Collaborative Research: Understanding the Effect of Powder Properties and Processing Conditions on the Performance of Pharmaceutical Tablets

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Pharmaceutical tablets account for a large fraction of oral solid dosage forms dispensed today. They are traditionally manufactured by directly compressing a blend of the active pharmaceutical ingredient and excipient powders. In spite of its long history, however, product quality control relies extensively on empirical methods. Evaluating the impact of excipient variability on the performance of pharmaceutical tablets, for example, still presents a great challenge. To address these problems, the U.S. Food and Drug Administration has released guidelines for the implementation of quality-by-design in the manufacturing process and manufacturers are increasingly focusing on raw materials and process controls. It is therefore of strategic importance to understand the interrelationship between raw material properties and manufacturing process parameters on product quality and performance. The collaborative research effort by researchers at Purdue and Rutgers will combine experiments, simulations and modeling to address this important issue in the case of pharmaceutical tablets manufactured by direct compression of powders. The broad nature of the collaboration also provides an excellent opportunity to train graduate and undergraduate students in engineering and pharmaceutical sciences in a wide range of experimental and computational techniques. The investigators will also engage in outreach efforts coordinated at both universities through different undergraduate research programs. In addition, the numerical methods resulting from the project will be broadly available to the pharmaceutical and process engineering communities and educators through NSF's supported open-access HUBzero platforms, such as pharmaHUB.org. The intellectual merit of the research work lies in developing a predictive multi-scale model that is based on a mechanistic understanding at the level of individual powder particles and captures the complex interrelationship between powder properties (e.g., wetting) and processing parameters (e.g., compression force) with critical quality attributes of dry tablets (e.g., hardness) and tablet performance (e.g., disintegration behavior in contact with water). The transformative nature of the research includes: (i) A novel mechanistic model of compressed powders under large deformations and high confinement to predict detailed structure and material strength, and a multi-scale approach to describe solvent uptake combined with ad-hoc experiments that decouple the dominant penetration mechanisms (capillary imbibition and case-II diffusion) and is able to describe disintegration behavior; (ii) A broad set of ad-hoc experiments (tablet hardness, free and constrained swelling, column imbibition with multiple fluids) that will allow iterative experiment-model synergy for increasingly complex systems. The model and the set of ad-hoc experiments will then be utilized to reveal and understand the interrelationship between the properties of the raw materials and manufacturing process parameters with the quality and performance of pharmaceutical tablets.