Improving the Solubility, Dissolution, and Bioavailability of Metronidazole via Cocrystallization with Ethyl Gallate

Li, Jinhui; Hao, Xinghui; Wang, Chenguang; Liu, Haiyan; Liu, Lianchao; He, Xin; Sun, Changquan Calvin

doi:10.3390/pharmaceutics13040546

Cited by 15 publications

(16 citation statements)

References 41 publications

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“…During the past 20 years, cocrystallization has proved to be an effective approach to tailor physicochemical properties of active pharmaceutical ingredients (APIs) through reliable supramolecular synthons based on various hydrogen-bonding interactions. − Solubility, dissolution, and bioavailability of APIs could be greatly enhanced by the formation of cocrystals. − Moreover, pharmaceutical cocrystals could be endowed with superior humidity, − thermal and photo stability. − Recently, some pharmaceutical cocrystals showing potential extended release properties have been prepared, which indicated that cocrystallization could be a new strategy for achieving extended release of APIs. − Like single APIs, however, polymorphism in pharmaceutical cocrystals is also quite common and the polymorphs of cocrystals can display significantly different properties. − Therefore, polymorphism is an important consideration in the development of pharmaceutical cocrystals. In view of the fact that a high proportion of drugs are available in racemic form, the preparation of cocrystal polymorphs based on racemic APIs should be an important topic.…”

Section: Introductionmentioning

confidence: 99%

Two Cocrystal Polymorphs of Palmatine Chloride with Racemic Hesperetin

Zhang

Liu

et al. 2021

Crystal Growth & Design

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Two polymorphic cocrystals of palmatine chloride with racemic hesperetin (Form I and Form II) have been prepared and investigated systematically. Crystal structure analysis reveals that reliable O-H•••Cl − hydrogen-bonding interactions exist in both cocrystal polymorphs. However, similar O-H•••Cl − hydrogen-bonding interactions resulted in completely different supramolecular arrangements. Cocrystal Forms I and II are non-hygroscopic and show high stability against temperature, humidity, and light. The cocrystal formation greatly lowers the solubility of palmatine chloride, while the solubility of hesperetin has been improved. Sustained release of palmatine chloride and enhanced release of hesperetin from two cocrystal polymorphs in pure water were achieved.

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Section: Introductionmentioning

confidence: 99%

Two Cocrystal Polymorphs of Palmatine Chloride with Racemic Hesperetin

Zhang

Liu

et al. 2021

Crystal Growth & Design

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“…Metronidazole (MTZ) is an effective antiprotozoal and antibiotic medicine, which is on the list of essential medicines worldwide [31]. It is used for the treatment of infections caused by anaerobic bacteria and various protozoan infections including giardiasis and trichomoniasis.…”

Section: Introductionmentioning

confidence: 99%

Fabrication of pH-Responsive Chitosan/Polyvinylpyrrolidone Hydrogels for Controlled Release of Metronidazole and Antibacterial Properties

Feyissa

Edossa

Bedasa

et al. 2023

International Journal of Polymer Science

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This research focused on preparing hydrogels with controlled drug release properties to control gastrointestinal tract bacterial infection. Chitosan (CS) and polyvinylpyrrolidone (PVP) were used as the base polymers, with the CS component crosslinked by glutaraldehyde for hydrogel preparation using the solution casting technique. The effect of varying glutaraldehyde content in the hydrogels was characterized by the extent of swelling in simulated physiological fluids of pH 1.2, 6.8, and 7.4; the development of porosity; and gel fraction. Functional groups and covalent and hydrogen bonds formed, thermal stability, phase structure, and morphology were characterized by Fourier-transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, and scanning electron microscopy. The results show that the components in the hydrogels have good compatibility and formed honeycomb-like structures. In vitro studies confirmed that the hydrogels have good biodegradability at pH 7.4. Based on these properties, a CS/PVP hydrogel of the ratio of 60 : 40 crosslinked with 600 μL glutaraldehyde was selected for the in-situ loading of 200 mg of the drug metronidazole (MTZ). The hydrogel was characterized for cumulative drug release in the simulated physiological fluids and drug release kinetics using different models and for its antibacterial activity. The best-fit Korsmeyer–Peppas model suggests that MTZ release followed diffusion and swelling-controlled time-dependent non-Fickian transport related to hydrogel erosion. This hydrogel displays enhanced antimicrobial activity against Staphylococcus aureus, and Escherichia coli showed substantial inhibition zones indicating the produced CS/PVP hydrogels are promising candidates for controlled drug release applications.

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“…The concept of supramolecular synthon or hydrogen-bonded building units was later developed by Desiraju . Cocrystal formation has become a powerful tool for enhancing key pharmaceutical properties, including stability, dissolution, , bioavailability, and manufacturability in the industry. Other applications, such as taste masking and toxicity reduction, have also been reported.…”

Section: Introductionmentioning

confidence: 99%

Bioavailability-Enhancing Cocrystals: Screening, In Vivo Predictive Dissolution, and Supersaturation Maintenance

Chen

Huang

Zhang

et al. 2022

Crystal Growth & Design

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Cocrystal engineering for bioavailability enhancement is still a serendipitous process, which requires systematic solution crystallization, in vivo predictive dissolution, and biopharmaceutical simulation. The purpose of this study is to improve bioavailability through cocrystal engineering, with a focus on understanding the mechanism of supersaturation maintenance during dissolution. BI 639667 is a poorly soluble and fast precipitating compound. The ability of its cocrystal with salicylic acid (SA) to maintain supersaturation was assessed using a modified two-step dissolution method, and its bioavailability was determined in rats. Biopharmaceutical simulation and dissolution modeling were performed to predict the in vivo performance in humans. Conductor-like screening model for realistic solvents and molecular dynamics (MD) simulation were used to study the interactions between the active pharmaceutical ingredient (API) and coformers in vacuum and aqueous media, respectively. A high melting cocrystal with SA, crystallized in dichloromethane, showed moderate solubility enhancement with prolonged supersaturation during dissolution, which was able to enhance bioavailability with reduced C max , compared to amorphous dispersion. The radial distribution function (RDF) between the API and selected coformers was calculated using MD simulation to determine the mean distance between the API and coformer molecules in aqueous media. The result suggests that SA could better compete against water for interactions with the API and could penetrate the API molecular clusters to inhibit nucleation. Thus, the RDF by MD simulation may be used to determine the disruptive effect of water on the interaction between the API and coformer and improve cocrystal engineering for bioavailability enhancement.

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Improving the Solubility, Dissolution, and Bioavailability of Metronidazole via Cocrystallization with Ethyl Gallate

Cited by 15 publications

References 41 publications

Two Cocrystal Polymorphs of Palmatine Chloride with Racemic Hesperetin

Two Cocrystal Polymorphs of Palmatine Chloride with Racemic Hesperetin

Fabrication of pH-Responsive Chitosan/Polyvinylpyrrolidone Hydrogels for Controlled Release of Metronidazole and Antibacterial Properties

Bioavailability-Enhancing Cocrystals: Screening, In Vivo Predictive Dissolution, and Supersaturation Maintenance

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