The design of novel metronidazole benzoate structures: exploring stoichiometric diversity

Oliveira, Yara Santiago de; Costa, Wendell Saraiva; Borges, Poliana Ferreira; Santana, Maria Silmara Alves de; Ayala, A. P.

doi:10.1107/s2053229619003838

Cited by 9 publications

(9 citation statements)

References 44 publications

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“…Additional support for cocrystal formation in the BZN-SAL system, as opposed to the salt formation, is provided by analyzing the C−O bond distances of the carboxylic acid group of SAL. 23,52,53 In the BZN-SAL system, the C−O distances of each carboxylic acid group were indicative of a protonated acid (∼1.23 and ∼1.32 Å, ΔD C−O ≈ 0.08 Å) with little deviation among all the forms. These values were in excellent agreement with those expected for a cocrystal, since in salts ΔD C−O is typically less than 0.03.…”

Section: Resultsmentioning

confidence: 97%

“…The weak C11–H11···O2′ interaction aligned API and coformer, forming a supramolecular dimer based on the D 2 2 (7) graph-set motif. , The imidazole···carboxylic supramolecular heterosynthon interaction was characteristic of all polymorphs and was observed in several multicomponent forms leading to the formation of salts and cocrystals. − A search in the CSD for crystalline structures having an imidazole group bonded to the hydroxyl group of a carboxylic acid produced 7998 hits, but only 0.57% resulted in cocrystals. Additional support for cocrystal formation in the BZN-SAL system, as opposed to the salt formation, is provided by analyzing the C–O bond distances of the carboxylic acid group of SAL. ,, In the BZN-SAL system, the C–O distances of each carboxylic acid group were indicative of a protonated acid (∼1.23 and ∼1.32 Å, Δ D C–O ≈ 0.08 Å) with little deviation among all the forms. These values were in excellent agreement with those expected for a cocrystal, since in salts Δ D C–O is typically less than 0.03.…”

Section: Results and Discussionmentioning

confidence: 98%

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Cocrystal Polymorphs and Solvates of the Anti-Trypanosoma cruzi Drug Benznidazole with Improved Dissolution Performance

Bezerra

Pogoda

Perry

et al. 2020

Crystal Growth & Design

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Benznidazole, the primary drug used in Chagas’ disease treatment, has known side effects, which may limit its widespread use. Its low solubility could negatively interfere in the bioavailability, even accentuating the toxic effects. Cocrystals have been extensively used to modify and optimize physicochemical properties, but, as single-component raw materials, they are susceptible to the phenomenon of polymorphism. In this work, we report a trimorphic cocrystal containing a 1:1 ratio of benznidazole and salicylic acid. The crystalline structures of three polymorphs were elucidated by single-crystal X-ray diffraction. Moreover, several isostructural solvates were also synthesized and analyzed. The same carboxylic acid-imidazole supramolecular heterosynthon is present in the four forms, but the main structural feature is an extended column based on amide–amide hydrogen bonds. On the basis of the crystalline structures, the trimorphic system was classified as conformational and packing polymorphism. Furthermore, the dissolution profiles of the stable forms were determined and showed a significant solubility improvement over the raw material.

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Section: Resultsmentioning

confidence: 97%

Section: Results and Discussionmentioning

confidence: 98%

Cocrystal Polymorphs and Solvates of the Anti-Trypanosoma cruzi Drug Benznidazole with Improved Dissolution Performance

Bezerra

Pogoda

Perry

et al. 2020

Crystal Growth & Design

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“…1). 13 BZMD is a nitroimidazole derivative with demonstrated antibacterial and antiprotozoal activity, effectively treating infections such as trichomoniasis, amebiasis, vaginosis, and gingivitis. 14,15 The crystal structures of the BZMD cocrystal polymorphs were determined using single-crystal X-ray diffraction (SCXRD) and characterized using powder X-ray diffraction (PXRD) and optical microscopy.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism in cocrystals of metronidazole benzoate

2023

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“…[6] If the composition of pharmaceutical cocrystals is carefullys elected, it can improve the physicochemical properties of ad rug without compromising its therapeutic benefits. [7][8][9][10][11] New drugs recently introduced into the market,S teglatro,amolecular cocrystal of ertugliflozin and l-pyroglutamic acid, [12] Odomzol,acocrystal of soni-degib and phosphoric acid, [13] Suglat,acocrystal of ipragliflozin and l-proline, [14] andE ntresto1,acocrystal of valsartan and sacubitril, [15] are straightforwarde videncec onfirming the powero ft his approach.…”

Section: Introductionmentioning

confidence: 99%

Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

Dudek

Śniechowska

Wróblewska

et al. 2020

Chemistry A European J

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Aw ell-defineda nd stable "AB" binarys ystem in the presence of "C" ac rystalline synthon ground in ab all mill undergoes selective transformation in the solid state according to the equation AB + C!AC + B. When the amount of Ci si ncreased two times then the equation AB + 2C! AC + BC is valid. The other variants are more complex. The pathway BC + Ai sa llowed and leads to the AC andBproducts. The pathway AC + Bi sn ot preferred, and no transformation is observed. These non-obviouscorrelations were observed for cocrystal of barbituric acid (BA):thiobarbituric acid (TBA) recently reported by Shemchuk et al. (Chem. Commun. 2016, 52,1 1815-11818) in the presence of 1-hydroxy-4,5-dimethyl-imidazole 3-oxide (HIMO). This synthon shows high affinity for the BA 0.5 TBA 0.5 cocrystal as well for its individual components,B Aa nd TBA. Single-quantum,d ouble-quantum (SQ-DQ) 2D 1 Hv ery fast MAS NMR with as pinning rate of 60 kHz was employed as ab asic and most diagnostic tool for the study of cocrystals transformations. Analysis of the experimental data was supported by theoretical calculations, including computation of the stabilization energy, E stab ,d efined as the energy difference between the energy of ac ocrystal and the sum of the energies of particular components in the respective stoichiometric ratios. Twom echanisms of synthon replacement have been proposed. Pathway 1a ssumes ac oncerted mechanism of substitution. In this approach, synthon attack is synchronized in time with the departure of one of the components of the binary system.P athway 2i mplies an on-concerted process, with an intermediate stage in whicht hree separate components are present.E vidence suggesting ap reference for Pathway2 is shown.

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The design of novel metronidazole benzoate structures: exploring stoichiometric diversity

Abstract: ÁC 7 H 5 O 4 À , and BZMD-3,5-dihydroxybenzoic acid (3/1), 3C 13 H 13 N 3 O 4 ÁC 7 H 6 O 4 , and their crystalline structures elucidated, confirming the robustness of the selected synthon.

Cited by 9 publications

References 44 publications

Cocrystal Polymorphs and Solvates of the Anti-Trypanosoma cruzi Drug Benznidazole with Improved Dissolution Performance

Cocrystal Polymorphs and Solvates of the Anti-Trypanosoma cruzi Drug Benznidazole with Improved Dissolution Performance

Polymorphism in cocrystals of metronidazole benzoate

Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

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