Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Abstract

The present invention relates to a substantially a solid form of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1, Solvate Form A and Compound 1, HCl Salt Form A), processes for making such forms, pharmaceutical compositions thereof, and methods of treatment therewith.

1 . A solid form of 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1), characterized as Compound 1, Solvate Form A or Compound 1, HCl Salt Form A. 
     
     
         2 . Compound 1, Solvate Form A of  claim 1 , wherein Compound 1, Solvate Form A is characterized as a crystalline lattice of Compound 1 containing a plurality of repeating cavities which are empty or at least partially occupied by a solvate. 
     
     
         3 . Compound 1, Solvate Form A of  claim 1 , wherein Compound 1, Solvate Form A is characterized as a crystalline lattice of Compound 1 containing a plurality of repeating cavities, wherein a plurality of the cavities are empty. 
     
     
         4 . Compound 1, Solvate Form A of  claim 1 , characterized by one or more peaks at 21.5 to 21.9 degrees, 8.8 to 9.2 degrees, and 10.8 to 11.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         5 . Compound 1, Solvate Form A of  claim 1 , characterized by one or more peaks at 21.5 to 21.9 degrees, 8.8 to 9.2 degrees, 10.8 to 11.2 degrees, 18.0 to 18.4 degrees, and 22.9 to 23.3 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         6 . Compound 1, Solvate Form A of  claim 1 , characterized by one or more peaks at 21.70, 8.98, 11.04, 18.16, and 23.06 degrees. 
     
     
         7 . Compound 1, Solvate Form A of  claim 1 , characterized by a peak at 21.5 to 21.9 degrees. 
     
     
         8 . Compound 1, Solvate Form A of  claim 1 , characterized by a peak at 21.70 degrees. 
     
     
         9 . Compound 1, Solvate Form A of  claim 8  further characterized by a peak at 8.8 to 9.2 degrees. 
     
     
         10 . Compound 1, Solvate Form A of  claim 9  further characterized by a peak at 8.98 degrees. 
     
     
         11 . Compound 1, Solvate Form A of  claim 10  further characterized by a peak at 10.8 to 11.2 degrees. 
     
     
         12 . Compound 1, Solvate Form A of  claim 11  further characterized by a peak at 11.04. 
     
     
         13 . Compound 1, Solvate Form A of  claim 12  further characterized by a peak at 18.0 to 18.4 degrees. 
     
     
         14 . Compound 1, Solvate Form A of  claim 13  further characterized by a peak at 18.16 degrees. 
     
     
         15 . Compound 1, Solvate Form A of  claim 14  further characterized by a peak at 22.9 to 23.3 degrees. 
     
     
         16 . Compound 1, Solvate Form A of  claim 15  further characterized by a peak at 23.06 degrees. 
     
     
         17 . Compound 1, Solvate Form A of  claim 2 , wherein the Compound 1, Solvate Form A is characterized by a diffraction pattern substantially similar to that of  FIG. 1 . 
     
     
         18 . Compound 1, Solvate Form A of  claim 2 , wherein the solvate is selected from the group consisting of an organic solvate of sufficient size to fit in the plurality of repeating cavities. 
     
     
         19 . Compound 1, Solvate Form A of  claim 18 , wherein the solvate is selected from the group consisting of methanol, ethanol, acetone, isopropanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, ethyl acetate, and 2-methyltetrahydrofuran. 
     
     
         20 . Compound 1, Solvate Form A of  claim 18 , wherein Compound 1, Solvate Form A is comprised of 1 to 10 wt. % solvate as determined by TGA. 
     
     
         21 . Compound 1, Solvate Form A of  claim 20 , wherein Compound 1, Solvate Form A is comprised of 2 to 5 wt. % solvate as determined by TGA. 
     
     
         22 . Compound 1, Solvate Form A of  claim 2 , wherein the melting point is from 185° C. to 190° C. 
     
     
         23 . Compound 1, Solvate Form A of  claim 2 , having a P2 1 /n space group, and the following unit cell dimensions:
 a=16.5235 (10) Å α=90°   b=12.7425 (8) Å β=103.736 (4)°   c=20.5512 (13) Å γ=90°.   
     
     
         24 . Compound 1, HCl Salt Form A of  claim 1  characterized by one or more peaks at 8.8 to 9.2 degrees, 17.3 to 17.7 degrees, and 18.2 to 18.6 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         25 . Compound 1, HCl Salt Form A of  claim 1  characterized by one or more peaks at 8.8 to 9.2 degrees, 17.3 to 17.7 degrees, 18.2 to 18.6 degrees, 10.1 to 10.5 degrees, and 15.8 to 16.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         26 . Compound 1, HCl Salt Form A of  claim 1  characterized by one or more peaks at 8.96, 17.51, and 18.45 degrees. 
     
     
         27 . Compound 1, HCl Salt Form A of  claim 1  characterized by one or more peaks at 8.96, 17.51, 18.45, 10.33, and 16.01 degrees. 
     
     
         28 . Compound 1, HCl Salt Form A of  claim 1  characterized by a peak at 8.8 to 9.2 degrees. 
     
     
         29 . Compound 1, HCl Salt Form A of  claim 1  characterized by a peak at 8.96 degrees. 
     
     
         30 . Compound 1, HCl Salt Form A of  claim 29  further characterized by a peak at 18.2 to 18.6 degrees. 
     
     
         31 . Compound 1, HCl Salt Form A of  claim 30  further characterized by a peak at 18.45 degrees. 
     
     
         32 . Compound 1, HCl Salt Form A of  claim 31  further characterized by a peak at 10.1 to 10.5 degrees. 
     
     
         33 . Compound 1, HCl Salt Form A of  claim 32  further characterized by a peak at 10.3 degrees. 
     
     
         34 . Compound 1, HCl Salt Form A of  claim 33  further characterized by a peak at 15.8 to 16.2 degrees. 
     
     
         35 . Compound 1, HCl Salt Form A of  claim 34  further characterized by a peak at 16.01 degrees. 
     
     
         36 . Compound 1, HCl Salt Form A of  claim 1  characterized by a diffraction pattern substantially similar to that of  FIG. 21 . 
     
     
         37 . Compound 1, HCl Salt Form A of  claim 1  characterized as a dimer as depicted in  FIG. 19 . 
     
     
         38 . Compound 1, HCl Salt Form A of  claim 1  characterized by the packing diagram depicted in  FIG. 20 . 
     
     
         39 . Compound 1, HCl Salt Form A of  claim 1  having a P − 1 space group, and the following unit cell dimensions: a=10.2702 (2) Å, b=10.8782 (2) Å, c=12.4821 (3) Å, α=67.0270 (10)°, β=66.1810 (10)°, and γ=72.4760 (10)°. 
     
     
         40 . Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 , wherein Compound 1, Solvate Form A or Compound 1, HCl Salt Form A has a particle size of 0.1 microns to 50 microns. 
     
     
         41 . Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 , wherein Compound 1, Solvate Form A or Compound 1, HCl Salt Form A has a particle size of 0.1 microns to 20 microns. 
     
     
         42 . Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 , wherein Compound 1, Solvate Form A or Compound 1, HCl Salt Form A has a particle size of 0.1 microns to 10 microns. 
     
     
         43 . Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 , wherein Compound 1, Solvate Form A or Compound 1, HCl Salt Form A has a particle size of 1.0 microns to 5 microns. 
     
     
         44 . Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 , wherein Compound 1, Solvate Form A or Compound 1, HCl Salt Form A has a particle size D50 of 2.0 microns. 
     
     
         45 . A pharmaceutical composition comprising Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         46 . The pharmaceutical composition of  claim 45 , further comprising an additional therapeutic agent. 
     
     
         47 . A method of treating a CFTR mediated disease in a mammal comprising administering to the mammal an effective amount of Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1 . 
     
     
         48 . The method of  claim 47 , wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, 1-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease due to prion protein processing defect, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, Gorham's Syndrome, chloride channelopathies, myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), inherited disorders of the structure and/or function of cilia, PCD with situs inversus, PCD without situs inversus, or ciliary aplasia. 
     
     
         49 . The method of  claim 48 , wherein the CFTR mediated disease is cystic fibrosis, emphysema, COPD, dry-eye disease, or osteoporosis. 
     
     
         50 . The method of  claim 48 , wherein the CFTR mediated disease is cystic fibrosis. 
     
     
         51 . The method of  claim 50 , wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a ΔF508 mutation. 
     
     
         52 . The method of  claim 50 , wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a R117H mutation. 
     
     
         53 . The method of  claim 50 , wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a G551D mutation. 
     
     
         54 . The method of  claim 50 , wherein the method comprises administering an additional therapeutic agent. 
     
     
         55 . A kit comprising Compound 1, Solvate Form A or Compound 1, HCl Salt Form A of  claim 1  and instructions for use thereof. 
     
     
         56 . The pharmaceutical formulation of  claim 46 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditertbutyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.