To improve the solubility and dissolution rate of etoposide, micro-particles were prepared using solution enhanced dispersion by supercritical CO2, and the transition of crystal form was investigated using scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, and differential scanning calorimetry. The effects of various operating parameters, including precipitation pressure, temperature, the etoposide concentration, and solution flow rate were investigated. The results showed that the particle size of etoposide can be controlled, and smaller particles of 586 nm were successively obtained. A reduction in the particle size led to an increase in the dissolution rate. Furthermore, at a precipitation pressure >= 18 MPa, a new polymorphic form was discovered, which exhibited higher solubility and faster dissolution rate. (C) 2016 Elsevier B.V. All rights reserved.