How Sugars Modify Caffeine Self-Association and Solubility: Resolving a Mechanism of Selective Hydrotropy

Abstract

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 selfassociation 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.

Thermodynamic Analysis of the Self‐Assembly of Pseudo Isocyanine Chloride in the Presence of Crowding Agents

“…However, unlike to PIC, the caffeine stacks eventually precipitate. The analysis revealed a preferential adsorption of sugars to caffeine monomers relative to the same units incorporated into the polymeric stacks, [18] similar to the type of interaction of TEG and PEG with PIC monomers revealed in the present work. Although this preferential interaction favors the monomeric state in comparison to the polymeric state in both cases, increasing amounts of a sugar additives decreases the solubility of caffeine leading also to increasing amounts of precipitate, whereas PIC is arrested in its fiber‐like state without further precipitation.…”

“…In a similar approach published recently by Shumilin et al [18] . the impact of sugars has been analysed on the self‐association and solubility of caffeine.…”

“…Caffeine precipitates do not expose a significant surface to the solution as fiber or stack‐like polymers would do, thereby entirely avoiding disfavoring contacts between stacks and sugar additives. This does not only promote monomer formation on the expense of destabilized polymers, but also diverts polymeric stacks towards the precipitate state thus decreasing overall solubility of caffeine as the sugar content increases [18] …”

“…In a similar approach published recently by Shumilin et al [18] the impact of sugars has been analysed on the self-association and solubility of caffeine. Caffeine molecules self-assemble towards oligomeric and polymeric stacks, in close analogy to the aggregation of PIC.…”

“…This does not only promote monomer formation on the expense of destabilized polymers, but also diverts polymeric stacks towards the precipitate state thus decreasing overall solubility of caffeine as the sugar content increases. [18] In order to obtain additional information on the thermodynamic properties of the systems, concepts from polymer chemistry are applied. As soon as the aggregation threshold is surpassed, monomeric PIC starts to self-assemble to J-aggregates.…”