The design of novel metronidazole benzoate structures: exploring stoichiometric diversity. Issue 5 (8th April 2019)

• Record Type: Journal Article
• Authors: Santiago de Oliveira, Yara; Saraiva Costa, Wendell; Ferreira Borges, Poliana; Silmara Alves de Santana, Maria; Ayala, Alejandro Pedro
• Is Part Of: Acta crystallographica. Volume 75:Issue 5(2019)
• Page Start: 483
• Page End: 495
• Publication Date: 2019-04-08
• Subjects: metronidazole benzoate -- crystal engineering -- cocrystal -- salt -- physicochemical -- crystal structure -- pharmaceutical -- API -- cocrystal; Crystallography -- Periodicals; Crystals -- Periodicals; 548.3
• DOI: 10.1107/S2053229619003838
• Languages: English
• ISSNs: 2053-2296

Abstract

Abstract : The imidazole–hydroxy synthon was explored by combining benzoylmetronidazole with several coformers containing phenol and carboxylic acid groups. Based on a rational design strategy, two salts and eleven cocrystals were obtained, with predefined stoichiometries (1:1, 2:1 and 3:1). 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‐1 H ‐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), C13 H13 N3 O4 ·C7 H6 O2, BZMD–β‐naphthol (1/1), C13 H13 N3 O4 ·C10 H8 O, BZMD–4‐methoxybenzoic acid (1/1), C13 H13 N3 O4 ·C8 H8 O3, BZMD–3, 5‐dinitrobenzoic acid (1/1), C13 H13 N3 O4 ·C7 H4 N2 O6, BZMD–3‐aminobenzoic acid (1/1), C13 H13 N3 O4 ·C7 H7 NO2, BZMD–salicylic acid (1/1), C13 H13 N3 O4 ·C7 H6 O3, BZMD–maleic acid (1/1) {as the salt 1‐[2‐(benzoyloxy)ethyl]‐2‐methyl‐5‐nitro‐1 H ‐imidazol‐3‐ium 3‐carboxyprop‐2‐enoate}, C13 H14 N3 O4 + ·C4 H3 O4 −, BZMD–isophthalic acid (1/1), C13 H13 N3 O4 ·C8 H6 O4, BZMD–resorcinol (2/1), 2C13 H13 N3 O4 ·C6 H6 O2, BZMD–fumaric acid (2/1), C13 H13 N3 O4 ·0.5C4 H4 O4, BZMD–malonic acid (2/1), 2C13 H13 N3 O4 ·C3 H2 O4, BZMD–2, 6‐dihydroxybenzoic acid (1/1) {as the salt 1‐[2‐(benzoyloxy)ethyl]‐2‐methyl‐5‐nitro‐1 H ‐imidazol‐3‐ium 2, 6‐dihydroxybenzoate}, C13 H14 N3 O4 + ·C7 H5 O4 −, and BZMD–3, 5‐dihydroxybenzoic acid (3/1), 3C13 H13 N3 O4 ·C7 H6 O4, and their crystalline structures elucidated, confirming the robustness of the selected synthon.