Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 118, Issue 35, Pages 10515-10524Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp505869m
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Funding
- Japan Society for the Promotion of Science [21300111, 23651202, 26240045]
- Ministry of Education, Culture, Sports, Science, and Technology [20118002]
- Computational Materials Science Initiative, Theoretical and Computational Chemistry Initiative, HPCI Strategic Program, HPCI System Research Project [hp120093, hp130022, hp140156, hp140214]
- Strategic Programs for Innovative Research of the Next-Generation Supercomputing Project
- Grants-in-Aid for Scientific Research [26240045, 23651202] Funding Source: KAKEN
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Drug molecules with low aqueous solubility can be solubilized by a class of cosolvents, known as hydrotropes. Their action has often been explained by an analogy with micelle formation, which exhibits critical micelle concentration (CMC). Indeed, hydrotropes also exhibit minimum hydrotrope concentration (MHC), a threshold concentration for solubilization. However, MHC is observed even for nonaggregating monomeric hydrotropes (such as urea); this raises questions over the validity of this analogy. Here we clarify the effect of micellization on hydrotropy, as well as the origin of MHC when micellization is not accompanied. On the basis of the rigorous Kirkwood-Buff (KB) theory of solutions, we show that (i) micellar hydrotropy is explained also from preferential drug-hydrotrope interaction; (ii) yet micelle formation reduces solubilization effeciency per hydrotrope molecule; (iii) MHC is caused by hydrotrope-hydrotrope self-association induced by the solute (drug) molecule; and (iv) MHC is prevented by hydrotrope self-aggregation in the bulk solution. We thus need a departure from the traditional view; the structure of hydrotrope-water mixture around the drug molecule, not the structure of the aqueous hydrotrope solutions in the bulk phase, is the true key toward understanding the origin of MHC.
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