A clay-drug nanohybrid was prepared by interfacial boundary ion exchange reaction, from which the release mechanism of a poorly water soluble drug, itraconazole, was studied systematically. The effect of cation types on drug release was investigated on the basis of a UPS 25 guide line and the effect of Laponite dissolution was also studied at pH=1.2. To describe the release patterns, mathematical modeling was preformed using first-order, Elovich, parabolic diffusion, and power function equations.