Crystalline pharmaceutical and methods of preparation and use thereof

Abstract

Novel crystalline polymorphic forms, Forms A, B, C, D, and E of a compound of Formula I, which has been found to be a potent inhibitor of LFA-1, are disclosed. Methods of preparation and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed in this invention.

What is claimed is: 
     
         1 . A composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         comprising a purity of greater than about 90%, and its pharmaceutically acceptable salts. 
       
     
     
         2 . The composition of  claim 1 , wherein the purity is greater than about 98%. 
     
     
         3 . The composition of  claim 1 , wherein the compound comprises at least about 95% of an S-enantiomer. 
     
     
         4 . The composition of  claim 1 , wherein the compound is not the calcium salt of the free acid. 
     
     
         5 . The composition of  claim 1 , wherein the compound is a crystalline form (Form A) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 18.2, 21.4, and 22.7 degrees. 
     
     
         6 . The composition of  claim 5 , wherein the form undergoes a predominant endotherm at about 145° C. 
     
     
         7 . The composition of  claim 5 , wherein the form is produced by isolating the form from a suspension of the compound in an organic solvent which is acetonitrile, methyl ethyl ketone, or water. 
     
     
         8 . The composition of  claim 1 , wherein the compound is a crystalline form (Form B) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 12.1, 17.1, and 18.5 degrees. 
     
     
         9 . The composition of  claim 1 , wherein the compound is a crystalline form (Form C) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 4.8, 17.8, and 21.5 degrees. 
     
     
         10 . The composition of  claim 1 , wherein the compound is a crystalline form (Form D) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 17.6, 21.7, and 24.8 degrees. 
     
     
         11 . The composition of  claim 1 , wherein the compound is a crystalline form (Form E) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 5.12, 8.26, and 17.8 degrees. 
     
     
         12 . The composition of  claim 1 , wherein the compound is an amorphous form. 
     
     
         13 . The composition of  claim 1 , wherein the compound comprises less than 0.5% of any one byproduct of chemical synthesis of the compound. 
     
     
         14 . The composition of  claim 1 , wherein the compound comprises less than a total of 1.5% of all byproducts of the chemical synthesis. 
     
     
         15 . A method of producing the form of the compound of  claim 5 : 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         a) suspending the compound of Formula I in a solvent; 
         b) filtering the suspension to isolate a crystalline product; and 
         c) washing the crystalline product with water thereby obtaining the form of the compound of  claim 5 . 
       
     
     
         16 . The method of  claim 15  wherein the solvent is acetonitrile or methyl ethyl ketone. 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of  claim 1 . 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the compound of  claim 1  has been converted to a salt. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the compound comprises the amorphous form or any of crystalline Forms A, A, C, D, or E, or a combination thereof, of the compound of  claim 1 . 
     
     
         20 . The pharmaceutical composition of  claim 17 , further comprising one or more pharmaceutically acceptable excipients. 
     
     
         21 . The pharmaceutical composition of  claim 17 , further comprising at least one additional therapeutic agent. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the additional therapeutic agent is an antioxidant, antiinflammatory agent, antimicrobial agent, antiangiogenic agent, anti-apoptotic agent, vascular endothelial growth factor inhibitor, antiviral agent, calcineurin inhibitor, corticosteriod, antihistamine, mast cell stabilizing agent, or immunomodulator. 
     
     
         23 . The pharmaceutical composition of  claim 17  wherein the pharmaceutical composition is a gel comprising about 1% W/V of the compound of  claim 1 ; up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol, up to about 0.15% W/V Methylparaben; up to about 0.05% W/V Propylparaben; up to about 1% W/V Hydroxyethyl Cellulose; and water. 
     
     
         24 . The pharmaceutical composition of  claim 17  wherein the pharmaceutical composition is an ointment comprising about 1% W/V of the compound of  claim 1 , up to about 10% WA Dimethyl Isosorbide; up to about 0.02% W/VButylated Hydroxytoluene; up to about 2% W/V Span 80; up to about 10% W/VWhite Wax; and White Petrolatum. 
     
     
         25 . The pharmaceutical composition of  claim 17  wherein the formulation is a water based lotion comprising about 1% W/V of the compound of  claim 1 , up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol; up to about 5% W/V Propylene Glycol; and pH 6.0 25% Trolamine, wherein the lotion is buffered to a pH of about pH4.0 to about pH7.5. 
     
     
         26 . The pharmaceutical composition of  claim 17  wherein the formulation is an aqueous solution buffered to a pH of about 6.0 to about 8.0 with Sodium Phosphate, Monobasic, comprising about 1% W/V of the compound of  claim 1 , up to about 0.1% W/V EDTA, and, optionally, up to about 0.4% w/w Methylparaben and up to about 0.02% w/w Propylparaben. 
     
     
         27 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is a biocompatible solid. 
     
     
         28 . The pharmaceutical composition of  claim 27  wherein the biocompatible solid is biodegradable. 
     
     
         29 . The pharmaceutical composition of  claim 17 , wherein the composition is suitable for administration via instillation, via aerosol, via inhalation, orally, topically, transdermally, via insert, or via injection. 
     
     
         30 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is formulated to deliver a therapeutically effective amount of the compound of Formula I locally. 
     
     
         31 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is formulated to deliver less than a therapeutically effective amount of the compound of Formula I systemically. 
     
     
         32 . A method of treating disease in a subject, comprising the steps of administering an effective amount of the pharmaceutical composition of  claim 17  to the subject in need thereof. 
     
     
         33 . The method of  claim 32 , wherein the disease is an inflammatory eye disorder which is intraocular, periocular and ocular surface inflammation, Keratoconjunctivitis, keratoconjunctivitis sicca (KCS, aka Dry Eye), KCS in patients with Sjogren's syndrome, allergic conjunctivitis, uveitis, inflammation of the eye, the cornea and periocular tissue from contact lens wear, inflammation of the eye following surgery including LASIK, intraocular inflammation including inflammation of the retina and the anterior and posterior segments of the eye, uveitis, retinitis, edema and retinopathies including diabetic macular edema and diabetic retinopathy, corneal inflammation including rejection of corneal transplants Graves' disease (Basedow disease), or Graves ophthalmopathy. 
     
     
         34 . The method of  claim 32 , wherein the disease is an allergic disease which is allergic conjunctivitis, allergic rhinitis, allergic asthma, or allergic contact dermatitis. 
     
     
         35 . The method of  claim 32 , wherein the disease is psoriasis, irritant contact dermatitis, eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, alopecia, alopecia areata, or scar formation. 
     
     
         36 . A pharmaceutical composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         which comprises a purity greater than about 90% and a pharmaceutically acceptable biocompatible matrix wherein the compound comprises a solid form within the biocompatible matrix. 
       
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the solid form is the amorphous form or any of crystalline Forms A, B, C, D, or E, or a combination thereof, of the compound of  claim 1 . 
     
     
         38 . The pharmaceutical composition of  claim 36 , wherein the biocompatible matrix is a gel or a solid. 
     
     
         39 . The pharmaceutical composition of  claim 36 , wherein the biocompatible matrix is a polyacrylate, methacrylate, polyolefin, polyamide, fluoropolymer, cellulose derivative, polyvinyl alcohol, polyvinylpyrrolidone, coated zeolite, or PLGA microsphere or nanosphere. 
     
     
         40 . The pharmaceutical composition of  claim 36 , wherein the biocompatible matrix is biodegradable. 
     
     
         41 . The pharmaceutical composition of  claim 36 , wherein a release of the compound from the biocompatible matrix comprises a slow release profile or a sustained release profile. 
     
     
         42 . A method of treating disease in a subject, comprising the steps of administering an effective amount of the pharmaceutical composition of  claim 36  to the subject in need thereof. 
     
     
         43 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salts. 
       
     
     
         44 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salts. 
       
     
     
         45 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salts. 
       
     
     
         46 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salts. 
       
     
     
         47 . A reaction mixture comprising the compound of  claim 43  or  44 , a solvent, and a coupling reagent 
     
     
         48 . The reaction mixture of  claim 47  further comprising a base. 
     
     
         49 . The reaction mixture of  claim 48  further comprising the compound of  claim 44 . 
     
     
         50 . The reaction mixture of  claim 49  wherein the compound of  claim 45  is produced. 
     
     
         51 . The reaction mixture of  claim 47  wherein the solvent is DMF. 
     
     
         52 . The reaction mixture of  claim 47  wherein the coupling reagent is 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). 
     
     
         53 . The reaction mixture of claim of  claim 48  wherein the base is triethylamine. 
     
     
         54 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         55 . A reaction mixture comprising the compound of  claim 46 , a solvent, and an acid. 
     
     
         56 . The reaction mixture of  claim 46  wherein the compound of  claim 54  is produced. 
     
     
         57 . The reaction mixture of  claim 55  wherein the solvent is dioxane. 
     
     
         58 . The reaction mixture of  claim 55  wherein the acid is HCl. 
     
     
         59 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salts. 
       
     
     
         60 . A reaction mixture comprising the compound of  claim 54 , a solvent, and a base. 
     
     
         61 . The reaction mixture of  claim 60  further comprising benzofuranonyl chloride. 
     
     
         62 . The reaction mixture of  claim 61  wherein the compound of  claim 61  is produced. 
     
     
         63 . The reaction mixture of  claim 60  wherein the solvent is methylene chloride. 
     
     
         64 . The reaction mixture of  claim 60  wherein the base is diisopropylethylamine. 
     
     
         65 . A method of synthesizing a compound of Formula I: 
       
         
           
           
               
               
           
         
         comprising the steps: 
         a) hydrogenolyzing an ester of Formula A with a palladium catalyst and a source of protons; and 
       
       
         
           
           
               
               
           
         
         b) isolating a compound of Formula i. 
       
     
     
         66 . The method of  claim 65 , wherein the palladium catalyst is 10% palladium on carbon. 
     
     
         67 . The method of  claim 65 , wherein the proton source is formic acid.