Pharmaceutical granulations of water-soluble active pharmaceutical ingredients

Abstract

Granulations with granules having a high loading of an active pharmaceutical ingredient are disclosed. The active pharmaceutical ingredient has a high aqueous water solubility. The granules have a narrow particle size distribution and a smooth exterior surface.

What is claimed is: 
     
         1 . Granules comprising:
 greater than 95 wt % of a compound of Formula (2a):   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; 
         
         from 0.1 wt % to 3.0 wt % of a binder; and 
         from 0.1 wt % to 2.0 wt % of an antistatic agent, 
         wherein wt % is based on the total weight of the granules. 
       
     
     
         2 . The granules of  claim 1 , wherein the granules comprise:
 greater than 97 wt % of a compound of Formula (2a);   from 0.1 wt % to 1.0 wt % of a binder; and   from 0.1 wt % to 2.0 wt % of an antistatic agent,   wherein wt % is based on the total weight of the granules.   
     
     
         3 . The granules of  claim 1 , wherein the granules comprise:
 from 98 wt % to 99 wt % of the compound of Formula (2a);   from 0.25 wt % to 0.75 wt % of the binder; and   from 0.5 wt % to 1.5 wt % of the antistatic agent,   wherein wt % is based on the total weight of the granules.   
     
     
         4 . The granules of  claim 1 , wherein the granules comprise from 97 wt % to 99 wt % of the compound of Formula (2a), wherein wt % is based on the total weight of the granules. 
     
     
         5 . The granules of  claim 1 , wherein the granules are solid and are characterized by a substantially homogenous composition throughout the granule. 
     
     
         6 . The granules of  claim 1 , wherein the granules are characterized by a sphericity greater than 0.90, wherein sphericity is determined using wet dispersion particle shape methods or by dynamic image analysis. 
     
     
         7 . The granules of  claim 1 , wherein the granules are characterized by a sphericity greater than 0.95, wherein sphericity is determined using wet dispersion particle shape methods or by dynamic image analysis. 
     
     
         8 . The granules of  claim 1 , wherein the granules have an average particle diameter (D50) less than 450 μm. 
     
     
         9 . The granules of  claim 1 , wherein the granules are characterized by a particle size distribution (PSD) D10 from 50 μm to 150 μm, a D50 from 150 μm to 350 μm, and a D90 from 475 μm to 725 μm, wherein the particle size distribution is determined by laser diffraction or by sieve analysis. 
     
     
         10 . The granules of  claim 1 , wherein the granules have a friability value less than 2 wt %, wherein friability is determined using a sonic sifter. 
     
     
         11 . The granules of  claim 1 , wherein the granules a bulk density from 0.50 g/mL to 1.20 g/mL, wherein bulk density is determined according to USP 616, Method I. 
     
     
         12 . The granules of  claim 1 , wherein the binder comprises hydroxypropyl cellulose. 
     
     
         13 . The granules of  claim 1 , wherein the antistatic agent comprises hydrophilic fumed silica. 
     
     
         14 . The granules of  claim 1 , wherein,
 the binder comprises hydroxypropyl cellulose; and   the antistatic agent comprises hydrophilic fumed silica.   
     
     
         15 . The granules of  claim 1 , wherein the granules comprise a coating. 
     
     
         16 . The granules of  claim 15 , wherein the coating comprises a controlled release coating. 
     
     
         17 . A pharmaceutical composition comprising the granules of  claim 1 . 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition comprises an oral suspension. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition comprises an immediate release formulation. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition comprises a controlled release formulation.