Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof

Abstract

The present invention relates to novel essentially pure venlafaxine and the process of preparation thereof. The present invention also relates to novel solvate forms of venlafaxine hydrochloride and the process of preparation thereof. Furthermore, the present invention provides a novel process for preparing venlafaxine hydrochloride from venlafaxine; the process comprises the steps of: i) preparing a mixture of venlafaxine with acetone; and ii) exposing the mixture in gaseous hydrochloric acid.

1 - 27 . (canceled) 
     
     
         28 . Venlafaxine hydrochloride Form II, characterized by powder x-ray diffraction peaks at 12.8, 20.5, 21.3±0.2 degrees two-theta. 
     
     
         29 . The venlafaxine hydrochloride of  claim 28 , further characterized by powder x-ray diffraction peaks at 6.8, 8.5, 10.3, 13.6, 15.6, 16.5, 19.1, 19.9, 21.9, 25.2, 28.7, 31.2, 31.7, 35.3±0.2 degrees two-theta. 
     
     
         30 . Venlafaxine hydrochloride Form III characterized by powder x-ray diffraction peaks at 7.4, 14.9, 26.5±0.2 degrees two-theta. 
     
     
         31 . The venlafaxine hydrochloride of  claim 30 , further characterized by powder x-ray diffraction peaks at 12.9, 16.4, 17.5, 18.6, 18.9, 20.5, 21.4, 38.2±0.2 degrees two-theta. 
     
     
         32 . The venlafaxine hydrochloride of  claim 30 , wherein the venlafaxine hydrochloride is a solvate. 
     
     
         33 . Venlafaxine hydrochloride Form IV characterized by powder x-ray diffraction peaks at 10.3, 13.5, 15.6, 20.3±0.2 degrees two-theta. 
     
     
         34 . The venlafaxine hydrochloride of  claim 33 , further characterized by powder x-ray diffraction peaks at 6.8, 21.8, 27.2, 35.2±0.2 degrees two-theta. 
     
     
         35 . The venlafaxine hydrochloride of  claim 33 , wherein the venlafaxine hydrochloride is a solvate. 
     
     
         36 . A process for preparing venlafaxine hydrochloride Form III comprising dissolving venlafaxine hydrochloride in a protic solvent and crystallizing venlafaxine hydrochloride Form III by the addition of an aprotic solvent. 
     
     
         37 . The process according to  claim 36 , wherein the protic solvent is selected from the group consisting of water, methanol and ethanol. 
     
     
         38 . The process according to  claim 36 , wherein the aprotic solvent is selected from the group consisting of acetone, ethyl acetate, isopropyl ether, and methylethylketone. 
     
     
         39 . A process for preparing venlafaxine hydrochloride Form III comprising crystallizing venlafaxine hydrochloride from a protic solvent. 
     
     
         40 . The process according to  claim 39 , wherein the protic solvent is selected from the group consisting of ethanol and isopropanol. 
     
     
         41 . A process for preparing venlafaxine hydrochloride Form IV comprising crystallizing venlafaxine hydrochloride from an aprotic polar solvent. 
     
     
         42 . The process according to  claim 41 , wherein the aprotic polar solvent is selected from the group consisting of dimethyl sulfoxide and dimethyl formamide. 
     
     
         43 . A process for preparing venlafaxine hydrochloride Form II comprising dissolving venlafaxine hydrochloride in a mixture of a protic solvent and an aprotic solvent, and crystallizing venlafaxine hydrochloride Form II. 
     
     
         44 . The process according to  claim 43 , wherein the protic solvent is methanol. 
     
     
         45 . The process according to  claim 43 , wherein the aprotic solvent is ethyl acetate. 
     
     
         46 . The process according to  claim 43 , wherein the ratio of the protic solvent: aprotic solvent: venlafaxine hydrochloride is 10 ml:30 ml:3 grams. 
     
     
         47 . A process for preparing venlafaxine hydrochloride Form I, venlafaxine hydrochloride Form II, or a mixture thereof comprising drying venlafaxine hydrochloride Form III for a sufficient time to obtain venlafaxine hydrochloride Form I, venlafaxine hydrochloride Form II, or a mixture thereof. 
     
     
         48 . A process of preparing venlafaxine hydrochloride Form III, venlafaxine hydrochloride Form IV, or a mixture thereof comprising drying venlafaxine hydrochloride Form IV for a sufficient time to obtain venlafaxine hydrochloride Form III, venlafaxine hydrochloride Form IV, or a mixture thereof. 
     
     
         49 . A process for preparing venlafaxine hydrochloride Form III comprising dissolving venlafaxine hydrochloride in chloroform and crystallizing venlafaxine hydrochloride Form III by the addition of any of hexane and toluene. 
     
     
         50 . A process for preparing venlafaxine hydrochloride Form III comprising triturating venlafaxine hydrochloride in an aprotic solvent under a reflux condition for at least 1 hour to obtain venlafaxine hydrochloride Form III. 
     
     
         51 . A process for preparing venlafaxine hydrochloride Form III comprising triturating venlafaxine hydrochloride in an aprotic solvent at room temperature for at least a period of about 20 hours to obtain venlafaxine hydrochloride Form III. 
     
     
         52 . A process for preparing venlafaxine hydrochloride Form II comprising triturating venlafaxine hydrochloride with acetone, and drying to obtain venlafaxine hydrochloride Form II. 
     
     
         53 . The venlafaxine hydrochloride of  claim 28  in the form of a white crystal having a purity of about 99.5% by HPLC. 
     
     
         54 . The crystalline venlafaxine hydrochloride solvate Form III according to  claim 32 , wherein the crystal form is a methanol solvate containing about 5.6% to about 6.0% methanol. 
     
     
         55 . The crystalline venlafaxine hydrochloride solvate Form III according to  claim 32 , wherein the crystal form is a ethanol solvate containing about 5.6% to about 6.0% ethanol. 
     
     
         56 . The crystalline venlafaxine hydrochloride solvate Form III according to  claim 32 , wherein the crystal form is a isopropyl alcohol solvate containing about 4.6% isopropyl alcohol. 
     
     
         57 . The crystalline venlafaxine hydrochloride solvate Form III according to  claim 32 , wherein the crystal form is a hexane solvate containing about 5.5% hexane. 
     
     
         58 . The crystalline venlafaxine hydrochloride solvate Form IV according to  claim 35 , wherein the crystal form is a dimethyl sulfoxide solvate containing about 41% dimethyl sulfoxide. 
     
     
         59 . The crystalline venlafaxine hydrochloride solvate Form IV according to  claim 35 , wherein the crystal form is a dimethyl formamide solvate containing about 33% dimethyl formamide. 
     
     
         60 . The crystalline venlafaxine hydrochloride solvate Form III according to  claim 32  containing a solvent in a stoichiometric ratio of ½ molecule of solvent per molecule of venlafaxine hydrochloride. 
     
     
         61 . The crystalline venlafaxine hydrochloride solvate Form III according to  claim 32  containing isopropyl alcohol in a stoichiometric ratio of ¼ molecule of isopropyl alcohol per molecule of venlafaxine hydrochloride. 
     
     
         62 . The crystalline venlafaxine hydrochloride solvate Form IV according to  claim 35  containing dimethyl sulfoxide in a stoichiometric ratio of 3 molecules of dimethyl sulfoxide per molecule of venlafaxine hydrochloride. 
     
     
         63 . The crystalline venlafaxine hydrochloride solvate Form IV according to  claim 35  containing dimethyl formamide in a stoichiometric ratio of 2 molecules of dimethyl formamide per molecule of venlafaxine hydrochloride.