Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Abstract

The present invention relates to solid state forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1), pharmaceutical compositions thereof and methods therewith.

What is claimed is: 
     
         1 . Solid amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         2 . The solid amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide of  claim 1 , comprising less than about 15% crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         3 . A preparation of amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide substantially free of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         4 . The preparation of  claim 3 , further comprising a surfactant, polymer, or inert pharmaceutically acceptable substance. 
     
     
         5 . The preparation of  claim 3  or  4 , wherein the preparation comprises a solid dispersion, a mixture or a liquid dispersion. 
     
     
         6 . The preparation of one of  claims 3 - 5 , wherein the preparation comprises solid particles. 
     
     
         7 . The preparation of one of  claims 3 - 6 , comprising less than about 15% of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         8 . The preparation of one of  claims 3 - 7 , wherein the amporphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a particle size distribution of D10, less than 5 μm. 
     
     
         9 . The preparation of one of  claims 3 - 8 , wherein the amporphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide have a particle size distribution of D50, less than 17 μm. 
     
     
         10 . The preparation of one of  claims 3 - 9 , wherein the amporphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide have a particle size distribution of D90, less than 100 μm. 
     
     
         11 . A solid dispersion comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         12 . The solid dispersion of  claim 11 , wherein the solid dispersion comprises less than about 40% of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         13 . The solid dispersion of  claim 11  or  12 , wherein the solid dispersion is substantially free of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         14 . The solid dispersion of one of  claims 11 - 13 , further comprising a surfactant, polymer, or inert pharmaceutically acceptable substance. 
     
     
         15 . The solid dispersion of one of  claims 11 - 14 , comprising a polymer, and wherein the polymer is one or more than one water-soluble polymer or partially water-soluble polymer. 
     
     
         16 . The solid dispersion of one of  claims 11 - 15 , wherein the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has improved physical or chemical stability relative to amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide without being in the presence of polymer. 
     
     
         17 . The solid dispersion of one of  claims 11 - 16 , wherein the solid dispersion has a higher glass transition temperature than the glass transition temperature of neat amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         18 . The solid dispersion of one of  claims 11 - 17 , wherein the polymer is hydroxypropylmethylcellulose (HPMC). 
     
     
         19 . The solid dispersion of one of  claims 11 - 17 , wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS). 
     
     
         20 . The solid dispersion of one of  claims 11 - 17 , wherein the polymer is vinylpyrrolidone/vinyl acetate copolymer (PVP/VA). 
     
     
         21 . The solid dispersion of one of  claims 11 - 20 , wherein the polymer is present in an amount of from about 10% by weight to about 80% by weight. 
     
     
         22 . The solid dispersion of  claims 21 , wherein the polymer is present in an amount of less than about 70% by weight. 
     
     
         23 . The solid dispersion of  claim 21 , wherein the polymer is present in an amount of about 50% by weight. 
     
     
         24 . The solid dispersion of  claim 21 , wherein the polymer is present in an amount of about 49.5% by weight. 
     
     
         25 . The solid dispersion of one of  claims 11 - 24 , wherein the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of from about 10% by weight to about 80% by weight. 
     
     
         26 . The solid dispersion of  claim 24 , wherein the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of less than about 70% by weight. 
     
     
         27 . The solid dispersion of  claim 24 , wherein the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of about 50% by weight. 
     
     
         28 . The solid dispersion of one of  claims 11 - 27 , comprising a surfactant. 
     
     
         29 . The solid dispersion of  claim 28 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         30 . The solid dispersion of one of  claims 11 - 29 , wherein the surfactant is present in an amount from about 0.1 to about 5%. 
     
     
         31 . The solid dispersion of  claim 30 , wherein the surfactant is present in 0.5%. 
     
     
         32 . The solid dispersion of one of  claims 11 - 31 , wherein at least about 80% by weight of the N N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is in an amorphous form. 
     
     
         33 . The solid dispersion of one of  claim 32 , wherein substantially all the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is in an amorphous form. 
     
     
         34 . The solid dispersion according to one of  claims 11 - 33 , wherein the solid dispersion is obtained by spray drying. 
     
     
         35 . A pharmaceutical composition comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         36 . The composition of  claim 35 , wherein the amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is substantially free of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         37 . A pharmaceutical composition comprising an amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide as a solid dispersion and one or more of a surfactant, polymer, inert pharmaceutically acceptable substance, or pharmaceutically acceptable carrier. 
     
     
         38 . The pharmaceutical composition of  claim 37 , comprising a polymer and wherein the polymer is one or more than one water-soluble polymer or partially water-soluble polymer. 
     
     
         39 . The pharmaceutical composition of  claim 37  or  38 , wherein the solid dispersion has a higher glass transition temperature than the glass transition temperature of neat amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         40 . The pharmaceutical composition of one of  claims 37 - 39 , wherein the polymer is HPMC or HPMCAS. 
     
     
         41 . The pharmaceutical composition of one of  claims 37 - 39 , wherein the polymer is PVP/VA. 
     
     
         42 . A pharmaceutical composition comprising:
 an amorphous solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide wherein said N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprises about 30-75% wt/wt of the pharmaceutical composition,   one or more polymer selected from the group of HPMC and HPMCAS, wherein said polymer is comprises about 30-75% wt/wt of the pharmaceutical composition, and   a surfactant, wherein said surfactant comprises about 0.25-1% wt/wt of the pharmaceutical composition.   
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the polymer is HPMCAS. 
     
     
         44 . The pharmaceutical composition of  claim 42 , wherein the polymer is HPMC. 
     
     
         45 . The pharmaceutical composition of one of  claims 42 - 44 , wherein the surfactant is sodium laurel sulfate. 
     
     
         46 . The pharmaceutical composition of one of  claims 42 - 45 , wherein:
 said N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprises about 50% wt/wt of the pharmaceutical composition,   said polymer is HPMCAS and comprises about 49.5% wt/wt of the pharmaceutical composition, and   a said surfactant is sodium laurel sulfate and comprises about 0.5% wt/wt of the pharmaceutical composition.   
     
     
         47 . A pharmaceutical composition comprising;
 an aqueous suspension comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide particles and a pharmaceutically acceptable carrier.   
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the pharmaceutically acceptable carrier is a polymer in solution selected from the group of HPMC and HPMCAS. 
     
     
         49 . The pharmaceutical composition of  claim 47 , wherein the pharmaceutically acceptable carrier is a polymer in solution is PVP/VA. 
     
     
         50 . The pharmaceutical composition of one of  claims 47 - 49 , wherein the amorphous compound is in the form of a solid dispersion. 
     
     
         51 . The pharmaceutical composition of one of  claims 47 - 50 , further comprising a surfactant, either in the solution or as a component of the solid dispersion. 
     
     
         52 . The pharmaceutical composition of one of  claims 47 - 51 , wherein the surfactant is SLS. 
     
     
         53 . The pharmaceutical composition of one of  claims 47 - 52 , wherein the polymer is either in the solution or as a component of the solid dispersion particles or both. 
     
     
         54 . The pharmaceutical composition of one of  claims 47 - 53 , wherein the aqueous suspension comprises from about 0.1% to about 20% by weight of the surfactant. 
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein the aqueous suspension comprises from about 0.1% to about 2.0% by weight of polymer. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the aqueous suspension comprises about 1% by weight of polymer. 
     
     
         57 . A process for preparing an amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprising spray-drying N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide to provide an amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         58 . The process of  claim 57 , comprising combining N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and a suitable solvent to form a mixture and then spray-drying the mixture to obtain the amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         59 . The process of  claim 58 , wherein the mixture is a solution N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and the suitable solvent. 
     
     
         60 . The process of one of  claims 58 - 59 , wherein the suitable solvent comprises acetone or MEK. 
     
     
         61 . The process of one of  claims 58 - 60 , wherein the suitable solvent comprises a mixture of solvents. 
     
     
         62 . The process of one of  claims 58 - 61 , wherein the solvent comprises a mixture of acetone and water or a mixture of MEK and water. 
     
     
         63 . The process of one of  claims 58 - 62 , wherein the water in the solvent mixture is present at about 10% wt. 
     
     
         64 . The process of one of  claims 58 - 63 , comprising
 a) forming a mixture comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, a polymer, and a solvent; and   b) spray-drying the mixture to form a solid dispersion comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.   
     
     
         65 . The process of  claim 64 , wherein the mixture comprises a solution of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, the polymer, and the solvent. 
     
     
         66 . The process of  claim 65 , wherein the polymer is selected from HPMC and HPMCAS. 
     
     
         67 . The process of  claim 65 , wherein the polymer is PVP/VA. 
     
     
         68 . The process of one of  claims 64 - 67 , wherein the polymer is present in an amount of from about 30% to about 70% by weight in the solid dispersion. 
     
     
         69 . The process of one of  claims 64 - 68 , wherein the mixture further comprises a surfactant. 
     
     
         70 . The process according to one of  claims 64 - 69 , wherein the surfactant is sodium lauryl sulfate (SLS). 
     
     
         71 . The process according to one of  claims 64 - 70 , wherein the solvent comprises acetone. 
     
     
         72 . The process of one of  claims 64 - 71 , wherein the solvent comprises a mixture of acetone and water. 
     
     
         73 . The process of one of  claims 64 - 72 , wherein the solvent comprises from about 0% to about 20% water and from about 70% to about 100% acetone. 
     
     
         74 . A solid dispersion prepared according to the process of one of  claims 64 - 73 . 
     
     
         75 . A method for treating a CFTR-mediated disease in a mammal comprising administering amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         76 . The method of  claim 75 , comprising administering an amorphous solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. 
     
     
         77 . The method according to  claim 75  or  76 , wherein the method comprises administering an additional therapeutic agent. 
     
     
         78 . A pharmaceutical pack or kit comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and a pharmaceutically acceptable carrier. 
     
     
         79 . A crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, characterized by one or more peaks at 5.0 and 15.6 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation. 
     
     
         80 . The crystal form of  claim 79 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further characterized by the following peak 7.8. 
     
     
         81 . The crystal form of one of  claims 79 - 80 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 8.5. 
     
     
         82 . The crystal form of one of  claims 79 - 81 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 9.2. 
     
     
         83 . The crystal form of one of  claims 79 - 82 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 9.9. 
     
     
         84 . The crystal form of one of  claims 79 - 83 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 11.9. 
     
     
         85 . The crystal form of one of  claims 79 - 84 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 12.6. 
     
     
         86 . The crystal form of one of  claims 79 - 85 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 13.9. 
     
     
         87 . The crystal form of one of  claims 79 - 86 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 14.9. 
     
     
         88 . The crystal form of one of  claims 79 - 87 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 16.5. 
     
     
         89 . The crystal form of one of  claims 79 - 88 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 18.1. 
     
     
         90 . The crystal form of one of  claims 79 - 89 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 18.5. 
     
     
         91 . The crystal form of one of  claims 79 - 90 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 20.7. 
     
     
         92 . The crystal form of one of  claims 79 - 91 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 22.0. 
     
     
         93 . The crystal form of one of  claims 79 - 92 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 23.5. 
     
     
         94 . The crystal form of one of  claims 79 - 93 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 25.3. 
     
     
         95 . The crystal form of one of  claims 79 - 94 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 28.0. 
     
     
         96 . The crystal form of one of  claims 79 - 95 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 29.4. 
     
     
         97 . The crystal form of one of  claims 79 - 96 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further characterized by the following peak 30.9. 
     
     
         98 . The crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to  claims 79 - 97 , wherein said crystal form is characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation substantially similar to  FIG. 4 . 
     
     
         99 . A pharmaceutical composition comprising the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to one of  claims 79 - 98 , and a pharmaceutically acceptable adjuvant or carrier. 
     
     
         100 . A process for preparing a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to  claims 79 - 98 , wherein said process comprises the step of heating N N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide to about 250° C. and cooling to room temperature. 
     
     
         101 . A method for treating a CFTR mediated disease in a mammal comprising administering N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to  claims 79 - 98 . 
     
     
         102 . The method of  claim 101 , wherein the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is a component of a pharmaceutical composition. 
     
     
         103 . The method according to  claim 101  or  102 , wherein the method comprises administering an additional therapeutic agent. 
     
     
         104 . A pharmaceutical pack or kit comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to  claims 79 - 98  and a pharmaceutically acceptable carrier. 
     
     
         105 . A crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, characterized by one or more peaks at 6.2, 7.6, 12.3, and 18.0 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation. 
     
     
         106 . The crystal form of  claim 105 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 8.40. 
     
     
         107 . The crystal form of  claim 105  or  106 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 11.0. 
     
     
         108 . The crystal form of one of  claims 105 - 107 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 14.8. 
     
     
         109 . The crystal form of one of  claims 105 - 108 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 16.1. 
     
     
         110 . The crystal form of one of  claims 105 - 109 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 17.1. 
     
     
         111 . The crystal form of one of  claims 105 - 110 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 18.6. 
     
     
         112 . The crystal form of one of  claims 105 - 111 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 19.4. 
     
     
         113 . The crystal form of one of  claims 105 - 112 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 21.1. 
     
     
         114 . The crystal form of one of  claims 105 - 113 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 22.6. 
     
     
         115 . The crystal form of one of  claims 105 - 114 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 23.4. 
     
     
         116 . The crystal form of one of  claims 105 - 115 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 23.9. 
     
     
         117 . The crystal form of one of  claims 105 - 116 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 24.9. 
     
     
         118 . The crystal form of one of  claims 105 - 117 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 25.5. 
     
     
         119 . The crystal form of one of  claims 105 - 118 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 26.7. 
     
     
         120 . The crystal form of one of  claims 105 - 119 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 27.5. 
     
     
         121 . The crystal form of one of  claims 105 - 120 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak 29.6. 
     
     
         122 . The crystal form of one of  claims 105 - 121 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro 4-oxoquinoline-3-carboxamide is further characterized by the following peak 33.5. 
     
     
         123 . The crystal form of one of  claims 105 - 122 , wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro 4-oxoquinoline-3-carboxamide is further characterized by the following peak 36.8. 
     
     
         124 . The crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to one of  claims 105 - 123 , characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation substantially similar to  FIG. 7 . 
     
     
         125 . A pharmaceutical composition comprising the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to one of  claims 105 - 124 , and a pharmaceutically acceptable adjuvant or carrier. 
     
     
         126 . A process for preparing the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to one of  claims 105 - 124 , wherein said process comprises the steps of alternatively heating and cooling a slurry of Compound 1 and acetonitrile. 
     
     
         127 . The process according to  claim 126 , wherein said heating step comprises heating said slurry at about 50 C. for about 12 hours. 
     
     
         128 . The process according to  claim 126  or  127 , wherein said cooling step comprises placing said slurry at room temperature for about 12 hours, followed by cooling at about 0° C. overnight. 
     
     
         129 . A crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, having a monoclinic crystal system, a P2 1  space grouping, and the following unit cell dimensions:
 a=11.8011 (7) Å =90°   b=5.9819 (3) Å β= 105 . 110  (4)°   c=14.7974 (8) Åγ=90°.   
     
     
         130 . A method of treating a CFTR mediated disease in a patient comprising the step of administering to said patient a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutical composition comprising a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to one of  claim 105 - 124  or  129 . 
     
     
         131 . The method according to  claim 75 ,  101 , or  130 , wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-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, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease. 
     
     
         132 . The method according to  claim 131 , wherein said disease is cystic fibrosis.