Validated stability-indicating HPLC method for the determination of pridinol mesylate. Kinetics study of its degradation in acid medium.

摘要

The stability of pridinol mesylate (PRI) was investigated under different stress conditions, including hydrolytic, oxidative, photolytic and thermal, as recommended by the ICH guidelines. Relevant degradation was found to take place under acidic (0.1N HCl) and photolytic (visible and long-wavelength UV-light) conditions, both yielding the product resulting from water elimination (ELI), while submission to an oxidizing environment gave the N-oxidation derivative (NOX). The standards of these degradation products were synthesized and characterized by IR, (1)H and (13)C NMR spectroscopy. A simple, sensitive and specific HPLC method was developed for the quantification of PRI, ELI and NOX in bulk drug, and the conditions were optimized by means of a statistical design strategy. The separation employs a C(18) column and a 51:9:40 (v/v/v) mixture of MeOH, 2-propanol and potassium phosphate solution (50mM, pH 6.0), as mobile phase, delivered at 1.0 ml min(-1); the analytes were detected and quantified at 220 nm. The method was validated, demonstrating to be accurate and precise (repeatability and intermediate precision levels) within the corresponding linear ranges of PRI (0.1-1.5 mg ml(-1); r=0.9983, n=18) and both impurities (0.1-1.3% relative to PRI, r=0.9996 and 0.9995 for ELI and NOX, respectively, n=18). Robustness against small modifications of pH and percentage of the aqueous mobile phase was ascertained and the limits of quantification of the analytes were also determined (0.4 and 0.5 microg ml(-1); 0.04% and 0.05% relative to PRI for ELI and NOX, respectively). Peak purity indices (>0.9997), obtained with the aid of diode-array detection, and satisfactory resolution (R(s)>2.0) between PRI and its impurities established the specificity of the determination, all these results proving the stability-indicating capability of the method. The kinetics of the degradation of PRI in acid medium was also studied, determining that this is a first-order process with regards to drug concentration, with an activation energy of 25.5 Kcal mol(-1) and a t(1/2)=10,830 h, in 0.1N HCl at 38 degrees C.