Two different spectrophotometric determinations of potential anticancer drug and its toxic metabolite

•No kinetic spectrophotometric study was published for assay of flutamide.•Developed methods were the first developed stability indicating ones for flutamide.•Degradation identification by IR and mass spectra analyses.•The drug degradation followed pseudo first order kinetics.•Degradation rate was highly sensitive to temperature and pH.

Flutamide is a hormone therapy used for men with advanced prostate cancer. Flutamide is highly susceptible to hydrolysis with the production of 3-(trifluoromethyl)aniline, which is reported to be one of its toxic metabolites, impurities and related substances according to BP and USP. Flutamide was found to be stable when exposed to oxidation by 30% hydrogen peroxide and direct sunlight for up to 4 h. Two accurate and sensitive spectrophotometric methods were used for determination of flutamide in bulk and in pharmaceutical formulations.Method (I) is the area under curve (AUC) spectrophotometric method that depends on measuring the AUC in the wavelength ranges of 275–305 nm and 350–380 nm and using Cramer’s rule. The linearity range was found to be 1–35 μg/mL and 0.5–16 μg/mL for the drug and the degradate, respectively. In method (II), combination of the isoabsorptive and dual wavelength spectrophotometric methods was used for resolving the binary mixture. The absorbance at 249.2 nm (λiso) was used for determination of total mixture concentration, while the difference in absorbance between 232 nm and 341.2 nm was used for measuring the drug concentration. By subtraction, the degradate concentration was obtained. Beer’s law was obeyed in the range of 2–35 μg/mL and 0.5–20 μg/mL for the drug and its degradate, respectively.The two methods were validated according to USP guidelines and were applied for determination of the drug in its pharmaceutical dosage form. Moreover AUC method was used for the kinetic study of the hydrolytic degradation of flutamide. The kinetic degradation of flutamide was found to follow pseudo-first order kinetics and is pH and temperature dependent. Activation energy, kinetic rate constants and t1/2 at different temperatures and pH values were calculated.

Graphical abstractFlutamide was highly sensitive to hydrolysis. Reaction kinetic was studied using AUC method and found to follow pseudo first order kinetics. Reaction rate constant (K) was found to be pH and temperature dependant.Figure optionsDownload full-size imageDownload as PowerPoint slide