Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation

Abstract

The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt.

1 . Crystalline solid zoledronic acid (Form I) characterized by a powder X-ray diffraction pattern having peaks at 12.1, 12.8, 15.7, and 18.9±0.2° 2θ.  
     
     
         2 . The crystalline solid zoledronic acid of  claim 1  further characterized by a powder X-ray diffraction pattern with peaks at 20.9, 21.3, 21.8, 22.2, 25.8, 27.6, 29.2, 32.5, and 32.9±0.2° 2θ.  
     
     
         3 . The crystalline solid zoledronic acid of  claim 1 , which contains less than about 5% of other polymorphic forms of zoledronic acid.  
     
     
         4 . The crystalline solid zoledronic acid of  claim 1 , of which no more than about 5% transforms to zoledronic acid Form II upon exposure to 100% relative humidity (RH) for 7 days.  
     
     
         5 . The crystalline solid zoledronic acid of  claim 4 , of which no more than about 5% transforms to other polymorphic forms of zoledronic acid upon exposure to 100% relative humidity (RH) for 7 days.  
     
     
         6 . The crystalline solid zoledronic acid of  claim 1 , which, upon exposure to 100% relative humidity (RH) for 7 days, absorbs less than about 0.2% water.  
     
     
         7 . The crystalline solid zoledronic acid of  claim 1 , which, upon exposure to 100% relative humidity (RH) for 7 days, retains its X-ray diffraction pattern substantially as shown in  FIG. 1 .  
     
     
         8 . The crystalline solid zoledronic acid of  claim 1 , of which no more than about 5% transforms to zoledronic acid form II upon exposure to 75% relative humidity (RH) at 40° C. for 3 months.  
     
     
         9 . The crystalline solid zoledronic acid of  claim 8 , of which no more than about 5% transforms to other polymorphic forms of zoledronic acid upon exposure to 75% relative humidity (RH) at 40° C. for 3 months.  
     
     
         10 . The crystalline solid zoledronic acid of  claim 1 , which, upon exposure to 75% relative humidity (RH) at 40° C. for 3 months, absorbs less than about 0.2% water.  
     
     
         11 . The crystalline solid zoledronic acid of  claim 1 , which, upon exposure to 75% relative humidity (RH) at 40° C. for 3 months, retains its X-ray diffraction pattern substantially as shown in  FIG. 1 .  
     
     
         12 . A pharmaceutical composition comprising the crystalline zoledronic acid of  claim 1 .  
     
     
         13 . The crystalline solid zoledronic acid of  claim 1 , which is a monohydrate.  
     
     
         14 . Crystalline solid zoledronic acid (Form II) characterized by a powder X-ray diffraction pattern having peaks at 14.6, 15.4, 19.1, 22.9, and 23.9±0.2° 2θ.  
     
     
         15 . The crystalline zoledronic acid of  claim 14 , further characterized by a powder X-ray diffraction pattern with peaks at 20.8, 21.7, 25.1, 26.7, 29.5, 29.9, and ±0.2° 2θ.  
     
     
         16 . The crystalline solid zoledronic acid of  claim 14 , which is a monohydrate.  
     
     
         17 . Crystalline solid zoledronic acid (Form XII) characterized by a powder X-ray pattern having peaks at 9.0, 13.9, 14.8, 21.5, 24.7, and 29.8±0.2° 2θ.  
     
     
         18 . The crystalline zoledronic acid of  claim 17 , further characterized by a powder X-ray diffraction pattern with peaks at 17.0, 20.6, 20.8, 22.4, 25.8, 27.7, 28.4, 28.7, 29.1, 30.8, 3.19, 32.3, and 32.9±0.2° 2θ.  
     
     
         19 . The crystalline solid zoledronic acid of  claim 17 , which is a monohydrate.  
     
     
         20 . Crystalline solid zoledronic acid (Form XV) characterized by a powder X-ray diffraction pattern having peaks at 10.1, 17.3, 19.3, and 23.2±0.2° 2θ.  
     
     
         21 . The crystalline zoledronic acid of  claim 20 , further characterized by a powder X-ray diffraction pattern with peaks at 14.5, 16.7, 18.1, 24.5, 25.1, 25.7, 28.5, 29.1, 29.6, and 30.4±0.2° 2θ.  
     
     
         22 . The crystalline solid zoledronic acid of  claim 20 , which is anhydrous.  
     
     
         23 . Crystalline solid zoledronic acid (Form XVIII) characterized by a powder X-ray diffraction pattern having peaks at 10.7, 13.0, 16.4, 17.4, and 28.5±0.2° 2θ.  
     
     
         24 . The crystalline zoledronic acid of  claim 23 , further characterized by a powder X-ray diffraction pattern with peaks at 13.3, 18.1, 19.3, 21.3, 23.7, 25.9, 31.5, and 34.5±0.2° 2θ.  
     
     
         25 . The crystalline solid zoledronic acid of  claim 23 , which is a monohydrate.  
     
     
         26 . Crystalline solid zoledronic acid (Form XX) characterized by a powder X-ray diffraction pattern having peaks at 12.2, 19.3, 20.2, 21.3, 25.1, and 27.25±0.2° 2θ.  
     
     
         27 . The crystalline zoledronic acid of  claim 26 , further characterized by a powder XRD pattern with peaks at 11.4, 14.9, 15.5, 17.2, 18.2 and 30.5±0.2° 2θ.  
     
     
         28 . The crystalline solid zoledronic acid of  claim 26 , which is anhydrous.  
     
     
         29 . Crystalline solid zoledronic acid (Form XXVI) characterized by a powder X-ray diffraction pattern having peaks at 9.8, 14.5, 17.1, 17.6, and 18.3±0.2° 2θ.  
     
     
         30 . The crystalline zoledronic acid of  claim 29 , further characterized by a powder X-ray diffraction pattern with peaks at 18.8, 19.7, 21.4, 25.7, 26.6, and 28.1±0.2° 2θ.  
     
     
         31 . The crystalline solid zoledronic acid of  claim 29 , which is anhydrous.  
     
     
         32 . A pharmaceutical composition comprising the crystalline solid zoledronic acid of  claim 14 .  
     
     
         33 . Crystalline solid zoledronate monosodium.  
     
     
         34 . Crystalline solid zoledronate monosodium hydrate.  
     
     
         35 . The crystalline solid zoledronate monosodium of  claim 33 , characterized by a powder X-ray diffraction pattern having peaks at 8.2, 15.5, 18.6, 23.6, and 26.8±0.2° 2θ (Form VIII).  
     
     
         36 . The crystalline solid zoledronate monosodium of  claim 35 , further characterized by a powder X-ray diffraction pattern with peaks at 11.8, 17.6, 20.1, 24.7, 25.0, 28.4, 31.7, and 32.8±0.2° 2θ.  
     
     
         37 . The crystalline solid zoledronate monosodium of  claim 35 , which is a trihydrate.  
     
     
         38 . The crystalline solid zoledronate monosodium of  claim 33 , characterized by a powder X-ray diffraction pattern having peaks at 7.3, 8.8, 14.7, 21.8, and 29.6±0.2° 2θ (form XVI).  
     
     
         39 . The crystalline solid zoledronate monosodium of  claim 38 , further characterized by a powder X-ray diffraction pattern with peaks at 13.8, 16.8, 20.4, 21.4, 24.4, 25.6, 27.5, 28.2, and 31.7±0.2° 2θ.  
     
     
         40 . The crystalline solid zoledronate monosodium of  claim 38 , which is a dihydrate.  
     
     
         41 . The crystalline solid zoledronate monosodium of  claim 33 , characterized by a powder X-ray diffraction pattern having peaks at 8.2, 9.0, 14.5, 21.4, 24.5, and 29.2±0.2° 2θ (Form XVII).  
     
     
         42 . The crystalline solid zoledronate monosodium of  claim 41 , further characterized by a powder X-ray diffraction pattern with peaks at 13.9, 15.5, 16.8, 18.6, 22.3, 23.6, 26.7, 27.7, and 32.3±0.2° 2θ.  
     
     
         43 . The crystalline solid zoledronate monosodium of  claim 41 , which is a dihydrate.  
     
     
         44 . Crystalline solid zoledronate disodium.  
     
     
         45 . Crystalline solid zoledronate disodium hydrate.  
     
     
         46 . Crystalline solid zoledronate disodium anhydrous.  
     
     
         47 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having at 11.3, 14.8, 15.5, 17.4, and 19.9±0.2° 2θ (Form V).  
     
     
         48 . The crystalline solid zoledronate disodium of  claim 47 , further characterized by a powder X-ray diffraction pattern with peaks at 18.0, 18.9, 19.7, 22.7, 25.0, 26.7, 30.9, and 34.5±0.2° 2θ.  
     
     
         49 . The crystalline solid zoledronate disodium of  claim 47 , which is a dihydrate.  
     
     
         50 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 7.2, 13.3, 13.7, 14.5, and 21.7±0.2° 2θ (Form VI).  
     
     
         51 . The crystalline solid zoledronate disodium of  claim 50 , further characterized by a powder X-ray diffraction pattern with peaks at 8.2, 16.6, 16.9, 17.3, 25.9, 26.6, 30.7, 31.9, and 32.9±0.2° 2θ.  
     
     
         52 . The crystalline solid zoledronate disodium of  claim 50 , which is a trihydrate.  
     
     
         53 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 6.2 11.6, 12.6, 13.7±0.2° 2θ (Form VII).  
     
     
         54 . The crystalline solid zoledronate disodium of  claim 53 , further characterized by a powder X-ray diffraction pattern with peaks at 22.0, 23.2, 26.4, 27.1, 28.6, 28.8, 34.2±0.2° 2θ.  
     
     
         55 . The crystalline solid zoledronate disodium of  claim 53 , which is a tetrahydrate.  
     
     
         56 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 6.7, 14.4, 18.2, 20.4, and 20.7±0.2° 2θ (Form X).  
     
     
         57 . The crystalline solid zoledronate disodium of  claim 56 , further characterized by a powder X-ray diffraction pattern with peaks at 8.8, 13.7, 17.0, 19.8, 21.3, 24.4, 27.5, 27.9, 30.9, and 33.4±0.2° 2θ.  
     
     
         58 . The crystalline solid zoledronate disodium of  claim 56 , which is a hemihydrate.  
     
     
         59 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 6.5, 13.0, 16.1, 17.2, and 30.7±0.2° 2θ (Form XIII).  
     
     
         60 . The crystalline solid zoledronate disodium of  claim 59 , further characterized by a powder X-ray diffraction pattern with peaks at 10.2, 19.0, 20.0, 20.6, 22.3, 27.4, 28.6, 28.9, and 34.8±0.2° 2θ.  
     
     
         61 . The crystalline solid zoledronate disodium of  claim 59 , which is a hemihydrate.  
     
     
         62 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 6.6, 19.9, 28.5, and 34.8±0.2° 2θ (Form XIV).  
     
     
         63 . The crystalline solid zoledronate disodium of  claim 62 , further characterized by a powder X-ray diffraction pattern with peaks at 13.0, 15.1, 17.1, 20.5, 27.7, 29.6, 30.7, and 33.5±0.2° 2θ.  
     
     
         64 . The crystalline solid zoledronate disodium of  claim 62 , which is anhydrous.  
     
     
         65 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 11.6, 12.5, 13.7, 22.0, and 23.1±0.2° 2θ (Form XIX).  
     
     
         66 . The crystalline solid zoledronate disodium of  claim 65 , further characterized by a powder X-ray diffraction pattern with peaks at 6.2, 14.3, 15.3, 16.0, 18.5, 24.3, and 28.6±0.2° 2θ.  
     
     
         67 . The crystalline solid zoledronate disodium of  claim 65 , which is a pentahydrate.  
     
     
         68 . The crystalline solid zoledronate disodium of  claim 44 , characterized by a powder X-ray diffraction pattern having peaks at 7.4, 13.7, 17.6, and 21.9±0.2° 2θ (Form XXV).  
     
     
         69 . The crystalline solid zoledronate disodium of  claim 68 , further characterized by a powder X-ray diffraction pattern with peaks at 6.3, 9.5, 12.6, 14.6, 26.2, 27.1, and 28.6±0.2° 2θ.  
     
     
         70 . The crystalline solid zoledronate disodium of  claim 68 , which is a sesquihydrate.  
     
     
         71 . The crystalline solid zoledronate disodium of  claim 44 , which is a monohydrate characterized by a powder X-ray diffraction pattern having peaks at 6.4, 8.2, 16.0, 17.4, 19.0, and 28.8±0.2° 2θ (Form XXVI).  
     
     
         72 . The crystalline solid zoledronate disodium of  claim 71 , further characterized by a powder X-ray diffraction pattern with peaks at 7.7, 10.2, 17.2, 18.1, 21.6, 25.7, and 25.9±0.2° 2θ.  
     
     
         73 . The crystalline solid zoledronate disodium of  claim 71 , which is a monohydrate.  
     
     
         74 . Crystalline solid zoledronate trisodium.  
     
     
         75 . The crystalline solid zoledronate trisodium of  claim 74 , characterized by a powder X-ray diffraction pattern having peaks at 8.3, 10.9, 15.0, 16.6, and 22.8±0.2° 2θ (Form IX).  
     
     
         76 . The crystalline solid zoledronate trisodium of  claim 75 , further characterized by a powder X-ray diffraction pattern with peaks at 13.1, 20.2, 20.6, 20.9, 25.0, 27.8, and 29.0±0.2° 2θ.  
     
     
         77 . The crystalline solid zoledronate trisodium of  claim 75 , which is a trihydrate.  
     
     
         78 . The crystalline solid zoledronate trisodium of  claim 74 , characterized by a powder X-ray diffraction pattern having peaks at 6.2, 7.9, 8.8, 10.6, and 12.2±0.2° 2θ (Form XI).  
     
     
         79 . The crystalline solid zoledronate trisodium of  claim 78 , further characterized by a powder X-ray diffraction pattern with peaks at 15.0, 15.4, 17.5, 18.8, 19.6, 20.5, 22.3, 23.7, 25.7, 29.6, and 31.7 0.2° 2θ.  
     
     
         80 . The crystalline solid zoledronate trisodium of  claim 78 , which is a dihydrate.  
     
     
         81 . A process for preparing a solid crystalline zoledronate sodium salt comprising: 
 a) dissolving zoledronic acid in water to form a solution;    b) adding a base to the solution; and    c) cooling the solution to precipitate crystalline zoledronate sodium.    
     
     
         82 . The process of  claim 81 , wherein the crystalline solid zoledronate sodium salt is the monosodium salt.  
     
     
         83 . The process of  claim 82 , wherein the crystalline solid zoledronate monosodium is selected from the group consisting of Form VIII, Form XVI and Form XVII.  
     
     
         84 . The process of  claim 81 , wherein the crystalline solid zoledronate sodium salt is the disodium salt.  
     
     
         85 . The process of  claim 84 , wherein the crystalline solid zoledronate disodium is selected from the group consisting of Form V, Form VI, Form VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, and Form XXVII.  
     
     
         86 . The process of  claim 81 , wherein the crystalline solid zoledronate sodium salt is the trisodium salt.  
     
     
         87 . The process of  claim 86 , wherein the crystalline solid zoledronate trisodium is selected from the group consisting of Form IX and Form XI.  
     
     
         88 . A process for preparing a crystalline solid zoledronate sodium salt comprising: 
 a) suspending zoledronic acid in a mixture of alcohol/water    b) adding to the suspension of a) a solution of a base, in an equivalent mixture of alcohol/water as that used in the suspension of a), to form a reaction mixture; and    c) stirring the reaction mixture for a time sufficient to precipitate a crystalline solid zoledronate sodium salt.    
     
     
         89 . The process of  claim 88 , wherein the reaction mixture is stirred at reflux for about 10 to about 20 hours.  
     
     
         90 . The process of  claim 88 , wherein the volume ratio of alcohol/water to zoledronic acid in a) and b) is 6-14 volumes.  
     
     
         91 . The process of  claim 88 , wherein the alcohol in a) and b) is selected from the group consisting of methanol, ethanol, isopropanol and dimethylformamide.  
     
     
         92 . The process of  claim 88 , wherein the zoledronic acid is zoledronic acid Form I and the ratio of acid to base is 1:1.  
     
     
         93 . The process of  claim 88 , wherein the zoledronic acid is zoledronic acid Form I and the ratio of acid to base is 1:2.  
     
     
         94 . The process of  claim 88 , wherein the zoledronic acid is zoledronic acid Form XII and the ratio of acid to base is 1:1.1.  
     
     
         95 . The process of  claim 92 , wherein the crystalline solid zoledronate sodium salt is the monosodium salt.  
     
     
         96 . The process of  claim 95 , wherein the crystalline solid zoledronate monosodium is selected from the group consisting of Form VIII, Form XVI and Form XVII.  
     
     
         97 . The process of  claim 93  or  claim 94 , wherein the crystalline solid zoledronate sodium salt is the disodium salt.  
     
     
         98 . The process of  claim 97 , wherein the crystalline solid zoledronate disodium is selected from the group consisting of Form V, Form VI, Form VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, and Form XXVII.  
     
     
         99 . The process of  claim 88 , wherein the zoledronic acid is zoledronic acid Form XII and the ratio of acid to base is 1:2.1.  
     
     
         100 . The process of  claim 99 , wherein the crystalline solid zoledronate sodium salt is the trisodium salt.  
     
     
         101 . The process of  claim 100 , wherein the crystalline solid zoledronate trisodium is selected from the group consisting of Form IX and Form XI.  
     
     
         102 . A process for preparing a solid crystalline zoledronate sodium salt comprising: 
 a) dissolving a crystal form of zoledronate sodium in water to form a solution; and    b) cooling the solution to precipitate a crystal form of zoledronate sodium which is different from the starting form in a).    
     
     
         103 . The process of  claim 102 , wherein the water is added in an amount of between 20-30 volumes per volume of zoledronate sodium.  
     
     
         104 . A process for preparing crystalline solid zoledronate monosodium Form VIII comprising: 
 a) adding a solution of a base in an 80%/20% v/v mixture of water/ethanol to a suspension of zoledronic acid form I in an 80%/20% v/v mixture of water/ethanol at elevated temperature;    b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours; and    c) precipitating zoledronate monosodium Form VIII.    
     
     
         105 . The process of  claim 104 , wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.  
     
     
         106 . The process of  claim 104 , wherein the volume ratio of water/ethanol to zoledronic acid form I in the suspension and the solution is between 6-14.  
     
     
         107 . A process for preparing crystalline solid zoledronate monosodium Form VIII comprising: 
 a) adding a solution of a base in an 80%/20% v/v mixture of water/methanol to a suspension of zoledronic acid form I in an 80%/20% v/v mixture of water/methanol at elevated temperature;    b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours; and    c) precipitating zoledronate monosodium Form VIII.    
     
     
         108 . The process of  claim 107 , wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.  
     
     
         109 . The process of  claim 107 , wherein the volume ratio of water/methanol to zoledronic acid form I in the suspension and the solution is between 6-14.  
     
     
         110 . A process for preparing crystalline solid zoledronate monosodium Form VII comprising: 
 a) adding a solution of a base in an 60%/40% v/v mixture of water/isopropanol to a suspension of zoledronic acid form I in an 60%/40% v/v mixture of water/isopropanol at elevated temperature;    b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours; and    c) precipitating zoledronate monosodium Form VIII.    
     
     
         111 . The process of  claim 110 , wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.  
     
     
         112 . The process of  claim 110 , wherein the volume ratio of water/isopropanol to zoledronic acid form I in the suspension and the solution is between 6-14.  
     
     
         113 . A process for preparing crystalline solid zoledronate monosodium Form XVI comprising: 
 a) adding a solution of a base in a 50%/50% v/v mixture of water/ethanol to a suspension of zoledronic acid form I in a 50%/50% v/v mixture of water/ethanol at elevated temperature;    b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours; and    c) precipitating zoledronate monosodium Form XVI.    
     
     
         114 . The process of  claim 113 , wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.  
     
     
         115 . The process of  claim 113 , wherein the volume ratio of water/ethanol to zoledronic acid form I in the suspension and the solution is between 6-14.  
     
     
         116 . A process for preparing crystalline solid zoledronate monosodium Form XVI comprising: 
 a) adding a solution of a base in a 50%/50% v/v mixture of water/isopropanol to a suspension of zoledronic acid Form I in a 50%/50% v/v mixture of water/isopropanol at elevated temperature;    b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours; and    c) precipitating zoledronate monosodium Form XVI.    
     
     
         117 . The process of  claim 116 , wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.  
     
     
         118 . The process of  claim 116  wherein the volume ratio of water/isopropanol to zoledronic acid form I in the suspension and the solution is between 6-14.  
     
     
         119 . A process for preparing crystalline solid zoledronate monosodium Form XVI comprising: 
 a) adding a solution of a base in a 50%/50% v/v mixture of water/methanol to a suspension of zoledronic acid form I in a 50%/50% v/v mixture of water/ethanol at elevated temperature;    b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours; and    c) precipitating zoledronate monosodium Form XVI.    
     
     
         120 . The process of  claim 119 , wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.  
     
     
         121 . The process of  claim 119 , wherein the volume ratio of water/methanol to zoledronic acid form I in the solution is between 6-14 and the volume ratio of water/ethanol in the suspension is between 6-14.  
     
     
         122 . A process-for preparing solid crystalline zoledronate sodium Form XVII comprising: 
 a) dissolving zoledronic acid Form I in water to form a solution;    b) adding a base to the solution; and    c) cooling the solution, optionally with the addition of an organic solvent, to precipitate crystalline zoledronate sodium Form XVII.    
     
     
         123 . A pharmaceutical composition comprising the crystalline solid zoledronate monosodium of  claim 33 .  
     
     
         124 . A pharmaceutical composition comprising the crystalline solid zoledronate disodium of  claim 44 .  
     
     
         125 . A pharmaceutical composition comprising the crystalline solid zoledronate trisodium of  claim 74 .  
     
     
         126 . Amorphous monosodium zoledronate.  
     
     
         127 . Amorphous disodium zoledronate.  
     
     
         128 . Amorphous trisodium zoledronate.  
     
     
         129 . A pharmaceutical composition comprising the amorphous solid zoledronate of  claim 126 .  
     
     
         130 . A process for preparing zoledronate amorphous sodium comprising: 
 treating zoledronic acid and a base, in water at room temperature and precipitating zoledronate amorphous sodium.    
     
     
         131 . The process of  claim 130 , wherein the ratio of acid:base is 1:1.1.  
     
     
         132 . The process of  claim 130 , wherein the ratio of acid:base is 1:2.1.