Self association and cyclodextrin solubilization of NSAIDs

The phase solubility profiles with HPbetaCD of the sodium salt of the NSAIDs (non-steriodal anti-inflammatory drugs) ibuprofen and diflunisal were studied. The slopes of the phase solubility diagrams were determined for the sodium salt of ibuprofen at pH 6.1, 6.3 and 6.7, and for the sodium salt of diflunisal at pH 6.1 and 8.4. In all cases the slope of the phase solubility diagram was greater than unity. These results suggested that the stoichiometry of the complex formed was greater than unity with respect to the drug. However molecular modeling, NMR and UV studies clearly showed that the complex stoichiometry was 1:1. These conflicting results can be explained by applying the theory developed for micellar forming compounds. Thus the solubilization of the drugs is due partially from inclusion complex formation and partially from solubilization by aggregation. We have therefore demonstrated that the solubility of drugs in a cyclodextrin solution is explained not only by inclusion complex formation but also by non-inclusion association of the uncomplexed drug with the complex.