The purpose of this study was to establish a relationship between the material properties of an active pharmaceutical ingredient (API) and its behavior during high-shear wet granulation. Using several actives and excipients as material probes, the influence of aqueous solubility, wettability, water holding capacity, mean and width of the particle size distribution, and surface area was examined. The effect of these variables on the processibility and performance of the granulations was evaluated by monitoring such responses as granule growth, compactability and flow changes upon wet granulation. The prominent findings from this study include: (a) controlled growth is highest in readily wettable APIs with low surface area, (b) uncontrolled growth is high in APIs of high solubility and low water holding capacity, (c) polydisperse granulations are produced from APIs of high contact angle and surface area, (d) improvement in compactability is high in APIs with large surface area and broader size distributions and (e) flow enhancement as a result of wet granulation is highest in APIs of large size distributions. These results are physically interpreted in this manuscript based on the prevailing wet granulation theories. Findings from this study are useful in mapping a new material to predict its performance in a high-shear wet granulation process.