Particle size distribution (PSD) variability in excipients is widely thought to affect the mixing process and the achievement of blend homogeneity. Yet, few studies have addressed this issue by attempting to ascertain the relationship and elucidate its mechanism. To address this, the model material, lactose, was modified to reflect commercially relevant PSD variations and mixed with microcrystalline cellulose and chlorpheniramine in a double-cone blender. Multivariate modelling and avalanche testing were applied to elucidate the relationship and mechanism. PSD variability can cause significant change in mixing time, by 8 times and 3 times (p ≈ 0.00) for high and low dose drug formulations, respectively. Achievement of blend homogeneity depended on the dispersive mixing mechanism (r2 = 0.99). Dispersive mixing was adversely affected by powder cohesiveness and powder dilation, which increased as the proportion of fine particles in lactose powder increased. This study yielded three conclusions. Firstly, PSD variability in pharmaceutical grade excipients can cause unacceptable prolongation in mixing time. Secondly, the impact of PSD variability on continuous mixing and other batch mixing of various scales, requires investigation. Lastly, the current findings can contribute to the development of robust mixing operations in the form of offline pre-emptive measures and inline process control strategies.
Keywords: Blending; Excipient variability; Lactose; Microcrystalline cellulose; Particle size distribution.
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