Origin of non-linearity in phase solubility: solubilisation by cyclodextrin beyond stoichiometric complexation

Abstract

The low solubility of drugs, which poses a serious problem in drug development, can in part be overcome by the use of cyclodextrins (CDs) and their derivatives. Here, the key to solubilisation is identified as the formation of inclusion complexes with the drug molecule. If inclusion complexation were the only contribution to drug solubility, it would increase linearly with CD concentration (as per the Higuchi-Connors model); this is because inclusion complexation is a 1 : 1 stoichiometric process. However, solubility curves often deviate from this linearity, whose mechanism is yet to be understood. Here we aim to clarify the origin of such non-linearity, based on the Kirkwood-Buff and the McMillan-Mayer theories of solutions. The rigorous statistical thermodynamic theory shows that non-linearity of solubilisation can be rationalised by two contributions: CD-drug interaction and the drug-induced change of CD-CD interaction.

The impact of the structuring of hydrotropes in water on the mesoscale solubilisation of a third hydrophobic component

“…[14][15][16][17] Only recently, the group of Shimizu et al developed an approach to describe hydrotropic solubilisation theoretically. [18][19][20][21] This approach derived from pure statistical thermodynamics uses the exact Kirkwood Buff theory to describe the cooperative phenomena in hydrotropic solubilisation such as (i) the sudden onset of solubilisation of hydrophobic compounds in H 2 O (commonly referred to as MHC) and (ii) solubility saturation of hydrophobic compounds at high hydrotrope concentrations. In a nutshell, they consider hydrotropic solubilisation to be the result of a subtle balance between solute-hydrotrope interaction and hydrotrope-hydrotrope interaction.…”

“…At first glance, our conclusions may appear contradictory to recent statistical thermodynamic considerations of hydrotropy. [19][20][21] These state that the predominant driving forces for hydrotropic solubilisation are (i) solute induced interactions between the solute and hydrotrope molecules leading to a solute-hydrotrope association. In contrast (ii) pre-structuring of hydrotropes (hydrotrope-hydrotrope interactions) in water is considered to be rather obstructive for good solubilisation of the solute.…”

Molecular Interpretation of Preferential Interactions in Protein Solvation: A Solvent-Shell Perspective by Means of Minimum-Distance Distribution Functions

“…[8][9][10][11] Such "interactions" are now defined rigorously in terms of the net excess or deficit of water and cosolvent concentrations from the bulk, referred to as the Kirkwood-Buff integrals (KBI). [8][9][10][11] KBIs serve not only as powerful tool for rationalizing and explaining experimental data on a variety of cosolvent-controlled effects (from biophysics, formulation science, pharmacy to food science) 5,[12][13][14][15] but also as a benchmark for simulation and force field determination. 4,16 KBIs are usually defined as the integrals of the solute-solvent distribution functions, most commonly the radial distribution functions (RDFs).…”

Effect of solute aggregation on solubilization

“…(10). For , we use (i) the well-known relationship between and the second virial coefficient , , [46] and (ii) , at the infinite dilution limit, as the upper limit of , because solubility increase by hydrotrope means favourable solvation of the solute, which reduces its self-association [39,40]. Thus a comparison between the maximum solubilization ln versus (where is the maximum solubility attained by hydrotrope addition) in Table 1 shows that the latter is much smaller than the former.…”