Continuous production of pharmaceutical granulation

Abstract

A single pass, continuous, automated system for producing a pharmaceutical granulation includes multiple feeders to feed powders and liquids, a twin screw processor to granulate, a radio frequency or microwave based drying apparatus to dry the granulation, and at least one mill to process the dried granulation to desired particle sizes. The system incorporates means for monitoring key process parameters on-line, all of which are controlled by a controller provided with feedback at each component of the system. The granulation produced can be compressed into a tablet or incorporated into a capsule, both having a uniform distribution of the active ingredient. The system produces product having consistent properties even when production is scaled up for manufacture of the tablet in commercial volume.

What is claimed:  
     
         1 . A single pass continuous processing system for producing pharmaceutical granulation, comprising: 
 (a) powder and liquid feeders to feed at least one pharmaceutically active ingredient and additives to;    (b) a twin screw wet granulator-chopper device for granulating the active ingredient and additives received from the powder and liquid feeders into a wet granular product said twin screw wet granulator-chopper including a housing surrounding said device, said housing including a non-extruding opening at the outlet thereof;    (c) conveying, loading, and leveling means for conveying the wet granulation from the outlet of said twin screw wet granulator-chopper, loading the wet granulation on a dryer belt, and leveling the wet granulation to the desired height;    (d) a drying apparatus for receiving the wet granulation from the dryer belt and drying the wet granulation using dielectric energy;    (e) conveying means for transporting the dried granulation from the drying tunnel for size reduction;    (f) a mill for reducing the dried granulation to particles of a desired size; and    (g) control means for controlling process variables of at least one of the powder and liquid feeders, the twin screw wet granulator-chopper, the conveying, loading, and leveling means, the drying apparatus, the conveying means, and the mill to optimize production of pharmaceutical granulation.    
     
     
         2 . The system of  claim 1  wherein the powder is fed through a side stuffer unit and the liquid is fed into a liquid injector for addition into the twin screw wet granulator-chopper.  
     
     
         3 . The system of  claim 1  wherein the twin screw wet granulator-chopper comprises a mechanism for chopping the granulation into discrete particles.  
     
     
         4 . The system of  claim 1  wherein the control means includes means for monitoring conditions of the system and controlling process variables of at least one of the powder and liquid feeders, the twin screw wet granulator-chopper, the conveying, loading, and leveling means, the drying apparatus, the conveying means, and the mill.  
     
     
         5 . The system of  claim 4  wherein the moisture content of the granulation is monitored on-line and the liquid feeder is controlled to adjust the moisture content.  
     
     
         6 . The system of  claim 4  wherein the uniformity of distribution of the active ingredient is monitored on-line and at least one of the powder and liquid feeders, the twin screw wet granulator-chopper, the conveying, loading, and leveling means, the drying apparatus, the conveying means, and the mill is controlled to adjust the uniformity of distribution.  
     
     
         7 . The system of  claim 1  wherein the twin screw wet granulator-chopper comprises two or more screws having interengaging threads adapted to rotate in the same or opposite directions and granulate the active ingredient and additives.  
     
     
         8 . The system of  claim 1  further comprising after step (b), the step of milling the wet granulation into particles of a desired size.  
     
     
         9 . In a method for making a compressible pharmaceutical granulation by mixing at least one pharmaceutically active ingredient with excipients, binders, and liquids to form a wet mixture, chopping said wet mixture into a wet granulation, and drying said wet granulation, the improvement comprising: 
 forming said wet granulation in a twin screw wet granulator-chopper by feeding at least one pharmaceutically active ingredient, excipients, binders, and liquids to said granulator-chopper at preselected locations along the length thereof removing said granulation continuously, without extrusion, at one end of said granulator-chopper, and drying said granulation.    
     
     
         10 . The method of  claim 9  wherein said wet mixture is granulated by the rotation of twin screws of said granulator-chopper, said screws having interengaging threads adapted to rotate in the same or opposite directions and granulate said mixture.  
     
     
         11 . The method of  claim 10  wherein said wet mixture is granulated by thread-free zones of said screws and said granulated mixture is chopped to form discrete granulation particles.  
     
     
         12 . The method of  claim 11  wherein the thread-free zones comprise at least one member from the group consisting of kneading discs, combing mixers, gear mixers, pin mixers, and calender gap mixers.  
     
     
         13 . In a method for making a compressible pharmaceutical granulation by mixing a pharmaceutically active compound with excipients, binders, and liquids to form a wet mixture which is then granulated and dried, the improvement comprising drying said granulation using dielectric energy in a single pass, continuous mode.  
     
     
         14 . The method of  claim 13  wherein said granulation is dried using radio frequency, low frequency microwave, or high frequency microwave energy in a drying apparatus, said drying apparatus having a gradient with progressively decreasing moisture content in said granulation as said granulation moves along said drying apparatus.  
     
     
         15 . The method of  claim 14  wherein said granulation is dried by an alternating electric field produced by a generator of radio frequency energy.  
     
     
         16 . An apparatus for drying a pharmaceutical granulation comprising: 
 a conveying belt for receiving and transporting the granulation to be dried;    a drying tunnel for receiving the granulation, said tunnel containing a source of dielectric energy and electrodes for producing an alternating electric field to heat the granulation;    a source of heated and cooled air;    a flow control mechanism for controlling the flow of heated and cooled air in the tunnel, the flow control mechanism removing moisture from the tunnel; and    control means for controlling the energy and air flow in the tunnel.    
     
     
         17 . The apparatus of  claim 16  wherein the dielectric energy is radio frequency energy.  
     
     
         18 . The apparatus of  claim 16  wherein the dielectric energy is low frequency or high frequency microwave energy.  
     
     
         19 . The apparatus of  claim 16  wherein the direction of the flow of heated and cooled air in the tunnel is co-current or counter current with the direction of the granulation being transported on the drying belt.  
     
     
         20 . A twin screw wet granulator-chopper for granulating an active ingredient and additives comprising: 
 a housing containing feed points for solids and liquids containing at least one active ingredient and additives;    twin screws within the housing, the screws having interengaging threads adapted to rotate in the same or opposite directions;    a motor for rotating the twin screws to mix the solids and liquids into a granulation;    an open end for discharging the granulation; and    means for chopping the granulation into discrete particles.    
     
     
         21 . The twin screw wet granulator-chopper of  claim 20  further comprising one or both of reverse threads and thread-free zones for granulating the solids and liquids.  
     
     
         22 . The twin screw wet granulator-chopper of  claim 20  further comprising at least one member from the group consisting of kneading discs, combing mixers, gear mixers, pin mixers, and calender gap mixers, for granulating the solids and liquids.  
     
     
         23 . The twin screw wet granulator-chopper of  claim 20  wherein the chopping means is flush with the open end or extends beyond the open end of the twin screw wet granulator-chopper.