title: Degradation mechanism and stability of 5-aminolevulinic acid.
abstract: The physiological substance and precursor of the heme synthesis 5-aminolevulinic acid (ALA) is a promising prodrug for photodiagnosis and photodynamic therapy of epithelial tumors, particularly in urological and gynecological tissues. For the clinical use of this substance, a chemically stable and sterile drug formulation is required. In the present study, degradation mechanism of ALA in aqueous solution and possibilities to improve its stability were examined. A capillary electrophoretic method was developed that was suitable for the quantification of ALA and of two degradation products. The intermediate degradation product was 2, 5-dicarboxyethyl-3,6-dihydropyrazine, which was further oxidized to 2,5-dicarboxyethylpyrazine. The structures of the degradation products were proven by (1)H and (13)C nuclear magnetic resonance spectroscopy. ALA degradation was very efficiently inhibited by adjusting the pH of the aqueous solution to a value <5 and by purging with nitrogen. Additives such as antioxidants did not improve the ALA stability. These results demonstrated that low pH ALA aqueous solution may be one possible dosage form to be considered for market introduction.
authors.affiliation: Swiss Federal Institute of Technology Zurich (ETH), Department of Applied BioSciences, Institute of Pharmaceutical Sciences, Winterthurer Strasse 190, 8057 Zürich, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Bunke
authors.forename: O
authors.initials: O
authors.lastname: Zerbe
authors.forename: H
authors.initials: H
authors.lastname: Schmid
authors.forename: G
authors.initials: G
authors.lastname: Burmeister
authors.forename: H P
authors.initials: HP
authors.lastname: Merkle
authors.forename: B
authors.initials: B
authors.lastname: Gander
mesh_terms: D000622:Aminolevulinic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D017319:Photosensitizing Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid