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DPC 963 is a non-nucleoside reverse transcriptase inhibitor with low aqueous solubility. The effect of DPC 963 drug substance particle size on the characteristics of granules manufactured by high-shear wet granulation was evaluated. The wet granulation process was used to manufacture a DPC 963 formulation with high drug loading. The formulation was manufactured using drug substance lots with different particle size distributions. Granulation particle size distribution, porosity, and compressibility were determined. A uniaxial compression test was also performed on moist compacts of the formulation prepared with different particle size distributions. Particle agglomeration behavior was affected by drug substance particle size. Granulation geometric mean diameter and fraction with particle size greater than 250 μm was inversely proportional to the drug substance particle size. Mercury intrusion porosimetry revealed higher pore volumes for the granules manufactured using the drug substance with the smaller particle size, suggesting lower tendency for granule densification than for that manufactured with the larger drug substance particle size. Granulation compressibility was also sensitive to changes in drug substance particle size. A decreased drug substance particle size led to increased granulation compressibility. Results from the uniaxial compression experiments suggested that the effect of particle size on granulation growth is the results of increased densification propensity, which in turn results from increased drug substance particle size.