The role of solvation in proton transfer reactions: implications for predicting salt/co-crystal formation using the ΔpK_a rule

Abstract

This paper reviews the theoretical background of the ΔpKa rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base.

Amorphous Drug–Polymer Salts: Maximizing Proton Transfer to Enhance Stability and Release

“…It is of interest to consider the proton transfer behavior observed in this work in light of the empirical rule for predicting salt formation from the p K a difference, Δp K a , between the reactants . According to this rule, Δp K a > 4 ensures salt formation.…”

“…It is of interest to consider the proton transfer behavior observed in this work in light of the empirical rule for predicting salt formation from the p K a difference, Δp K a , between the reactants. 27 According to this rule, Δp K a > 4 ensures salt formation. This condition is met for PAA reacting with both LMF and CFZ (primary protonation) and the rule would predict proton transfer.…”

Structural features, dissolution performance and anthelmintic efficacy of multicomponent solid forms of fenbendazole with maleic and oxalic acids

“…72)) equals to 0.68 and 1.37, respectively, indicating that both solid forms fall in the Δp K a range of uncertain results in terms of proton transfer. According to the recently revised model proposed by Cruz-Cabeza et al , 67 the preference for non-solvated cocrystal or salt formation in this region can be quantitatively evaluated using the following equation: P obs (ion, %) = 14Δp K a + 32Implementation of the correlation (1) to the studied systems resulted in an almost equal chance of salt and cocrystal formation for [FNB + Ox] (1 : 1) (51% probability salt), while a slight bias towards cocrystal formation was calculated for [FNB + Mal] (1 : 1) (41% probability salt) (Table 1). It should be noted that a similar probability of salt formation has been reported for the flubendazole–maleic acid pair, which was confirmed to be a salt via X-ray photoelectron spectroscopy.…”

“…The ΔpK a rule (ΔpK a = pK a (base) − pK a (acid) ) is widely recognized in the literature for predicting whether an API and a guest molecule form a salt or cocrystals. [65][66][67] When the ΔpK a value exceeds 4, the components tend to form a salt. A cocrystal is likely to occur if ΔpK a ≤ −1.…”

“…65,70,71 As Table 1 illustrates, the difference between the pK a values of FNB (pK a = 2.6 (ref. , 67 the preference for non-solvated cocrystal or salt formation in this region can be quantitatively evaluated using the following equation:…”