Insight into amoxicillin sodium heterosolvates and non-solvated form: crystal structures, phase transformation behaviors, and desolvation mechanism

Abstract

Amoxicillin sodium heterosolvates, including S_M–M (methanol–methyl acetate solvate), S_E–M (ethanol–methyl acetate solvate), and S_M–E (methanol–ethyl acetate solvate), were obtained for the first time in this work. The single crystal of non-solvated crystal form (form I) was successful obtained via the phase transformation of amoxicillin sodium heterosolvate. The crystallographic data of amoxicillin sodium form I and heterosolvate were obtained via single crystal X-ray diffraction. Amoxicillin sodium molecules in form I and S_M–M exhibited a similar conformation. In comparison with S_M–M, the relative positions of the benzene ring and Na⁺ ion in form I was changed, thus facilitating the formation of a new coordinate bond between Na⁺ ion and phenolic hydroxyl group during the desolvation of S_M–M. Methanol and methyl acetate molecules played different roles in the formation of S_M–M. Methanol molecules formed strong coordinate bonds with amoxicillin sodium molecules, while methyl acetate molecules helped in improving the packing efficiency. The phase transformation behavior was explored via thermal analyses. The two-step desolvation mechanism of the heterosolvates was proposed and further verified via density functional theory computational analysis. Finally, the accelerated stability tests showed high relative humidity break the desolvation of heterosolvates and form I exhibited higher physical stability than the three heterosolvates.