In this study, the incompatibility of doxepin in solid physical mixtures with lactose (monohydrate and anhydrous) was investigated. The compatibility testing was made using various physicochemical techniques, such as differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and mass spectrometry. Non-isothermally stressed physical mixtures were used to analyze the solid-state kinetic parameters. Data were fitted to different thermal models, such as Friedman, Flynn-Wall-Ozawa (FWO) and Kissinger-AkahiraSunose (KAS) for different drug-excipient mixtures separately. Overall, the incompatibility of doxepin as a tertiary amine, with lactose as a reducing carbohydrate was successfully evaluated. DSC based kinetic analysis provided a simple and fast comparative data in different drug-excipient mixtures. It can be recommended to exclude lactose from doxepin's solid dosage formulations, and also to use the described procedure in the kinetic evaluation of drug-excipient incompatibility studies. (C) 2015 Elsevier B.V. All rights reserved.