The newly proposed hard–soft net analyte signal (HS-NAS) method was employed to determine the acidity constants of drugs. The spectrophotometric data obtained through monitoring of the pH-metric titrations of the acids (both experimental and simulated data) were analyzed by the HS-NAS method, and accurate results were obtained. As experimental data sets, tetracycline as a triprotic acid and p-aminobenzoic acid, m-aminobenzoic acid, and piroxicam as diprotic acids were studied. In addition, the acidity constants of the drugs were determined in the presence of Triton X-100 as an inert light-absorbing interference. The data for such systems, which are rank-deficient in nature, were successfully analyzed by the HS-NAS method. This method is based on changing the acidity constants of the drugs to maximize the correlation coefficient between the NAS vector obtained for one species of the reaction and the theoretical concentration profile of that species. Unlike existing methods, it needs neither previous inform...