Self-association of nicotinamide in aqueous solution: mass transport, freezing-point depression, and partition coefficient studies.

The steady-state flux (SSF) of nicotinamide from an aqueous donor phase across a model Silastic membrane did not increase proportionally with increasing donor phase concentration. The suspected self-association of the drug in aqueous solution was evaluated by studying the concentration-dependent changes in (i) the molal osmotic coefficient of nicotinamide (freezing-point depression studies) and (ii) the partition coefficient between water and n-octanol. The freezing points of aqueous solutions of nicotinamide were measured and a plot of osmolality vs molality was nonlinear. The partition coefficient of nicotinamide, studied at 15, 25, and 32 degrees C, also decreased with increasing concentration of drug. Mathematical models describing dimerization and higher orders of association were applied to the data. The results indicated the involvement of higher orders of association and it was found that an isodesmic (step-association) model was an adequate description of the freezing-point depression and partition coefficient data. The association constant, K, ranged between 1.59 +/- 0.02 M-1 at the freezing point and 0.48 +/- 0.01 M-1 as estimated from the partition coefficient data at 32 degrees C. These models for the self-association of nicotinamide allowed estimation of the apparent concentration of "monomeric" nicotinamide in the donor phase solutions studied in the SSF experiments. When the SSF data were analyzed with regard to the concentration of monomeric nicotinamide in the donor phase, a relationship close to linearity was observed.