Polymorphic form XVI of fexofenadine hydrochloride

Abstract

Provided is a crystalline (polymorphic) form of fexofenadine hydrochloride, denominated fexofenadine hydrochloride Form XVI.

What is claimed is:  
     
         1 . A crystalline fexofenadine hydrochloride in the solid state characterized by data selected from the group consisting of a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1+0.2 degrees two theta; a DSC profile with two endothermic peaks at a temperature range of up to about 125° C. and an additional endotherm at a temperature of about 135° C.; and a TGA thermogram with a loss on drying (LOD) of about 6% to about 10% at a temperature range of up to about 145° C.  
     
     
         2 . The crystalline fexofenadine hydrochloride of  claim 1 , characterized by a DSC profile with two endothermic peaks at a temperature range of up to about 125° C. and an additional endotherm at a temperature of about 135° C.  
     
     
         3 . The crystalline fexofenadine hydrochloride of  claim 2 , wherein one of the two endothermic peaks is at a temperature of about 67° C. and the other at a temperature of about 120° C.  
     
     
         4 . The crystalline fexofenadine hydrochloride of  claim 3 , wherein the crystalline form is characterized by a DSC thermogram as substantially depicted in FIG. 2.  
     
     
         5 . The crystalline fexofenadine hydrochloride of  claim 1 , characterized with a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1±0.2 degrees two theta.  
     
     
         6 . The crystalline fexofenadine hydrochloride of  claim 5 , further characterized by a PXRD pattern with peaks at 5.2, 15.5, 17.0, 17.3, 19.6, 21.7, 22.5, 23.2, 24.0, 24.3, 25.6+0.2 degrees two theta.  
     
     
         7 . The crystalline fexofenadine hydrochloride of  claim 6 , further characterized by a PXRD pattern as substantially depicted in FIG. 1 
     
     
         8 . The crystalline form of  claim 5 , wherein the crystalline form is substantially free of other polymorphic forms of fexofenadine hydrochloride.  
     
     
         9 . The crystalline form of  claim 8 , wherein the crystalline form contains less than about 2% by weight of other polymorphic forms of fexofenadine hydrochloride.  
     
     
         10 . A pharmaceutical formulation comprising an effective amount of fexofenadine hydrochloride of  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         11 . The pharmaceutical formulation of  claim 10 , further comprising pseudoephedrine hydrochloride as an adjuvant.  
     
     
         12 . A method of inhibiting binding between an H 1  receptor and histamine in a patient suffering from contraction of the bronchi, vasodilation, itching or other inflammation response to histamine comprising administering to the patient the pharmaceutical composition of  claim 10 .  
     
     
         13 . A process for preparing the crystalline fexofenadine hydrochloride of  claim 1  comprising the steps of 
 a) combining fexofenadine free base, HCl and methanol to obtain a solution;  
 b) precipitating fexofenadine hydrochloride of  claim 1  in the presence of methanol; and  
 c) recovering the fexofenadine hydrochloride of  claim 1 .  
 
     
     
         14 . The process of  claim 13 , further comprising a step of drying the fexofenadine hydrochloride recovered in step (c).  
     
     
         15 . The process of  claim 14 , wherein the fexofenadine hydrochloride is recovered substantially free of other polymorphic forms of fexofenadine hydrochloride.  
     
     
         16 . The process of  claim 15 , wherein the fexofenadine hydrochloride recovered contains less than about 2% of other polymorphic forms of fexofenadine hydrochloride.  
     
     
         17 . The process of  claim 13 , wherein the crystalline form recovered has a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1±0.2 degrees two theta.  
     
     
         18 . The process of  claim 13 , further comprising the step of seeding the solution with fexofenadine hydrochloride Form XVI.  
     
     
         19 . The process of  claim 13 , wherein the solution further comprises a polar organic solvent.  
     
     
         20 . The process of  claim 19 , wherein the polar organic solvent is selected from the group consisting of an ether, an alcohol, an ester, a ketone and mixtures thereof.  
     
     
         21 . The process of  claim 20 , wherein the polar organic solvent is an alcohol.  
     
     
         22 . The process of  claim 21 , wherein the alcohol is iso-propyl alcohol.  
     
     
         23 . The process of  claim 13 , further comprising introducing an anti-solvent in step (b).  
     
     
         24 . The process of  claim 23 , wherein the anti-solvent is a hydrocarbon.  
     
     
         25 . The process of  claim 24 , wherein the hydrocarbon is saturated.  
     
     
         26 . The process of  claim 25 , wherein the hydrocarbon is selected from the group consisting of heptane and hexane.  
     
     
         27 . The process of  claim 13 , further comprising the step of reducing the solution of step (a) to a residue by removing the methanol and adding methanol to the residue.  
     
     
         28 . The process of  claim 27 , further comprising adding an anti-solvent to the residue.  
     
     
         29 . The process of  claim 28 , wherein the anti-solvent is a hydrocarbon.  
     
     
         30 . The process of  claim 29 , wherein the hydrocarbon is saturated.  
     
     
         31 . The process of  claim 30 , wherein the hydrocarbon is selected from the group consisting of heptane and hexane.  
     
     
         32 . The process of  claim 27 , wherein the methanol is removed by evaporation.  
     
     
         33 . The process of  claim 13 , further comprising the step of concentrating the solution before precipitation.  
     
     
         34 . The process of  claim 33 , wherein the solution is concentrated to a level of about 2 to about 2.5 volumes of methanol in comparison to the weight of fexofenadine base (ml/g).  
     
     
         35 . The process of  claim 34 , wherein the concentrating is carried out by evaporation.  
     
     
         36 . The process of  claim 33 , further comprising the step of seeding the solution with fexofenadine hydrochloride Form XVI.  
     
     
         37 . The process of  claim 33 , further comprising the step of stirring and cooling during step (b).  
     
     
         38 . The process of  claim 13 , wherein the fexofenadine hydrochloride recovered is substantially free of other polymorphic forms of fexofenadine hydrochloride.  
     
     
         39 . The process of  claim 38 , wherein the fexofenadine hydrochloride recovered contains less than about 2% of other polymorphic forms of fexofenadine hydrochloride.  
     
     
         40 . The process of  claim 13 , further comprising the step of stirring the precipitate before the recovery step at a temperature of from about minus 15° C. to about 10° C. for a sufficient time to increase the yield.  
     
     
         41 . A process for preparing crystalline fexofenadine hydrochloride of  claim 1  comprising the steps of 
 a) combining fexofenadine base, HCl and methanol to obtain a solution,  
 b) evaporating the methanol to obtain a residue;  
 c) adding methanol and a C 5  to C 12  hydrocarbon to the residue to precipitate fexofenadine hydrochloride of  claim 1;  and  
 d) recovering the fexofenadine hydrochloride of  claim 1 .  
 
     
     
         42 . The process of  claim 41 , wherein the hydrocarbon is heptane.  
     
     
         43 . A process for preparing crystalline fexofenadine hydrochloride of  claim 1  comprising the steps of: 
 a) combining a solution of HCl in a mixture of methanol and isopropyl alcohol, with fexofenadine base, to obtain a solution;  
 b) evaporating the methanol and the isopropyl alcohol to obtain a residue;  
 c) adding a mixture of methanol and heptane to the residue to precipitate crystalline fexofenadine hydrochloride of  claim 1;  and  
 d) recovering the fexofenadine hydrochloride of  claim 1 .  
 
     
     
         44 . A process for preparing crystalline fexofenadine hydrochloride of  claim 1  comprising the steps of 
 a) combining fexofenadine free base, HCl and methanol to obtain a solution;  
 b) removing the methanol to concentrate the solution;  
 c) seeding the solution with fexofenadine hydrochloride Form XVI;  
 d) stirring the solution;  
 e) cooling the solution; and  
 d) recovering the fexofenadine hydrochloride.  
 
     
     
         45 . A process for preparing fexofenadine hydrochloride of  claim 1 , comprising the step of stirring a slurry of fexofenadine hydrochloride amorphous in methanol for a sufficient time to obtain fexofenadine hydrochloride of  claim 1 .  
     
     
         46 . The process of  claim 45 , further comprising an anti-solvent in mixture with methanol.  
     
     
         47 . The process of  claim 46 , wherein the antisolvent is a hydrocarbon.  
     
     
         48 . The process of  claim 47 , wherein the hydrocarbon is a saturated hydrocarbon.  
     
     
         49 . The process of  claim 48 , wherein the hydrocarbon is heptane.  
     
     
         50 . The process of  claim 47 , wherein the ratio of methanol to the hydrocarbon is from about 3% to about 26% volume of methanol compared to volume of the hydrocarbon.  
     
     
         51 . A crystalline form of fexofenadine hydrochloride characterized by a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1+0.2, wherein the crystalline form has a water content of from about 6% to about 10% by weight.  
     
     
         52 . The crystalline form of  claim 51 , wherein the crystalline form has about 10% water by weight.  
     
     
         53 . A crystalline form of fexofenadine hydrochloride characterized by a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1+0.2, wherein the crystalline form with said PXRD peaks is substantially stable under storage at relative humidity of about 100% for at least about 1 week, and storage at about 40° C. and about a 75% relative humidity for at least about 6 months.  
     
     
         54 . A process for preparing a crystalline form of fexofenadine hydrochloride having a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1+0.2, comprising the steps of crystallizing the crystalline form with said PXRD peaks from a solution of fexofenadine hydrochloride in methanol and recovering the crystalline form.