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

  • Luca Fusaro ORCID logo EMAIL logo , Nikolay Tumanov , Giacomo Saielli ORCID logo and Riccardo Montis
Published/Copyright: April 27, 2023
Pure and Applied Chemistry
From the journal Pure and Applied Chemistry Volume 95 Issue 10

Abstract

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.

Keywords: Crystallisation; Italian-French NMR conference; liquid-state NMR; molecular dynamics; preferential solvation; solid-state NMR; X-ray diffraction
Corresponding author: Luca Fusaro, NISM – Namur Institute of Structured Matter, University of Namur, 5000 Namur, Belgium, e-mail:

Article note: A collection of invited papers based on presentations at the Italian-French International Conference on Magnetic Resonance, Milan, Italy, 27–30 September 2022.

Funding source: Fonds De La Recherche Scientifique – FNRS

Award Identifier / Grant number: Call large equipment 2018 – Application ID: 329041

Award Identifier / Grant number: Research Credit 2021 – Application ID: 40007887

Acknowledgments

The authors acknowledge the PC2 platform of the University of Namur for access to NMR and XRD facilities. LF acknowledges the National Fund for Scientific Research – FNRS, for the CDR Research Credit (NMR COMPASS, Application ID: 40007887 and the Large Equipment Call (Application ID: 32904189). Calculations were run on the CINECA parallel supercomputers thanks to ISCRA projects nr. HP10B8AOVV. We also thank the C3P community of the Department of Chemical Sciences of the University of Padova for the allocation of computational time.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/pac-2022-1208).

Published Online: 2023-04-27
Published in Print: 2023-10-26

© 2023 IUPAC & De Gruyter

Articles in the same Issue

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  2. In this issue
  3. Editorial
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  5. Conference papers
  6. Multinuclear solid state nuclear magnetic resonance for studying CsPbBr3 nanocubes
  7. Insights into the self-assembly of fampridine hydrochloride: how the choice of the solvent affects the crystallization of a simple salt
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https://doi.org/10.1515/pac-2022-1208
Keywords for this article
Crystallisation; Italian-French NMR conference; liquid-state NMR; molecular dynamics; preferential solvation; solid-state NMR; X-ray diffraction

Articles in the same Issue

  1. Frontmatter
  2. In this issue
  3. Editorial
  4. Preface, first Italian-French International Conference on Magnetic Resonance
  5. Conference papers
  6. Multinuclear solid state nuclear magnetic resonance for studying CsPbBr3 nanocubes
  7. Insights into the self-assembly of fampridine hydrochloride: how the choice of the solvent affects the crystallization of a simple salt
  8. NMR approaches to study proteins integrating globular and disordered domains: the case of c-Src
  9. 1H NMR spectroscopy of strongly J-coupled alcohols acquired at 50 mT (2 MHz) using a Carr–Purcell–Meiboom–Gill echo technique
  10. Skin, soap, and spaghetti: investigations of co-existing solid and liquid phases in organic materials using solid-state NMR with dynamics-based spectral editing
  11. Low-cost MRI devices and methods for real-time monitoring of flow and transfer phenomena in milli-channels
  12. IUPAC Technical Reports
  13. Chemical data evaluation: general considerations and approaches for IUPAC projects and the chemistry community (IUPAC Technical Report)
  14. A brief guide to polymer characterization: structure (IUPAC Technical Report)
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