Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base

Abstract

The present invention relates to the crystalline base of the well known antidepressant drug escitalopram, S-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, formulations of said base, a process for the preparation of purified salts of escitalopram, such as the oxalate, using the base, the salts obtained by said process and formulations containing such salts, and a process for the preparation of purified escitalopram free base or salts of escitalopram, such as the oxalate, using the hydrobromide, the salts obtained by said process and formulations containing such salts. Finally the present invention relates to an orodispersible tablet having a hardness of at least 22 N and an oral-disintegration time of less than 120 s and comprising an active pharmaceutical ingredient adsorbed onto a water soluble filler wherein the active pharmaceutical ingredient has a melting point in the range of 40-100° C., as well as a method for making such an orodispersible tablet.

1 . A process for the manufacture of escitalopram free base or a salt thereof characterised in that escitalopram hydrobromide is precipitated in crystalline form from a solvent and separated from the solvent, optionally re-crystallised one or more times, and then transformed into escitalopram free base or a salt thereof provided that the escitalopram salt manufactured is not the hydrobromide. 
     
     
         2 . The process according to  claim 1  for the manufacture of escitalopram free base or a salt thereof characterised in that the escitalopram hydrobromide is precipitated from a crude escitalopram. 
     
     
         3 . The process according to  claim 1  for the manufacture of escitalopram free base or a salt thereof characterised in that one or more impurities of the formulas (II) or (III) 
       
         
           
           
               
               
           
         
       
       wherein Z is halogen, cyano or —CONH 2 ,
 R 1  and R 2  independently are hydrogen or methyl, provided that if both of R 1  and R 2  are methyl, then Z can not be cyano, 
 
       and the bond drawn as a zigzag line in formula (III) indicates that the configuration around the double bond may be E- or Z-; 
       are removed from or reduced in the escitalopram by the process. 
     
     
         4 . The process according to  claim 3 , wherein the impurities are of formula (II) wherein
 Z is bromo or chloro and R 1  and R 2  are both methyl,   Z is —CONH 2  and R 1  and R 2  are both methyl, or   Z is cyano, R 1  is hydrogen and R 2  is methyl;   
       or of the formula (III) wherein the configuration around the double bond is Z. 
     
     
         5 . The process according to  claim 2  wherein the crude escitalopram is subjected to initial purification before the escitalopram hydrobromide is precipitated in crystalline form. 
     
     
         6 . The process according to  claim 1  characterised in that the escitalopram hydrobromide is transformed into escitalopram free base or escitalopram oxalate. 
     
     
         7 . The crystalline base of escitalopram, or an oxalate salt of escitalopram prepared by the process of  claim 1 . 
     
     
         8 . The base or the oxalate salt of  claim 7  characterised in that it contains less than 0.20% impurities other than R-citalopram, particularly less than 0.10%. 
     
     
         9 . The crystalline base or oxalate salt according to  claim 8  characterised in that it contains less than 0.10% of any particular impurity other than R-citalopram. 
     
     
         10 . An orodispersible tablet having a hardness of at least 22 N and an oral-disintegration time of less than 120 s and comprising an active pharmaceutical ingredient adsorbed onto a water soluble filler, one or more disintegrants and optionally additional water soluble filler, wherein said active pharmaceutical ingredient has a melting point in the range of 40-100° C. 
     
     
         11 . The orodispersible tablet according to  claim 10  characterised in that the active pharmaceutical ingredient has a melting point in the range of 40-90° C. 
     
     
         12 . The orodispersible tablet according to  claim 10  characterised in that the active pharmaceutical ingredient is selected from the group consisting of escitalopram, ethosuximide, trimethadione, chlorambucil, disulfuram, fenofibrate, guaifenesin, lomustine, carisoprodol and perphenazine. 
     
     
         13 . The orodispersible tablet according to  claim 12  characterised in that the active pharmaceutical ingredient is escitalopram. 
     
     
         14 . The orodispersible tablet according to  claim 13  characterised in that the water-soluble filler is selected from the group consisting of: monosaccharides, disaccharides, sugar alcohols and polysaccharides. 
     
     
         15 . The orodispersible tablet according to  claim 14  characterised in that the water-soluble filler is selected from the group consisting of: mannitol, sorbitol, glucose, mannose and lactose. 
     
     
         16 . The orodispersible tablet according to  claim 15  characterised in that it has a hardness of at least 22 N. 
     
     
         17 . The orodispersible tablet according to  claim 16  characterised in that it has an oral-disintegration time of less than 60 s. 
     
     
         18 . The orodispersible tablet according to  claim 17  characterised in that the disintegrants are selected from the group consisting of: microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone and povidone. 
     
     
         19 . The orodispersible tablet according to  claim 18  characterised in that it has a friability of no more than 1%. 
     
     
         20 . A method of manufacture of an orodispersible tablet according to  claim 10  comprising:
 a) mixing the water-soluble filler and the active pharmaceutical ingredient at a temperature above, around or slightly below the melting point of the active pharmaceutical ingredient, whereby the active pharmaceutical ingredient is adsorbed onto the water-soluble filler; 
 b) followed by cooling to a temperature below 40° C.; 
 c) mixing the mixture of the active pharmaceutical ingredient and the water-soluble filler with one or more disintegrants and optionally other excipients; 
 d) pressing the mixture into tablets with a hardness of at least 22 N.