Hydrotrope accumulation around the drug: the driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea.
Nicotinamide is an effective non-micellar hydrotrope (solubilizer) for drugs with low aqueous solubility. To clarify the molecular basis of nicotinamide's hydrotropic effectiveness, we present here a rigorous statistical thermodynamic theory, based on the Kirkwood-Buff theory of solutions, and our recent application of it to hydrotropy. We have shown that (i) nicotinamide self-association reduces solubilization efficiency, contrary to the previous hypothesis which claimed that self-association drives solubilization and (ii) the minimum hydrotrope concentration (MHC), namely, the threshold concentration above which solubility suddenly increases, is caused not by the bulk-phase self-association of nicotinamides as has been postulated previously, but by the enhancement of nicotinamide-nicotinamide interaction around the drug molecules. We have thus established a new view of hydrotropy - it is nicotinamide's non-stoichiometric accumulation around the drug that is the basis of solubility increase above MHC.
York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. seishi.shimizu@york.ac.uk.
Jonathan J
JJ
Booth
Muhiadin
M
Omar
Steven
S
Abbott
Seishi
S
Shimizu
D001555:Benzene Derivatives / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D014508:Urea / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D001555:Benzene Derivatives; D004364:Pharmaceutical Preparations; D014867:Water; D009536:Niacinamide; D014508:Urea; C004912:ethylbenzene