Structural insights into the multi-component solid forms of aminocaproic acid and aminomethyl benzoic acid: mechanochemical approach for the preparation of salt forms

Abstract

Mechanochemical preparation of multi-component systems, such as cocrystals and salts, is at the forefront of crystal engineering, driven by its dual benefits of environmental friendliness and efficient material exploration. The intrinsic relationship between mechanochemical milling and supramolecular chemistry arises from the solvent-free nature of the milling process. This study reports the new salts of antifibrinolytic agents, aminocaproic acid (ACA) and aminomethylbenzoic acid (AMA), with various coformers, namely oxalic acid (OXA), tartaric acid (TAT), caffeic acid (CAF), 2-chloro-4-nitrobenzoic acid (CNB), saccharin (SAC), and orotic acid (ORA). Additionally, the crystal structure of the anhydrous AMA compound was determined and reported in this work. The crystal structures of the developed salts were elucidated using single-crystal X-ray diffraction analysis and further analysed by spectroscopic (FT-IR) and thermal methods (DSC and TGA). The salts of ACA with OXA resulted in two solid forms with varying stoichiometry of water molecules (ACA–OXA–H₂O (1 : 1 : 2); ACA–OXA–H₂O (1 : 1 : 1.5)), while ACA–CAF–H₂O was obtained in a 3 : 2 : 2.6 stoichiometric ratio of ACA, CAF, and H₂O in the asymmetric unit. AMA–TAT and AMA–CNB were obtained as hydrates, while AMA–OXA, AMA–SAC, and AMA–ORA were obtained as anhydrous salts. Bulk quantities of ACA and AMA salts were synthesised using both solution-based and mechanochemical ball milling techniques. Unlike conventional solution-based approaches, which typically consume significant amounts of solvents and energy, this study highlights the influence of various ball milling parameters, such as milling media, ball size, frequency, and duration, under both solvent-assisted and neat grinding conditions for the preparation of multicomponent solids of ACA and AMA. A linear correlation was observed between the percentage completion and milling frequency of the ball mill, as well as the time required for completion of the salification process. Interestingly, the different hydrate forms of ACA–OXA (ACA–OXA–H₂O (1 : 1 : 2) and ACA–OXA–H₂O (1 : 1 : 1.5)) were prepared in bulk quantities by ball milling, by fine-tuning the milling parameters, whereas the solvent-based slurry method resulted in only the ACA–OXA–H₂O (1 : 1 : 2) form.