Addressing Segregation of a Low-Dosage Direct Blend - Pharmaceutical Technology

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Addressing Segregation of a Low-Dosage Direct Blend
The authors modified equipment and the manufacturing process to re-establish content uniformity among tablets.


Pharmaceutical Technology
Volume 35, Issue 2, pp. 78-82


Figure 1: Fluidization-segregation test results showing drug content across individual layers. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
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)
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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