The supercritical fluid expansion depressurization (SFED) process is a novel technique proposed recently to prepare microparticles with controlled particles size distribution which are suitable for inhalant drug delivery. It has shown a great potential in drug micronization especially for watersoluble drugs. Tetracycline microparticles were prepared successfully from water-ethanol mix-solvent by SFED process. The influences of operation parameters, including the pressure and the temperature in the mixing vessel, the solution concentration and the solution feed rate, on the particle morphology, size, size distribution and the production mass ratio (the mass ratio of the collected final particles to the raw material) were investigated in detail. The results show that well spherical tetracycline microparticles for pulmonary drug delivery can be prepared by SFED process in the suitable conditions. The pressure and the temperature in the mixing vessel are two most effective parameters on particle characteristics while the solution concentration is the next. The solution feed rate has little effect. The particle characteristics could be controlled by adjusting the operation conditions. The temperature has notable influence on the production mass ratio comparing with other operation parameters. The optimal operation parameters for preparing tetracycline microparticles in the range of this work are: the pressure of 12 MPa and the temperature of 60 degrees C in the mixing vessel, the solution feed rate of 5 ml/min, and the solution concentration of 30 mg/ml. (c) 2007 Elsevier B.V. All rights reserved.