Impact of powder composition on processing-relevant properties of pharmaceutical materials: An experimental study.

• Simple linear mixture rules do not apply for all binary mixtures. • A non-linear dependence of powder properties on composition. • A relation between size ratio of the binary mixtures and random packing structure. In this work, we studied the influence of powder composition on packing density and other processing-relevant properties of binary mixtures, including powder flowability. Binary mixtures of pharmaceutical powders with different particle size ratios, α and varying fractions of large and small particles were analyzed systematically. Mixtures of three excipients and one API with different composition (2, 5, 10, 30, 50, 70, 90, 95 and 98 wt%) were prepared in a Turbula mixer. Powders with different properties and particle size distribution were chosen, in order to obtain three binary mixtures with different size ratios. Then, macroscopic powder properties including bulk (poured) and tapped density (BD and TD) were measured. A powder rheometer was used to measure the flow function coefficient (ffc), cohesion, compressibility and permeability of the binary mixtures. We considered experimentally three classes of binary mixtures, which are characterized by two critical ratios of particle diameter: the critical size ratio of entrance (α c) and the critical size ratio of replacement (α r), where α c = 0.154 and α r = 0.741. Below the critical size ratio of entrance (α c), the particle asymmetry (ratio between large and small particle diameters) is high and small particles can fill the voids between larger ones. Between α c and the critical size ratio of replacement (α r), the smaller particles are too large to fit in the voids between larger particles (packing structure changes). Above α r , the particles are more or less symmetric in size and overall packing structure does not change by mixing the particles. Our experiments show that there is a non-linear and non-monotonic dependence of all relevant properties on composition for powder mixtures that have an α < α r. This non-linear behavior is even more significant for strongly asymmetric binary mixtures with α < α c. We argue that this behavior is related to the composition dependence of random packing of particulate systems. Our results have relevance to pharmaceutical particle processing operations where constant powder mixture properties are needed to ensure quality standards are met; such operations include capsule or die filling during tableting, and the continuous feeding of powders via screw feeders. Our results suggest that for pharmaceutical particle processing operations, where constant powder mixture properties are a prerequisite for process robustness, the size ratio of API and excipient particles, α should not be smaller than α r = 0.741. [ABSTRACT FROM AUTHOR]