Macro and micro characterization of powder mixing processes

Powder mixing is a critical operation in pharmaceuticals and other industries. Despite much research, there is still a lack of understanding of the mixing mechanisms, their effects on blend properties, and how these affect the quality of the final product. In addition, commonly used and new batch mixing technologies are not well established to handle the growing number of products involving cohesive and highly potent active pharmaceutical ingredients (APIs). The work presented in this dissertation focuses on the macro- and micro-mixing characterization of a resonant acoustic mixer (RAM), and the micro-mixing dynamic characterization of bin-blending for pharmaceutical powders, with an emphasis on mixing cohesive APIs. First, the mixing performance of the RAM as a function of processing parameters (acceleration, fill level and blending time) was characterized. Then the effects of the RAM processing parameters on the final blend properties, and tableting and tablet characteristics were investigated. This was followed by the micro-mixing characterization of blends obtained from the RAM using near-infrared chemical imaging (NIR-CI). In the second part of this dissertation, the micro-mixing dynamics of three APIs, chlorpheniramine maleate (very cohesive), acetaminophen (cohesive) and caffeine (slightly cohesive), were characterized using in situ NIR-CI and compared. Overall, blends in the RAM reached the required blend uniformity (RSD < 5%) in as low as 30 seconds. Resonant acoustic mixing significantly affected the final properties of lubricated blends, increasing their density with increases in acceleration and blending time. These changes in blend properties affected the final properties of tablets by increasing weight, decreasing hardness, and decreasing dissolution. All blend and tablet properties, except hydrophobicity, followed a power law when correlated to the energy per unit mass. The aggregation of the API in the blends decreased with increasing mixing intensity (acceleration) and blending time. In the bin-blending studies, the most cohesive API followed the expected trends (e.g. higher RSDs and larger aggregate sizes), while the trends for APAP and caffeine were dependent on their concentrations. NIR-CI was useful in monitoring the distribution and aggregate size of APIs and excipients, demonstrating agglomeration as a function of cohesion and API concentration in the blends.Ph. D.Includes bibliographical referencesby Juan Guillermo Osorio Caiced