Synergistic approach of salt formation and polymer-mediated stabilization to enhance the biopharmaceutical performance of Mebendazole

Mebendazole (MBZ), a brick dust molecule with poor aqueous solubility tends to precipitate at intestinal pH, impeding its gastrointestinal absorption. Moreover, the amorphous MBZ tends to recrystallize in conventional amorphous solid dispersion (ASD) during long-term storage, reducing its physical stability and solubility. The present investigation explored amorphous salt solid dispersion (ASSD), an emerging approach combining salt formation with ASD, where the counterion and polymer are crucial in forming a stable supersaturated system. The maximal supersaturation holding capacity of hydroxypropyl methylcellulose acetate succinate polymer and its potential to lower the melting endotherm of MBZ demonstrate its suitability for ASSD preparation, via acid-base reaction between HCl and MBZ. P-XRD and DSC confirmed the amorphization of MBZ in ASSD, exhibiting a higher T_g and improved physical stability. ¹H NMR and FTIR spectroscopy confirmed the protonation of nitrogen during salt formation, with stronger salt-polymer interactions that stabilized the amorphous MBZ in ASSD, preventing recrystallization for 12 months, compared to ASD. Additionally, ASSD exhibited synergistic enhancement in solubility (7.58-folds) and dissolution (11.17-folds) of MBZ, which translated into in vivo studies, demonstrating 2.99-folds increase in C_max. Hence, findings revealed ASSD as a potential approach for augmenting the biopharmaceutical performance of MBZ over ASD.