Novel crystalline forms of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt

Abstract

The present invention relates to novel crystalline forms of sodium salt of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide (e.g., NXL-104) thereof. The present invention relates to compositions comprising a crystalline form of sodium salt of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide (e.g., NXL-104) alone or in combination with an antibacterial agent (e.g., ceftaroline fosamil). Processes for the preparation of the crystalline forms and methods of treating bacterial infections by administering the crystalline forms alone or in combination with an antibacterial agent (e.g., ceftaroline fosamil) are also described.

What is claimed is: 
     
         1 . A crystalline form of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The crystalline form according to  claim 1 , wherein the salt is a sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         3 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peak at about 13.0+/−0.5 degrees 2θ. 
     
     
         4 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peak at about 16.5+/−0.5 degrees 2θ. 
     
     
         5 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peaks at about 17.5+/−0.5 degrees 2θ. 
     
     
         6 . The crystalline form according to any one of  claims 3  to  5 , wherein the crystalline form has an X-Ray powder diffraction pattern further comprising a characteristic peak at about 17.3; about 22.3+/−0.5 degrees 2θ or a combination thereof. 
     
     
         7 . The crystalline form according to any one of  claims 3  to  5 , wherein the crystalline form has an X-Ray powder diffraction pattern further comprising a characteristic peak at about 19.2; about 19.5+/−0.5 degrees 2θ or a combination thereof. 
     
     
         8 . The crystalline form according to any one of  claims 3  to  5 , wherein the crystalline form has an X-Ray powder diffraction pattern further comprising a characteristic peak at about 19.9; about 22.0; about 25.2; about 28.2+/−0.5 degrees 2θ or a combination thereof. 
     
     
         9 . The crystalline form according to any one of  claims 3  to  5 , wherein the crystalline form has an X-Ray powder diffraction pattern further comprising a characteristic peak at about 23.2; about 30.2; about 30.9; about 36.1+/−0.5 degrees 2θ or a combination thereof. 
     
     
         10 . The crystalline form according to  claim 1 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peak at about 13.0; about 16.5; about 17.3; about 17.5; about 19.2; about 19.5; about 19.9; about 22.0; about 22.3; about 25.2; about 28.2+/−0.5 degrees 2θ or a combination thereof. 
     
     
         11 . The crystalline form according to  claim 1 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising characteristic peaks at about 13.0; about 16.5; about 17.3; about 17.5; about 19.2; about 19.5; about 19.9; about 22.0; about 22.3; about 23.2; about 25.2; about 28.2; about 30.2; about 30.9 and about 36.1+/−0.5 degrees 2θ. 
     
     
         12 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a d-spacing value at about 6.8+/−2 nm. 
     
     
         13 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a d-spacing value at about 5.1+/−2 nm. 
     
     
         14 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a d-spacing value at about 5.4+/−2 nm. 
     
     
         15 . The crystalline form according any one of  claims 12  to  14 , wherein the crystalline form has an X-Ray powder diffraction pattern further comprising a d-spacing value at about 3.2; about 3.5; about 4.0; about 4.5; about 4.6+/−2 nm or a combination thereof. 
     
     
         16 . The crystalline form according to  claim 1 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising d-spacing values at about 2.5; about 2.9; about 3.0; about 3.2; about 3.5; about 3.8; about 4.0; about 4.5; about 4.6; about 5.1; about 5.4; about 6.8+/−2 nm or a combination thereof. 
     
     
         17 . The crystalline form according to  claim 1 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising d-spacing values at about 2.5; about 2.9; about 3.0; about 3.2; about 3.5; about 3.8; about 4.0; about 4.5; about 4.6; about 5.1; about 5.4; and about 6.8+/−2 nm. 
     
     
         18 . A pharmaceutical composition comprising a crystalline form of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A pharmaceutical composition comprising a crystalline form of a sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide according to any one of  claims 3  to  5 . 
     
     
         20 . The composition according to  claim 18 , wherein the composition comprises loss than about 1.5% of a decarbonyl compound of Formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         21 . The composition according to  claim 20 , wherein the composition comprises about 0.05% to about 1.5% of the decarbonyl compound. 
     
     
         22 . The composition according to  claim 18 , further comprising an antibacterial agent. 
     
     
         23 . The composition according to  claim 22 , wherein the antibacterial agent is ceftaroline or a prodrug of ceftaroline. 
     
     
         24 . The composition according to  claim 23 , wherein the antibacterial agent is ceftaroline fosamil. 
     
     
         25 . The composition according to  claim 23 , wherein the antibacterial agent is anhydrous ceftaroline fosamil. 
     
     
         26 . The composition according to  claim 23 , wherein the antibacterial agent is ceftaroline fosamil monohydrate acetic acid solvate. 
     
     
         27 . The composition according to  claim 23 , wherein the composition comprises less than about 10% of impurities. 
     
     
         28 . The composition according to  claim 23 , wherein the composition comprises less than about 0.6% of a compound of Formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         29 . The composition according to  claim 23 , wherein the composition comprises less than about 0.6% of a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         30 . The composition according to  claim 23 , wherein the composition comprises less than about 5% of compound of Formula (V): 
       
         
           
           
               
               
           
         
       
     
     
         31 . The composition according to  claim 23 , wherein the composition comprises less than about 0.2% of a compound of Formula (VI): 
       
         
           
           
               
               
           
         
       
     
     
         32 . The composition according to  claim 23 , wherein the composition comprises less than about 0.2% of a compound of Formula (VII): 
       
         
           
           
               
               
           
         
       
     
     
         33 . The composition according to  claim 23 , wherein the composition comprises less than about 0.6% of a compound of Formula (VIII): 
       
         
           
           
               
               
           
         
       
     
     
         34 . The composition according to  claim 23 , wherein the composition comprises less than about 0.2% of a compound of Formula (IX): 
       
         
           
           
               
               
           
         
       
     
     
         35 . The composition according to  claim 23 , wherein the composition comprises less than about 0.2% of a compound of U Formula (X): 
       
         
           
           
               
               
           
         
       
     
     
         36 . The composition according to  claim 23 , wherein the composition comprises less than about 1.0% of a compound of Formula XI: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The composition according to  claim 23 , wherein the composition comprises less than about 1.5% of a compound of Formula (XII) 
       
         
           
           
               
               
           
         
       
     
     
         38 . A composition comprising about 200 mg to about 1200 mg of a crystalline form of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof wherein the composition provides an in vivo plasma profile for the crystalline form comprising a mean Cmax of less than about 100 ug/ml. 
     
     
         39 . The composition according to  claim 38 , wherein the composition comprises the sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         40 . The composition according to  claim 38 , wherein the composition comprises about 400 mg of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         41 . The composition according to  claim 38 , wherein the composition comprises about 600 mg of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         42 . The composition according to  claim 38 , wherein the composition comprises Form I. 
     
     
         43 . The composition according to  claim 38 , wherein the in vivo plasma profile comprises a mean Cmax of about 10 to 50 ug/ml. 
     
     
         44 . The composition according to  claim 38 , further comprising about 200 mg to 1200 mg of ceftaroline or a prodrug of ceftaroline wherein the composition provides an in vivo plasma profile for ceftaroline comprising a mean Cmax of less than about 100 ug/ml. 
     
     
         45 . The composition according to  claim 44 , wherein the composition comprises about 400 mg ceftaroline fosamil. 
     
     
         46 . The composition according to  claim 44 , wherein the composition comprises about 600 mg ceftaroline fosamil. 
     
     
         47 . The composition according to any one of  claim 45  or  46 , wherein the composition comprises ceftaroline fosamil monohydrate acetic acid solvate. 
     
     
         48 . A composition comprising about 200 mg to 1200 mg of a crystalline form of trans-?-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof wherein the composition provides an in vivo plasma profile for the crystalline form comprising a mean AUC 0-∞  of more than about 10 ug h/ml. 
     
     
         49 . The composition according to  claim 48 , wherein the composition comprises the sodium salt of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         50 . The composition according to  claim 48 , wherein the composition comprises about 400 mg of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         51 . The composition according to  claim 48 , wherein the composition comprises about 600 mg of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         52 . The composition according to  claim 48 , wherein the composition comprises Form I. 
     
     
         53 . The composition according to  claim 48 , wherein the in vivo plasma profile comprises a mean AUC 0-∞  of about 10 to 200 ug h/ml. 
     
     
         54 . The composition according to  claim 48 , further comprising about 200 mg to 1200 mg of ceftaroline or a prodrug of ceftaroline wherein the composition provides an in vivo plasma profile for ceftaroline comprising a mean AUC 0-∞  of more than about 10 ug h/ml. 
     
     
         55 . The composition according to  claim 54 , wherein the composition comprises about 400 mg ceftaroline fosamil. 
     
     
         56 . The composition according to  claim 54 , wherein the composition comprises about 600 mg ceftaroline fosamil. 
     
     
         57 . The composition according to any one of  claim 55  or  56 , wherein the composition comprises ceftaroline fosamil monohydrate acetic acid solvate. 
     
     
         58 . A composition comprising about 200 mg to 1200 mg of a crystalline form of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof wherein the composition provides an in vivo plasma profile for the crystalline form comprising a mean Tmax of more than about 10 minutes. 
     
     
         59 . The composition according to  claim 58 , wherein the composition comprises the sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         60 . The composition according to  claim 58 , wherein the composition comprises about 400 mg of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         61 . The composition according to  claim 58 , wherein the composition comprises about 600 mg of sodium salt of (1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. 
     
     
         62 . The composition according to  claim 58 , wherein the composition comprises Form I. 
     
     
         63 . The composition according to  claim 58 , wherein the in vivo plasma profile comprises a mean Tmax of about 30 minutes to about 2 hours. 
     
     
         64 . The composition according to  claim 58 , further comprising about 200 mg to 1200 mg of ceftaroline or a prodrug of ceftaroline wherein the composition provides an in vivo plasma profile for ceftaroline comprising a mean Tmax of more than about 10 minutes. 
     
     
         65 . The composition according to  claim 54 , wherein the composition comprises about 400 mg ceftaroline fosamil. 
     
     
         66 . The composition according to  claim 54 , wherein the composition comprises about 600 mg ceftaroline fosamil. 
     
     
         67 . The composition according to any one of  claim 55  or  56 , wherein the composition comprises ceftaroline fosamil monohydrate acetic acid solvate. 
     
     
         68 . A method of treating a bacterial infection comprising administering to a patient in need thereof, a therapeutically effective amount of a crystalline form of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         69 . A method of treating a bacterial infection comprising administering to a patient in need thereof, a therapeutically effective amount of a crystalline form of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof according to any one of  claims 3  to  5 . 
     
     
         70 . The method of  claim 69 , wherein the bacterial infection is selected from the group consisting of complication skin and structure infection and community acquired pneumonia. 
     
     
         71 . A method of treating a bacterial infection comprising administering to a patient in need thereof, the pharmaceutical composition according to  claim 18 . 
     
     
         72 . The method of  claim 71 , wherein the bacterial infection is selected from the group consisting of complication skin and structure infection and community acquired pneumonia. 
     
     
         73 . The crystalline form according to  claim 2 , wherein the crystalline form is Form II. 
     
     
         74 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peak at about 17.1+/−0.5 degrees 2θ. 
     
     
         75 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peak at about 16.4+/−0.5 degrees 2θ. 
     
     
         76 . The crystalline form according to  claim 2 , wherein the crystalline form has an X-Ray powder diffraction pattern comprising a characteristic peak at about 8.5+/−0.5 degrees 2θ. 
     
     
         77 . A composition comprising the crystalline form according to any one of  claims 74  to  76 . 
     
     
         78 . A method of treating a bacterial infection comprising administering to a patient in need thereof, a therapeutically effective amount of the crystalline form according to any one of  claims 74  to  76 .