Investigation of supramolecular synthons and structural characterisation of aminopyridine-carboxylic acid derivatives

Abstract

BackgroundCo-crystal is a structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts. The main advantage of co-crystals is their ability to generate a variety of solid forms of a drug that have distinct physicochemical properties from the solid co-crystal components. In the present investigation, five co-crystals containing 2-amino-6-chloropyridine (AMPY) moiety were synthesized and characterized.ResultsThe crystal structure of 2-amino-6-chloropyridine (AMPY) (I), and the robustness of pyridine-acid supramolecular synthon were discussed in four stoichiometry co-crystals of AMPY…BA (II), AMPY…2ABA (III), AMPY…3CLBA (IV) and AMPY…4NBA (V). The abbreviated designations used are benzoic acid (BA), 2-aminobenzoic acid (2ABA), 3-chlorobenzoic acid (3CLBA) and 4-nitrobenzoic acid (4NBA). All the crystalline materials have been characterized by 1HNMR, 13CNMR, IR, photoluminescence, TEM analysis and X-ray diffraction. The supramolecular assembly of each co-crystal is analyzed and discussed.ConclusionsExtensive N---H · · · N/N---H · · · O/O---H · · · N hydrogen bonds are found in (I-V), featuring different supramolecular synthons. In the crystal structure, for compound (I), the 2-amino-6-chloropyridine molecules are linked together into centrosymmetric dimers by hydrogen bonds to form homosynthon, whereas for compounds (II-V), the carboxylic group of the respective acids (benzoic acid, 2-aminobenzoic acid, 3-chlorobenzoic acid and 4-nitrobenzoic acid) interacts with pyridine molecule in a linear fashion through a pair of N---H · · · O and O---H · · · N hydrogen bonds, generating cyclic hydrogen-bonded motifs with the graph-set notationR228, to form heterosynthon. In compound (II), another intermolecular N---H · · · O hydrogen bonds further link these heterosynthons into zig-zag chains. Whereas in compounds (IV) and (V), these heterosynthons are centrosymmetrically paired via N---H · · · O hydrogen bonds and each forms a complementary DADA [D = donor and A = acceptor] array of quadruple hydrogen bonds, with graph-set notation R238, italicR228 and italicR238.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…Supramolecular homosynthons, i.e., those between the like functional groups, such as acid–acid and amide–amide, form the basis for crystal structure analysis of simple molecular crystals. Systematic examples of supramolecular heterosynthons (i.e., those between unlike functional groups) are reported, e.g., those involving the most common functional groups − such as acid–pyridine, acid–amide, hydroxyl–pyridine, amino-pyridinium–carboxylate, as well as less common groups such as iodo–nitro, amide–N-oxide, , sulfonamide–N-oxide, OH/NH-pyridine–N-oxide, sulfonamide–lactam/ syn -amide, − ­(Figure ), and halogen bonding. − Heterosynthons between unlike functional groups can be exploited for the design of multicomponent cocrystals, with a different functional coming from each molecule, by keeping an eye on their hydrogen bonding complementarity (heterosynthons). The reported functional groups in crystal engineering (COOH, CONH 2 , pyridine, OH, NH 2 ) between 1990 and 2005 were supplemented with new supramolecular synthons for pharmaceutical cocrystals, such as that for the sulfonamide group, cyclic carboxamides (lactams), and pyridine N-oxides between 2005 and 2020.…”

Insight into Concept and Progress on Pharmaceutical Co-Crystals: An overview

“…20,28 Figure 2 shows the schematic formation of co-crystal. Supramolecular synthons, homo-synthons and hetero-synthons 29 refer to structural units within supramolecules which are formed by intermolecular interaction by known synthetic operations. 30 A comparison between FDA and EMA guidelines of Pharmaceutical co-crystals was discussed in Table 1.…”

Engineering and manufacturing of pharmaceutical co-crystals: a review of solvent-free manufacturing technologies

“…51 There are two types of supramolecular synthons: supramolecular homosynthons, composed of selfcomplementary functional groups and supramolecular heterosynthons composed of different but complementary functional groups. 52 Supramolecular heterosynthons are formed due to non-covalent bonding between different, but complementary functional groups. It is the formation of the supramolecular heterosynthon between APIs that facilitates cocrystal formation.…”

“…Numerous weaker interactions limit cocrystal design and the use of the CSD to identify and overcome any factors, beyond synthon formation, which influences the failure or success of the cocrystal. 52 Through analysing the simple atom, bond and group counts, hydrogen bond donor and acceptor counts, size and shape descriptors, surface area descriptors (with partitioned and charge weighted variants), and molecular electrostatic descriptors and polarity descriptors of cocrystals found in the CSD, one can far more accurately predict the complementary of their cocrystal components. [59][60][61][62] It is possible to filter out any suspicious crystal structures, such as duplicates and incomplete structures from the CSD by using the van de Streek 63 list for best representatives of each unique polymorph, which further simplifies the process.…”