Salt effects on caffeine solubility, distribution, and self-association

In this investigation, salt effects on monomeric solubility and distribution are separated from self-association for caffeine. For self-associating compounds, the Setschenow equation is inadequate because it does not separate salt effects into their different contributions. Solubilities of caffeine, theophylline, and theobromine were determined in water and salt solutions at 25degreesC. Caffeine, theophylline, and theobromine solubilities decreased with added Na2SO4 or NaCl (i.e., salting-out) and increased with added NaClO4 or NaSCN (i.e., salting-in). Caffeine distribution coefficients (D-W/O) also decreased with added Na2SO4 or NaCl and increased with added NaClO4 or NaSCN. To separate salt-caffeine effects from salt effects on caffeine self-interaction, salting parameters (k(s)) were calculated from D-W/O at infinite dilution instead of solubilities with the Setschenow equation. Caffeine k(s) values were smaller than the Setschenow constants (K) indicating that, for caffeine, K is not simply a salting-in/out parameter. Distribution data were used to characterize caffeine self-association using either a dimerization model (k(d), dimerization constant) or an isodesmic model (k(iso), stepwise association constant). Caffeine self-association constants (k(d) or k(iso)) decreased with NaClO4 or NaSCN and increased with Na2SO4 or NaCl. (C) 2002 Wiley-Liss, Inc.