Polymorphs of valsartan

Abstract

Provided are crystalline and amorphous form of valsartan, and processes for their preparation.

What is claimed is:  
     
         1 . A process for preparing amorphous form of valsartan comprising the steps of: 
 a) precipitating amorphous valsartan from a solution of valsartan in a solvent selected from the group consisting of methyl t-butyl ether and acetone; and    b) recovering valsartan amorphous form.    
     
     
         2 . The process of  claim 1 , wherein the solvent is methyl t-butyl ether.  
     
     
         3 . A process for preparing amorphous form of valsartan comprising the steps of: 
 a) precipitating amorphous valsartan from a mixture of water and a solvent selected from the group consisting of ethanol, DMF, acetone and mixtures thereof; and    b) recovering the precipitated amorphous valsartan    
     
     
         4 . The process of  claim 3 , wherein precipitating is carried out by combining water as an anti-solvent with the solution of valsartan in the solvent.  
     
     
         5 . A process for preparing amorphous form of valsartan comprising the steps of: 
 a) preparing a solution of valsartan in a solvent selected from the group consisting of tetrahydrofuran, dioxane, ethanol, isopropanol, diethyl ether and methanol; and    b) removing the solvent.    
     
     
         6 . The process of  claim 5 , wherein removing is carried out by evaporation.  
     
     
         7 . The process of  claim 5 , wherein the solvent is selected from the group consisting of tetrahydrofuran, dioxane, ethanol, isopropanol and diethyl ether.  
     
     
         8 . A process for preparing amorphous form of valsartan comprising the steps of: 
 a) suspending valsartan in a solvent selected from the group consisting of water and C 5  to C 12  saturated hydrocarbon to obtain amorphous valsartan; and    b) recovering the amorphous valsartan.    
     
     
         9 . The process of  claim 8 , wherein the suspending step includes heating.  
     
     
         10 . The process of  claim 8 , wherein the solvent is water.  
     
     
         11 . The process of  claim 8 , wherein the hydrocarbon is heptane or cyclohexane.  
     
     
         12 . A process for preparing amorphous form of valsartan comprising the steps of: 
 a) acidifying a basic aqueous solution of valsartan, wherein the acidifying results in precipitation of amorphous valsartan; and    b) recovering the precipitated amorphous valsartan.    
     
     
         13 . The process of  claim 12 , wherein the acidifying results in a pH of from about 2 to about 5.  
     
     
         14 . A process for preparing amorphous form of valsartan comprising the steps of: 
 a) heating valsartan in diisopropyl ether to obtain amorphous valsartan; and    b) recovering the amorphous valsartan.    
     
     
         15 . A process for preparing amorphous valsartan comprising the step of heating a crystalline form of valsartan selected from the group consisting of Form III or Form VII.  
     
     
         16 . The process of  claim 15 , wherein the valsartan Form III is prepared by crystallization out of n-butyl acetate.  
     
     
         17 . Amorphous form of valsartan, wherein the amorphous form has a DSC thermogram that lacks a melting point above about 1 J/g.  
     
     
         18 . The amorphous valsartan of  claim 17 , wherein the melting point is lacking in the region of from about 80° C. to about 100° C.  
     
     
         19 . A process for preparing the crystalline valsartan (Form I) having an XRPD pattern with peaks at 5.4, 13.0, 16.3, 19.5, 20.7, 23.4±0.2 degrees 2-theta comprising the steps of: 
 a) heating a solution of valsartan in a solvent selected from the group consisting of methyl ethyl ketone and ethyl acetate;  
 b) cooling the solution to a temperature of about negative 20° C. to about 20° C. to induce crystallization; and  
 c) recovering the crystalline valsartan without heating.  
 
     
     
         20 . The process of  claim 19 , wherein the solvent is methyl ethyl ketone.  
     
     
         21 . A process for preparing crystalline valsartan having an XRPD pattern with peaks at about 5.7, 13.6, 18.0±0.2 degrees 2-theta (Form VIII) further comprising the step of heating the valsartan of  claim 20 .  
     
     
         22 . A crystalline valsartan (Form II) characterized by an XRPD pattern with peaks at 5.8, 12.7, 14.0, 17.6, 20.8, 22.5±0.2 degrees 2-theta  
     
     
         23 . The crystalline valsartan of  claim 22  having an XRPD pattern as substantially depicted in FIG. 5.  
     
     
         24 . A process for preparing crystalline valsartan of  claim 22  comprising the steps of: 
 a) crystallizing the crystalline valsartan from an emulsion or solution of valsartan in a C 5  to C 12  aromatic hydrocarbon; and  
 b) recovering the crystalline valsartan.  
 
     
     
         25 . The process of  claim 24 , wherein the aromatic hydrocarbon is toluene.  
     
     
         26 . The process of  claim 24 , further comprising drying the crystalline valsartan.  
     
     
         27 . The crystalline valsartan prepared by the process of  claim 24 .  
     
     
         28 . A crystalline valsartan (Form III) with an XRPD pattern with peaks at 5.1, 10.1, 15.3, 18.6±0.2 degrees 2-theta  
     
     
         29 . The crystalline valsartan of  claim 28  having an XRPD pattern as substantially depicted in FIG. 6.  
     
     
         30 . A process for preparing crystalline valsartan of  claim 28  comprising the steps of: 
 a) crystallizing the crystalline valsartan from a solution of valsartan in t-butyl acetate; and  
 b) recovering the crystalline valsartan.  
 
     
     
         31 . The crystalline valsartan prepared by the process of  claim 30 .  
     
     
         32 . A crystalline valsartan (Form IV) having an XRPD pattern with peaks at 6.2, 10.7, 14.5, 15.7, 19.0, 23.5, 24.8±0.2 degrees 2-theta.  
     
     
         33 . The crystalline valsartan of  claim 32  having an XRPD pattern as substantially depicted in FIG. 7.  
     
     
         34 . A process for preparing crystalline valsartan of  claim 32  comprising the steps of: 
 a) crystallizing the crystalline valsartan from a solution of valsartan in acetonitrile; and  
 b) recovering the crystalline valsartan.  
 
     
     
         35 . The crystalline valsartan prepared by the process of  claim 34 .  
     
     
         36 . A process for preparing valsartan Form IX further comprising the step of heating the recovered crystalline valsartan of  claim 34 .  
     
     
         37 . A crystalline valsartan (Form VI) characterized by an XRPD pattern with peaks at 5.5, 13.3, 14.3, 17.7, 21.1, 22.3±0.2 degrees 2-theta  
     
     
         38 . The crystalline valsartan of  claim 37  having an XRPD pattern as substantially depicted in FIG. 8.  
     
     
         39 . A process for preparing the crystalline valsartan of  claim 37  comprising the step of heating crystalline valsartan Form VII.  
     
     
         40 . The process of  claim 39 , wherein the Form VII is obtained by crystallization from 2-hexanone.  
     
     
         41 . A crystalline valsartan (Form VII) characterized by an XRPD pattern with peaks at 5.2, 15.2, 15.9, 18.6, 22.8, 23.6±0.2 degrees 2-theta.  
     
     
         42 . The crystalline valsartan of  claim 41  having an XRPD pattern as substantially depicted in FIG. 9.  
     
     
         43 . A process for preparing crystalline valsartan of  claim 41  comprising the steps of: 
 a) Crystallizing the crystalline valsartan from a solution of valsartan in a solvent selected from the group consisting of 2-hexanone and n-butyl acetate; and  
 b) recovering the crystalline valsartan.  
 
     
     
         44 . A process for making crystalline valsartan Form VI comprising the step of heating the crystalline valsartan of  claim 41 .  
     
     
         45 . A crystalline valsartan (Form VIII) characterized by an XRPD pattern with peaks at about 5.7, 13.6, 18.0±0.2 degrees 2-theta.  
     
     
         46 . The crystalline valsartan of  claim 45  having an XRPD pattern as substantially depicted in FIG. 10.  
     
     
         47 . A process for preparing crystalline valsartan Form VIII comprising the step of heating crystalline valsartan Form I.  
     
     
         48 . A crystalline valsartan (Form IX) characterized by an XRPD pattern with peaks at 6.3, 14.0, 17.9±0.2 degrees 2-theta.  
     
     
         49 . The crystalline valsartan of  claim 48  having an XRPD pattern as substantially depicted in FIG. 11.  
     
     
         50 . A process for preparing crystalline valsartan of  claim 48  comprising the step of heating crystalline valsartan Form IV.  
     
     
         51 . A process for preparing crystalline valsartan of  claim 48  comprising the steps of: 
 a) crystallizing the crystalline valsartan from a solution of valsartan in nitromethane; and  
 b) recovering the crystalline valsartan.  
 
     
     
         52 . The crystalline valsartan prepared by the process of  claim 51 .  
     
     
         53 . A process for preparing crystalline valsartan of  claim 48  comprising the steps of: 
 a) crystallizing the crystalline valsartan from a solution of valsartan in acetonitrile;  
 b) recovering the crystalline valsartan; and  
 c) heating the crystalline valsartan.  
 
     
     
         54 . A crystalline form of valsartan (Form X), wherein the crystalline form is characterized by an XRD pattern with peak at 5.6±0.2 degrees 2 theta and with two broad peaks at 15.0 and 20.6 degrees 2 theta.  
     
     
         55 . The crystalline form of  claim 54 , wherein the crystalline form is characterized by the XRD pattern as substantially depicted in FIG. 20.  
     
     
         56 . A process for preparing crystalline valsartan of  claim 54  comprising the steps of: 
 a) preparing a solution of valsartan in  n-butyl acetate;  
 b) crystallizing the crystalline form from the solution; and  
 c) recovering the crystalline form.  
 
     
     
         57 . The process of  claim 56 , wherein crystallizing is carried out by cooling to a temperature of about negative 10° C. to about 10° C.  
     
     
         58 . The process of  claim 56 , further comprising the step of drying.  
     
     
         59 . A crystalline form of Valsartan, wherein the crystalline form (Form XI) is characterized by an XRD pattern with peaks at 5.2, 10.5, 12.9, 13.9, 18.8±0.2 degrees 2 theta.  
     
     
         60 . The crystalline form of  claim 59 , wherein the crystalline form is further characterized by peaks at 9.7, 16.1, 20.7, 22.9, 24.1±0.2 degrees 2 theta degrees two-theta.  
     
     
         61 . The crystalline form of  claim 60 , wherein the crystalline form is characterized by the XRD pattern as substantially depicted in FIG. 21.  
     
     
         62 . A process for preparing crystalline valsartan of  claim 59  comprising the steps of contacting a crystalline form of valsartan with toluene to obtain a transformation in the crystalline form.  
     
     
         63 . The process of  claim 62 , wherein the contacting is carried out by trituration.  
     
     
         64 . The process of  claim 63 , wherein the crystalline form triturated is Form II.  
     
     
         65 . The process of  claim 62 , wherein the trituration is carried out at a temperature of about 40° C. to about 60° C., followed by cooling to a temperature of about negative 10° C. to about 10° C.  
     
     
         66 . The process of  claim 62 , wherein contacting is carried out by placing crystalline valsartan in toluene vapor atmosphere.  
     
     
         67 . The process of  claim 66 , wherein the form contacted is Form VII.  
     
     
         68 . A process for preparing amorphous valsartan comprising the steps of: 
 a) preparing a solution of valsartan in ethyl acetate;    b) cooling the solution;    c) recovering a solid from the ethyl acetate; and    d) drying the solid to obtain amorphous valsartan.    
     
     
         69 . The process of  claim 68 , wherein the solution is cooled to a temperature of about negative 20° C. to about 20° C.  
     
     
         70 . The process of  claim 68 , further comprising the step of seeding the solution.  
     
     
         71 . The process of  claim 68 , wherein the drying is carried out at a temperature of about 40° C. to about 50° C.  
     
     
         72 . A process for preparing amorphous valsartan comprising the step of heating crystalline valsartan Form I.  
     
     
         73 . A process for preparing amorphous valsartan comprising the steps of contacting a crystalline form of valsartan with hexane vapor atmosphere to obtain a crystalline transformation, and recovering the transformed crystalline form.  
     
     
         74 . The process of  claim 73 , wherein the form contacted is selected from the group consisting of Form VI and Form VII.  
     
     
         75 . A crystalline form of valsartan, wherein the crystalline form is a solvate of heptane.  
     
     
         76 . A crystalline form of Valsartan (Form XIII), wherein the crystalline form is characterized by an XRD pattern with peaks at 5.1, 11.6, 15.8, 18.6, 26.2±0.2 degrees 2 theta.  
     
     
         77 . The crystalline form of  claim 76 , wherein the crystalline form is further characterized by peaks at 10.4, 15.3, 16.4, 19.9, 23.8±0.2 degrees two-theta.  
     
     
         78 . The crystalline form of  claim 77 , wherein the crystalline form is characterized by the XRD pattern as substantially depicted in FIG. 22.  
     
     
         79 . A process for preparing crystalline valsartan of  claim 76  comprising the steps of contacting valsartan in solid state with a water vapor atmosphere to obtain a transformation to the crystalline form.  
     
     
         80 . The process of  claim 79 , wherein the valsartan contacted is selected from the group consisting of III, VI, VII, VIII, IX or amorphous form.  
     
     
         81 . A crystalline form of valsartan, wherein the crystalline form is a hydrate.  
     
     
         82 . A pharmaceutical composition comprising valsartan in the solid state with a thermogram lacking a melting point above about 1 J/g, and a pharmaceutically acceptable excipient.  
     
     
         83 . A method for treating hypertension in a mammal comprising the step of administering the pharmaceutical composition of  claim 82  to the mammal in need thereof.  
     
     
         84 . A pharmaceutical composition comprising a crystalline valsartan selected from the group consisting of Form II, III, IV, VI, VII, VIII, IX, X, XI and XIII, and a pharmaceutically acceptable excipient.  
     
     
         85 . A method for treating hypertension comprising the step of administering the pharmaceutical composition of  claim 84  to the mammal in need thereof.