A zero-crossing derivative spectrophotometric method was used for the simultaneous determination of acetaminophen, ibuprofen and caffeine. The derivative spectra of standard solutions of each compound were obtained at different orders to find out the suitable zero-crossing points. Under the optimized conditions, determination of acetaminophen was performed at wavelengths of 311 and 270 nm using the third order (Δλ = 24.5) and fourth order (Δλ = 12.0) derivative spectra, respectively. Ibuprofen and caffeine were determined at wavelengths of 235 and 300 nm using the second order (Δλ = 21.0) and fourth order (Δλ = 27.0) derivative spectra. The method was found to be linear (r2 > 0.998) in the range of (μg/mL) 5–50 for acetaminophen, 5–30 for ibuprofen and 1–7 for caffeine in the presence of other compounds. The within-day and between-day precision and accuracy of the proposed method were acceptable (CV < 3% and error < 2%) for all three components and the proposed method was satisfactory for quality control purposes. The method was successfully applied to the simultaneous determination of acetaminophen, ibuprofen and caffeine in pharmaceutical dosage forms without any interference from excipients and there was no need to any prior separation before analysis.
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