Figure 1: Fluidization-segregation test results showing drug content across individual layers. (ALL FIGURES ARE COURTESY OF
THE AUTHORS)
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To confirm the root-cause hypothesis, bench-scale segregation tests were conducted to confirm the dominant segregation mechanism
for the blend. A test was conducted on the blend to assess its potential to experience fluidization segregation. The test
method, described in detail in the literature, is conducted by fluidizing a column of material by injecting air at the bottom
of the test column, and allowing it to deaerate in a controlled manner (5). When the test is concluded, the column is split
into 16 equal sections, and selected sections are assayed for drug content. If the blend were prone to fluidization segregation,
samples from the bottom (i.e., Layer 1) would have a coarser particle size and contain a lower concentration of the drug than
the samples from the top (i.e., Layer 14). The concentration of drug from the various layers from the fluidization segregation
test data are graphically depicted in Figure 1. A trend of increasing drug concentration toward the top layers of the blend
confirmed that the blend had a high tendency to segregate, predominantly because of fluidization.
Figure 2: Sifting segregation test results showing drug content across slot locations. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
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Although fluidization was the primary factor, the authors performed a sifting segregation test by filling a narrow test cell
to one side, thus allowing a pile of the dry blend to form within the cell. If a material segregates by sifting, the coarse
particles flow to the far side, away from the fill point, while fine particles accumulate under the fill point. After the
cell was filled, the samples were extracted from the bottom of the tester in layers, with a given layer subdivided into five
slots. The first layer extracted was designated Layer 1, and as many as 14 layers were collected, depending on the surcharge
angle of the material. Slot locations were designated A through E, with A being away from the fill point, and E under the
fill point. If the blend is prone to sifting segregation, samples collected below the fill point (i.e., slot E) are drug-rich
and finer than those collected away from the fill point (i.e., slot A). However, an increase in drug-rich fines away from
the fill point (i.e., at slot A) is consistent with a fluidization or dusting segregation mechanism. The sifting segregation
test data, as shown in Figure 2, demonstrated that the blend had a low tendency to segregate by sifting.
The segregation test results confirmed that both the blender-to-bin and bin-to-press transfer steps could result in fluidization
or dusting segregation, thereby leading to CU problems. Subsequently, flow-properties tests, including cohesive-strength and
wall-friction tests, were conducted at the bench scale to confirm the flow pattern of the blend during the blender-to-press
discharge (6). Based on the wall-friction test results, the authors concluded that the rectangular-to-round hopper angles
for the bin used for the first demonstration batch were not smooth or steep enough to provide mass-flow discharge, and that
the bin discharged the blend in funnel flow, thereby resulting in higher variation of the drug content in the tablets. Based
on the flow-properties test results, a specially designed bin (i.e., a cone-in-cone) was used for the second demonstration
batch. This bin design provided mass-flow discharge, thus minimizing the effects of dusting segregation during transfer.
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