Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-<i>N</i>,<i>N</i>′-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions

• Main Authors: Sayuri Chong-Canto, Efrén V. García-Báez, Francisco J. Martínez-Martínez, Angel A. Ramos-Organillo, Itzia I. Padilla-Martínez
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: Pharmaceutics
• Subjects: metformin cocrystal; mechanochemical synthesis; dicationic metformin; water channels; pi-interactions; mesoporous anhydrate
• Online Access: https://www.mdpi.com/1999-4923/12/10/998

A new organic salt of metformin, an antidiabetic drug, and <i>N</i>,<i>N</i>′-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H₂Mf(HpOXA)₂∙4H₂O. X-ray powder, IR, ¹³C-CPMAS, thermal and BET adsorption–desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H₂Mf(HpOXA)₂. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA⁻, as well as its structure in the solid, is herein reported for the first time. Regular O(δ−)∙∙∙C(δ), O(δ−)∙∙∙N⁺ and bifacial O(δ−)∙∙∙C(δ)∙∙∙O(δ−) of n→π * charge-assisted interactions are herein described in H₂MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns.