The Effect of Shear Mixing on the Blending of Cohesive Lubricants and Drugs - Pharmaceutical Technology

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The Effect of Shear Mixing on the Blending of Cohesive Lubricants and Drugs
Manufacturers must find the appropriate amount of shear mixing to attain the desired drug properties.


Pharmaceutical Technology



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.
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 2: The effect of rotation speed on the shear rates of the process.
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.

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 homogeneous mixtures.


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