This study presents a way of preventing a highly hydrophobic bioactive drug encapsulated in polycaprolactone (PCL) nanoparticles from forming drug crystals aqueous systems. Thymol trimethoxycinnamate was selected as a hydrophobic bioactive model drug. Four PCL-drug nanoparticles were prepared: their internal structures and sizes were regulated by introducing different types of PCL or by changing polymer compositions during the preparation of the nanoparticles. The formation of drug crystals from the PCL-drug nanopartides was observed by optical microscopy at two temperatures (25 and 40 degrees C) and in three aqueous mediums (deionized water or aqueous solutions containing 5 wt % butylene glycol or ethanol). In deionized water, the formation of drug crystals could be prevented if PCL-drug nanoparticles have highly crystalline cores. In aqueous solutions containing butylene glycol or ethanol, both the internal crystalline core and the size of the nanoparticles could be important in preventing the drug crystal formation. The present study provides both scientific and practical information to those who involve the drug delivery system and pharmaceutical sciences where drugs are engineered to increase the therapeutic efficiency through polymeric nanoparticles.