Effect of molar ratios on formation, dissolution and physical stability of naringenin-meglumine co-amorphous by integrating theoretical-modeling-experimental techniques

Abstract

Although the molar ratio is a crucial parameter for co-amorphous formulations, the selection of molar ratio on their formation and important physicochemical properties is rarely studied during development process. Herein, this study attempted to explore the influence of molar ratios (3:1 ~ 1:3) on formation, dissolution and physical stability of naringenin-meglumine co-amorphous (i.e., NAR-MEG CM) by integrating theoretical-modeling-experimental techniques. The formed NAR-MEG CMs with molar ratios of 1:1, 1:2 and 1:3 were driven by the strong hydrogen bond interactions between C=O group of NAR and -OH/-NH groups of MEG as confirmed by FTIR and RDF analyses. Among them, NAR-MEG CM (1:1) showed a significantly enhanced dissolution with long-time supersaturated concentration than crystalline NAR, while NAR-MEG CM (1:2) and NAR-MEG CM (1:3) easily aggregated into clumps during dissolution with the increase of MEG ratio, causing the gradual decrease in dissolution performance. Meanwhile, NAR-MEG CM (1:1) exhibited superior physical stability than NAR-MEG CM (1:2) and NAR-MEG CM (1:3), because of the decreased binding energy of NAR-MEG molecules with the increase of MEG ratio from a molecular dynamics perspective. Therefore, 1:1 as the optimal molar ratio for NAR-MEG CMs could effectively overcome the water solubility problem of NAR and maintain excellent physical stability. This study offers a unique perspective on the influence of molar ratios on formation, dissolution and stability of co-amorphous systems through theory-model-experiment techniques, which can be employed as a practicable methodology to guide the further design and performance forecast for co-amorphous formulations.