Separation of lithium isotopes (Li-6, Li-7) is a key technology to the development and utilization of nuclear energy. In this work, we present an efficient method to theoretically estimate the separation factors of Li-6/Li-7 in solvent extraction system based on Urey model. The approach was implemented by calculating the equilibrium separation factor of Li-6/Li-7 in the crown ether/Li aqueous solution [15-crown-5 (15C5), Benzo-15-crown-5 (B15C5), 12-crown-4 (12C4), Dicyclohexyl-18-Crown-6 (DH18C6)/LiX-H2O, X = Cl/I] exchange system utilizing the calculated harmonic vibration frequencies obtained by Density Functional Theory (DFT). The results showed that Urey model can correctly predict the direction of the Li-6/Li-7 separation as observed in the experiments. With this model, the underlying mechanisms driving the equilibrium isotope separation were elucidated further. The coordination structure of the Li complex played a dominant role in the separation of Li-6/Li-7. For the solvent extraction system comprising crown ether phase and LiX aqueous solution, the crown ether with strong ability of excluding the hydrated water of Li gives a higher separation factor. The ways by which Li-O bonding of the Li-crown ether complex can be weakened, such as reducing the coordinated water molecules, applying high polar solvents, performing separation from Li salt with a softer anion, are helpful to improve the separation factor of Li-6/Li-7 at a fixed temperature. The lithium isotopic exchange is an exothermic reaction. Decreasing temperature favors the exchange reaction. This work is expected to provide guidance for the design of the exchanger and screening of the chemical exchange system for the separation of Li-6/Li-7.