Insights into the self-assembly of fampridine hydrochloride: how the choice of the solvent affects the crystallization of a simple salt

Crystalline materials and crystallization processes play an important role in several fields of science, such as pharmaceuticals, material science, pigments, optoelectronics, catalysis and energy storage. Understanding and defining the right conditions of crystallization is therefore crucial. Among the several factors influencing the crystallization of a given compound, the choice of the solvent system is perhaps one of the most important. The nature of solvent–solute interactions can indeed have a role in promoting specific molecular assemblies, therefore affecting crystallisation rates of a crystal and often resulting in the nucleation of different polymorphs and solvates. Here we investigated the role of a binary mixture of solvent (water/acetone) in the crystallisation of a simple salt of 4-aminopyridinium chloride. Previous results on this compound showed that when crystallised from water it forms a simple hydrate structure, while in the presence of acetone, it undergoes a liquid-liquid phase separation, followed by the crystallisation of a complex structure belonging to the Frank–Kasper (FK) phases, a particular family of topologically close-packed structures never observed in small and rigid molecules. To broaden the understanding of how such a simple molecule may crystallise as an FK phase, we carried out the crystallization of the complex phase by antisolvent diffusion (in a mixture of water/acetone) and that of the monohydrate phase in water, monitoring the liquid precursors by liquid-state NMR. In particular, we applied 1H, 13C, 14N, 17O, and 35/37Cl NMR as a function of the concentration of 4APH+Cl− until the moment when precipitation of the crystalline phases occurred. Variations of chemical shifts, T1 relaxation times of 13C signals, and full-width at half-maximum of the signals of quadrupolar nuclei were also measured. The spatial proximity between the different species in the solution was investigated by NOE experiments. In order to support these results, we also performed Molecular Dynamics simulations, investigating the potential solute/solvents interactions. The results strongly suggest that acetone, instead of behaving as an anti-solvent, interacts directly with the solute, preventing the formation of the simple monohydrate structure and, at the same time, promoting specific molecular aggregations.