Crystalline composition containing escitalopram

Abstract

The present invention discloses crystalline particles of escitalopram oxalate which either have a broad particle size distribution or comprise at least 0.01% (w/w) of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile, said particles being suitable for use in direct compression. Furthermore, the invention discloses a novel pharmaceutical unit dosage form containing such crystalline particles of escitalopram oxalate as well as methods for manufacture of such crystalline particles of escitalopram oxalate Finally, the invention provides a method for reduction of the amount of hydroxyl containing impurities in a solution of citalopram or escitalopram.

1 . Crystalline particles of escitalopram oxalate, characterised in that the ratio between the median particle size and the particle size at the 95% quantile is less than 0.42.  
     
     
         2 . Crystalline particles of escitalopram oxalate according to  claim 1 , characterised in that the ratio between the median particle size and the particle size at the 95% quantile is less than 0.40.  
     
     
         3 . Crystalline particles of escitalopram oxalate according to  claim 1 , wherein the median particle size is at least 40 μm.  
     
     
         4 . Crystalline particles according to  claim 3 , characterised in that the median particle size of the crystals is in the range of 50-200 μm.  
     
     
         5 . Crystalline particles of escitalopram oxalate, characterised in that the median particle size is at least 40 μm and the content of E- or Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile is at least 0.01% (w/w).  
     
     
         6 . Crystalline particles according to  claim 5 , characterised in that the median particle size of the crystals is in the range of 50-200 μm.  
     
     
         7 . Crystalline particles of escitalopram oxalate according to  claim 5 , wherein the ratio between the median particle size and the particle size at the 95% quantile is less than 0.42.  
     
     
         8 . Crystalline particles of escitalopram oxalate, characterised in that the median particle size is at least 40 μm and the content of E- or Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile in the solution, from which the escitalopram oxalate is crystallised, prior to the crystallisation is at least 0.01% (W/W) relative to escitalopram.  
     
     
         9 . Crystalline particles according to  claim 8 , characterised in that the median particle size of the crystals is in the range of 50-200 μm.  
     
     
         10 . Crystalline particles of escitalopram oxalate according to  claim 8 , wherein the ratio between the median particle size and the particle size at the 95% uantile is less than 0.42.  
     
     
         11 . A solid unit dosage form comprising crystalline particles of escitalopram oxalate according to  claim 1 .  
     
     
         12 . The solid unit dosage form according to  claim 11 , wherein the solid unit dosage form is a tablet prepared by direct compression, dry granulation (compaction), wet granulation or melt granulation of a mixture of escitalopram oxalate and pharmaceutically acceptable excipients.  
     
     
         13 . The solid unit dosage form according to  claim 12 , wherein the tablet is coated.  
     
     
         14 . The solid unit dosage form according to  claim 11 , wherein the solid solid unit dosage form is prepared by filling a mixture of escitalopram oxalate and pharmaceutically acceptable excipients in a hard gelatine capsule.  
     
     
         15 . The solid unit dosage form according to  claim 11 , wherein the solid unit dosage form does not contain a binder.  
     
     
         16 . The solid unit dosage form according to  claim 11 , wherein the solid unit dosage form contains 1-60% w/w active ingredient calculated as escitalopram base.  
     
     
         17 . The solid unit dosage form according to  claim 11 , wherein the solid unit dosage form contains a filler selected from lactose, sugars, calcium phosphates, starch, modified starches, microcrystalline cellulose, calcium sulfate and/or calcium carbonate.  
     
     
         18 . The solid unit dosage form according to  claim 17 , wherein the filler is a microcrystalline cellulose.  
     
     
         19 . The solid unit dosage form according to  claim 11 , wherein the solid unit dosage from comprises a lubricant selected from metallic stearates, stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.  
     
     
         20 . The solid unit dosage form according to  claim 19 , wherein the lubricant is selected from talic, magnesium stearate, and/or calcium stearate.  
     
     
         21 . The solid unit dosage form according to  claim 20 , characterised in the lubricant is a combination of talc and magnesium stearate.  
     
     
         22 . The solid unit dosage form according to  claim 21 , wherein the weight percent of magnesium stearate in the solid dosage form is 0.4% to 2% (w/w)  
     
     
         23 . The solid unit dosage form according to  claim 11 , wherein the solid unit dosage form is substantially free of lactose.  
     
     
         24 - 39 . (canceled)  
     
     
         40 . Crystalline particles of escitalopram oxalate according to  claim 5 , wherein the ratio between the median particle size and the particle size at the 95% quantile is less than 0.40.  
     
     
         41 . Crystalline particles of escitalopram oxalate according to  claim 8 , wherein the ratio between the median particle size and the particle size at the 95% quantile is less than 0.40.  
     
     
         42 . The solid unit dosage form according to  claim 16 , wherein the solid unit dosage form contains 1-30% w/w active ingredient calculated as escitalopram base.  
     
     
         43 . The solid unit dosage form according to  claim 42 , wherein the solid unit dosage form contains 4-20% w/w active ingredient calculated as escitalopram base.  
     
     
         44 . The solid unit dosage form according to  claim 43 , wherein the solid unit dosage form contains 6-10% w/w active ingredient calculated as escitalopram base.  
     
     
         45 . The solid unit dosage form according to  claim 17 , wherein the filler is a sugar selected from sorbitol, mannitol, dextrose, and/or sucrose.  
     
     
         46 . The solid unit dosage form according to  claim 17 , wherein the filler is a calcium phosphate selected from dibasic, tribasic, hydrous, and/or anhydrous calcium phosphate.  
     
     
         47 . The solid unit dosage form according to  claim 11 , wherein the lubricant is a metallic stearate selected from magnesium, calcium, and/or sodium stearate.  
     
     
         48 . The solid unit dosage form according to  claim 22 , wherein the weight percent of magnesium stearate in the solid dosage form is 0.7% to 1.4% (w/w).  
     
     
         49 . Crystalline particles of escitalopram oxalate according to  claim 8 , wherein the content of E- or Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile in the solution is 0.01% to 0.5% (w/w) relative to escitalopram.  
     
     
         50 . Crystalline particles of escitalopram oxalate according to  claim 49 , wherein the content of E- or Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile in the solution is 0.01% to 0.3% (w/w) relative to escitalopram.  
     
     
         51 . Crystalline particles of escitalopram oxalate according to  claim 50 , wherein the content of E- or Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile in the solution is 0.02% to 0.2% (w/w) relative to escitalopram.  
     
     
         52 . Crystalline particles of escitalopram oxalate according to  claim 51 , wherein the content of E- or Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile in the solution is 0.03% to 0.1% (w/w) relative to escitalopram.