First- and second-derivative spectrophotometric methods have been proposed for the determination of glibenclamide, mebeverine hydrochloride and clopamide with their corresponding degradation products. Solutions of these drugs were analysed by measuring the first- and second-derivative spectral response at certain wavelengths where the respective degradation products exhibit no contribution. Also, clopamide can be determined in a mixture with reserpine and dihydroergocristine by utilising the second-derivative method. Kinetic investigation of the alkaline degradation rate of these drugs revealed that the proposed methods were stability indicating. The different pharmaceutical preparations were assayed and were found to give results of the same accuracy and reproducibility as the corresponding official method or “maximum absorbance” methods of assay.