Stability of Ternary Drug-Drug-Drug Coamorphous Systems Obtained Through Mechanochemistry

This study explores the successful preparation of coamorphous systems composed entirely of ac-tive pharmaceutical ingredients, namely praziquantel, niclosamide, and mebendazole. Using a mixture design approach, ten different (binary and ternary) mixtures were formulated and pre-pared by neat grinding in a lab-scale vibrational mill. The solvent-free one-step process was re-producible, requiring only 4 hours to generate the coamorphous systems in the whole experi-mental domain. Structural analysis by PXRD and FTIR confirmed the absence of crystalline do-mains and presence of molecular interactions. The glass transition (Tg) temperature was calcu-lated theoretically according to Gordon-Taylor equation for a three-component system and then determined by DSC. In most cases a single Tg was seen, indicating the formation of homogene-ous multicomponent systems. Stability studies on seven systems, stored for six months under different temperature conditions (-30 °C, 5 °C, 25 °C, and 40 °C), demonstrated that all systems were physically stable according to the "Tg – 50 °C" stability rule, with only two exceptions out of seven. Humidity effects were minimal, as shown by DVS data, which revealed only superfi-cial water sorption and no recrystallization. Additionally, the investigation of recrystallization pathways revealed that, depending on the system's interactions, some coamorphous systems separated into their original crystalline phases and others formed new entities such cocrystals.