Novel flucytosine salt: Structure, Hirshfild surface analysis, morphology, FIMs, and computational studies.

Abstract

5-Flucytosine (FC) exhibits an advanced solid-state structure, which presents challenges for its pharmaceutical development. This paper presents experimental, and theoretical studies of a novel pharmaceutical salt, fluorocytosinium chloride, HFC⁺.Cl^-. Single crystal X-ray diffraction (SCXRD) investigation indicates that HFC⁺.Cl^- forms crystals in the monoclinic system and P2₁/c space group. The structure is maintained by a series of hydrogen bonding interactions, comprising N-H···Cl, N-H···O, and C-H···F. In addition, noncovalent anion···π interactions between chloride anions and HFC⁺ cations play a role in establishing a three-dimensional network. Hirshfeld surface analysis (HS) and two-dimensional fingerprinting were used to enumerate the intermolecular interactions within the crystal. The results demonstrate that the H···Cl/Cl···H, O···H/H···O, and F···H/H···F interactions are the most significant. Full Interaction Maps (FIMs) analysis predicts the positions of hydrogen bond acceptors and donors, confirming the supramolecular arrangement observed in HFC⁺.Cl^-. Computational modeling studies using the Bravais-Friedel, Donnay-Harker (BFDH), and Growth Morphology (GM) methods predict the morphology of the HFC⁺.Cl^- crystal. Both approaches estimate a comparable crystal shape characterized by six principal facets. Density functional theory (DFT) calculations were conducted utilizing the DMol³ software to investigate the electronic structure and comprehensive reactivity features of HFC⁺.Cl^-. The low HOMO energy suggests significant stability against electrophilic attacks, while the high HOMO-LUMO band gap indicates high chemical hardness. Fukui functions were also calculated to identify atomic sites susceptible to nucleophilic and electrophilic attacks. This study offers a comprehensive insight into the structural and electronic properties of HFC⁺.Cl^-, offering valuable information for the development of new pharmaceutical compositions.