Synthesis and preparations of duloxetine salts

Abstract

The invention relates to an improved process for the preparation of duloxetine hydrochloride. More particularly, the invention relates to a process for the enantiomeric enrichment of duloxetine, and to a process for increasing the enantiomeric excess of enantiomerically-enriched duloxetine and salts thereof.

1 . A process for the enantiomeric enrichment of a duloxetine salt, in which the counterion of duloxetine is an achiral acid, comprising at least one of direct crystallization and solvent slurrying of a starting duloxetine salt to recover the enriched duloxetine salt remaining in a solid phase component. 
   
   
       2 . The process of  claim 1 , wherein said recovered duloxetine salt is (S)-duloxetine hydrochloride. 
   
   
       3 . The process of  claim 2 , wherein said recovered duloxetine salt contains less than approximately 1% area by HPLC of (R)-duloxetine hydrochloride. 
   
   
       4 . The process of  claim 2 , wherein said recovered duloxetine salt contains less than approximately 0.5% area by HPLC of (R)-duloxetine hydrochloride. 
   
   
       5 . The process of  claim 2 , wherein said recovered duloxetine salt contains less than approximately 0.1% area by HPLC of (R)-duloxetine hydrochloride. 
   
   
       6 . A formulation containing said recovered salt prepared according to the process of any of  claims 3 . 
   
   
       7 . The formulation of  claim 6 , further comprising at least one excipient material. 
   
   
       8 . The process of  claim 1 , wherein the starting duloxetine salt is racemic. 
   
   
       9 . The process of  claim 1 , wherein the starting duloxetine salt contains less than about 99.5% of (S)-duloxetine. 
   
   
       10 . The process of  claim 1 , wherein the starting duloxetine salt contains less than about 90% of (S)-duloxetine. 
   
   
       11 . The process of  claim 1 , wherein the starting duloxetine salt contains less than about 85% of (S)-duloxetine. 
   
   
       12 . The process of  claim 1 , further comprising the step of seeding a supersaturated solution of said starting duloxetine salt with an enantiomerically-enriched form of the salt. 
   
   
       13 . A duloxetine hydrochloride solvate. 
   
   
       14 . The duloxetine hydrochloride solvate of  claim 13 , wherein said solvate is duloxetine hydrochloride acetone solvate. 
   
   
       15 . The duloxetine hydrochloride acetone solvate of  claim 14 , wherein said duloxetine hydrochloride acetone solvate is characterized by an X-Ray powder diffraction pattern (2θ) (±0.2°) (XRD) having its main peaks at approximately 5.5, 10.5, 12.2, 16.6, 17.9, 18.2, 18.8, 21.1, 22.1, 23.9, 24.5, 24.8, 25.7 and 27.7±0.2 degrees. 
   
   
       16 . The duloxetine hydrochloride acetone solvate of  claim 15 , further characterized by an X-Ray powder diffraction pattern (2θ) (±0.2°) (XRD) having additional peaks at approximately 13.2, 14.1, 15.4, 16.0, 19.3, 22.6, 23.3, 26.2, 26.5, 28.2, 29.2, 29.6, 32.0, 33.2, 34.5, 36.2, 37.5, 38.0, 38.7, 39.6, 41.2, 42.8, 43.4, 47.7 and 49.0°. 
   
   
       17 . The duloxetine hydrochloride acetone solvate of  claim 14 , wherein said duloxetine hydrochloride acetone solvate is characterized by an IR spectrum substantially as shown in  FIG. 5 . 
   
   
       18 . A process for preparing duloxetine hydrochloride Form I comprising converting duloxetine hydrochloride acetone solvate into duloxetine hydrochloride Form I. 
   
   
       19 . The process of  claim 18 , wherein said process comprises at least one of recrystallizing and slurrying duloxetine hydrochloride acetone solvate into duloxetine hydrochloride Form I.