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

Abstract

A new organic salt of metformin, an antidiabetic drug, and N,N′-(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.

Microcrystalline solid–solid transformations of conformationally-responsive solvates, desolvates and a salt of N,N′-(1,4-phenylene)dioxalamic acid: the energetics of hydrogen bonding and n/π → π* interactions

“…In this context, the carboxylic acid endings in H-I are proposed to form R 4 4 (14) HB motifs with water, similar to the motif shown in the (H 2 pOx·2W) 2 bilayer of the mixed solvate 3H 2 pOx·2MeOH·4W, as well as in H 2 Mf(HpOx) 2 ·4W. 38 Besides, H-II is proposed to form R 4 4 (12) HB motifs with water similar to that found in the double-hydrate of oxalic acid. To support this proposal, it is worth recalling that crystals of 3H 2 pOx·2MeOH·4W dried at RT form H-I, whereas the water molecules in H-II are weakly bound, and they are removed at 92.4 °C, similar to the dehydration of oxalic acid ( vide supra ).…”

“…The vacant sites left behind after water removal are preserved in the mc-solids A-I and A-II, whose crystal networks are stable and capable of rearranging in the presence of moisture to restore the mc-lattice of the original double-hydrates under suitable conditions, as has also been observed in the tetrahydrate salt of HpOx − . 38 Conversely, hydration of A-III, obtained from either DMSO or DMF solvates, slowly progresses to form the mc-solid hydrate H-II. This result suggests that H 2 pOx molecules are arranged into a more compact lattice in A-III than in A-I or A-II.…”

“…It is worth mentioning that this conformation has only been observed in anionic dinuclear M( ii ) metallacyclic complexes of the paracyclophane-type [M 2 L 2 ] 4− (M = Cu, Pd) 14,17 and is in contrast to the almost planar conformation adopted in the monoanionic HpOx − salt. 38…”

Versatile Solid Modifications of Multicomponent Pharmaceutical Salts: Novel Metformin–Rhein Salts Based on Advantage Complementary Strategy Design

“…Based on clinical studies, nausea, vomiting, diarrhea, and other gastrointestinal side effects occur in 20-30% of patients taking metformin hydrochloride [30]. Considering the above problems, researchers have carried out multicomponent co-crystallization studies on MET via salification strategy [6,11,[31][32][33][34][35][36][37][38][39][40][41][42]. However, these literature reports mainly focused on the optimization of MET physicochemical properties, and no pharmacological evaluation has been conducted on the hypoglycemic effect of multicomponent salts in vivo.…”