Solid state form of pladienolide pyridine compounds and methods of use

Abstract

The present disclosure provides a novel solid state form of pladienolide pyridine compounds, compositions comprising at least one such solid state form, and methods of preparation and use and the same. The novel solid state form of pladienolide pyridine compounds may be useful in the treatment of cancer, such as, for example, cancers in which agents that target the spliceosome and mutations therein are known to be useful.

1 - 17 . (canceled) 
     
     
         18 . A method of making a crystalline Form 1 of a free base compound of Formula I, 
       
         
           
           
               
               
           
         
         comprising evaporating a solution comprising the free base compound of Formula I and at least one solvent chosen from toluene, acetone, ethyl acetate, methyl tert-butylether (MTBE), and dichloromethane (DCM). 
       
     
     
         19 . The method of  claim 18 , wherein the one solvent solvent is a 9:1 (v/v) mixture of methyl tert-butylether (MTBE) and dichloromethane (DCM). 
     
     
         20 . The method of  claim 18 , wherein the free base compound of Formula I is present in the solution in an amount of 5 mg and the at least one solvent is present in the solution in a volume of 5 mL prior to evaporation. 
     
     
         21 . The method of  claim 18 , wherein the crystalline Form 1 of a free base compound of Formula I exhibits an XRPD diffractogram substantially the same as in  FIG. 2 . 
     
     
         22 . The method of  claim 18 , wherein the one solvent solvent is chosen from a solution of 5% methanol in ethyl acetate, a solution of 5% methanol in MTBE, a solution of 5% methanol in 1:1 (v/v) MTBE/heptane, a solution of 5% methanol in 1:1 (v/v) ethyl acetate/heptane, a solution of 5% ethanol in ethyl acetate, a solution of 5% ethanol in MTBE, a solution of 5% ethanol in 1:1 (v/v) MTBE/heptane, and a solution of 5% ethanol in 1:1 (v/v) ethyl acetate/heptane. 
     
     
         23 . A method of making a crystalline Form 1 of the free base compound of Formula I, 
       
         
           
           
               
               
           
         
         comprising slow cooling from 50° C. to room temperature a solution comprising the free base compound of Formula I and one solvent, optionally followed by cooling the solution to −5 ° C., and filtering the solution. 
       
     
     
         24 . The method of  claim 23 , wherein the solution is heated at 50° C. for 30 minutes. 
     
     
         25 . The method of  claim 23 , wherein the at least one solvent is a mixture of MTBE and heptane 
     
     
         26 . The method of  claim 23 , wherein the at least one solvent is a mixture of ethyl acetate and heptane. 
     
     
         27 . The method of  claim 23 , wherein the at least one solvent is 1:1 (v/v) MTBE/heptane or 1:1 (v/v) ethyl acetate/heptane. 
     
     
         28 . The method of  claim 23 , wherein the free base compound of Formula I is present in the solution in an amount ranging from 0.2 g to 9 g and the at least one solvent is present in the solution in a volume ranging from 8 mL to 172 mL total solvent volume. 
     
     
         29 . A method of making a crystalline Form 1 of the free base compound of Formula I, 
       
         
           
           
               
               
           
         
         comprising crash cooling a solution comprising the free base compound of Formula I and at least one solvent, wherein said crash cooling comprises cooling the solution from 80° C. to −20° C., and filtering the crash cooled solution. 
       
     
     
         30 . The method of  claim 29 , wherein the at least one solvent is a mixture of MTBE and heptane. 
     
     
         31 . The method of  claim 29 , wherein the at least one solvent is a mixture ethyl acetate and heptane. 
     
     
         32 . The method of  claim 29 , wherein the at least one solvent is 1:1 (v/v) MTBE/heptane or 1:1 (v/v) ethyl acetate/heptane. 
     
     
         33 . The method of  claim 29 , wherein the solution is maintained at 80° C. for 10 minutes. 
     
     
         34 . The method of  claim 29 , wherein the solution is maintained at −20° C. for 30 minutes. 
     
     
         35 . The method of  claim 29 , wherein the free base compound of Formula I is present in the solution in an amount of 3.9 g and the at least one solvent is present in the solution in a volume of 105 mL.