Dissertation - Martins, Pedro_DPversion.pdf
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PARTICLE MECHANICS APPROACH TO MODELING DISINTEGRATION OF CONFINED GRANULAR SYSTEMS DUE TO HYDRATION AND SWELLING
thesisposted on 29.04.2021, 01:16 by Pedro Henrique Cidreiro Martins
Tablets are the most common form of pharmaceutical solid oral dosages, and they are manufactured by die-compaction of powder blends comprised of active pharmaceutical ingredients (APIs) and excipients. Excipients (such as absorbents, disintegrants, dissolution modifiers, and wetting agents) are responsible for controlling the tablet disintegration time and dissolution rate and, ultimately, the drug release profile--making each tablet formulation unique. However, the understanding of the underlying coupled mechanics of imbibition, swelling, and disintegration still poses open questions. Therefore, developing a new formulation for a desired drug release profile is challenging and frequently guided by trial and error. This dissertation contributes to understanding these coupled mechanisms in compacted powder mixtures by developing mechanistic particle-based models and numerical techniques that can potentially assist and accelerate product development. In order to model the disintegration of granular material due to liquid sorption, we identify four modeling milestones: (i) a particle mechanics approach to model microstructure formation during die-compaction and particles interaction during swelling, (ii) a network-like, particle-to-particle solvent diffusion model to account for imbibition across the contact interfaces created during the compaction process, (iii) an efficient grain-based pore-network construction model, to characterize the pores-space of die-compacted granular materials, and (iv) an absorptive, dynamic, two-phase flow, pore-network model to account for capillary imbibition. This dissertation covers the first three modeling milestones, aiming to model pharmaceutical tablets disintegration from a particle-pore scale perspective. However, our models can be easily extended to any sorptive granular media. The proposed multi-physics modeling approach then predicts disintegration by accounting for solid-bridge breakage during the stress relaxation process induced by particle swelling and softening upon sorption. Furthermore, we demonstrate that the seamless integration of experimental and computational methods is paramount for advancing the development of pharmaceutical solid dosage formulations.