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.
Dec 01, 2005

Almost all pharmaceutical manufacturing processes require handling and processing cohesive powders. The application of sufficient shear (i.e., the total deformation that the bulk of granular material undergoes under applied shear stress) is an essential factor in such processes. Sufficient shear is required to mill and de-lump materials, achieve sufficient flow, and homogenize cohesive ingredients. Shear mixing plays a critical role in the blending of dry powders, particularly for those that contain a minor cohesive component such as a solid lubricant or a drug. This mechanism is necessary to achieve a satisfactory homogeneity and disintegrate possible agglomerates. Excessive shear can be disadvantageous, however, and can lead to electrostatic buildup, attrition, and overlubrication.

Shear mixing is caused by a velocity gradient within the material. Because powder flows are poorly understood at the present time, the effect of variables such as blender size, fill level, or speed of rotation of the blender have on shear rate can be established only qualitatively at best. Present technology does not allow the measuring of shear rates in situ for granular processes, and the assessment of shear conditions is done through blend homogeneity. Nonetheless, the evolution of homogeneity is intimately associated with the constitutive characteristics (cohesion and density) of the powders being blended. Moreover, homogeneity is not the only important parameter (otherwise the results obtained in a screen mill would be the epitome of mixing performance). The exposure of a lubricant to high intensity of shear entails the risk of overlubrication, with resulting degradation of tablet hardness and dissolution. Processes for which shear is a critical variable present additional challenges during scale-up.

This article reviews the lubrication and de-agglomeration phenomena in which shear plays a critical role. The last section of this article briefly addresses scale and presents conclusions and recommendations for future work.

Effects of shear mixing in the lubrication of a blend

Magnesium stearate is one of the most widely used lubricants in the pharmaceutical industry, and its functionality is based on the formation of a film of lubricant on the carrier particles. Magnesium stearate exhibits various morphologies with distinctive shear strengths and abilities to form a film that reduces the friction between particles and the tablet press die. The excessive coating of carrier particles by hydrophobic magnesium stearate, however, reduces tablet solubility and prevents direct interaction among particles of other ingredients. As a result, the strength of the entire tablet is determined by the low shear strength of magnesium stearate, and the hardness of the tablets is proportionally reduced.

For many systems, the ideal lubrication operation provides the mildest mixing conditions that guarantee sufficient homogeneity of the magnesium stearate. The extent of shear applied during the mixing process is a critical variable. If the mixing process is too short, magnesium stearate might be inhomogeneously distributed; thus, some portions of the blend will contain excessive amounts of magnesium stearate, show an increased tendency to overlubrication, exhibit a decreased tablet mechanical strength, and have decreased dissolution. If excessive shear is applied, however, magnesium stearate particles become finely divided, flowability can be adversely affected, excessive coating of active pharmaceutical ingredients (APIs) and excipients by magnesium stearate might occur, and the entire blend might be overlubricated.

At the present time, shear rate cannot be assessed easily inside a blender, and therefore blend and tablet properties must be correlated with indirect variables such as mixing time (1), fill level, and the blender's rotational speed and scale (2). This article examines a case study, focusing on the blend's lubrication in a 30-L blender (L.B. Bohle, Warminster, PA). The flowability of granulated materials, which is a function of particle properties, is what mainly determines the formation of a film of magnesium stearate (3). Poor flow properties usually retard the formation of a lubricant film. This fact, expressed in terms of mixing mechanisms, indicates that shear rates in the bulk of the material determine the formation of the film. This article analyzes the effect of fill level (40, 60, and 85), blender rotation speed (6, 14, and 16 rpm), presence of internal baffles, and mixing time on the homogeneity of magnesium stearate for specific granulated materials. The blender was sampled using a groove sampler, and the content of magnesium stearate in samples was analyzed using near-infrared spectroscopy. The various shear conditions and mixing efficiencies for each speed or fill level result in different cohesive-powder homogeneities. The experimental results indicate how several variables affect the shear conditions.