Pharmaceutical Manufacturing Handbook: Production and

EFFECT OF PARTICLE SIZE REDUCTION ON TABLETING PROCESSES 1185
6.7.4.1 Wet Granulation Processes
The particle size of an active pharmaceutical ingredient can have signifi cant effect
on the processing behavior of a formulation, such as granule growth during wet
granulation and hence the resulting granule characteristics. The particle size of the
starting material can affect the strength and deformability of moist granules and
hence their behavior during the wet granulation process.
The effect of particle size on granule growth is a function of several interacting
factors, the balance of which largely depends on the nature of the material and the
experimental conditions. Differences in granule structure and porosity, resulting
from changes in starting material particle size, can also affect other characteristics
(e.g., compressibility) of the granulation.
Badawy et al. [57] studied the effect of DPC 963 (a nonnucleoside reverse transcriptase
inhibitor) particle size on the granule growth, porosity, and compressibility
of granules manufactured by a high - shear wet granulation process. It was found that
DPC 963 granule growth in the high - shear granulator and the resulting granule
compressibility and porosity were sensitive to relatively small changes in drug substance
particle size. Decreasing the particle size resulted in more pronounced
granule growth and enhanced the porosity and compressibility of the granulation.
Higher pore volume for the granulation manufactured using the active ingredient
with a smaller particle size may be the reason for its higher compressibility. The
high granulation porosity resulted in an increased fragmentation propensity and
volume reduction behavior of the granulation that led to increased compressibility.
The more porous granulation has higher tendency to densify upon application of
the compression force, resulting in closer packing of the particles.
6.7.4.2 Mixing Processes
Mixing may be defi ned as a unit operation that aims to treat two or more components,
initially in an unmixed or partially mixed state, so that each unit of the components
lies as nearly as possible in contact with a unit of each of the other
components [2] . Whenever a product contains more than one component, mixing
will be required in the manufacturing process in order to ensure an even distribution
of the active component(s).
It is well accepted that mixing solid ingredients is usually more effi cient and
uniform if the active ingredient and excipients are approximately the same size,
which ultimately provides a greater uniformity of dose [1] . Particle size and particle
size distribution are important in the powder - mixing process since they largely
determine the magnitude of forces, gravitational and inertial, that can cause interparticulate
movement relative to surface forces, which resist such motion. As a
consequence of high interparticulate forces, as compared with the gravitational
forces, powders of less than 100 μ m mean particle diameter sizes are not free
fl owing. Powders that have high cohesive forces due to interaction of their surfaces
can be expected to be more resistant to intimate mixing than those whose surfaces
do not interact strongly [2] .
In moving from one location to another, relative to neighboring particles, a particle
must surmount a certain potential energy barrier that arises from forces resisting
movement. This effect is a function of both particle size and shape and is most