Strong impact of concentration of aqueous solutions on molecular and supramolecular structure of para-aminobenzoic acid and its conjugate with 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine (drug Xymedon)

Combined Raman, UV–Vis and quantum chemical studies of the structural flexibility of the para-aminobenzoic acid (PABA), 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine (Xymedon) and their conjugate in aqueous solutions revealed strong dependence of molecular and supramolecular structures of PABA and the conjugate on concentration of the solutions. Deprotonated form of PABA, i.e. PABA⁻ anion, dominates in highly diluted solutions with c ≤ 2∙10⁻⁵ M. At 2∙10⁻⁵ M < c < 10⁻⁴ M, PABA and PABA⁻ are at equilibrium, which steadily shifts to full predomination of neutral species upon increase of concentration till 5∙10⁻⁴ M. At c ≥ 10⁻² M PABA forms self-associated species, represented by head-to-head and stacked dimers. Highly diluted solutions of the PABA-Xymedon conjugate are shown to consist of separate PABA⁻ anions and neutral Xymedon, whereas concentrated solutions contain about 70 % of mixture of neutral PABA dimers and Xymedon molecules, and about 30 % of contact ion pairs formed by PABA⁻ anions and protonated XymedonH⁺ cations. Protonated XymedonH⁺ cation is shown to be less conformationally flexible than neutral Xymedon. Good agreement of the results of quantum chemical calculations with the experimental observations allowed identification of UV–Vis and Raman spectroscopic markers of all the above-mentioned structural entities.