Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it

Abstract

A new crystalline form of the Zoledronic acid, characterized by its X-rays diffractogram as well as by its spatial atomic distribution in the red crystalline and its curves of thermal analysis. There is also included a method to obtain this crystalline form, which includes the synthesis of the corresponding acid and the pharmaceutical composition this crystalline form comprises.

1 . A procedure to prepare crystalline zoledronic acid trihydrate, comprising: 
 (a) dissolving zoledronic acid in a solvent at an elevated temperature to obtain a concentrate; and    (b) progressively contacting the solution of step (a) with a lower temperature phase to crystallize zoledronic acid, such that substantially all crystallization occurs within the range of 5 to 35° C.    
     
     
         2 . The procedure as in  claim 1 , further comprising: 
 (c) further cooling the (suspension) of step (b), filtering the solid and washing the filtrated solid with water; and    (d) drying the washed solid.    
     
     
         3 . The procedure as in  claim 1 , wherein substantially all crystallization occurs within the range of 15 to 25° C.  
     
     
         4 . The procedure as in  claim 1 , wherein said solvent is water.  
     
     
         5 . The procedure as in  claim 1 , wherein said lower temperature phase is water.  
     
     
         6 . The procedure as in  claim 1 , wherein said lower temperature phase is metal or glass.  
     
     
         7 . The procedure as in  claim 6 , wherein said metal or glass are in the form of a tube.  
     
     
         8 . The procedure as in  claim 1 , wherein an X-ray powder diffraction pattern of the product of step (d), at a K-alpha wavelength of 1.54060, presents peaks in angles of 2θ at the following values: 9.2; 10.4; 10.8; 14.7; 16.4; 17.1; 18.4; 21.5; 21.8; 22.8; 25.0; 25.4; 27.8°±0.2°.  
     
     
         9 . The procedure as in  claim 8 , wherein X-ray powder diffraction was executed with scans performed over the range of 5°-40° 2θ, at a 0.02° step size for 2 s per step.  
     
     
         10 . The procedure as in  claim 1 , wherein thermogravimetry demonstrates that the zoledronic acid trihydrate has an activation energy of 179.9 kJ/ mole at 50.0 percent of conversion level.  
     
     
         11 . The procedure as in  claim 1 , wherein a study by means of X rays of a single crystal shows that the distribution of its atoms in the crystalline network corresponds to the special group P-i, characterized by the following cell parameters (A): a: 6.874; b: 9.450; c: 10.825; α (alpha): 65.140; β (beta): 76.830; γ (gamma): 81.390.  
     
     
         12 . The procedure as in  claim 1 , wherein the crystalline trihydrate upon exposure in an environment with 75 to 96% relative humidity at 30-40° C. during 24 hours, does not absorb water and maintains its X-rays powder diffractogram and its thermal profile (TGA and DSC) unchanged.  
     
     
         13 . The procedure as in  claim 1 , wherein thermal analysis (TGA and DSC) of the crystalline trihydrate shows an endotherm between 68-128° C. associated with a loss of mass of around 16-17%, which corresponds to a trihydrate, and a melting endotherm followed by decomposition at around 211-215° C.  
     
     
         14 . A crystalline trihydrate of zoledronic acid characterized by: 
 an X- ray powder diffraction pattern with peaks in angles of 2θ at the following values: 9.2; 10.4; 10.8; 14.7; 16.4; 17.1.; 18.4; 21.5; 21.8; 22.8; 25.0; 25.4; 27.8°±0.2°.    a thermogravimetric analysis in which a loss of mass is seen, corresponding to a loss of water, of 16-17%;    a Differential Scanning Calorimetry curve showing an endotherm at 211-215° C., which corresponds to the melting process; and    an Infrared Spectrum (KBr) Absorption at 3578-3011; 1643.6; 1579.9; 1549.1; 1443.0; 1414.0; 1387.0; 1294.4; 1155.5; 966.5 cm 1 .    
     
     
         15 . The crystalline trihydrate of  claim 14 , wherein thermogravimetry demonstrates that the zoledronic acid trihydrate has an activation energy of 179.9 kJ/mole at 50.0 percent of conversion level.  
     
     
         16 . The crystalline trihydrate of  claim 14 , wherein a study by means of X rays of a single crystal shows that the distribution of its atoms in the crystalline network corresponds to the special group P-i, characterized by the following cell parameters (A): a: 6.874; b: 9.450; c: 10.825; α (alpha): 65.140; β (beta): 76.830; γ (gamma): 81.390.  
     
     
         17 . The crystalline trihydrate of  claim 14 , wherein the crystalline trihydrate upon exposure in an environment with 75 to 96% relative humidity at 30-40° C. during 24 hours, does not absorb water and maintains its X-rays powder diffractogram and its thermal profile (TGA and DSC) unchanged.  
     
     
         18 . A procedure to prepare a crystalline form of trihydrated zoledronic acid, comprising the following steps: 
 a. reacting 1-imidazol-1-yl acetic acid with phosphorous trichloride and water, using methanesulphonic acid as a solvent, in an absence of phosphorous acid;    b. hydrolyzing, by adding water and heating, the intermediate substances generated in the reaction;    c. precipitating the crude acid of the reaction means, through partial neutralization and cooling;    d. dissolving the crude zoledronic acid in solvent at elevated temperature to form a concentrated solution;    e. introducing the concentrated solution into refrigerated water, so that crystallization occurs at a temperature below the elevated temperature;    f. once the crystallization is completed, further cooling down the product of step (e), filtering the precipitate and washing it with water; and    g. drying the product of step (f).    
     
     
         19 . The procedure according to  claim 18 , wherein the molar ratio in step a. of phosphorous trichloride: 1-imidazol-1-yl acetic acid is from 3:1 to 8:1.  
     
     
         20 . The procedure according to  claim 18 , wherein the molar ratio in step a. of phosphorous trichloride: water is from 0.8:1 to 1.2:1.  
     
     
         21 . The procedure according to  claim 18 , wherein the hydrolysis in step b. is conducted at a temperature between 80 and 125° C., during at least half an hour.  
     
     
         22 . The procedure according to  claim 18 , wherein the neutralization of step is conducted by means of an aqueous solution of hydroxides or carbonates of alkaline metals.  
     
     
         23 . The procedure according to  claim 18 , wherein in the partial neutralization, the solution is adjusted to a pH from 0 to 0.9.  
     
     
         24 . The procedure according to  claim 18 , wherein in the partial neutralization, the solution is adjusted to a pH from 0 to 0.4.  
     
     
         25 . The procedure according to  claim 18 , wherein the concentration of the zoledronic acid in the hot solution of the step d. is from 1 to 3.5% (w/v).  
     
     
         26 . The procedure according to  claim 18 , wherein the dissolution temperature of the step d. is comprised from 50 to 105° C., 17.  
     
     
         27 . The procedure according to  claim 26 , wherein the dissolution temperature is within the range from 80 to 100° C.  
     
     
         28 . The procedure according to  claim 18 , wherein the crystallization temperature of the step e. is from 5 to 35° C., inclusive.  
     
     
         29 . The procedure according to  claim 18 , wherein the crystallization temperature is from 15 to 25° C.  
     
     
         30 . The procedure according to  claim 18 , wherein the drying of step g. is at atmospheric pressure and at a temperature from 20 to 80° C.  
     
     
         31 . The procedure according to  claim 30 , wherein the drying is made at the atmospheric pressure and at a temperature from 30 to 60° C.  
     
     
         32 . A solid form of zoledronic acid suitable for formulating a pharmaceutical composition, said solid form comprising a crystalline form of trihydrated zoledronic acid as an active ingredient and less than 5% monohydrate and/or anhydride based on the total zoledronic acid content.  
     
     
         33 . The solid form of zoledronic acid according to  claim 32 , wherein an X-ray powder diffraction pattern of the crystalline zoledronic acid trihydrate presents peaks in angles of 2θ at the following values: 9.2; 10.4; 14.7; 16.4°±0.2°.