Green deep eutectic solvents as carriers for Azelaic acid: A comparative study of delivery systems and development of high-performance transdermal gels

Abstract

Azelaic acid (AZA) is widely used in the topical therapy of acne vulgaris and rosacea but suffers from poor solubility and limited skin permeability, leading to high clinical dosages and associated irritation. Herein, two deep eutectic solvents (DESs)-based delivery strategies were systematically compared for sustainable transdermal delivery of AZA, including betaine (BET)-based DESs acting as green carriers and a therapeutic DES (THEDES) incorporating AZA as a structural component. Among the systems investigated, a BET-Urea-H₂O DES enhanced AZA solubility by up to 142-fold relative to water and achieved higher cumulative release at only 5% drug loading than both a commercial 20% AZA gel and the AZA-loaded THEDES (18.7% AZA content). Molecular analysis combining the Artificial Bee Colony algorithm and Atoms in Molecules theory suggests that the more diverse hydrogen-bonding network in the carrier-type DES enhances structural adaptability, allowing the system to accommodate compositional changes while suppressing crystallization during drug delivery. The optimized DES was further formulated into transdermal gels, with the 20% AZA-loaded formulation exhibiting a 2.6-fold increase in skin permeation compared with the commercial product, alongside antibacterial activity and biocompatibility. This work provides mechanistic insight into DESs-based delivery strategies and offers a green approach for enhancing the transdermal delivery of poorly soluble active ingredients.

Introduction

Transdermal drug delivery systems (TDDS) have attracted increasing attention due to their ability to bypass first-pass metabolism [1], maintain stable drug levels [2], and improve patient compliance [3]. However, the highly organized lipid structure of the stratum corneum presents a major barrier to drug permeation [4], particularly for active pharmaceutical ingredients (APIs) with poor solubility in both aqueous and oily media [5], [6]. Although technologies like chemical penetration enhancers, microemulsions, and microneedles have been applied to address this issue [7], [8], they frequently rely on volatile organic solvents, synthetic surfactants [9], or invasive techniques, raising concerns regarding skin safety, long-term biocompatibility, and environmental sustainability [10], [11]. Therefore, the development of green, safe, and efficient transdermal delivery systems remains a critical challenge for sustainable pharmaceutical engineering.

Deep eutectic solvents (DESs) have emerged as a promising class of green solvents composed of hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs) in specific molar ratios [12], [13]. Owing to their low vapor pressure, structural tunability [14], [15], and potential biodegradability [16], DESs, particularly those derived from natural or biocompatible components [17], have been increasingly explored in pharmaceutical and biomedical applications [18], [19]. In TDDS, DESs can be employed as carrier matrices to solubilize and deliver APIs [20], [21]; alternatively, APIs themselves can participate in DESs formation to form therapeutic deep eutectic solvents (THEDES) [22], eliminating polymorphism-related issues and enhancing delivery efficiency [23], [24]. Although both strategies have demonstrated advantages in enhancing drug delivery, most studies have focused on either approach independently. It can hypothesize that carrier-type DESs possess a more diverse hydrogen bonding network, enabling effective solubilization of APIs with different chemical structures and flexible drug loading. This flexibility allows the system to better accommodate concentration changes during drug delivery, thereby maintaining stability and reducing the tendency to crystallize. In contrast, THEDES systems are typically formed at fixed stoichiometric ratios, with less interaction diversity and limited drug loading tunability. As a result, changes in API concentration may disrupt the supramolecular balance of the system, increasing the likelihood of crystallization. A systematic comparison of carrier-type DESs and THEDESs for the same drug, particularly with respect to their structure-performance relationships [25], remains largely unexplored, limiting the rational design of DESs-based transdermal systems [26], [27].

Azelaic acid (AZA) is a clinically important agent widely used in the treatment of acne vulgaris and rosacea due to its antibacterial, anti-inflammatory, and keratolytic properties [28], [29]. However, AZA is practically insoluble in both water and oils and exhibits limited skin permeability [30], necessitating high clinical concentrations (15–20%), which are often associated with skin irritation, dryness, and crystal precipitation during storage and use [31], [32]. These challenges make AZA an ideal model drug for evaluating sustainable strategies aimed at improving the transdermal delivery of poorly soluble APIs. Luhaibi et al. reported that choline chloride-malonic acid-PEG 400-based DESs could enhance the solubility, skin permeability and antibacterial activity of AZA. However, choline chloride carries potential skin irritation risks, while betaine (BET) offers superior biocompatibility, lower irritation, and better adaptability for cosmetic transdermal delivery systems [33].

In this work, we systematically compare two DESs-based delivery strategies for AZA, including BET-based DESs acting as green carriers and a BET-AZA-H2O THEDES in which AZA is incorporated as a structural component. The solubility/drug loading capacity, pH, diffusion behavior, and intermolecular interactions of both systems were compared. Furthermore, the Artificial Bee Colony algorithm combined with Atoms in Molecules theory was employed to elucidate the intermolecular interactions governing their distinct delivery performances. Finally, the optimal DES formulation was translated into transdermal gel systems, and their permeability, antibacterial activity, and biocompatibility were assessed. This study provides mechanistic insight and practical guidance for the green and effective design of DESs-based transdermal delivery systems for poorly soluble active ingredients.

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Materials

AZA (99%) and BET (96%) were purchased from Anhui Zesheng Technology Co., Ltd. (Anhui, China). Urea (UR), malic acid (MA) and citric acid (CA) were purchased from Aladdin Reagent Inc. (Shanghai, China). DL-lactic acid (LA), 1,3-propanediol (PG), glycerol (GLY) and carbomer 940 (CP940) were purchased from Macklin Co., Ltd. (Shanghai, China). Polyacrylate crosspolymer-6 (ZEN) was purchased from Seppic (French).

Shuang-Shuang Wang, Bo-Wen Pang, Xia-Lin Dai, Jia-Miao Hao, Juan Xu, Jia-Mei Chen, Tong-Bu Lu, Green deep eutectic solvents as carriers for Azelaic acid: A comparative study of delivery systems and development of high-performance transdermal gels, Journal of Molecular Liquids, 2026, 129679, ISSN 0167-7322, https://doi.org/10.1016/j.molliq.2026.129679.

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