Effects of rotation rate, mixing angle, and cohesion in two continuous powder mixers—A statistical approach

a r t i c l e i n f o Keywords: Continuous powder mixing Statistical analysis ANOVA Homogeneity Residence time In this paper we examine the effect of rotation rate, mixing angle, and cohesion on the powder residence time and the content uniformity of the blend exiting from two continuous powder mixers. In addition, differences in mixing performance between the two blenders are examined. Analysis of variance is used to determine significance of main effects and their interactions. The results show that the effect of powder cohesion is scale-dependent, having a significant effect in the larger mixer. The overall rotation rate was the least influential parameter in terms of content uniformity. The residence time is significantly affected by both rotation rate and mixing angle. As part of their product development process, pharmaceutical companies carry out intensive research efforts focused on examining and optimizing the production of homogeneous solid mixtures. Minimizing variability in powder blends is critical to pharmaceutical (and many other) manufacturing operations because blend uniformity has direct impact on product quality and performance. Deviations from desired mixing performance, which often lead to batch failures, usually trigger costly process investigations and corrective actions required to maintain regulatory compliance [1]. Unfortunately, powder flow and powder mixing are topics that are far from being well understood. Often, powder mixing processes are designed ad-hoc, based on a limited set of experimental information. Not surprisingly, the need to understand blending has been a central focus of regulatory interest in the past 15 years, and remains a key target of QbD and PAT efforts. In the recently issued Q8(R1) guidance [2], the FDA has recently published their current thinking on using QbD methods to identify critical quality attributes (CQAs), stating that product quality should be studied and controlled by systematically identifying the material attributes and process parameters that can affect the products CQA. Among emerging technologies for improving the performance of blending operations, continuous mixing (and continuous processing in general) currently commands enormous interest at pharmaceutical companies. Continuous processing has numerous known advantages, including reduced cost, increased capacity, facilitated scale up, mitigated segregation, and more easily applied and controlled shear. However, development of a continuous powder blending process requires venturing into a process that has a large and unfamiliar param-etric space. While continuous blending processes have been used in other industries, in general such applications operate at much larger flow rates and have less …