Supramolecular Organization in Salts of Riluzole with Dihydroxybenzoic Acids—The Key Role of the Mutual Arrangement of OH Groups

Abstract

Intermolecular interactions, in particular hydrogen bonds, play a key role in crystal engineering. The ability to form hydrogen bonds of various types and strengths causes competition between supramolecular synthons in pharmaceutical multicomponent crystals. In this work, we investigate the influence of positional isomerism on the packing arrangements and the network of hydrogen bonds in multicomponent crystals of the drug riluzole with hydroxyl derivatives of salicylic acid. The supramolecular organization of the riluzole salt containing 2,6-dihydroxybenzoic acid differs from that of the solid forms with 2,4- and 2,5-dihydroxybenzoic acids. Because the second OH group is not at position 6 in the latter crystals, intermolecular charge-assisted hydrogen bonds are formed. According to periodic DFT calculations, the enthalpy of these H-bonds exceeds 30 kJ·mol−1. The positional isomerism appears to have little effect on the enthalpy of the primary supramolecular synthon (65–70 kJ·mol−1), but it does result in the formation of a two-dimensional network of hydrogen bonds and an increase in the overall lattice energy. According to the results of the present study, 2,6-dihydroxybenzoic acid can be treated as a promising counterion for the design of pharmaceutical multicomponent crystals.

Dioxygen–halogen bonding exemplified by crystalline peroxosolvates of N,N′-bis(haloacetyl) bispidines

“…Identification of non-covalent interactions in molecular crystals typically rests on the analysis of periodic (crystalline) electron density. 68–70 Bond critical point (BCP) localization 71 is sufficient to identify intermolecular H-bonds but not other non-covalent interactions due to their different nature. 72 Therefore, reduced density gradient (RDG) was used to identify the dioxygen–halogen bonding in crystals 1–3 and 6 .…”

“…Details of DFT calculations, Bader analysis of periodic electron density, and estimates of non-covalent interaction energies can be found elsewhere. 69,70…”

“…Details of DFT calculations, Bader analysis of periodic electron density, and estimates of non-covalent interaction energies can be found elsewhere. 69,70 The three-dimensional grid files of electron density r, Laplacian of the electron density r 2 r, and magnitude of the gradient of electron density |rr| were obtained for relaxed geometries of crystals 1-3 and 6 using Topond14 interfaced with the Crystal17 code. 78 The obtained 3D grids were postprocessed by the NCIMilano public code, 79 which allows the study of non-covalent interactions through the RDG tool.…”

Efficient Suppression of Dynamic Disorder in Organic Semiconductors via Electron-Donating and -Withdrawing Substituents

“…Bader analysis of the crystalline wave function was performed using Topond14 . The calculation methodology is presented elsewhere …”

“…39 The calculation methodology is presented elsewhere. 40 Transfer Integrals and Their Vibrational Modulation. The transfer integrals J mn were calculated using the dimer projection method (DIPRO).…”