- Mechanochemistry for "no solvent, no base" preparation of hydantoin-based active pharmaceutical ingredients: Nitrofurantoin and dantrolene
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The eco-compatible, base- and waste-free, energy-efficient, low-environmental-impact, gram-scale, mechanochemical preparation of marketed drugs such as nitrofurantoin (Furantin), dantrolene (Dantrium) and their structurally related derivatives is herein reported. Not a drop of organic solvent was used for the entire process and high yields of pure compounds were obtained without post-reaction work-up. Hydrazones were stable in the presence of water and gaseous HCl, formed as by-products during the synthesis. Comparative mechanochemical experiments were performed using diverse milling devices and jar materials, the active pharmaceutical ingredients were analyzed by PXRD and green metrics are calculated.
- Colacino, Evelina,Porcheddu, Andrea,Halasz, Ivan,Charnay, Clarence,Delogu, Francesco,Guerra, Ruben,Fullenwarth, Julien
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- Nitrofuran drugs beyond redox cycling: Evidence of Nitroreduction-independent cytotoxicity mechanism
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Nitrofurans (5-nitro-2-hydrazonylfuran as pharmacophore) are a group of widely used antimicrobial drugs but also associated to a variety of side effects. The molecular mechanisms that underlie the cytotoxic effects of nitrofuran drugs are not yet clearly understood. One-electron reduction of 5-nitro group by host enzymes and ROS production via redox cycling have been attributed as mechanisms of cell toxicity. However, the current evidence suggests that nitrofuran ROS generation by itself is uncapable to explain the whole toxic effects associated to nitrofuran consumption, proposing a nitro-reduction independent mechanism of toxicity. In the present work, a series of nitrated and non-nitrated derivatives of nitrofuran drugs were synthesized and evaluated in vitro for their cytotoxicity, ROS-producing capacity, effect on GSH-S-transferase and antibacterial activity. Our studies showed that in human cells non-nitrated derivatives were less toxic than parental drugs but, unexpectedly preserved the ability to generate intracellular ROS in similar amounts to nitrofurans despite not entering into a redox cycle mechanism. In addition, some non-nitrated derivatives although being uncapable to generate ROS exhibited the highest cell toxicity among all derivatives. Inhibition of cytosolic glutathione-S-transferase activity by some derivatives was also observed. Finally, only nitrofuran derivatives displayed antibacterial effect. Results suggest that the combined 2-hydrazonylfuran moiety, redox cycling of 5-nitrofuran, and inhibitory effects on antioxidant enzymes, would be finally responsible for the toxic effects of the studied nitrofurans on mammalian cells.
- Gallardo-Garrido,Cho,Cortés-Rios,Vasquez,Pessoa-Mahana,Araya-Maturana,Pessoa-Mahana,Faundez
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- Synthetic method of nitrofurantoin
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The invention provides a synthetic method of nitrofurantoin. The synthetic method comprises the following steps: reacting aminohydantoin hydrochloride as a substrate with 5-nitrofuraldehyde diethyl ester to obtain a 1-[[(5-nitro-2-furanyl) methylene] amino]-2,4-imidazolidinedione crude product; and then mixing the 1-[[(5-nitro-2-furanyl) methylene] amino]-2,4-imidazolidinedione crude product and N,N-dimethylformamide in proportion, stirring for 40-60 minutes at a room temperature, performing pressure filtering treatment to obtain a filtrate, stirring the filtrate for 30 minutes in a crystallizing pan, dropwise adding purified water, then filtering to obtain a filter cake and purifying the filter cake to obtain the nitrofurantoin. The synthetic method of the nitrofurantoin, provided by theinvention, has the benefits that as acid anhydride is not required to be used, the defect in the prior art that a lot of nitrogen oxide gas is produced is overcome, and the synthesis difficulty is reduced; and moreover, through the synthetic method, the content of impurities in the finally-prepared nitrofurantoin is significantly reduced, so that the synthetic method can adapt to industrial mass production.
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Paragraph 0020; 0021; 0023; 0024
(2018/09/12)
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- Process for formulating a synthetic drug for use in animal feed, and resulting formulation
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A method of formulating a synthetic drug for use in animal feed, for the purpose of reducing carry-over of the synthetic drug to subsequent lots of animal feed in the feed mill.
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- Process for preparing microcapsules in a liquid vehicle
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The invention relates to a process for preparing microcapsules in a liquid vehicle, allowing to microencapsulate both water soluble and water insoluble substances, using either ionic or non-ionic systems, in which the membrane enclosing the core of the microcapsules is formed by a polymer selected from the group of the phthalates, and more particularly by hydroxypropylmethylcellulose phthalate.
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