The first insight into the supramolecular structures of popular drug repaglinide: Focus on intermolecular interactions in antidiabetic agents

Abstract

This work is the first, according to our knowledge, complete structural report on the solid-state supramolecular architecture of antidiabetic drug repaglinide. Here, we present a series of four crystal structures, namely: an un-solvated form of repaglinide (1), repaglinide hydrochloride (2), repaglinide monohydrate (3) and repaglinide methanol solvate (4), successfully determined and fully characterized by the single-crystal X-ray diffraction method (SC-XRD) at 100 K. The (1) and (2) crystallize in the orthorhombic P212121 space group with Z = 1, while solvates exist in triclinic P-1 with Z = 2. The hierarchy and interplay of various intra- and intermolecular interactions in the creation of a 3-D supramolecular assembly using different finite groups (D), rings (R) and infinite chains (C) graph-set motifs are discussed in detail. A particular focus is put on unique halogen-bonded supramolecular synthons. Interestingly, in (2) structure, an intramolecular cyclic ring S(8) synthon was found as a consequence of the NH+ group. Solvent and water molecules play a significant role in the formation of supramolecular architectures in the context of large synthons, the so-called long-range synthon Aufbau modules (LSAM) at the higher level of the crystal organization. A qualitative and quantitative comparative investigation of intercontacts nature between the adjacent molecules in the crystal, govering the supramolecular assemblies, with respect to other members of the glinides family - nateglinide and also related antidiabetic benzoic acid derivatives, retrieved from the Cambridge Structural Database (version 5.39, update February 2018 release) was supported by 3-D Hirshfeld surface maps and the associated 2-D fingerprint plots analysis visualizing all intercontacts at once and contributing them to the total surface for each compound. It revealed numerous interactions mainly H⋯H, O⋯H, C⋯H (CH…π), but also Cl⋯H(O, C) C⋯C (π…π), N⋯H(O), C⋯O (π…lone pair), O⋯O (lone pair…lone pair) cooperatively participating in stabilization of the supramolecular structures of this class of APIs.