Anti-cancer agents; Aqueous solutions; Association constant; Association equilibria; Carboplatin; Drug concentration; Electrosprays; Long term stability; Monomeric forms; Oxaliplatin; Self-associations; Shelf life
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 1H 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.
Di Pasqua, Anthony J.; Kerwood, Deborah J.; Shi, Yi; Goodisman, Jerry; and Dabrowiak, James C., "Stability of Carboplatin and Oxaliplatin in their Infusion Solutions is Due to Self-Association" (2011). Chemistry - All Scholarship. 29.
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