Two case studies were studied in a high shear wet granulator using a hydrophobic API and a hydrophilic excipient An increase in granule growth was observed with an increase in percentage composition of the hydrophobic API Regime map analyses and granule characterization tests were performed confirming that in addition to wettability differences, granule deformability was a dominating factor in the type of growth mechanisms exhibited. In this study, a more physics-based approach was pursued to investigate the effect of wettability differences in bicomponent granule systems on critical quality attributes such as granule size distribution (GSD) and content uniformity across size fractions. Two bi-component formulations: 1) ibuprofen-USP and microcrystalline cellulose (Case-I) and; 2) APAP and microcrystalline cellulose (Case-II), were systematically selected and only their net hydrophobicity was varied as a consequence of change in percentage composition. Both case studies resulted in a similar increase in mean granule size and GSD as a function of increased net hydrophobicity; however, they exhibited key differences in terms of content uniformity across size fractions. Case-I produced content uniform granules, while Case-II produced content non-uniform granules, with the increase in percentage composition of ibuprofen and acetaminophen respectively. This difference in component distribution was studied using growth regime maps and granule image analyses. Results showed that with the change in percentage composition (or increasing the amount of the hydrophobic material), the granule growth mechanism shifted between capillary-force-dominated layering mechanism and viscous-force-dominated aggregation mechanism. It was concluded that, uniform distribution of materials observed in Case-I granules was due to strong viscous-force-dominated aggregation mechanism; whereas, non-uniform distribution of materials observed in Case-II granules was due to much weaker capillary force dominated layering mechanism. This work seeks to improve the theoretical understanding of granule growth behavior in a bi-component wet granulation systems with components of differing wettabilities or hydrophobicities. (C) 2020 Elsevier B.V. All rights reserved.