Complications May Thwart Reliable Measurement Of Aqueous Solubility

There are numerous experimental complications in the measurement of solubility. Solid phases, formed incipiently, are often metastable with respect to a thermodynamically more stable phase, especially with highly insoluble compounds. An ''active'' form of a solid, a very fine crystalline precipitate with a disordered lattice, can drop out of a strongly oversaturated solution, which then ''ages'' only slowly into a more stable ''inactive'' form [465]. Hence, if measurements are done following initial precipitation, higher solubilities are observed. Amorph-ism [464] and polymorphism [466] can be troubling complications. Various sol-vates of a solid (either water or cosolvent in the crystal lattice) have different solubilities [43].

Certain surface-active compounds [499], when dissolved in water under conditions of saturation, form self-associated aggregates [39,486-488] or micelles [39,485], which can interfere with the determination of the true aqueous solubility and the pKa of the compound. When the compounds are very sparingly soluble in water, additives can be used to enhance the rate of dissolution [494,495]. One can consider DMSO used in this sense. However, the presence of these solvents can in some cases interfere with the determination of the true aqueous solubility. If measurements are done in the presence of simple surfactants [500], bile salts [501], complexing agents such as cyclodextrins [489-491,493], or ion-pair-forming counterions [492], extensive considerations need to be applied in attempting to extract the true aqueous solubility from the data. Such corrective measures are described below.


Two sensibly priced commercial databases for solubility exist [366,507]. An article in the journal Analytical Profiles of Drug Substances carries solubility data [496]. Abraham and Le [508] published a list of intrinsic aqueous solubilities of 665 compounds, with many ionizable molecules. It is difficult to tell from published lists what the quality of the data for ionizable molecules is. Sometimes, it is not clear what the listed number stands for. For example, Sw, water solubility, can mean several different things: either intrinsic value, or value determined at a particular pH (using buffers), or value measured by saturating distilled water with excess compound. In the most critical applications using ionizable molecules, it may be necessary to scour the original publications in order to be confident of the quality of reported values.

0 0

Post a comment