Mesoscopic modeling, experimental and thermodynamic approach for the prediction of agglomerates structures in granulation processes

Wet granulation process requires the addition of a coating agent or binder, typically composed of surfactants, water, plasticizers and fillers. In dry granulation however, the coating agent is added to the system in the form of fine solid particles. Our goals are to investigate the particles behaviour and agglomeration mechanism in dry and aqueous systems at the micro and meso scales, and also, to develop predictive methodologies and theoretical tools of investigation allowing to choose the adequate binder and to formulate the right coating solution. In this study we chose materials widely used in food and pharmaceutical industries, including; coating agents such as Hydroxypropyl-methylcellulose (HPMC) and Ethyl cellulose (EC), binders such as Polyvinylpyrrolidone (PVP) and Microcrystalline cellulose (MCC), hydrophobic filler such as Stearic acid (SA) and plasticizer such as Polyethylene glycol (PEG). A successful granulation requires good affinity between host and guest particles. In this context, in the first part of this work, two approaches to predict the binder-substrate affinity in dry and in aqueous media were compared; one based on the work of adhesion and the other based on the ideal tensile strength. The concept of ideal tensile strength was extended to ternary systems and applied for granulation in aqueous media. The developed approaches were thereafter tested for various systems (composed of PVP, MCC, HPMC, SA, EC, PEG and water) and compared to experimental observations. Approaches yielded results in good agreement with the experimental observations, but the work of adhesion approach might give more accurate affinity predictions on the particles affinity than the ideal tensile strength approach. Both approaches predicted that HPMC is a good binder for MCC. Results also indicated that PEG has a good affinity with HPMC and SA. In a second part of our work, we used mesoscale simulations and experimental techniques to investigate the structure of agglomerates formed in aqueous colloidal formulations used in coating and granulation processes. For the simulations, dissipative particle dynamics (DPD) and a coarse-grained approach were used. In the DPD method, the compounds were described as a set of soft beads interacting according to the Flory-Huggins model. The repulsive interactions between the beads were evaluated using the solubility parameter (δ) as input, where, δ was calculated by all-atom molecular simulations. The mesoscale simulation results were compared to experimental results obtained by Cryogenic-SEM, particle size distribution analysis and DSC technique. According to the DPD simulations, HPMC polymer is a better stabilizing agent for SA than PVP and MCC. In addition, HPMC is able to cover the SA particle with a thick layer ant to adsorb in depth into its inner core, preventing SA agglomeration and crystal growth. But, for high amounts of SA (above 10% (w/w)), HPMC is unable to fully stabilize SA. We also found that PEG polymer diffuses inside HPMC chains thereby extending and softening the composite polymer. Experimental results presented similar trends; particle size distribution analysis showed that in the presence of HPMC, for low percentages of SA (below 10% (w/w)), the majority of SA particles are below 1 μm in diameter. SEM images revealed that HPMC surrounds SA crystals with a hatching textured film and anchors on their surface