Co-processing method and formulation for hiv attachment inhibitor prodrug compound and excipients

Abstract

A process for the production of a formulation of HIV attachment inhibitor piperazine tris salt prodrug compound involves dissolving the prodrug compound in a solvent to form a solution; adding a first quantity of a first anti-solvent to the solution; then dispersing a first quantity of HPMC in the solution; adding a second quantity of the first anti-solvent to the solution; dispersing a second quantity of HPMC in the solution; then adding a second anti-solvent to the solution so as to crystallize the compound with the HPMC and thereby form the formulation, wherein the second anti-solvent is a combination of acetone and isopropyl acetate (IPAC). The formulation is then washed, and dried.

What is claimed is: 
     
         1 . A process for the production of a formulation of HIV attachment inhibitor piperazine tris salt prodrug compound, comprising:
 a) dissolving said prodrug compound in solvent to form a solution;   b) adding a first quantity of a first anti-solvent to said solution;   c) dispersing a first quantity of HPMC in said solution;   d) adding a second quantity of said first anti-solvent to said solution;   e) dispersing a second quantity of HPMC in said solution; and   adding a second anti-solvent to said solution so as to crystallize said compound with said HPMC and thereby form said formulation, wherein said second anti-solvent is a combination consisting essentially of acetone and isopropyl acetate (IPAC).   
     
     
         2 . The process of  claim 1 , further comprising the steps of filtering, washing and drying said crystallized compound. 
     
     
         3 . The process of  claim 1 , wherein said solvent is water. 
     
     
         4 . The process of  claim 3 , wherein said first anti-solvent is acetone. 
     
     
         5 . The process of  claim 1 , wherein said first quantity of HPMC is approximately 40 to 60% of the total quantity. 
     
     
         6 . The process of  claim 4 , wherein said second anti-solvent is a combination of acetone and IPAC in about a 20:80 v/v ratio. 
     
     
         7 . The process of  claim 6 , wherein said second anti-solvent is substantially free of additional compounds. 
     
     
         8 . The process of  claim 7 , wherein said additional compounds comprise ethyl acetate and n-butyl acetate. 
     
     
         9 . The process of  claim 2 , wherein said filtering and washing is done with acetone. 
     
     
         10 . The process of  claim 9 , wherein said drying is done under agitation. 
     
     
         11 . The process of  claim 10 , wherein said crystallized compound has improved powder flow and compactability. 
     
     
         12 . The process of  claim 11 , wherein said crystallized compound is in the form of spherical shaped agglomerates. 
     
     
         13 . The process of  claim 12 , wherein said compound is substantially crystallized within said HPMC. 
     
     
         14 . The process of  claim 1 , wherein in step a) said compound is substantially crystalline and is characterized by highly chargeable, fragile needles with high aspect ratio and poor flow characteristics. 
     
     
         15 . The process of  claim 6 , wherein in step f) said second anti-solvent is added over the course of approximately 1 to 5 hours. 
     
     
         16 . The process of  claim 1 , wherein after step f) the ratio of said compound to said HPMC is approximately 3:1. 
     
     
         17 . The formulation obtained according to the process of  claim 1 . 
     
     
         18 . A process for the production of a formulation of HIV attachment inhibitor piperazine tris salt prodrug compound, comprising:
 a) adding a first anti-solvent to a first vessel;   b) dispersing HPMC in said first vessel;   c) dissolving said prodrug compound in a solvent to form a solution, and adding said solution to said first vessel;   d) adding a second anti-solvent to said solution in said first vessel so as to crystallize said compound with said HPMC and thereby form said formulation, wherein said second anti-solvent is a combination consisting essentially of acetone and isopropyl acetate (IPAC).   
     
     
         19 . The process of  claim 18 , wherein said first anti-solvent is acetone. 
     
     
         20 . The process of  claim 18 , wherein said solvent is water.