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

Abstract

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.

Keywords: binary coamorphous; drug-to-drug-to-drug coamorphous; glass transition; physical stability; storage temperature; ternary coamorphous.

Figure 1

(a) Praziquantel, (b) niclosamide, and (c) mebendazole molecular structures.

Figure 2

Ternary diagram representing the experimental design space. X1, X2, and X3 represent the molar ratios of the drugs.

Figure 3

FT-IR spectra of NCM-MBZ 1–1 coamorphous (black) compared with its physical mixture (red) and pure components (blue line represents NCM and light green line MBZ).

Figure 4

FT-IR spectra of PZQ-NCM 1–1 coamorphous (black) compared with its physical mixture (red) and pure components (blue line represents PZQ and light green line NCM).

Figure 5

FT-IR spectra of PZQ-MBZ 1–1 coamorphous (blue) compared with its physical mixture (orange) and pure components (light blue line represents PZQ and red line MBZ).

Figure 6

FT-IR spectra of PZQ-NCM-MBZ 1–1-1 coamorphous (black) compared with its physical mixture (red) and pure components (light blue line represents PZQ, blue NCM, and light green line, MBZ).

Figure 7

Physical stability of seven coamorphous systems after 6 months of storage at different temperatures. Full sticks indicate that sample meets expectations according to “Tg—50 °C” rule. Full green ticks stand for “stable as expected according to “T_g—50 °C” rule”; full red crosses stand for “unstable, as expected according to “T_g—50 °C” rule”; empty green ticks stand for “stability superior to expectations”; empty red crosses stand for “stability inferior to expectations”. * T_g value calculated from G-T equation.

Figure 8

Sorption–desorption curves for exp. N° 3 (dark blue–light blue), 6 (dark green–light green), 9 (red–orange), and 10 (purple–grey).

Figure 9

Cartoon depicting the recrystallization of binary PZQ-MBZ 1–1 coamorphous systems into individual components through PXRD analyses. Black dotted lines represent PZQ peaks, while light blue dotted lines MBZ reflections.

Figure 10

Cartoon depicting the recrystallization of binary PZQ-NCM 1–1 coamorphous system into polymorph C of PZQ and the PZQ-NCM 1–3 anhydrous cocrystal. Yellow dotted lines represent PZQ polymorph C reflections, while light blue dotted lines PZQ-NCM 1–3 anhydrous cocrystal reflections.