Amphiprotic cosolvent

Most solubilization curves, as shown in Figure 14.21.2.1, exhibit significant curvatures which are not accounted for by the log-linear model. A closer look at the solubilization curves in Figure 14.21.2.1 reveals that the deviation can be concave, sigmoidal, or convex. In many cases, especially with amphiprotic cosolvents, a negative deviation from the end-to-end log-linear line is often observed at low cosolvent concentrations, followed by a more significant positive deviation as cosolvent fraction increases. 

The extent of the ionization step depends on the relative strength of the conjugate acid-conjugate base pairs. The amphiprotic properties of the solvent have an essential effect on the equilibrium constant of this reaction step. The extent of the dissociation step is influenced by the polarity of the solvent, increasing with the dielectric constant of the solvent. In water, all products of acid-base reactions of moderate to low concentrations are essentially completely dissociated into solvated ions (Pecsok et al., 1976). The dissociation step is suppressed by addition or substitution with cosolvents of lower polarity, e.g., alcohols in aqueous formulations. The ion-pair aggregates may have absorption spectra different from the dissociated species. Thus, the amphiprotic properties and polarity (expressed as the dielectric constant) of the solvent are essential for the acid-base equilibrium of the drug and thus the absorption spectrum of the compound. This subject is further discussed in Section 14.2.3. 

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