The objective of the study was to investigate the effect of fine lactose on the in vitro dissolution of indomethacin in interactive mixtures containing spray-dried lactose and lactose monohydrate (106-250 microm). Dissolution of the indomethacin was measured using an automated dissolution apparatus following the USP paddle method at 100 rpm. The particle size distributions of indomethacin mixtures were measured using a Mastersizer S under non-sink conditions. Data fitted bi-exponential or tri-exponential dissolution models, representing dissolution from dispersed and agglomerated particle distributions. The addition of fine lactose (VMD 3.8+/-0.4 microm) to 20% indomethacin-coarse lactose mixtures resulted in significantly increased rates of dissolution caused by increases in the estimated dissolution rate constants for dispersed particles (Kd) and by de-agglomeration. Agglomerates in the mixture showed little tendency to comminute under shear pressure. De-agglomeration in the dissolution medium was attributed to increased porosity of agglomerates, caused by dissolution of water soluble fine lactose in the agglomerate structure. The median particle size (D50) of the dispersed particle distribution decreased with increasing concentrations of added fine lactose, indicating increasing extents of de-agglomeration, and a good correlation between Kd and (D50)2 resulted for the coarse lactose-based mixtures (R2>0.984).