Abstract:To overcome the issue of multidrug resistant (MDR) microbes, the exploration of ways to improve the antimicrobial efficiency of existing antibiotics is one of the promising approaches. In search of synthons with higher efficiency, in current investigations, cocrystal and amorphous salt of levofloxacin hemihydrate (LEV) were developed with phthalimide (PTH) and caffeic acid (CFA). New materials were characterized with the help of FT-IR, Raman spectroscopy, powder X-ray diffraction (PXRD), differential scanning … Show more
“…Based on the “W” profile of the phase diagrams in Figure 1 , the formation of the LF–DHBA multicomponent system occurred in the (1:1) molar ratio, which is shown by the melting point between the two eutectic points. This stoichiometric ratio was also found in the reaction of LF with other organic compounds, namely, phthalimide [ 21 ], caffeic acid [ 21 ], and citric acid [ 24 ].…”
Section: Resultsmentioning
confidence: 61%
“…Solid multicomponent systems of fluoroquinolone with other drugs [ 1 , 2 , 3 , 19 ] and excipients [ 20 ] have been reported before. In addition, the combination of LF with phthalimide and caffeic acid has recently been reported to increase potency [ 21 ], as have other antibiotic solid multicomponent systems, such as azithromycin with paracetamol [ 22 ] and cefixime [ 23 ]. Furthermore, we recently found that salt from LF with the antioxidant citric acid can improve stability and increase potency two-fold [ 24 ].…”
Section: Introductionmentioning
confidence: 99%
“…Moreover, microbial tests are conducted to investigate antibiotic potency improvement. These findings may enrich the scientific information in the chemistry and pharmaceutical fields to strengthen solid-state arrangement as a strategy for antibiotic development, including the development of LF [ 19 , 20 , 21 , 22 , 23 , 24 ].…”
Recently, solid-state engineering has become a promising approach to improving the stability and potency of antibiotics. Levofloxacin (LF) is a broad-spectrum fluoroquinolone antibiotic marketed in solid and solution dosage forms. However, this substance forms solid hydrates under ambient conditions and degrades due to lighting, which may change its solid properties and dose. In addition, resistance cases have been reported due to long-time antibiotic usage. This research aims to allow LF to react with antioxidant dihydroxybenzoic acid (DHBA), which has low antimicrobial activity, to produce a more stable compound under water and lighting conditions and improve LF’s potency. The experiment begins with a screening to select potential DHBA isomers that can react with LF and predict the stoichiometric ratio using phase diagrams, which show that 2,6-DHBA and 3,5-DHBA are prospective antioxidants that can react with LF in a (1:1) molar ratio. Multicomponent systems are prepared by dissolving the LF–DHBA mixture in (1:1) ethanol–methanol (95% grade) and evaporating it. Then, the new solid phase formation is confirmed by thermal analysis and powder X-ray diffractometry. Next, infrared spectrophotometry and neutron magnetic resonance analyses are used to identify the LF–DHBA’s interactions. Finally, single-crystal X-ray diffractometry is used to solve the three-dimensional structure of the multicomponent system. We then conduct a hygroscopicity and stability test followed by a lighting and potency test using the microdilution method. Our data reveal that both reactions produce salts, which are named LF-26 and LF-35, respectively. Structurally, LF-26 is found in an anhydrous form with a triclinic crystal packing, while LF-35 is a hemihydrate in a monoclinic system. Afterward, both salts are proven more stable regarding water adsorption and UV lighting than LF. Finally, both multicomponent systems have an approximately two-fold higher antibiotic potency than LF. LF-26 and LF-35 are suitable for further development in solid and liquid dosage formulations, especially LF-35, which has superior stability compared with LF-26.
“…Based on the “W” profile of the phase diagrams in Figure 1 , the formation of the LF–DHBA multicomponent system occurred in the (1:1) molar ratio, which is shown by the melting point between the two eutectic points. This stoichiometric ratio was also found in the reaction of LF with other organic compounds, namely, phthalimide [ 21 ], caffeic acid [ 21 ], and citric acid [ 24 ].…”
Section: Resultsmentioning
confidence: 61%
“…Solid multicomponent systems of fluoroquinolone with other drugs [ 1 , 2 , 3 , 19 ] and excipients [ 20 ] have been reported before. In addition, the combination of LF with phthalimide and caffeic acid has recently been reported to increase potency [ 21 ], as have other antibiotic solid multicomponent systems, such as azithromycin with paracetamol [ 22 ] and cefixime [ 23 ]. Furthermore, we recently found that salt from LF with the antioxidant citric acid can improve stability and increase potency two-fold [ 24 ].…”
Section: Introductionmentioning
confidence: 99%
“…Moreover, microbial tests are conducted to investigate antibiotic potency improvement. These findings may enrich the scientific information in the chemistry and pharmaceutical fields to strengthen solid-state arrangement as a strategy for antibiotic development, including the development of LF [ 19 , 20 , 21 , 22 , 23 , 24 ].…”
Recently, solid-state engineering has become a promising approach to improving the stability and potency of antibiotics. Levofloxacin (LF) is a broad-spectrum fluoroquinolone antibiotic marketed in solid and solution dosage forms. However, this substance forms solid hydrates under ambient conditions and degrades due to lighting, which may change its solid properties and dose. In addition, resistance cases have been reported due to long-time antibiotic usage. This research aims to allow LF to react with antioxidant dihydroxybenzoic acid (DHBA), which has low antimicrobial activity, to produce a more stable compound under water and lighting conditions and improve LF’s potency. The experiment begins with a screening to select potential DHBA isomers that can react with LF and predict the stoichiometric ratio using phase diagrams, which show that 2,6-DHBA and 3,5-DHBA are prospective antioxidants that can react with LF in a (1:1) molar ratio. Multicomponent systems are prepared by dissolving the LF–DHBA mixture in (1:1) ethanol–methanol (95% grade) and evaporating it. Then, the new solid phase formation is confirmed by thermal analysis and powder X-ray diffractometry. Next, infrared spectrophotometry and neutron magnetic resonance analyses are used to identify the LF–DHBA’s interactions. Finally, single-crystal X-ray diffractometry is used to solve the three-dimensional structure of the multicomponent system. We then conduct a hygroscopicity and stability test followed by a lighting and potency test using the microdilution method. Our data reveal that both reactions produce salts, which are named LF-26 and LF-35, respectively. Structurally, LF-26 is found in an anhydrous form with a triclinic crystal packing, while LF-35 is a hemihydrate in a monoclinic system. Afterward, both salts are proven more stable regarding water adsorption and UV lighting than LF. Finally, both multicomponent systems have an approximately two-fold higher antibiotic potency than LF. LF-26 and LF-35 are suitable for further development in solid and liquid dosage formulations, especially LF-35, which has superior stability compared with LF-26.
“…The solid-state arrangement may improve a wide range of APIs' physicochemical properties, including their solubility, stability, flowability, and permeability. Many also enhance activities and performances, as recently reported [30,[51][52][53][54][55]. However, the first benefit is solubility enhancement, which is stated to be the most crucial characteristic of the particles.…”
Recently, non-covalent reactions have emerged as approaches to improve the physicochemical properties of active pharmaceutical ingredients (API), including antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs). This review aimed to present and discuss the non-covalent reaction products of antibiotics, including salt and neutral multi-component solid forms, by framing their substituents and molar ratios, manufacturing techniques, characterization methods, benefits, potency changes, and toxicity, and is completed with an analysis of the development of computational models used in this field. Based on the data, NSAIDs are the most-developed drugs in multi-component system preparations, followed by antibiotics, i.e., antituberculosis and fluoroquinolones. They have reacted with inorganic elements, excipients, nutraceuticals, natural products, and other drugs. However, in terms of treatments for common infections, fluoroquinolones are more frequently used. Generally, NSAIDs are acquired on an over-the-counter basis, causing inappropriate medication. In addition, the pKa differences between the two groups of medicine offer the potential for them to react non-covalently. Hence, this review highlights fluoroquinolone–NSAID multi-component solid systems, which offer some benefits. These systems can increase patient compliance and promote the appropriate monitoring of drug usage; the dual drug multi-component solids have been proven to improve the physicochemical properties of one or both components, especially in terms of solubility and stability. In addition, some reports show an enhancement of the antibiotic activity of the products. However, it is important to consider the possibility of activity changes, interaction, and toxicity when using drug combinations. Hence, these aspects also are discussed in this review. Finally, we present computational modeling, which has been utilized broadly to support multi-component system designs, including coformer screening, preparation methods, and structural modeling, as well as to predict physicochemical properties, potency, and toxicity. This integrated review is expected to be useful for further antibiotic–NSAID multi-component system development.
“…A drug-drug cocrystal of LV and metacetamol (LV:AMAP) was produced via cogrinding and heating method for full dehydration, that surpassed the parent drugs physiochemically, especially during dissolution tests, hygroscopicity, physical and humidity stability ( Figure 6 (I, II)) in addition to photostability, due to hydrogen bonds formation between the hydroxyl group of metacetamol and the N-methyl piperazine group of LV [ 41 ]. Meanwhile, another drug-drug of LV and phthalimide (LV:PTH) has recently been reported with better dissolution rate and antibacterial efficiency in-vitro [ 42 ] Figure 6 (I) Water sorption/desorption isotherm of Levofloxacin hemihydrate and Levofloxacin:Metacetamol (LVFX:AMAP) cocrystal at 25 °C. (II) XRPD patterns of (a) Levofloxacin hemihydrate marked with blue circles and (b) LVFX:AMAP cocrystal marked with pink square, stored at each stressed condition for 4 weeks.…”
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