Physicochemical profile of nimesulide. Exploring the interplay of lipophilicity, solubility and ionization

The lipophilicity and solubility profile of nimesulide was investigated over a broad pH range. Lipophilicity was assessed by direct partitioning experiments in the octanol-water system using the shake flask method, as well as by reversed-phase HPLC using methanol as organic modifier with or without addition of n-octanol. In the latter case the extrapolated retention factors logk(w) were considered as lipophilicity indices. The presence of n-octanol in the mobile phase proved to be a crucial factor for the establishment of a logk(w)/pH profile very similar to the logD/pH profile of nimesulide. Solubility was determined by the shake flask method using saturated buffer solutions. Both lipophilicity and solubility--pH profiles of nimesulide showed deviations from the theoretically expected behavior as dictated by the Henderson-Hasselbach equation and the usually recorded difference of 4 log units between the corresponding values of the neutral and ionized species in the case of a weak acid. As a consequence the lipophilicity and solubility profiles were found not to be mirror images of each other. However, the pK(a) value of nimesulide could be accurately calculated using part of both lipophilicity and solubility profiles since deviations affected mostly the values at increased ionization.