Polymorphic forms of 6-11 bicyclic ketolide derivatives

Abstract

The present invention includes EP-13420 polymorphic crystalline forms: Form I, Form II, Form Ia, and monohydrate and amorphous EP-13420 which posses distinct physical properties. In another embodiment of the present invention, there are provided methods of producing the various polymorphic forms in pure form or in combination with one another. The present invention also provides pharmaceutical compositions and formulations comprising the polymorphic and amorphous forms and methods of treating bacterial infections by administering the pharmaceutical compositions to a subject in need of such treatment.

1 . A polymorphic form of EP-13420, designated Form II, having an X-ray diffraction pattern with at least one strong peak located at a 2-Theta (2θ) angle selected from: 11.2, 17.0, 19.9, 21.6, 25.5, 30.1, and 33.3°. 
     
     
         2 . The polymorphic Form II of  claim 3  having a differential scanning calorimetry endotherm at 163° C. (onset at 158° C.). 
     
     
         3 . The polymorphic Form II of  claim 1  in substantially pure form. 
     
     
         4 . A polymorphic form of EP-13420, designated Form Ia, having an X-ray diffraction pattern with at least one strong peak located at a 2-Theta (2θ) angle selected from: 9.7, 11.8, 13.2, 14.2, 14.9, 20.4, 21.7, 25.4, 27.8, 34.0, 40.6, and 44.7°. 
     
     
         5 . The polymorphic Form Ia of  claim 4  having a differential scanning calorimetry endotherm at 169° C. (onset at 164° C.). 
     
     
         6 . The polymorphic Form I of  claim 4  in substantially pure form. 
     
     
         7 . An amorphous form of EP-13420 with a X-ray diffraction pattern displayed in  FIG. 8 . 
     
     
         8 . The amorphous form of EP-13420 of  claim 4  having a differential scanning calorimetry endotherm at 170° C. (onset at 159° C.). 
     
     
         9 . A polymorphic form of EP-13420 characterized by the XRD pattern of  FIG. 3 . 
     
     
         10 . A polymorphic form of EP-13420 characterized by the XRD pattern of  FIG. 5 . 
     
     
         11 . A polymorphic form of EP-13420 characterized by the XRD pattern of  FIG. 7 . 
     
     
         12 . EP-13420 monohydrate. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of a form of EP-13420 selected from Form Ia, Form II, monohydrate, amorphous or any combination thereof, in combination with a pharmaceutically acceptable carrier. 
     
     
         14 . The pharmaceutical composition according to  claim 13  for oral administration. 
     
     
         15 . The pharmaceutical composition according to  claim 14  in capsule form. 
     
     
         16 . The pharmaceutical composition according to  claim 14  in tablet form. 
     
     
         17 . The pharmaceutical composition according to  claim 14  in elixir form. 
     
     
         18 . The pharmaceutical composition according to  claim 13  wherein at least one pharmaceutically acceptable carrier is selected from the group consisting of fillers, extenders, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, buffering agents, coatings, and opacifying agents. 
     
     
         19 . A method of treating a bacterial infection in a subject in need of such treatment comprising the step of administering to the patient the pharmaceutical composition of  claim 13 . 
     
     
         20 . A pharmaceutically active ingredient comprising a form of EP13420 selected from Form Ia, Form II, monohydrate, amorphous, or any combination thereof. 
     
     
         21 . A pharmaceutical formulation having a masked taste comprising an active ingredient of  claim 20 , which comprises from about 15 to about 30% (w/w) of active ingredient mixed with from about 60% to about 80% (w/w) of an ester of glycerol or of a fatty acid, to which a wax is optionally added, and to which a surfactant is added, and wherein the pharmaceutical formulation is prepared by a spray-cooling process which can produce a particle size of less than about 350 microns. 
     
     
         22 . A pharmaceutical formulation having a masked taste, comprising an active ingredient of  claim 20  in the form of a suspension in an aqueous vehicle, and further comprising a) a cellulosic polymer which is soluble in organic solvents and substantially insoluble in water at any pH; b) a methacrylic polymer which is soluble in an acid medium and substantially insoluble at a neutral or alkaline pH wherein the active ingredient is distributed in a homogeneous manner and in the molecular state in the mixture, which is in the form of an atomized matrix; c) a pharmaceutically acceptable alkaline agent of an organic nature or an alkaline salt; and d) an adsorbent agent. 
     
     
         23 . The pharmaceutical formulation of  claim 22  wherein the proportions of cellulosic and methacrylic polymers in the matrix range respectively from about 40% to about 45% and from about 15% to about 20% by weight, and wherein the maximum amount of the active ingredient in the matrix is about 30% by weight. 
     
     
         24 . A capsule for oral administration comprising a formulation selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                   Weight Composition 
                 
                     
                   Blend 
                   for 100 mg Strength capsule 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   #1) EP-013420 amorphous 
                   25.0 
                 
                     
                   Anhydrous Lactose 
                   72.25 
                 
                     
                   Crospovidone 
                   2.0 
                 
                     
                   Magnesium Stearate 
                   0.75 
                 
                     
                   Full Weight 
                   400 
                 
                     
                   #2) EP-013420 amorphous 
                   30.8 
                 
                     
                   Microsrystalline Cellulose 
                   66.45 
                 
                     
                   Sodium Starch Glycolate 
                   2.0 
                 
                     
                   Magnesium Stearate 
                   0.75 
                 
                     
                   Full Weight 
                   325 
                 
                     
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         25 . A pharmaceutical formulation comprising, an active ingredient of  claim 20 , an alginate matrix consisting of a water soluble alginate salt, a complex salt of alginic acid, and an inorganic salt, characterized in that the inorganic salt is capable of donating a proton and has a pKa value in water of 4.0-9.0. 
     
     
         26 . A pharmaceutical formulation for a fast melt lozenge or tablet comprising: a non-compressed, free flowing plurality of particles comprising an active ingredient of  claim 20 , and a water-soluble excipient, the particles having a mean diameter of greater than 10 microns to about 1 mm, the particles comprising at least about 50% active ingredient, and the formulation dissolving in the patients mouth within 1 minute after administration without the co-administration of fluid. 
     
     
         27 . A pharmaceutical formulation for a soft-bite gelatin capsule for transmucosal administration comprising about 0.01-85% by weight of an active ingredient of  claim 20 , about 4-99.99% by weight of a non-polar solvent, and about 0-20% by weight of emulsifier. 
     
     
         28 . A pharmaceutical formulation for a propellant-free buccal spray formulation for transmucosal administration comprising an active ingredient of  claim 24  and a polar or non-polar solvent in an amount between about 30-99%. 
     
     
         29 . A pharmaceutical formulation for a buccal spray formulation for transmucosal administration comprising an active ingredient of  claim 20 , a polar or non-polar solvent in an amount between abut 30-99% by weight, and a propellant in the amount of about 2-10% by weight. 
     
     
         30 . A pharmaceutical formulation for pulmonary delivery formulation comprising an active ingredient of  claim 20  in a nebulized formulation. 
     
     
         31 . A pharmaceutical formulation for pulmonary delivery formulation comprising an active ingredient of  claim 20  in an aerosolized formulation. 
     
     
         32 . A method of treating inflammation in a subject in need of such treatment comprising the step of administering to the patient, the pharmaceutical composition of  claim 13 . 
     
     
         33 . A method of treating cystic fibrosis in a subject in need of such treatment comprising the step of administering to the patient, the pharmaceutical composition of  claim 13 .