Structure-Permeability relationships of Vitamin-B-Based quaternary ammonium salts for oral drug development

Effective oral drug delivery requires compounds with suitable solubility, permeability, and physicochemical properties to ensure efficient absorption in the gastrointestinal tract. This study evaluates vitamin-derived quaternary ammonium salts (QASs) based on nicotinamide, nicotinic acid, and p-aminobenzoic acid, together with their nonionic counterparts, as potential orally administrable molecules. In silico pharmacokinetic predictions identified nicotinate QASs as the most promising candidates, exhibiting favorable permeability, intestinal absorption, and solubility profiles. PAMPA experiments confirmed high passive permeability for all compounds, with 6-hour P_app values exceeding 1.1·10⁻⁶ cm·s⁻¹, and demonstrated that membrane transport depends strongly on alkyl chain length and counterion identity. Permeability decreased notably for derivatives with octyl chains, whereas nicotinate QASs displayed values comparable to diclofenac sodium, and the shortest-chain p-aminobenzoate and its nonionic analogue slightly surpassed the reference drug. Surface activity analysis revealed that reductions in solution surface tension significantly enhance membrane transport, overriding limitations associated with increased molecular size. Overall, the synergistic influence of alkyl chain length, anion selection, and surface activity underscores the potential of vitamin-derived QASs as tunable, multifunctional candidates for oral drug development.