The hydrolysis of l-phenylalanine mustard (melphalan)

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Abstract

The chemical stability of l-phenylalanine mustard (melphalan) was studied in aqueous solution using an HPLC procedure. The kinetics of degradation was investigated as a function of pH (1–13), ionic strength (0.12–1.0 M), temperature (25–50°C) and chloride concentration (0–0.5 M). In addition, the kinetics of the production of chloride ions arising from the degradation of melphalan was studied using an ion-specific electrode. No evidence of specific acid/base or general acid/base catalysis was found and the results were explained in terms of the conversion of melphalan to hydroxymelphalan occurring via a unimolecular, rate-determining reaction in which the drug is converted to an ethyleneimmonium ion. The effect of pH on stability was explained in terms of the degree of protonation of the various ionic species of melphalan (MH2+3, MH+2, MH and M) present in solution and their abilities to take on an additional positive charge and form the corresponding ethyleneimmonium ions (MH3+3, MH2+2, MH+ M). The kinetically determined pKa for the tertiary amine of melphalan was found to be 1.42. The pKas for the carboxylate and amino functional groups were found to be 2.75 and 9.17, respectively, which compare well with the corresponding literature values of 2.59 and 9.25 for the respective groups of phenylalanine.

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