Tetracycline has been obtained as amorphous agglomerates in the supercritical antisolvent process. This phenomenon has been postulated to occur due to weak solvent/antisolvent interaction. In order to verify the hypothesis and prevent the coalescence of nanoparticles, we micronized tetracycline hydrochloride using supercritical and liquid CO2 in the precipitation with compressed fluid antisolvent process (PCA). PCA experiments were performed by varying temperature, pressure and initial concentration of the solution. SEM and BET were used to understand the coalescence behavior. Mean surface area (S-BET) of the precipitates from liquid conditions was 58.91 m(2)/g, which was approximately two times higher than the mean surface area of the precipitates from supercritical conditions (S-BET = 29.98 m(2)/g). Hansen distance (R), an indicator of solvent/antisolvent interaction, was used to understand the macroscopic phase behavior and solvent/antisolvent interactions. The result implied that both surface diffusion of the precipitates and solvent/antisolvent interactions affected the coalescence behavior. As a result, we successfully formulated tetracycline nanoparticles without extensive coalescence using liquid CO2 as an antisolvent. (C) 2015 Elsevier B.V. All rights reserved.