A new in silico approach allowing to compute HPLC–UV response coefficients using Time Dependent-Density Functional Theory (TD-DFT) is here reported. Based on the use of a non linear least squares with bound restricted algorithm, this model exploits theoretical and experimental data to simulate UV–visible spectra, the starting point to compute response coefficients. The protocol proposed here is applied to determine the response coefficient between two molecules of pharmaceutical interest. The good results obtained show that this computationally efficient methodology could routinely be used in pharmaceutical industries as analytical tool.