Enhancing acetaminophen solubility and stability using an aqueous betaine chloride–acetic acid natural deep eutectic solvent: experimental and mechanistic insights
- 1Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue University Hue City Vietnam
Abstract
Improving the aqueous solubility of moderately soluble drugs using safe and sustainable solvent systems remains an important challenge in pharmaceutical formulation. In this study, a series of aqueous natural deep eutectic solvents (NADESs) were systematically designed and evaluated to enhance the solubility, stability, and biocompatibility of acetaminophen (ACP). The effects of hydrogen bond donor type, hydrogen bond acceptor type, molar ratio, and NADES concentration were investigated to identify the optimal formulation. Among the tested systems, the aqueous betaine chloride–acetic acid NADES (BeCl–Ace) at a molar ratio of 1 : 4 and a concentration of 70% exhibited the highest solubilization capacity, increasing ACP solubility by 25.28 and 22.14-fold at 25 and 37 °C, respectively, compared with water. Computational analyses based on electrostatic potential mapping, binding energy calculations, and interaction region indicator analysis revealed that the enhanced solubility originates from cooperative hydrogen bonding, electrostatic attraction, and van der Waals interactions between ACP and the BeCl–Ace components, particularly BeCl. In addition, the selected NADES formulation significantly improved ACP stability under thermal stress, retaining 89.13% of the initial drug content after 30 days at 37 °C, compared with 70.20% in water. Cytotoxicity evaluation on HEK-293A cells further confirmed good biocompatibility, with cell viability remaining above 92% across the tested concentration range. These findings indicate that aqueous BeCl–Ace NADESs represent a promising and sustainable solvent system for improving ACP formulation performance.
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BibTeX
@article{tran2026enhancing,
title = {{Enhancing acetaminophen solubility and stability using an aqueous betaine chloride–acetic acid natural deep eutectic solvent: experimental and mechanistic insights}},
author = {The-Huan Tran and Thao Nhu Thi Nguyen and Quynh Phuong Nguyen and Nhan Trong Le and Hoai Thi Nguyen},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra05672e},
url = {https://europepmc.org/article/PMC/PMC13655794},
note = {CC BY},
}
RIS
TY - JOUR
TI - Enhancing acetaminophen solubility and stability using an aqueous betaine chloride–acetic acid natural deep eutectic solvent: experimental and mechanistic insights
AU - The-Huan Tran
AU - Thao Nhu Thi Nguyen
AU - Quynh Phuong Nguyen
AU - Nhan Trong Le
AU - Hoai Thi Nguyen
PY - 2026
DA - 2026/10/12
JO - RSC advances
DO - 10.1039/d6ra05672e
UR - https://europepmc.org/article/PMC/PMC13655794
AB - Improving the aqueous solubility of moderately soluble drugs using safe and sustainable solvent systems remains an important challenge in pharmaceutical formulation. In this study, a series of aqueous natural deep eutectic solvents (NADESs) were systematically designed and evaluated to enhance the solubility, stability, and biocompatibility of acetaminophen (ACP). The effects of hydrogen bond donor type, hydrogen bond acceptor type, molar ratio, and NADES concentration were investigated to identify the optimal formulation. Among the tested systems, the aqueous betaine chloride–acetic acid NADES (BeCl–Ace) at a molar ratio of 1 : 4 and a concentration of 70% exhibited the highest solubilization capacity, increasing ACP solubility by 25.28 and 22.14-fold at 25 and 37 °C, respectively, compared with water. Computational analyses based on electrostatic potential mapping, binding energy calculations, and interaction region indicator analysis revealed that the enhanced solubility originates from cooperative hydrogen bonding, electrostatic attraction, and van der Waals interactions between ACP and the BeCl–Ace components, particularly BeCl. In addition, the selected NADES formulation significantly improved ACP stability under thermal stress, retaining 89.13% of the initial drug content after 30 days at 37 °C, compared with 70.20% in water. Cytotoxicity evaluation on HEK-293A cells further confirmed good biocompatibility, with cell viability remaining above 92% across the tested concentration range. These findings indicate that aqueous BeCl–Ace NADESs represent a promising and sustainable solvent system for improving ACP formulation performance.
SN - 2046-2069
ER -