The pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state was investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and a combination of thermal analyzer with Fourier transform infrared microspectroscopy (thermal FT-IR microscopic system). The results indicate that the dehydration from the solid-state lisinopril dihydrate had a two-step process from dihydrate to monohydrate at 76 degrees C and then from monohydrate to anhydrate at 99-101 approximately C, which could be clearly observed from the above three methods. Only the thermal FT-IR microscopic system could give vital information on diketopiperazine (DKP) formation via intramolecular cyclization in anhydrous lisinopril. A new peak at 1670 cm(-1) assigned to the carbonyl band of DKP formation was clearly evidenced. The water of reaction byproduct was liberated at a temperature >157 degrees C and appeared on the IR spectra near 3200-3400 cm(-1). Moreover, the peak at 1574 cm(-1) assigned to carboxylate shifted to 1552 cm(-1) due to the DKP formation. The peak at 1670 cm(-1) related to the DKP formation changed slightly in intensity from 147 degrees C and significantly near 157 degrees C. DSC and TGA methods were poor for use in supplying information on DKP formation in lisinopril. The thermal FT-IR microscopic system is useful from the view point that it can quickly and directly show the solid-state stability of drug.