title: Stability of carboplatin and oxaliplatin in their infusion solutions is due to self-association.
abstract: Carboplatin and oxaliplatin are commonly used platinum anticancer agents that are sold as ready-to-use aqueous infusion solutions with shelf lives of 2 and 3 years, respectively. The observed rate constants for the hydrolysis of these drugs, however, are too large to account for their long shelf lives. We here use electrospray-trap mass spectrometry to show that carboplatin and oxaliplatin are self-associated at concentrations in their ready-to-use infusion solutions (~27 mM and 13 mM, respectively) and, as expected, when the drug concentration is reduced to more physiologically relevant concentrations (100 μM and 5 μM, respectively) the association equilibrium is shifted in favor of the monomeric forms of these drugs. Using (1)H NMR we measure the intensity of the NH resonance of the two symmetry-equivalent NH(3) molecules of carboplatin, relative to the intensity of the γ-methylene CH resonance, as a function of total drug concentration. Then, by fitting the data to models of different molecularity, we show that the association complex is a dimer with a monomer-dimer association constant of K (M(-1)) = 391 ± 127. The work presented here shows that carboplatin and oxaliplatin mainly exist as association complexes in concentrated aqueous solution, a property that accounts for the long term stability of their ready-to-use infusion solutions, and that these association complexes may exist, to some extent, in the blood after injection.
authors: Department of Chemistry, Syracuse University, 1-014 CST, 111 College Place, Syracuse, New York 13244, USA.
authors: Anthony J
authors: AJ
authors: Di Pasqua
authors: Deborah J
authors: DJ
authors: Kerwood
authors: Yi
authors: Y
authors: Shi
authors: Jerry
authors: J
authors: Goodisman
authors: James C
authors: JC
authors: Dabrowiak
mesh_terms: D016190:Carboplatin / Q000737:chemistry*; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000737:chemistry*; D000077150:Oxaliplatin; D012996:Solutions / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D009944:Organoplatinum Compounds; D012996:Solutions; D000077150:Oxaliplatin; D014867:Water; D016190:Carboplatin