Background/Objectives: This study investigates the preparation of coamorphous systems composed entirely of active pharmaceutical ingredients (APIs), namely praziquantel, niclosamide, and mebendazole. The objective was to formulate and characterize binary and ternary coamorphous systems to evaluate their structural, thermal, and stability properties. Methods: Ten different mixtures (binary and ternary) were designed through a mixture design approach and prepared using a sustainable, one-step neat grinding process in a lab-scale vibrational mill. The systems were prepared reproducibly within 4 h across the entire experimental domain. Structural characterization was performed using PXRD and FTIR to confirm the absence of crystalline domains and the presence of molecular interactions. The glass transition temperature (T_g) was theoretically calculated using the Gordon–Taylor equation for three-component systems and determined experimentally via DSC. Stability studies were conducted on seven systems under different storage conditions (−30 °C, 5 °C, 25 °C, and 40 °C) for six months. Results: PXRD analysis confirmed the formation of coamorphous systems with no crystalline phases. DSC revealed a single T_g for most systems, indicating homogeneity. Stability studies demonstrated that five out of seven systems adhered to the “T_g—50 °C” stability rule, remaining physically stable over six months. Recrystallization studies indicated diverse pathways: some systems reverted to their original crystalline phases, while others formed new entities such as cocrystals. Conclusions: This study highlights the feasibility of coamorphous systems composed of multiple APIs using a simple, solvent-free grinding approach. The findings underscore the importance of molecular interactions in determining stability and recrystallization behavior, offering insights for designing robust coamorphous formulations.

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.