Crystal modification

Abstract

A novel crystal form of ,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride, processes for its preparation and its pharmaceutical use are disclosed.

We claim:  
     
         1 . The compound α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride having a melting point in the range from 138° C. to 148° C.  
     
     
         2 . The compound α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride having a melting point in the range from about 142° C. to about 145° C.  
     
     
         3 . A crystal modification of α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride characterized by powder x-ray diffraction peaks at d spacings of about 10.5, 8.1, 5.5, 5.4, 5.2, 4.42, 4.15, 3.82, 3.35.  
     
     
         4 . The crystal modification of  claim 3  having the powder x-ray diffraction pattern depicted in FIG. 1.  
     
     
         5 . The crystal modification of  claim 3  characterized by a melting point in the range from about 142° C. to about 145° C.  
     
     
         6 . A crystal modification of α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride characterized by solid state carbon-13 NMR signals at chemical shifts of about 187.4, 180.3, 74.5, 48.8, and 29.8 ppm.  
     
     
         7 . The crystal modification of  claim 6  having the solid state carbon-13 NMR spectrum depicted in FIG. 2.  
     
     
         8 . The crystal modification of  claim 6  having powder x-ray diffraction peaks at d spacings of about 10.5, 8.1, 5.5, 5.4, 5.2, 4.42, 4.15, 3.82, 3.35.  
     
     
         9 . The crystal modification of  claim 8  having a melting point in the range from about 142° C. to about 145° C.  
     
     
         10 . The crystal modification of  claim 8  having a melting point in the range from about 138° C. to 148° C.  
     
     
         11 . The crystal modification of  claim 7  having the powder x-ray diffraction pattern depicted in FIG. 1.  
     
     
         12 . The crystal modification of  claim 11  having the Fourier Transform Infrared Spectrum depicted in FIG. 3 as a Nujol oil mull.  
     
     
         13 . The crystal modification of  claim 12  having a melting point in the range from about 138° C. to about 148° C. in substantially pure form.  
     
     
         14 . The crystal modification of  claim 13  having a melting point in the range from about 142° C. to about 145° C. in pure form.  
     
     
         15 . The crystal modification of  claim 14  in highly pure form.  
     
     
         16 . A process for preparing the Form A crystal modification of α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride, which comprises 
 (a) preparing an aqueous solution of α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride; and  
 (b) crystallizing the α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride from the aqueous solution at a temperature of from 5° C. to 50° C.  
 
     
     
         17 . A process of  claim 16  wherein the temperature is in the range from 20° C. to 40° C.  
     
     
         18 . A process of  claim 17  wherein the temperature is in the range from 25° C. to 35° C.  
     
     
         19 . A process of  claim 18  wherein the temperature is about 30° C.  
     
     
         20 . A process of  claim 16  wherein the crystallization step is effected by reducing the volume of water in the aqueous solution by an amount sufficient to promote crystallization.  
     
     
         21 . A process of  claim 19  wherein the crystallization step is effected by reducing the volume of water in the aqueous solution by an amount sufficient to promote crystallization.  
     
     
         22 . A process of  claim 21  wherein the volume of water is reduced by evaporation.  
     
     
         23 . A process of  claim 16  wherein the α,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride produced is pure Form A crystal modification.