Synthesis and Structural Characterization of Novel Salts of Ticlopidine with Enhanced Solubility and Dissolution Rate

Abstract

Ticlopidine (TPD), a Biopharmaceutics Classification System (BCS) class II drug, suffers from poor aqueous solubility, which limits its oral bioavailability. Herein, the enhancement of solubility and dissolution performance of TPD has been demonstrated through salt formation with maleic acid, mandelic acid, and oxalic acid. The salts of TPD are stabilized by charge-assisted N⁺–H···O⁻ hydrogen bonds. The solubility studies conducted in water and pH 2.5 buffer revealed a significant enhancement in solubility for all three salts compared to pure TPD. The maleate and oxalate salts also exhibited improved intrinsic dissolution rates in both media. In contrast, the mandelate salt displayed hygroscopic behavior, which hindered reliable assessment of its dissolution performance. Hirshfeld surface analysis provided quantitative insights into the intermolecular interactions that govern crystal packing and helped rationalise the observed differences in solid-state behaviour. Overall, the results demonstrate that salt formation is an effective strategy for improving the biopharmaceutical performance of poorly soluble drugs such as ticlopidine.