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

Abstract

Although the molar ratio is a crucial parameter for co-amorphous formulations, the selection of the molar ratio for their formation and important physicochemical properties is rarely studied during the development process. Herein, this study attempted to explore the influence of molar ratios (3 : 1–1 : 3) on the formation, dissolution and physical stability of co-amorphous naringenin–meglumine (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 the CO group of NAR and the –OH/–NH groups of MEG as confirmed by FTIR and RDF analyses. Among them, NAR–MEG CM (1 : 1) showed significantly enhanced dissolution with long-term supersaturated concentration compared to crystalline NAR, while NAR–MEG CM (1 : 2) and NAR–MEG CM (1 : 3) easily aggregated into clumps during dissolution with the increase of the MEG ratio, causing the gradual decrease in dissolution performance. Meanwhile, NAR–MEG CM (1 : 1) exhibited superior physical stability to 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 the 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 the 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.