The aggregation of drugs and nutraceuticals in aqueous media is an outstanding problem for their efficacy and bioavailability. A common solution is to add excipients or hydrotropes that increase solubility and limit aggregation. Here we study caffeine, a widely consumed drug that undergoes oligomerization and aggregation in aqueous solutions. Combining partition and solubility experiments with molecular dynamics simulations, we determined the effect of sugars (mono- and disaccharides) on caffeine self-association and solubility. We find that sugars selectively increase the concentration of caffeine in its monomeric state, but decrease its solubility in all oligomeric forms. Thus, we determine that, in contrast to common hydrotropes, sugars act as selective hydrotropes toward caffeine, since they differentially act on specific solvated forms of the drug. We furthermore unravel the molecular mechanism for this selectivity, and comment on the general design principles that should help develop targeted excipients for bioavailability and taste modification in drugs and foods.
Bibliographical noteFunding Information:
We thank T. Higashiyama (Hayashibara) for the gift of trehalose, M.Y. Niv for helpful discussions, and U. Raviv for allowing us use of his instrumentation. IS thanks B. Borin for help in data analysis and CA thanks L. Sapir for providing sugar topology. IS thanks the Harvey M. Kruger center for Nanoscience & Nanotechnology for their fellowship and CA thanks the Minerva foundation for a postdoctoral fellowship. The financial support from the Israel Science Foundation (ISF Grant No. 1246/17) is gratefully acknowledged. The Fritz Haber Research Center is supported by the Minerva Foundation, Munich, Germany.
© 2019 American Chemical Society.