INTRODUCTIONThe purpose of this research was to form stable suspensions of submicron particles of cyclosporine A, a water-insoluble drug, by rapid expansion from supercritical to aqueous solution (RESAS). A solution of cyclosporine A in CO 2 was expanded into an aqueous solution containing phospholipid vesicles mixed with nonionic surfactants to provide stabilization against particle growth resulting from collisions in the expanding jet. The products were evaluated by measuring drug loading with high performance liquid chromatography (HPLC), particle sizing by dynamic light scattering (DLS), and particle morphology by transmission electron microscopy (TEM) and x-ray diffraction. The ability of the surfactant molecules to orient at the surface of the particles and provide steric stabilization could be manipulated by changing process variables including temperature and suspension concentration. Suspensions with high payloads (up to 54 mg/mL) could be achieved with a mean diameter of 500 nm and particle size distribution ranging from 40 to 920 nm. This size range is several hundred nanometers smaller than that produced by RESAS for particles stabilized by Tween 80 alone. The high drug payloads (~10 times greater than the equilibrium solubility), the small particle sizes, and the long-term stability make this process attractive for development.The often low bioavailability of water-insoluble drugs leads to poor pharmacokinetic performance in the body. Techniques to improve bioavailability in oral or parenteral applications of water-insoluble drugs include powder micronization, the formation of micron-and submicron-size dispersions, solubility enhancement in aqueous solution by addition of appropriate surfactants, organic solvents or buffers, or drug-carrier systems such as liposomes. The payloads for drugs in liposomes are often limited because of the low volume fraction of hydrophobic regions. 1 The use of surfactants or organic solvents in parenteral administration can lead to phlebitis, anaphylaxis, hypotension, or even vasodilation.