A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics

Abstract

β-lactam antibiotics, such as penicillin share a very unstable chemical structure. In water-based solutions, such as those used for clinical applications, the β-lactam ring is readily opened due to a nucleophilic or electrophilic attack, leading to the loss of antimicrobial activity. Since the achievement and maintenance of optimum therapeutic levels of β-lactam antibiotics is critical for the resolution of many infectious clinical situations, and to avoid antibiotic resistance generation, the design of new non-aqueous dosage forms is urgent. Recently, natural deep eutectic solvents (NADES) have emerged as alternative non-toxic and non-aqueous solvents for different biomedical applications. In this work, we formulated and characterized a NADES composed by betaine and urea (BU). Using this solvent, we evaluated the stability of clavulanic acid (CLV) and imipenem (IMP) and characterized their antimicrobial activities calculating the minimal inhibitory concentration. Characterization of BU solvent by infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that the obtained solvent has a microstructure mainly based on hydrogen bonding interactions and water addition strongly affects its dynamic. The stability of β-lactam antibiotic IMP and CLV using this solvent was increased by 7 fold and 2.5 fold respectively compared to water when analysed seven days after being dissolved. Microbiological assays showed that antibacterial activity at day seven was significantly decreased for both CLV and IMP when dissolved in water, while no change in their antibacterial properties was observed when antibiotics were dissolved in BU. The increased stability of IMP and CLV in BU may be related to the inert behaviour of the solvent and the higher dynamic restriction that helps antibiotics to maintain a more stable conformation. These data suggest the potential use of BU as a solvent to prevent degradation of β-lactam antibiotics.

Natural Deep Eutectic Solvents for the Extraction of Bioactive Steroidal Saponins from Dioscoreae Nipponicae Rhizoma

“…DESs are composed of a mixture consisting of hydrogen bond acceptors (HBAs) with hydrogen bond donors (HBDs), which are able to form intermolecular hydrogen bonds and van der Waals interactions. Owing to their superior properties, such as negligible volatility, non-flammability, adjustable viscosity, cost-effectiveness, and facile production processes, DESs have been extensively used in many different fields such as pharmaceuticals, catalysis, electrochemistry, and extractions [13][14][15][16][17]. When DESs were prepared by mixing two or more naturally occurring and biodegradable components, they were called natural deep eutectic solvents (NADESs).…”

Extraction of Alkaloids from Coptidis Rhizoma via Betaine‐Based Deep Eutectic Solvents

“…DESs show many advantageous properties, such as easy to produce, non‐flammable, non/low‐toxic, relatively high solubility, biocompatible and biodegradable . These properties enable DESs to be used in various fields, such as in pharmaceutics, synthesis of porous materials, electrochemistry and extraction processes . The most common DESs are based on choline chloride, which is an inexpensive and easily accessible compound.…”

Band-Gap Energies of Choline Chloride and Triphenylmethylphosphoniumbromide-Based Systems

“…for the indirect band gap, and Y = (2.303 × absorbance × X) 2 (8) for the direct band gap. By employing Equations (5) and 7or (8), it is possible to obtain for each system analyzed by UV-VIS the plots corresponding to the indirect (Equation 7) and direct (Equation 8 The value of Eg was employed to convert UV-VIS data acquired through direct measurements into energy values for the X axis, employing the formula X = Eg/absorbance 5)…”

“…These organic mixtures are named deep eutectic systems or, sometimes, deep eutectic solvents (DESs) and are exploitable in several fields. To cite only some applications of DESs, they have been proposed as new solvents [1][2][3][4], catalysts [5], electrodeposition agents [6,7], and stabilizing agents for antibiotics [8].…”