The aim of this study was to investigate the pharmacokinetics (PK) of poorly soluble compounds when administered intramuscularly (i.m.) as crystalline particles of different sizes. Three uncharged compounds (griseofulvin, AZ'72, and AZ'07) with varying aqueous solubility were dosed to mice at 10 and 50mg/kg as nano- and microparticle formulations. The PK of the compounds was evaluated. The smaller particles of the drugs resulted in higher maximum plasma concentration (Cmax) and area under the plasma concentration-time profile (AUC) at 50mg/kg. There was a dose-proportional increase in AUC but less than dose dose-proportional increase in Cmax. The evaluation at 10mg/kg was more complex as increased exposure for nanoparticles was only observed for griseofulvin which has the highest solubility. In addition, there was an increase in half-life with an increase in dose. This study highlights that general expectations based on in vitro dissolution (i.e. that smaller particles dissolve faster than larger particles when surrounded by liquid) do not always translate to in vivo and demonstrates the importance of understanding the physicochemical properties of the drug, the characteristics of the formulations and the microphysiology at the delivery site.