process for the preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram is dissolved in a suitable solvent and oxalic acid is added to the solution. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, dioxane and acetonitrile. The Form I of (S)-citalopram oxalate is precipitated from the solution by the techniques such as cooling, partial removal of the solvent or addition of anti-solvent.  
         [0008]     According to one aspect of the present invention, there is provided a novel crystalline form of (S)-citalopram oxalate, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 6.6, 10.0, 11.0, 11.9, 15.2, 16.8, 17.8, 20.3, 21.1, 21.4, 22.6, 23.0, 26.4, 28.4 degrees.  FIG. 2  shows typical Form II x-ray powder diffraction pattern.  
         [0009]     According to another aspect of the present invention there is provided a process for preparation of the Form II of (S)-citalopram oxalate. Thus (S)-citalopram oxalate is mixed with an alcohol. (S)-Citalopram oxalate prepared by the process described in, for example, EP 0347066 or the Form I of (S)-citalopram oxalate may be used. The alcohol is either methanol or ethanol or isopropyl alcohol. The solubility of (S)-citalopram oxalate depends on the alcohol used and volume of the alcohol to (S)-citalopram oxalate. For example, 5 gm of (S)-citalopram oxalate is soluble in 35 ml of methanol at 25° C. If (S)-citalopram oxalate is soluble in the conditions of experiment, the Form II of (S)-citalopram oxalate is precipitated from the solution. The techniques such as cooling, partial removal of the solvent, addition of anti-solvent like diisopropyl ether may be used to precipitate the Form II of (S)-citalopram oxalate. If the (S)-citalopram oxalate is insoluble in the alcohol, after mixing (S)-citalopram oxalate and the alcohol the solid is filtered from the contents to obtain Form II of (S)-citalopram oxalate.  
         [0010]     According to another aspect of the present invention, there is provided an alternative process for the preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram is dissolved in an alcoholic solvent and oxalic acid is added to the solution. The alcoholic solvent is either methanol or ethanol or isopropyl alcohol. (S)-citalopram prepared by the process described in, for example, EP 0347066 may be used. The Form II of (S)-citalopram oxalate is precipitated from the solution by the techniques such as partial removal of the solvent or addition of anti-solvent.  
         [0011]     According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form I or Form II of (S)-citalopram oxalate. The forms of (S)-citalopram oxalate may be formulated in a form suitable for oral administration or injection. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0012]      FIG. 1  is a x-ray powder diffraction pattern of Form I (S)-citalopram oxalate.  
         [0013]      FIG. 2  is a x-ray powder diffraction pattern of Form II (S)-citalopram oxalate. 
     
    
       [0014]     x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Kα radiation.  
         [0015]     The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.  
       EXAMPLE 1  
       [0016]     (S)-Citalopram oxalate (5 gm, obtained as in example 2 of EP 0347066) is mixed with acetone (30 ml), heated to reflux and is cooled to 20° C. The separated crystals are filtered and dried to give Form I of (S)-citalopram oxalate (4.5 gm).  
       EXAMPLE 2  
       [0017]     (S)-Citalopram (10 gm, obtained as in example 2 of EP 0347066) is dissolved in acetone (100 ml) and oxalic acid dihydrate (5 gm) is added to the solution. The contents are maintained for 30 minutes at 0° C. and the separated solid is filtered and dried to give Form I of (S)-citalopram oxalate (10.5 gm).  
       EXAMPLE 3  
       [0018]     (S)-Citalopram oxalate(5 gm, obtained as in example 2 of EP 0347066) is dissolved in methanol (35 ml) at 25° C. Then diisopropyl ether (50 ml) is added to the solution and maintained for 2 hours at 25° C. The separated crystals are filtered and dried to give Form II of (S)-citalopram oxalate (4 gm).  
       EXAMPLE 4  
       [0019]     (S)-Citalopram (10 gm, obtained as in example 2 of EP 0347066) is dissolved in isopropyl alcohol (125 ml) and oxalic acid dihydrate (5 gm) is added to the solution. The contents are maintained for 30 minutes at 40° C. and cooled to 0° C. The separated solid is filtered and dried to give Form II of (S)-citalopram oxalate (9.5 gm).  
       EXAMPLE 5  
       [0020]     Example 1 is repeated using Form II of (S)-citalopram oxalate instead of (S)-citalopram oxalate (obtained as in example 2 of EP 0347066) to give Form I of (S)-citalopram oxalate.  
       EXAMPLE 6  
       [0021]     Example 3 is repeated using Form I of (S)-citalopram oxalate instead of (S)-citalopram oxalate (obtained as in example 2 of EP 0347066) to give Form II of (S)-citalopram oxalate.

Technology Classification (CPC): 2