Fill level. Fill level can lead to the most striking differences in mixing performance (see Figure 1). The mixing process is the slowest,
and the homogeneity of magnesium stearate is the poorest, at the highest fill level (85%). Hindered mixing, often observed
at a high fill level, produces a slow homogenization of magnesium stearate. Even though long mixing times can compensate for
the slow mixing conditions of a high fill level, this step is often a poor solution: in a scaled-up operation, long mixing
times will almost certainly result in overlubrication.
Figure 1: The effect of fill level on the outcome of the lubrication process is evidenced by the differences in the evolution
for magnesium stearate homogeneity.
Rotation speed. Although vessel rotation speed has little effect on the mixing process (when measured as a function of vessel revolutions)
of free-flowing granulated materials, the speed of the vessel is critical for cohesive materials such as magnesium stearate.
The vessel rotation speed determines the shear rate, and thus has a direct effect on the outcome of the process (see Figure
2). The homogenization process is slower at 6 rpm than at 26 rpm. For long mixing times (320 revolutions), however, the same
overall level of homogeneity is attained for both speeds. This effect suggests that the de-aggregation of the lubricant is
a function both of shear rate and total shear.
Figure 2: The effect of rotation speed on the shear rates of the process.
Internal baffles. The presence of properly designed baffles can increase the axial mixing rate. In fact, a blender operating at 60% fill level
achieves homogeneity slightly faster with the aid of baffles. Baffles do not affect shear rate substantially and, although
they do not increase the risk of overlubrication, they do not improve the homogeneity of a cohesive-powder blend or promote
the disintegration of agglomerates substantially.
Effects of shear mixing in the blending of drugs: avoiding agglomerates
In general, the blending of a cohesive API does not have problems associated with exposure to high shear rates or total shear
such as those encountered in the blending of lubricants. To the contrary, most problems in homogenizing cohesive drugs are
the consequence of low shear rates in blenders. Agglomerates containing a high proportion of API can form within a blender
producing blends characterized by fine API particle size, hygroscopic material, or, in some instances, when the API tends
to acquire an electrostatic charge. Such agglomerates can result in a small subpopulation of superpotent tablets that are
observed only occasionally, but that can throw a manufacturing operation into disarray.
The case study presented here focuses on the blending of a cohesive drug using rotating bins of different sizes, followed
by the passage of the blend through a high-shear device such as a conical mill at the discharge of the blender. The conical
mill provides high shear rates and guarantees that the blend will be entirely and uniformly exposed to shear. Conical mills
improve the distribution of the API and minimize drug agglomerates (4).
Shear rates increase as the scale of the blender increases. This effect is supported by the experimental results obtained
for the blending of a cohesive drug and free-flowing excipients in a 56-L (relative standard deviation 57%) versus a 300-L bin blender (relative standard deviation 8.5%). The large-scale bin provides higher shear rates and renders more