Carbohydrate-surfactant interplay: structural effects of Saccharides on Micellar Behavior of Kolliphor® EL and Kolliphor® HS15

Abstract

Carbohydrates play a pivotal role in reshaping micellar organization. This study explores how glucose (a monosaccharide), trehalose (a disaccharide), and inositol (a polyol) influence the self-assembly of two pharmaceutically important nonionic surfactants, Kolliphor® EL and Kolliphor® HS15. The characterization was carried out using several techniques, namely cloud point (CP) analysis, dynamic light scattering (DLS), small-angle neutron scattering (SANS), and in vitro drug release. These studies revealed that the aforementioned saccharides act as water-structure modifiers, which disrupt hydrogen-bonding networks and enhance the growth of micelles. The addition of saccharides decreased the CP of both surfactants, which indicated enhanced micellization due to the change in water structure. DLS exhibited concentration-dependent micellar enlargement along with a temperature effect. SANS analysis revealed spherical micelles for both surfactants, whereas the addition of trehalose induced a spherical to ellipsoidal micellar transition in Kolliphor® HS15. The cumulative release profiles confirmed a sustained and near-linear release of quercetin over 96 h, with Kolliphor® EL exhibiting a slightly faster release rate compared to Kolliphor® HS15. Collectively, these studies highlight how carbohydrate structure influences surfactant phase behavior, providing a framework for designing nonionic surfactant nanocarriers that respond to carbohydrates for advanced pharmaceutical applications.

Introduction

Carbohydrates occupy a central place in molecular recognition and binding events due to their excellent solubility, targeted action on specific organs, broad pharmacological effects, sustained action, and favorable safety profiles. They are major energy sources, building blocks of life, and play an important role in various biological processes(Di et al., 2022; Oliva et al., 2024; Ramaprabha et al., 2024). One such example is saccharides, an important group of carbohydrates that are not just a sweetener, but possess certain special physicochemical properties which make them useful in both pharmaceuticals and in biomedical applications(Benalaya, Alves, Lopes & Silva, 2024; Mohammed et al., 2021). They have become common in the pharmaceutical sector as excipients, in the development of drugs, and in the process of packaging and delivery. The dosage forms that are available include suspensions, gels, inhalation products, tablets, capsules, oral strips, and liquids in a tremendous number. They are generally regarded as safe, structurally diverse, and versatile in their functional properties, which render them to have long-term significance in drug applications(Alvani, Qi & Tester, 2011).

These benefits also render carbohydrates compatible with modern nanocarrier drug delivery systems, which aim to enhance the performance of therapeutics. Nanocarriers have emerged as a highly effective strategy for drug delivery, offering improved therapeutic efficacy through enhanced solubility, controlled release, and targeted delivery, ultimately leading to optimized pharmacological effects (Desai et al., 2025a). Commonly explored nanocarrier platforms include surfactant micelles, dendrimers, and liposomes (Karmakar et al., 2023; Kundu et al., 2025; Mandal, Bisht, Rupenthal & Mitra, 2017; Sarkar et al., 2024; Torchilin, 2001). Among these systems, surfactant-based micelles rely on amphiphilic molecules that self-assemble in aqueous media and play a crucial role in improving the solubility and bioavailability of poorly water-soluble drugs (Torchilin, 2001). While carbohydrates, particularly sugars, are extensively employed in pharmaceutical formulations both as excipients and as functional additives and in some cases as sugar-derived surfactants, the present focus emphasizes the use of sugars as formulation additives rather than as primary surfactant components. Conventional nonionic surfactants remain advantageous as the core amphiphiles in nanocarrier systems due to their well-defined molecular architectures and extensively characterized physicochemical behavior, which allow for predictable self-assembly and reliable formulation performance (Müller et al., 2017; Tancredi et al., 2025; Veronico, Colafemmina & Gentile, 2025). Given their increasing importance in advanced pharmaceutical formulations, it is therefore essential to focus on specific nonionic surfactants with well-established structure–property relationships. When combined with sugars as stabilizing or performance-modifying additives, these surfactants enable the rational design of nanocarrier systems applicable across a broad range of dosage forms, from solid formulations to PEG-based drug delivery platforms, ultimately enhancing the bioavailability of poorly water-soluble therapeutic agents.

Kolliphor® EL (Cremophor® EL) and Kolliphor® HS15 (Solutol® HS15) are amongst the nonionic surfactants that have a multifunctional application(Christiansen, Backensfeld & Weitschies, 2010; Grillo & Penfold, 2011; Kunieda, Kabir, Aramaki & Shigeta, 2001; Suys et al., 2019). These surfactants are commonly used in drug formulations and cosmetics because of their capacity to dissolve drugs that are not readily soluble in water (Suys et al., 2019). Kolliphor® EL is a biocompatible, non-toxic surfactant that is suitable for delivering drugs because it can form micelles to encapsulate hydrophobic drugs effectively(Cervantes-Martínez et al., 2019). Kolliphor® HS15 (macrogol 15 hydroxystearate), a nonionic amphiphilic surfactant, is a compound made up of mono- and diesters of 12-hydroxystearic acid, about 70 % of which is incorporated in polyglycol and 30 % of which is incorporated in free polyethylene glycol (PEG) (Ezegbe et al., 2022). It effectively enhances the stability and solubility of insoluble drugs, has low in vivo toxicity, and acts as a multi-drug resistance modifier. Its unique properties make it suitable for ophthalmic drug therapy, suppositories, macromolecules, and protein formulations. It is safe for pharmaceuticals and food applications, compatible with saccharides and oleochemicals, and has low viscosity, ideal for parenteral and intravenous solutions(Ali & Kolter, 2019; Bergonzi, Vasarri, Marroncini, Barletta & Degl’Innocenti, 2020; Buckingham, Balasubramanian, Emanuele, Clodfelter & Coon, 1995; Coon, Knudson, Clodfelter, Lu & Weinstein, 1991; Ding et al., 2019; Liu et al., 2016; Sai et al., 2019; Wu et al., 2020; Younes, Abdel-Halim & Elassasy, 2018; Yuan et al., 2015; Zhou et al., 2022). The effect of saccharides on the structural and functional characteristics of nonionic surfactants has been explored in many studies. Rathod et al.(Rathod et al., 2022) investigated the effects of monosaccharides on d-α-Tocopherol polyethylene glycol succinate (TPGS) self-assembly and revealed that glucose, mannose and galactose cause micellar dehydration and reorganization that results in the formation of enlarged micelles with enhanced stability. Patidar et al.(Patidar, Pillai, Bahadur & Bahadur, 2017) examined the influence of glucose on micellization of Pluronic® P104 and Tetronic® T1304 and discovered that it enhanced micellar growth by increasing the micellar core stabilization, thus enhancing the solubilization of hydrophobic drugs into the micelles. A few studies have also explored how saccharides affect the micellar characteristics and solubilization efficiency of Kolliphor® EL and Kolliphor® HS15. Ahmad et al.(Haj-Ahmad, Elkordy, Chaw & Moore, 2013) investigated that this study aimed to evaluate the role of Kolliphor® EL, β-cyclodextrin, and inulin (as sugars) in enhancing the stability and biological activity of lysozyme in spray-dried and crystallized solid protein formulations. Chakrabarti et al.(Chakrabarti et al., 2022) investigated the self-assembly behavior of Kolliphor® HS15 and demonstrated that interactions with sugars govern micellar integrity and amphiphilic behavior, highlighting the importance of carbohydrate additives in biomedical and drug delivery applications. Wu et al.(Wu, Gao, Liu, Pan & Liu, 2024) investigated the effect of sugars on the micellization processes and stability of paclitaxel-loaded HS15/Tween® 80 micelles and demonstrated that hydroxyl groups of sugars increase hydrogen bonding between surfactants and water, leading to the formation of micelles.

This study aims to address the gaps in knowledge regarding the effects of structural differences in nonionic surfactants, specifically Kolliphor® EL and Kolliphor® HS15, on their interactions with saccharides, as well as the impact of these structural variations on drug delivery systems. The objective is to examine how different saccharides, ranging from monosaccharides, such as glucose, to disaccharides like trehalose, and polyols like inositol, affect the physicochemical properties of both nonionic surfactants. To investigate this, the study will evaluate the influence of glucose, trehalose, and inositol on the regulation of micellar properties, phase behavior, solubilization, and drug release. Complementary methods will be employed to gain insights into the mechanisms of saccharide-surfactant interactions. These methods include cloud point (CP) analysis, dynamic light scattering (DLS), small-angle neutron scattering (SANS), and in vitro drug release experiments using the drug quercetin. Ultimately, the findings of this research are expected to contribute to the rational advancement of surfactant-based drug delivery systems, leading to improved stability and enhanced therapeutic performance.

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Materials

Kolliphor® EL and Kolliphor® HS15, both nonionic surfactants, were provided by BASF Corp. in India. Glucose, inositol, and trehalose of analytical grade, with around 99 % purity, were sourced from HiMedia Laboratories. All reagents were of high purity and were used as received, without further purification. Milli-Q deionized water was utilized for all sample preparations. SANS samples were prepared using deuterium oxide (D₂O, 99.99 atom % D), procured from Sigma-Aldrich, India. The chemical structures of the compounds investigated in this study are shown in Fig. 1.

Jyoti Vyas, Deep Bhalani, Gaurang Dalsaniya, Sugam Kumar, Vinod K. Aswal, Sadafara A. Pillai, Carbohydrate-surfactant interplay: structural effects of Saccharides on Micellar Behavior of Kolliphor® EL and Kolliphor® HS15, Food Hydrocolloids for Health, Volume 9, 2026, 100274, ISSN 2667-0259, https://doi.org/10.1016/j.fhfh.2026.100274.

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