A tangential-inlet swirl nozzle for preparing nano-drug during a solution-enhanced dispersion by supercritical CO2 (SEDS) process has been designed to enhance mixing in a micro-mixing volume. The structure and dimensions of the nozzle are presented. A three-dimensional simulation by using computational fluid dynamics (CFD) and heat transfer during a SEDS process has been performed. The solver used was a commercial code, Fluent 6.3. The length of the swirl chamber and the outlet diameter of the nozzle were chosen as the main factors to be analyzed and optimized. Volume fraction of ethanol and turbulence intensity of mixture were the main indicators to optimize the structure of the nozzle. Results indicated that when the length of swirl chamber was 6mm and the outlet diameter was 0.3mm, supercritical CO2 and ethanol can mix thoroughly, and the turbulence intensity was high enough to ensure full precipitation of the solute and reduce the time of nucleation growth. The method of CFD analysis used in this work can also be applied to similar systems and can help to improve the performance of the SEDS micronization apparatuses.