Stability and Antibiotic Potency Improvement of Levofloxacin by Producing New Salts with 2,6- and 3,5-Dihydroxybenzoic Acid and Their Comprehensive Structural Study

Abstract

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 Benefits and Challenges of Antibiotics–Non-Steroidal Anti-Inflammatory Drugs Non-Covalent Reaction

“…Both ionic and non-ionic reactions of the fluoroquinolone group, i.e., ciprofloxacin and levofloxacin, with some substituents increase the solubility of these compounds [6,9], as well as showing increased stability towards humidity and light, which is the main advantage of these systems. For example, the combination of levofloxacin-citric acid [6] and levofloxacin-dihydroxybenzoic acid [7], and ciprofloxacin with cyclodextrin and cucurbit (7)-uril (CB7) improves photostability up to three-fold [27].…”

“…One of the common strategies is reacting antibiotics with inorganic chemicals (metals/halogens) or organic compounds, such as other drugs, excipients, nutraceuticals, etc. Moreover, in addition to improving the solid characteristics, experiments have shown that fluoroquinolone antibiotics can enhance potency by changing the polarity and penetrability of the bacteria's membrane through non-covalent reactions [6,7].…”

“…Furthermore, combining both medicines to enhance patient convenience and compliance and improve their physicochemical properties without changing their activity is an exciting prospect. This effort is supported by the fact that many NSAIDs tend to be acidic [8]; inversely, many antibacterial compounds are basic [6,7], or they may be amphoteric [6][7][8]. Hereafter, many antibiotics-NSAID combinations are feasible, resulting in non-covalent interactions and the production of multi-component solid systems.…”

“…After this process, reliable analysis methods can be used to confirm the new solid phase formation. Firstly, the thermal analysis may be performed using an electrothermal measurement [6,7], thermogravimetry analysis (TG) [18,19], differential thermal analysis (DTA) [19,20], and differential scanning calorimetry (DSC) [6,7,11,12,21] can be used to identify a new phase. An endothermic curve and the melting point may represent the water released from the hydrate system.…”

“…An endothermic curve and the melting point may represent the water released from the hydrate system. Meanwhile, recrystallization is shown by an exothermic curve and degradation, with irregular exothermic curves [6,7,20]. Therefore, a new structure's thermogram has a different pattern from a single component or physical mixture.…”