The design of novel metronidazole benzoate structures: exploring stoichiometric diversity

Abstract

The use of supramolecular synthons as a strategy to control crystalline structure is a crucial factor in developing new solid forms with physicochemical properties optimized by design. However, to achieve this objective, it is necessary to understand the intermolecular interactions in the context of crystal packing. The feasibility of a given synthon depends on its flexibility to combine the drug with a variety of coformers. In the present work, the imidazole–hydroxy synthon is investigated using as the target molecule benzoylmetronidazole [BZMD; systematic name 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl benzoate], whose imidazole group seems to be a suitable acceptor for hydrogen bonds. Thus, coformers with carboxylic acid and phenol groups were chosen. According to the availability of binding sites presented in the coformer, and considering the proposed synthon and hydrogen-bond complementarity as major factors, different drug–coformer stoichiometric ratios were explored (1:1, 2:1 and 3:1). Thirteen new solid forms (two salts and eleven cocrystals) were produced, namely BZMD–benzoic acid (1/1), C13H13N3O4 C7H6O2, BZMD– -naphthol (1/1), C13H13N3O4 C10H8O, BZMD–4-methoxybenzoic acid (1/1), C13H13N3O4 C8H8O3, BZMD–3,5-dinitrobenzoic acid (1/1), C13H13N3O4 C7H4N2O6, BZMD–3-aminobenzoic acid (1/1), C13H13N3O4 C7H7NO2, BZMD–salicylic acid (1/1), C13H13N3O4 C7H6O3, BZMD–maleic acid (1/1) {as the salt 1-[2-(benzoyloxy)- ethyl]-2-methyl-5-nitro-1H-imidazol-3-ium 3-carboxyprop-2-enoate}, C13H14- N3O4 + C4H3O4 , BZMD–isophthalic acid (1/1), C13H13N3O4 C8H6O4, BZMD– resorcinol (2/1), 2C13H13N3O4 C6H6O2, BZMD–fumaric acid (2/1), C13H13N3O4 0.5C4H4O4, BZMD–malonic acid (2/1), 2C13H13N3O4 C3H2O4, BZMD–2,6-dihydroxybenzoic acid (1/1) {as the salt 1-[2-(benzoyloxy)ethyl]-2- methyl-5-nitro-1H-imidazol-3-ium 2,6-dihydroxybenzoate}, C13H14N3O4 + C7H5O4 , and BZMD–3,5-dihydroxybenzoic acid (3/1), 3C13H13N3O4 C7H6O4, and their crystalline structures elucidated, confirming the robustness of the selected synthon.