Crystalline ppar-delta agonist

Abstract

Described herein is crystalline sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate, uses of such crystalline material in the preparation of pharmaceutical compositions for the treatment of diseases or conditions that would benefit by administration with a PPARS agonist compound.

1 - 56 . (canceled) 
     
     
         57 . Crystalline sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II) that is characterized as having:
 an XRPD pattern substantially the same as shown in  FIG.  24   ;   a DSC thermogram substantially the same as shown in  FIG.  25   ;   a DSC thermogram with five endothermic events having:
 i. an onset at about 54.7° C. and peak at about 81.5° C.; 
 ii. an onset at about 90.1° C. and peak at about 92.2° C.; 
 iii. an onset at about 115.9° C. and peak at about 124.6° C.; 
 iv. an onset at about 131.3° C. and peak at about 132.5° C.; and 
 v. an onset at about 146.8° C. and peak at about 150.6° C.; 
   or combinations thereof.   
     
     
         58 . A pharmaceutical composition comprising the crystalline Compound II of  claim 57  and at least one pharmaceutically acceptable excipient. 
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration. 
     
     
         60 . The pharmaceutical composition of  claim 58 , wherein the pharmaceutical composition is in the form of a solid form pharmaceutical composition. 
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein the pharmaceutical composition is in the form of a tablet, a pill, or a capsule; and wherein the pharmaceutical composition comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of crystalline Compound II. 
     
     
         62 . Amorphous sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II) that is characterized as having:
 an XRPD pattern showing a lack of crystallinity;   a DSC thermogram substantially the same as shown in  FIG.  22   ;   a DSC thermogram with:
 i. a broad endotherm with onset at 43.1° C. and peak at about 60.3° C.; 
 ii. a broad exotherm with onset at 107.0° C. and peak at 112.9° C.; and 
 iii. an endotherm with onset at 125.0° C. peak a 130.4° C.; 
   a TGA pattern substantially the same as shown in  FIG.  23   ;   a TGA pattern with a 3.7% w/w loss from 25 to 150° C., and a degradation onset at about 260° C.;   an unchanged XRPD after storage at ambient temperature over 24 hours, 48 hours, 7 days, or 10 days;   an unchanged XRPD after storage at 75% RH and 40° C. over 10 days;   or combinations thereof.   
     
     
         63 . A pharmaceutical composition comprising the amorphous Compound II of  claim 62  and at least one pharmaceutically acceptable excipient. 
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration. 
     
     
         65 . The pharmaceutical composition of  claim 63 , wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration in the form of a tablet, a pill, a capsule, a suspension, or a solution. 
     
     
         66 . The pharmaceutical composition of  claim 63 , wherein the pharmaceutical composition is in the form of a solid form pharmaceutical composition. 
     
     
         67 . The pharmaceutical composition of  claim 66 , wherein the pharmaceutical composition is in the form of a tablet, a pill, or a capsule; and wherein the pharmaceutical composition comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of crystalline Compound II. 
     
     
         68 . A process for the preparation of crystalline Compound II: 
       
         
           
           
               
               
           
         
         comprising adding sodium hydroxide in water to an acetone solution of Compound I: 
       
       
         
           
           
               
               
           
         
         
           or the alkyl ester of Compound I, or a salt thereof: 
         
       
       
         
           
           
               
               
           
         
         
           wherein R is C 1 -C 6  alkyl; 
         
         filtering the reaction mixture and adding the filtered reaction mixture to acetonitrile; 
         filtering the crystalline Compound II that is formed from the solution; and 
         filtering drying the solids to provide crystalline Compound II. 
       
     
     
         69 . The process of  claim 68 , wherein the crystalline Compound II is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at about 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as measured using Cu Kα radiation. 
     
     
         70 . The process of  claim 68 , wherein the filtered reaction mixture is added to acetonitrile that is seeded with crystalline Compound II that is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at about 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as measured using Cu Kα radiation. 
     
     
         71 . The process of  claim 68 , wherein the process comprises adding sodium hydroxide in water to an acetone solution of Compound I;
 filtering the reaction mixture and adding the filtered reaction mixture to acetonitrile comprising seeds of the crystalline Compound II; and   filtering the crystalline Compound II that is formed from the solution; wherein the crystalline Compound II is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at about 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as measured using Cu Kα radiation.