title: Kinetics of degradation of 4-imidazolidinone prodrug types obtained from reacting prilocaine with formaldehyde and acetaldehyde.
abstract: The kinetics of decomposition of 4-imidazolidinone prodrug types obtained by reacting prilocaine (I) with formaldehyde and acetaldehyde has been studied in aqueous solution in the pH range 1-7.4 at 60 and 37 degrees C, respectively. At pH<5 the hydrolysis of the derivative derived from formaldehyde (II) to yield I obeyed apparent first-order kinetics. At higher pH, the decomposition reactions proceeded to an equilibrium and the reactions could be described by first- and second-order reversible kinetics. A plot of the logarithm of the apparent first-order rate constants for hydrolysis of II against pH resulted in a sigmoidal-shaped pH-rate profile characteristic for the hydrolysis of many N-Mannich bases. A half-life at pH 7.4 (60 degrees C) of 6.9h for compound II was calculated. Compared to II the 4-imidazolidinone derived from acetaldehyde (III) exhibited enhanced instability in aqueous buffer solutions. The decomposition was followed at 37 degrees C monitoring the decrease in concentration of intact (III). At acidic pH the reactions displayed strict first-order kinetics and the disappearance of III was accompanied by a concomitant formation of I. At pH 7.4, the rate data also applied reasonably well to first-order kinetics despite the observation that small amounts of III was formed at pH 7.4 from a solution containing equimolar concentrations of acetaldehyde and prilocaine (10(-4)M). In case of III, a bell-shaped pH-rate profile was obtained by plotting the logarithm of the pseudo-first-order rate constants against pH indicating the involvement of a kinetically significant intermediate in the reaction pathway and a change of the rate-limiting step in the overall reaction with pH. For the stability studies performed at pH 6.9 and 7.4 product analysis revealed that parallel to formation of (I) an unknown compound (X) emerged. Compared to III, compound X is hydrolysed to give I at a slower rate (t(50%)=30 h at 37 degrees C). Based on LC-MS data it is suggested that (X) is an isomeric form of III, which may exist in four diastereomeric forms. Thus, at physiological pH an initial relatively fast regeneration of I from III is to be expected followed by a slower drug activation resulting from hydrolysis of the isomeric form of III.
authors.affiliation: Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Susan Weng
authors.initials: SW
authors.lastname: Larsen
authors.forename: Martin
authors.initials: M
authors.lastname: Sidenius
authors.forename: Michael
authors.initials: M
authors.lastname: Ankersen
authors.forename: Claus
authors.initials: C
authors.lastname: Larsen
mesh_terms: D000079:Acetaldehyde / Q000737:chemistry*; D002021:Buffers; D005557:Formaldehyde / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007093:Imidazoles / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008352:Mannich Bases; D011318:Prilocaine / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility
chemical_list: D002021:Buffers; D007093:Imidazoles; D008352:Mannich Bases; D011355:Prodrugs; D011318:Prilocaine; D005557:Formaldehyde; D000079:Acetaldehyde