Nature Meets Science: The Role of Food-Grade Oils and Green Excipients in Pharmaceutical Nanoemulsion Formulation

Abstract

Nanoemulsions are pivotal carriers which are increasingly adopted as carriers for poorly soluble active molecules. This review provides a critical overview of ‘green’ nanoemulsions, which are systems based on renewable, biodegradable, and non-toxic components and/or using sustainable production techniques. We here focus on the role of food-grade oils (including poly-unsaturated fatty acid-rich sources) and green excipients, with special attention on the interfacial properties of biosurfactants such as proteins, polysaccharides, and small-molecule surfactants. This review provides a critical overview of the formulation principles, interfacial phenomena, and physicochemical stability of green nanoemulsions, with reference to topical and pharmaceutical applications. The performance of nanoemulsions as delivery systems for bioactive lipids, essential oils, vitamins, carotenoids, phenolic compounds, and conventional drugs is examined through representative case studies. Known limitations, including oxidative instability, compositional variability, and difficulties in large scale production, are analyzed along with future opportunities in multifunctional formulations and sustainable processing. Overall, green nanoemulsions emerge as promising next-generation platforms for safe, effective, and environmentally friendly drug delivery.

Introduction

Nanoemulsions (NEs) are liquid heterogeneous systems, typically in an oil-in-water (O/W) or water-in-oil (W/O) form (Figure 1), characterized by an ultra-fine droplet diameter, ranging from tens to hundreds of nm [1,2].

Figure 1. Structure of single and double nanoemulsions. Water-in-oil (W/O) and oil-in-water (O/W) nanoemulsions (left). Water-in-oil-in-water (W/O/W) and oil-in-water-in-oil (O/W/O) double emulsions (right). Created with BioRender.com.

NEs are described by the volume ratio between the phases (Φ), stabilized using one or more appropriate surfactants [3]. The preparation of an emulsion requires mechanical work to disperse the internal phase into the external one, which leads to a strong increase in the total surface area of the system [3,4,5]. Once the mechanical action is completed, the emulsions are thermodynamically unstable and spontaneously tend to phase separation to minimize the free energy of the system (ΔG), as will be discussed in Section 7 [3].

In the most frequent case of O/W NEs, in accordance with Bancroft’s rule, water-soluble surfactants are used since they are more soluble in the continuous phase [6,7]. The stability against coalescence in O/W NEs is widely attributed to interfacial films and repulsive interactions arising from the polar headgroups [8,9]. Consequently, O/W NEs can be formed using relatively high internal phase volume ratios [7,10]. Phase inversion can occur when comparable volumes of the oil and water phase are mixed together (roughly for Φ ranging between 0.5 and 0.7 and higher, depending on the formulation conditions) [6,7,10,11,12].

A significant challenge in drug delivery is that 40% of currently marketed drugs and a higher percentage of new chemical entities are poorly water-soluble, and this severely limits their dissolution rate and subsequent oral bioavailability. NEs, particularly the O/W type, emerge as a remarkable strategy to overcome this limitation by efficiently solubilizing hydrophobic active pharmaceutical ingredients (APIs), thereby improving their solubility and, accordingly, their systemic bioavailability [13]. Furthermore, NEs often exhibit optical transparency, and a high surface area, intrinsically linked to nanoscale size [1,14,15].

NEs are characterized by high encapsulation efficiency, loading capacity, and feasibility of preparation. Thus, they have been extensively explored for the encapsulation of both food-based bioactives and drugs [16,17], offering the possibility to overcome the limitations of conventional pharmaceutical formulations [18,19].

It should be noted, however, that NEs in the pharmaceutical field also have some limitations. For instance, APIs with a high melting point are not suitable for loading into these systems. Furthermore, if they are intended for human use, NEs must be made of non-toxic (generally regarded as safe, GRAS) substances. This necessity, combined with the energy consumption of high-energy preparation methods, raises significant questions about the overall sustainability and environmental impact of NE production [18,19,20,21].

This perspective addresses the recent advances in the design and development of “green” NEs, that align with sustainability and eco-friendly principles. Specifically, green NEs are composed of natural, renewable, and biodegradable components, such as food-grade oils, and plant-derived surfactants. Furthermore, they are formulated with sustainable fabrication processes and/or green synthesis methods, which avoid toxic solvents and harmful chemicals, enhancing biocompatibility and minimizing the environmental impact. Furthermore, the adoption of green excipients and processes supports regulatory compliance and consumer demand for environmentally responsible products [22].

Within this broader context, the present review is primarily focused on pharmaceutical NE formulation within a materials and physicochemical framework. References to food and cosmetic applications are included to highlight shared formulation principles and broader technological relevance.

2. Food-Grade Oils in Nanoemulsions

The formulation of NEs requires careful selection of excipients in both the aqueous and oil phases. Indeed, the organic (oily) phase largely determines the solubility, protection, and bioavailability of lipophilic compounds. From a green perspective, food-grade oils offer a safe and biocompatible solution, capable of serving both as carriers and therapeutic adjuvants [23].

Quality and regulatory requirements for food-grade oils depend on their intended use, i.e., food, cosmetic, or pharmaceutical. While food and cosmetic applications are governed by their respective safety regulations, food-grade oils can be employed in pharmaceutical formulations if they meet pharmacopeial quality standards, in terms of purity, compositional consistency, and reproducibility. In this context, specifications vary according to the route of administration (oral, topical, parenteral, etc.), and therefore suitability must be evaluated on a case-by-case basis.

So far, a number of food ingredients and additives, including bioactive lipids, vitamins and flavorings, have been used in NE formulation, as shown in Figure 2 and summarized in Table 1 [24,25].

Figure 2. Examples of food-grade excipients used in green nanoemulsions: food-grade oils (e.g., fish, coconut, avocado oils) and natural biosurfactants (e.g., plant-derived compounds, egg and milk proteins) such as phospholipids (A) and saponin (B). Created with BioRender.com.

Table 1. Composition, oxidation, and solubility parameters of food-grade oil.

SFA, saturated fatty acids; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; OSI, Oxidative Stability Index; PV, Peroxide Value.

Essential polyunsaturated (PUFA) fatty acids, such as omega-3 oils and α-linolenic acid, are the main bioactive lipids [24,25], which reportedly possess substantial health benefits, especially for the neuroplasticity of nerve membranes and synaptogenesis [26]. However, bioactive lipids are highly unstable against oxidation and show persistent odor thresholds. Therefore, their encapsulation in NEs can reduce autoxidation and mask unpleasant tastes [27].

Lipophilic vitamins are biologically sensitive substances, displaying marginal chemical stability and water solubility [28]. For instance, Vitamins A, and Vitamins E are easily oxidized, particularly when exposed to light, heat, light, and metal ions. Furthermore, visible and fluorescent light possessed the ability to dramatically alter the vitamin K structure. They are usually fabricated to improve their chemical stability, solubility and oral bioavailability. As reported by Lv et al., NEs containing vitamin E were fabricated by dual-channel microfluidizer, using corn oil as a carrier oil resulting in an improved vitamin bioavailability (53.9%) [29]. In another example, a curcumin-containing NE was produced. This molecule is a polyphenol extracted from the rhizome of Curcuma longa Linn, endowed with anti-inflammatory, antioxidant, and antimicrobial properties. Curcumin applicability is limited due to its negligible aqueous solubility and consequently very low bioavailability [30]. These limitations were overcome by preparing a phospholipid-stabilized NE, whose organic phase consists of curcumin in flaxseed oil, showing a drastic increase in its bioavailability in rats [31].

3. Green Surfactants in Nanoemulsion Formulation

In NEs, surfactants drive the formation and stabilization of the colloidal structure. By adsorbing at the oil–water interface, they lower interfacial tension and facilitate the generation of finely dispersed droplets, ultimately enhancing the physical stability of the NE [32,33]. However, increasing concerns regarding the ecological and health impacts of synthetic surfactants are stimulating the development of “green” alternatives, such as natural surfactants, which offer a lower environmental footprint compared to conventional options [34]. In this context, the term “green” refers to materials derived from renewable sources, showing improved biocompatibility, biodegradability, lower toxicity, and reduced environmental impact compared to conventional options [34].

As with any industrial material, the production of green excipients may still involve environmental burdens depending on source, extraction method, and scale. Nevertheless, bio-based excipients are generally associated with biodegradability properties and reduced toxicity compared to conventional synthetic surfactants, which supports their increasing adoption in sustainable formulations [35,36]. These considerations further motivate the shift towards more sustainable surfactant systems [37]. Green surfactants include several molecular classes, such as phospholipids, proteins, saponins, and polysaccharides, which ensure the physical stability of nanoscale dispersions through steric and/or electrostatic mechanisms, similarly to conventional chemical surfactants (Figure 2).

Phospholipids (PLs) are a major class of amphiphilic molecules widely employed as natural emulsifiers owing to their distinctive structural organization. They consist of a glycerol backbone esterified with two non-polar fatty acid chains and a polar phosphate group, which is further linked to various polar organic moieties. This structural arrangement provides PLs with their characteristic amphiphilic nature, thus reducing the interfacial tension [33].

Proteins are being increasingly studied as natural emulsifiers due to their biodegradability, versatility and amphiphilic nature, which allow them to adsorb at the oil–water interface and form stable interfacial layers [38].

Saponins are a class of natural surfactants characterized by an amphiphilic structure composed of a lipophilic aglycone (typically a triterpenoid or steroid) and a hydrophilic glycone portion containing one or more sugar moieties [21,39].

Polysaccharides are not amphiphilic molecules and therefore cannot be classified as true emulsifiers; for this reason, they are often used in combination with other surfactants and co-surfactants. Nevertheless, they can act as effective stabilizing agents due to their hydrophilicity, highly branched structure, and high molecular weight, which provide thickening and gelling capabilities. These properties increase the viscosity of the continuous phase and create a steric barrier that limits destabilizing mechanisms [34]. Furthermore, they can form a compact hydrophilic shell around the oil droplets, providing strong three-dimensional steric repulsion [23]. Table 2 reports an overview of green surfactants, classified according to their different physico-chemical parameters.

Table 2. Classification of surfactants.

HLB range, CMC, pH/ionic sensitivity, regulatory limits. HLB: Hydrophilic–Lipophilic Balance; CMC: Critical Micelle Concentration; pI: isoelectric point. For high-molecular-weight biopolymers, HLB and CMC are approximate or not strictly defined and are reported when available from literature.

Gao et al. [40] developed NEs based on fractionated coconut oil using both natural and synthetic surfactants, with the aim of comparing their performance. PLs such as whey protein isolate and soy lecithin, in addition to the widely employed tea saponin, were employed as natural surfactants, whereas Tween 80 served as synthetic reference. The authors examined how emulsifier type and concentration, as well as pH, ionic strength, and heat treatment, influenced droplet size, ζ-potential, and stability. Tea saponin and soy lecithin generated smaller droplets than whey protein isolate, and also showed emulsifying performance comparable to Tween 80, likely due to a combined electrostatic and steric stabilization. The stability of the resulting NEs was influenced by many factors: as for whey protein isolate, it was affected by acidic pH and high temperature; for soy lecithin, by low pH and high ionic strength, while tea saponin provided the most robust stability across tested conditions and maintained long-term stability even at 27 and 50 °C. Overall, tea saponin emerged as the most effective natural emulsifier, offering stability and droplet size control comparable to Tween 80 and superior to protein or phospholipid based emulsifiers.

Also Najmeh Oliyaei et al. [41] compared natural and synthetic surfactants. They investigated the potential of stabilizing fucoxanthin-loaded NE using natural emulsifiers. Specifically, they compared Tween 80 with protein-based natural emulsifiers (sodium caseinate) and polysaccharide-based natural emulsifiers (fucoidan and gum Arabic). The study evaluated NE stability, particle size, ζ-potential, encapsulation efficiency, morphology, and in vitro release. The results indicated that, although fucoidan and gum Arabic achieved higher encapsulation efficiency and fucoxanthin release than sodium caseinate and Tween 80, they exhibited poor stabilizing properties. This highlighted the importance of combining polysaccharides with other natural emulsifiers or with a small amount of synthetic emulsifiers, to improve NE stability.

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Villapiano, F.; Capuano, M.; D’Aria, F.; Giancola, C.; Campani, V.; De Rosa, G.; Biondi, M.; Mayol, L. Nature Meets Science: The Role of Food-Grade Oils and Green Excipients in Pharmaceutical Nanoemulsion Formulation. Materials 2026, 19, 1294. https://doi.org/10.3390/ma19071294