Section 2
           Tablet Processing
           By Dr. Cecil W. Propst
           Table of Contents
           Tablet Processing........................................................................................................................1
             Table of Contents....................................................................................................................1
             Process Objective...................................................................................................................2
               Content Uniformity..............................................................................................................2
               Material Composition..........................................................................................................2
             Wet Granulation.......................................................................................................................5
               Advantages of Wet Granulation..........................................................................................6
               Disadvantages of Wet Granulation......................................................................................7
               Dry Mixing...........................................................................................................................7
               Wet Mixing...........................................................................................................................7
               Ingredients fir Wet Granulation............................................................................................8
                 Binders..........................................................................................................................10
                 Avicel® PH Microcrystalline Cellulose (MCC) in Wet Granulation.................................10
               Wet Milling.........................................................................................................................11
               Drying of Granules ............................................................................................................11
               Drying of Milling ................................................................................................................14
             Direct Compression...............................................................................................................14
               Advantage of Direct Compression....................................................................................14
               Disadvantages of Direct Compression .............................................................................14
               Final Blending....................................................................................................................15
                 Adhesive mixing—Fines................................................................................................15
                 Adhesive mixing—Coarse.............................................................................................15
                 Carrier Blends ...............................................................................................................16
                 Mixing by Dilution..........................................................................................................16
             Dry Granulation .....................................................................................................................16
               Advantages of Dry Granulation.........................................................................................19
               Disadvantages of Dry Granulation....................................................................................19
               Special Procedures...........................................................................................................19
               Special Procedures: Extrusion-Spheronization.................................................................19
               Extrusion Equipment.........................................................................................................20
               Liquid Carrier-Based Granulations....................................................................................22
               Cushion-Based Blends.....................................................................................................22
               Handling of Powders.........................................................................................................22
               Containment......................................................................................................................22
                                               1
        Process Objectives
       The objective of pharmaceutical processing       The choice of excipients greatly depends 
       in manufacturing solid dosage forms is to        on the properties of the drug substance, 
       prepare the running powder to feed the           the behavior of the product as it is being 
       tablet press and/or capsule-filling machine.     processed, and the properties required for
                                                        the final dosage form. In order to deliver a
       There are a number of required                   stable, uniform, and effective drug product,
       characteristics for the running powder, and      it is essential to know the properties of the
       many of the requirements vary, depending         active ingredient, the active ingredient in
       on the equipment used to manufacture the         combination with the required excipients,
       dosage form. Of these properties,                and the requirements of the dosage form,
       homogeneity of the mix, material flow,           and then to apply these requirements to 
       controlled bulk density, and proper lubricity    the process.
       are the most important. For tablets and
       some of the capsule-filling machines, both       To better understand these process 
       compressibility and consolidation                objectives, a focus on the general 
       characteristics of the running powder are        requirements of the solid dosage form 
       also key.                                        is required.
       Three main manufacturing methods are             Content Uniformity
       used to prepare the running powder:
                                                        The content uniformity of the solid dosage
       •Wet granulation                                 form is controlled by two components: 
       •Direct compression                              First, the variation in the weight of the
       •Dry granulation or slugging                     dosage form, and second, the variation 
                                                        in the direct distribution in the running 
       Almost all formulations require                  powder.
       supplemental materials (excipients) to be
       added to the recipe in addition to the active    The dosage weight is controlled mainly 
       ingredient to increase the dosage form size.     by he bulk density of the running powder. 
       and for other essential functions, such as       Variation in flow of the feed material can 
       binding and disintegration. The ingredient       vary the weight of fill of the dosage form
       classification used is:                          only if the flow rate is insufficient to fill the
                                                        cavity in the time allowed by the machine 
       •  Fillers                                       for the filling process. If the powder flow is
       •  Binders                                       fast enough (Figure 1), a reserve of fill time
       •  Disintegrants                                 will be available so that a small change in
       •  Lubricants                                    flow rate will have little or no effect on the
       •Wetting agents                                  weight of the final dosage form. Thus, a 
       •  Glidants                                      process that creates a freely flowing feed
       •  Antiadherents                                 material with a controlled narrow range 
                                                        bulk density is to be considered ideal 
       •  Colors and flavors                            for controlling dosage weight.
       •Preservatives
                                                    2
                  e 1: Flow versus Bulk Density
             Figur
                                Bulk density control
                 ablet weight
                 T
                                 Flow (g/min)
             Among other things, a shift in the particle         Fines fill the voids present in a powder 
             size distribution can change bulk density.          bed of larger (coarser) particles (Figure 3). 
             As shown in Figure 2, a change in the               Once the voids created by the coarse
             amount of smaller particles (fines) can             particles are close to being fully occupied, 
             cause a dramatic change in the bulk density         the fines begin to displace particles and, 
             of the powder bed. Fines in the context of          in the displacement, leave behind fine 
             this section and for pharmaceutical powders         particles in the space formerly occupied 
             are defined as passing through a 210-µm             by he coarse particle. These fine particles 
             screen.                                             have void spaces between them. As a 
                                                                 result, the bulk density falls due to the
             As the amount of fines increases from 0%            coarse particle displacement. Note that 
             to approximately 40%, so does the bulk              the maximum bulk density reaches a peak 
             density of the feed material (also Figure 2).       (Figure 2), which limits the change in bulk
             This increase in bulk density occurs until          density of the bed. If the process particle
             the amount of fines in the mix reaches a            size distribution is controlled at this 
             critical content. After this critical amount is     maximum, the bulk density will be less 
             reached, adding more fines causes the               variable.
             density to decrease.
                                                               3
    Figure 2: Effect of Fines on Bulk Density
       1.2
       1.1
        1
     Bulk density g/mL0.9
       0.8
         0102030405060708090100
                    Fines (%)
    Figure 3: Effect of fines on Voids Created by Coarse Particles
                 +=
         0%                    35%
                            60%
                              4