HCl Polymorphs of 3-((2-(Dimethylamino)methyl-(cyclohex-1-yl))phenol

Abstract

A crystalline salt of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol and hydrogen chloride, preferably in a 1:1 composition, including various crystalline forms of this salt, processes for preparing the various crystalline forms of this salt, pharmaceutical compositions containing the various crystalline forms of this salt, and the use of this salt as a pharmacologically active agent in a pharmaceutical composition to treat or inhibit pain or other disorders or disease states.

1 . A crystalline salt of hydrogen chloride and 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol. 
   
   
       2 . A crystalline salt according to  claim 1 , wherein said salt is 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride corresponding to formula (1) 
     
       
         
         
             
             
         
       
     
   
   
       3 . A crystalline salt according to  claim 1 , wherein said salt is in the form of a diastereomer or a mixture of enantiomeric diastereomers wherein the phenol ring and the dimethylaminomethyl group are in a trans configuration. 
   
   
       4 . A crystalline salt according to  claim 3 , wherein said salt is in the form of an enantiomer with a (1R,2R) absolute configuration. 
   
   
       5 . A crystalline salt according to  claim 1 , wherein said salt exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with characteristic lines corresponding to the following 2theta values: 11.2 (w), 14.1 (m), 17.1 (w), 19.5 (w), 19.8 (vs), 20.5 (w), 21.5 (m), 24.1 (m), 26.1 (s), 26.8 (w), and 31.3 (m). 
   
   
       6 . A crystalline salt according to  claim 1 , which exhibits the X-ray diffraction pattern of  FIG. 1 . 
   
   
       7 . A crystalline salt according to  claim 1 , which exhibits the Raman spectrum of  FIG. 2 . 
   
   
       8 . A crystalline salt according to  claim 1 , wherein said salt is crystalline form III and exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with pronounced characteristic lines corresponding to the following 2theta values: 6.9 (s), 13.9 (m), 16.3 (m), 17.7 (w), 20.9 (vs), 22.1 (w), 22.5 (w), and 27.8 (w). 
   
   
       9 . A crystalline salt according to  claim 1 , wherein said salt is crystalline form III and exhibits the X-ray diffraction pattern of  FIG. 5 . 
   
   
       10 . A crystalline salt according to  claim 1 , wherein said salt is crystalline form III and exhibits the Raman spectrum of  FIG. 6 . 
   
   
       11 . A crystalline salt according to  claim 1 , wherein said salt exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with pronounced characteristic lines corresponding to the following 2theta values: 12.0 (m), 13.0 (m), 17.3 (m), 17.7 (m), 19.2 (s), 19.7 (m), 20.2 (m), 21.3 (m), 23.4 (m), 24.2 (m), 24.6 (m), 43.1 (vs), and 44.2 (vs). 
   
   
       12 . A crystalline salt according to  claim 1 , wherein said salt exhibits the X-ray diffraction pattern of  FIG. 7 . 
   
   
       13 . A crystalline salt according to  claim 1 , wherein said salt exhibits the Raman spectrum of  FIG. 8 . 
   
   
       14 . A crystalline salt according to  claim 1 , wherein said salt is a hydrate which exhibits a proportion of water of crystallization within the range from 1% to 10%, relative to the weight of hydrate. 
   
   
       15 . A crystalline salt according to  claim 14 , wherein the proportion of water of crystallization lies within the range from 5% to 9%. 
   
   
       16 . A crystalline salt according to  claim 14 , wherein the proportion of water of crystallization lies within the range from 6% to 8.5%. 
   
   
       17 . A crystalline salt according to  claim 14 , wherein the proportion of water of crystallization lies within the range from 7% to 8%. 
   
   
       18 . A crystalline salt according to  claim 1 , wherein said salt is crystalline form V and is a hydrate which exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with pronounced characteristic lines corresponding to the following 2theta values: 11.4 (m), 12.1 (m), 16.7 (w), 19.2 (m), 19.4 (w), 20.1 (m), 21.1 (m), 22.4 (vs), 24.0 (m), and 31.3 (w). 
   
   
       19 . A crystalline salt according to  claim 1 , wherein said salt is crystalline form V and exhibits the X-ray diffraction pattern of  FIG. 9 . 
   
   
       20 . A crystalline salt according to  claim 1 , wherein said salt is crystalline form V and exhibits the Raman spectrum of  FIG. 10 . 
   
   
       21 . A process for preparing crystalline form I of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride according to  claim 5 , said process comprising:
 a) stirring crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride and crystalline form IV or V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent until complete formation of crystalline form I occurs, or   b) stirring crystalline form II of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride and crystalline form I of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent until complete formation of crystalline form I occurs.   
   
   
       22 . Crystalline form I of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride obtained by the process of  claim 21 . 
   
   
       23 . A process for preparing crystalline form III of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride according to  claim 11 , said process comprising:
 a) dissolving 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the form of an ethanol solvate or acetone solvate in a solvent, stirring the resulting solution and subsequently precipitating crystalline form III; or   b) stirring a suspension of amorphous 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent as a carrier at a temperature between 30° C. and 80° C. until complete formation of crystalline form III occurs.   
   
   
       24 . A process according to  claim 23 , wherein said solvent in b) is a solvent that does not form solvates, and said stirring in b) is effected at a temperature between 35° C. and 50° C. 
   
   
       25 . Crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride obtained by the process of  claim 23 . 
   
   
       26 . A process for preparing crystalline form IV of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride according to  claim 11 , said process comprising:
 a) heat treating crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride at a temperature between 150° C. and 160° C. until complete formation of crystalline form IV occurs, or   b) stirring a suspension of amorphous 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent as a carrier at a temperature between 40° C. and 120° C. until complete formation of crystalline form IV occurs; or   c) stirring crystalline form IV of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride and crystalline form III of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride in a solvent until complete formation of crystalline form IV occurs.   
   
   
       27 . A process according to  claim 26 , wherein:
 the heat treatment in a) is effected at a temperature between 154° C. and 158° C.; or   the solvent in b) is a solvent that does not form solvates, and the heat treatment in b) is effected at a temperature between 40° C. and 100° C.   
   
   
       28 . Crystalline form IV of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride obtained by the process of  claim 26 . 
   
   
       29 . A process for preparing crystalline form V of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride according to  claim 18 , said process comprising:
 a) allowing crystalline form I, II, III or IV of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride to stand in air, or treating crystalline form I, II, III or IV of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride with water vapor, or   b) stirring a suspension of amorphous 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride in water optionally mixed with at least one solvent as a carrier at a temperature between 20° C. and 60° C., and subsequently removing remaining water and solvent.   
   
   
       30 . A process according to  claim 29 , wherein the stirring in b) is carried out at a temperature between 20° C. and 30° C. 
   
   
       31 . Crystalline form V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride obtained by the process of  claim 29 . 
   
   
       32 . A pharmaceutical composition comprising a crystalline salt of 3-[2-(dimethyl-amino)methyl(cyclohex-1-yl)]phenol hydrochloride according to  claim 1  and at least one pharmaceutical carrier or diluent. 
   
   
       33 . A pharmaceutical composition according to  claim 32 , wherein said salt is present as crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V or a mixture of two or more of crystalline forms I, II, III, IV and V. 
   
   
       34 . A pharmaceutical composition according to  claim 32 , wherein said salt is present as crystalline form V. 
   
   
       35 . A method of treating pain in a subject in need thereof, said method comprising administering to said subject an analgesically effective amount of a crystalline salt according to  claim 1 .