The design of novel metronidazole benzoate structures: exploring stoichiometric diversity

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-β-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}, C₁₃H₁₄N₃O₄⁺·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.