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Physicochemical Properties of CWJ-a-5, a New Antitumor 3-Arylisoquinoline Derivative

ABSTRACT The compound CWJ-a-5 [1-(4-methylpiperazinyl)-3-phenylisoquinoline hydrochloride] is a novel 3-arylisoquinoline derivative which has exhibited potent antitumor activity. As part of an effort to develop a useful formulation for clinical evaluation of this compound, the aqueous stability of CWJ-a-5 as a function of pH, ionic strength, and temperature, as well as its various physicochemical properties, have been examined. The pKa value obtained by potentiometric titration in methanol–water mixtures was 3.61, at 25°C. The aqueous solubility and the apparent partition coefficient of CWJ-a-5 over the pH range 2.08–9.88 were consistent with those expected of a weak acid of similar pKa value. The degradation of CWJ-a-5 was found to follow apparent first-order kinetics. The pH–rate profiles generated at 80°C were accounted for by acid-catalyzed degradation at low pH and base-catalyzed degradation at high pH. The activation energy was determined as 22.12 kcal/mol for the degradation of CWJ-a-5 in a pH 2.92 solution with a constant ionic strength of 0.2. Increasing the ionic strength up to 0.9 led to a higher degradation rate constant at pH 2.92. However, CWJ-a-5 was very stable even in a pH 2.92 solution, and its shelf-life was calculated to be 2.03 years at 25°C from the Arrhenius plot.