Crystalline Beta-Lactamase Inhibitor

Abstract

A crystalline compound of formula (I): The compound of formula (I) is a β-lactamase inhibitor and may be administered in combination with an antibacterial agent for prevention or treatment of bacterial infection.

1 . A crystalline compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         2 . A crystalline compound according to  claim 1  characterized by an XRPD spectrum comprising four or more peaks selected from peaks with 2θ angles of: 8.82±0.1 degrees 2θ, 12.07±0.1 degrees 2θ, 14.43±0.1 degrees 2θ, 14.92±0.1 degrees 2θ, 16.26±0.1 degrees 2θ, 18.25±0.1 degrees 2θ, 19.06±0.1 degrees 2θ, 19.78±0.1 degrees 2θ, 20.82±0.1 degrees 2θ and 23.51±0.1 degrees 2θ. 
     
     
         3 . A crystalline compound according to  claim 1 , with an XRPD spectrum substantially as shown in  FIG. 1 . 
     
     
         4 . A crystalline compound according  claim 2  characterized by a Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 163° C.±2° C. 
     
     
         5 . A crystalline compound according to  claim 2  characterized by a Differential Scanning Calorimetry (DSC) curve showing an endothermic event at about 163° C.±2° C. 
     
     
         6 . A crystalline compound according to  claim 1  characterized by an XRPD spectrum comprising four or more peaks selected from peaks with 2θ angles of: 9.37±0.10 degrees 2θ, 10.34±0.10 degrees 2θ, 12.59±0.10 degrees 2θ, 13.17±0.10 degrees 2θ, 15.00±0.10 degrees 2θ, 15.63±0.10 degrees 2θ, 18.51±0.10 degrees 2θ, 19.10±0.10 degrees 2θ, 20.79±0.10 degrees 2θ and 23.93±0.10 degrees 2θ. 
     
     
         7 . A crystalline compound according to  claim 1 , with an XRPD spectrum substantially as shown in  FIG. 2 . 
     
     
         8 . A crystalline compound according to  claim 6  characterized by a Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 155° C.±2° C. 
     
     
         9 . A crystalline compound according to  claim 6  characterized by a Differential Scanning Calorimetry (DSC) curve showing an endothermic event at about 180° C.±2° C. 
     
     
         10 . A crystalline compound according to  claim 1  characterized by an XRPD spectrum comprising four or more peaks selected from peaks with 2θ angles of: 9.33±0.1 degrees 2θ, 10.73±0.1 degrees 2θ, 14.85±0.1 degrees 2θ, 15.29±0.1 degrees 2θ, 15.77±0.1 degrees 2θ, 16.16±0.1 degrees 2θ, 18.60±0.1 degrees 2θ, 20.12±0.1 degrees 2θ, 21.00±0.1 degrees 2θ and 23.22±0.1 degrees 2θ. 
     
     
         11 . A crystalline compound according to  claim 1 , with an XRPD spectrum substantially as shown in  FIG. 3  or in  FIG. 20 . 
     
     
         12 . A crystalline compound according to  claim 10  characterized by a Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 149° C.±2° C. 
     
     
         13 . A crystalline compound according to  claim 10  characterized by a Differential Scanning Calorimetry (DSC) curve showing an endothermic event at about 185° C.±2° C. 
     
     
         14 . A crystalline compound according to  claim 1  characterized by an XRPD spectrum comprising four or more peaks selected from peaks with 2θ angles of: 6.7824±0.05 degrees 2θ, 15.4567±0.05 degrees 2θ, 16.3961±0.05 degrees 2θ, 17.1082±0.05 degrees 2θ, 20.0651±0.05 degrees 2θ, 20.6373±0.05 degrees 2θ, 23.2376±0.05 degrees 2θ, 23.6811±0.05 degrees 2θ, 26.1802±0.05 degrees 2θ and 32.4753±0.05 degrees 2θ. 
     
     
         15 . A crystalline compound according to  claim 1 , with an XRPD spectrum substantially as shown in  FIG. 25 . 
     
     
         16 . A crystalline compound according to  claim 1  characterized by an XRPD spectrum comprising four or more peaks selected from peaks with 2θ angles of: 6.8269±0.05 degrees 2θ, 15.0475±0.05 degrees 2θ, 15.6848±0.05 degrees 2θ, 16.4735±0.05 degrees 2θ, 17.1773±0.05 degrees 2θ, 18.4488±0.05 degrees 2θ, 20.6999±0.05 degrees 2θ, 23.3436±0.05 degrees 2θ, 23.8843±0.05 degrees 2θ and 25.3818±0.05 degrees 2θ. 
     
     
         17 . A crystalline compound according to  claim 1 , with an XRPD spectrum substantially as shown in  FIG. 27 . 
     
     
         18 . A crystalline compound according to  claim 1  characterized by an XRPD spectrum comprising four or more peaks selected from peaks with 2θ angles of: 12.7398±0.05 degrees 2θ, 15.3615±0.05 degrees 2θ, 15.9547±0.05 degrees 2θ, 16.4290±0.05 degrees 2θ, 18.1207±0.05 degrees 2θ, 20.4870 0.05 degrees 2θ, 22.8548±0.05 degrees 2θ, 23.2204±0.05 degrees 2θ, 27.0457±0.05 degrees 2θ, 27.6934±0.05 degrees 2θ and 32.4785±0.05 degrees 2θ. 
     
     
         19 . A crystalline compound according to  claim 1 , with an XRPD spectrum substantially as shown in  FIG. 29 . 
     
     
         20 . A crystalline compound according to  claim 18  characterized by a Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 160° C. 
     
     
         21 . A crystalline compound according to  claim 18  characterized by a DSC profile showing an exothermic peak at approximately 184° C. 
     
     
         22 . A process for preparing a crystalline compound of formula (I): 
       
         
           
           
               
               
           
         
         the process comprising the steps of: 
         forming a formulation by dissolving or suspending an amorphous compound of formula (I) in a solvent or solvent mixture; and 
         crystallizing the compound of formula (I) from the formulation. 
       
     
     
         23 - 31 . (canceled) 
     
     
         32 . A crystalline compound of formula (I) according to  claim 1  wherein the compound comprises more than 90% of a single crystalline polymorph of the compound. 
     
     
         33 . A crystalline compound of formula (I) according to  claim 1  having a chemical purity of at least 95 wt %. 
     
     
         34 . A pharmaceutical composition comprising a crystalline compound of formula (I) according to  claim 1 . 
     
     
         35 . A pharmaceutical composition according to  claim 34  further comprising an antibiotic. 
     
     
         36 . (canceled) 
     
     
         37 . A method of treating a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 34 . 
     
     
         38 . A method of treating a bacterial infection comprising co-administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 34  with a therapeutically effective amount of an antibiotic.