From Liquid SNEDDS to Solid SNEDDS: A Comprehensive Review of Their Development and Pharmaceutical Applications

Abstract

The liquid and solid formulations of self-nano-emulsifying drug delivery systems (SNEDDS) have garnered significant attention in the pharmaceutical field for their ability to enhance the solubility and absorption of hydrophobic drugs. While both liquid and solid SNEDDS result in improved bioavailability; portability, patient compliance, desired administration route, and ease of preparation are some factors that contribute to the decision-making of the final SNEDDS dosage form. This review provides a comprehensive analysis of SNEDDS formulations in the liquid and solid state, including production and performance factors that researchers ought to consider when developing their final dosage form. We investigate excipient characteristics, stability concerns, liquid-to-solid preparation methods and their challenges, and in vivo and in vitro comparisons of both dosage forms. Finally, we explore the potential of artificial intelligence in the design of SNEDDS formulations.

Introduction

Poor aqueous solubility is the primary limiting factor for drug design via the oral route. According to some estimates, 40% of marketed drugs and 90% of drug candidates respectively, are poorly water soluble (1). These drugs exhibit poor solubility in gastrointestinal (GI) fluids, and further low and variable oral bioavailability. While methods such as nanoparticles, solid dispersions/solutions, lipid-based systems, pH modification, salt formation and cyclodextrins, have been used to enhance drug solubility, self-nano-emulsifying drug delivery systems (SNEDDS) offer the combined benefit of nanotechnology and lipid-based drug delivery. SNEDDS comprise an isotropic mixture of oil, surfactant, and co-solvent, which spontaneously form an oil-in-water nano-emulsion once exposed to the aqueous media of the GI environment as shown in Figure 1 (2, 3). SNEDDS are characterized by their globule droplet size of ~10–200 nm, and often poor thermodynamic stability (4,5,6,7,8). SNEDDS can improve oral bioavailability, increase the dissolution rate, enhance drug absorption and overall therapeutic outcome (9). Furthermore, the activation of the lymphatic route caused by the presence of oils in the GI tract completely shields the absorbed drug from first-pass metabolism effects (10).

SNEDDS have potential applications in oral, parenteral, ophthalmic, intranasal, and cosmetic drug delivery (11,12,13). Particularly, they are often designed to target the oral route, and their dosage form is either liquid or solid. Both forms have a significant influence on the production process, behaviour and fate of the drug. Solid SNEDDS, characterized by their pre-dissolved state and subsequent conversion into nano-emulsions upon exposure to GI fluids, offer unique opportunities for controlled drug release and improved stability. On the other hand, liquid SNEDDS, already in a dispersed form, exhibit rapid emulsification properties, facilitating faster drug absorption and onset of action. Current trends in SNEDDS exploration reflect a growing interest in not only optimizing liquid SNEDDS but also transforming them into solid dosage forms to overcome limitations associated with liquid formulations such as stability concerns, leakage from capsules, and dosing inaccuracy. Solid SNEDDS can be developed either by converting liquid SNEDDS to solid SNEDDS or by preparing de novo formulations using solid/semi-solid excipients. Solidification techniques such as adsorption onto carriers, spray drying, freeze-drying, and melt extrusion have opened new avenues for developing more stable, patient-friendly, and commercially viable SNEDDS-based products.

While there have been several studies on SNEDDS formulations, there remains a lack of comparative analysis on the transition of SNEDDS from the liquid to the solid state (14,15,16,17). The review delves into the critical formulation parameters and design attributes for synthesizing both liquid and solid SNEDDS for improving drug solubility and bioavailability in orally administered dosage forms using various conversion techniques. Furthermore, we highlight benchtop to bedside challenges and advances of both liquid and solid SNEDDS formulations.

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Choice of Excipients

The primary constituents of SNEDDS are oil, surfactant, and co-solvent. The choice and concentration of each of these excipients can dictate the performance of the delivery system as a loading system for the drug, as well as the stability of the formulation. During SNEDDS formulation, the right concentration and combination of excipients are carefully selected to ensure that the end result is an emulsion size below 200 nm. The oil/surfactant/co-solvent ratio is usually 10–70%/30–75%/0–25% to obtain the self-emulsifying effect (23, 24). The selection of oil is primarily based on the drug’s solubility in the oil, and the concentration of the oil also informs the degree of emulsification. Studies have noted that lower contents of oil (10–20% w/w) could produce rapid emulsification and small droplet size (25, 26). However, oils could also be selected because of their high degree of emulsification despite poor drug solubility in the oil (27). Oils with long-chain hydrocarbons (> 10 carbons), such as fixed oils (e.g. sesame oil, peanut oil and olive oil) are challenging to form nano-emulsions; however, their resulting droplet size is much smaller than oils with medium (~8–10 carbons) or short-chain length oils (< 8 carbons) (28, 29). Oils with medium-chain and short-chain lengths, such as capric triglycerides and triacetin, respectively, easily form nano-emulsions compared to long-chain triglycerides, but tend to have lower solubilizing capacity towards hydrophobic drugs (28, 29).

Examples of some oils used in SNEDDS formulations include essential oils such as lavender oil, avocado oil, and lemon oil; fatty acids such as oleic acid, fish oil, castor oil, and linolenic acid; and synthetic oils such as Maisine® CC and the Labrafil family of polyglycolysed oils (30, 31). Essential oils are a safe excipient choice and their antioxidant property, antibacterial activity and ability to enhance drug penetration in the small intestines make them an ideal candidate for SNEDDS delivery (32,33,34,35). On the other hand, synthetic oils have gained increasing attention in SNEDDS formulation because of their rapid ability to solubilise pharmaceutical drugs (36). A higher drug solubility in the oil phase will decrease the concentration of surfactant and co-solvent needed for emulsification of drug-loaded oil droplets. Moreover, some oils such as oleic acid can function as surfactants. Above the pKa, oleic acid has ionic surfactant properties, while below the pKa, oleic acid is protonated, and its properties change to that of oil (37). This property can be advantageous in providing solubility and nano-emulsion.

A surfactant’s high hydrophilicity is important for the instantaneous formation of nano-emulsion droplets, but it is often challenging for a single surfactant to produce transient negative interfacial tension (38,39,40). Therefore, co-surfactants/co-solvents are employed and selected based on their ability to maximize the nano-emulsion area with the selected surfactant. Surfactants such as polysorbate 20/80, Labrasol, Cremophor EL, and medium to short chain length co-surfactants/co-solvents, such as PEG 200/400, Transcutol® HP and ethanol have been used in SNEDDS formulation (26, 41, 42). A more detailed list of examples of SNEDDS excipients is presented in Figure 2. Some studies have revealed that surfactants with branched alkyl structures such as Cremophor® RH 40 and Cremophor® EL are better for self-nano-emulsification (43, 44). An increase in the surfactant concentration can result in smaller globule sizes; this may be because surfactant molecules tend to absorb the oil-water interface, where they can stabilize the oil globules and prevent coalescence (20, 45, 46). However, excessively increasing the surfactant concentration increases the viscosity of the liquid SNEDDS, which limits the pourability of liquid SNEDDS into soft gelatin capsules, increases droplet size and reduces emulsification rate.

Non-ionic surfactants are typically preferred for SNEDDS formulation because of their lower toxicity and maintained nano-emulsion stability over pH changes in the GI tract (47). According to the value of the lipophilic-hydrophilic equilibrium (HLB), surfactants can be categorized as lipophilic (HLB < 10) or hydrophilic (HLB > 10) surfactants (48). Lipophilic surfactants with HLB < 10 preferentially stabilize water-in-oil emulsions, whereas SNEDDS for oral delivery require oil-in-water nano-emulsions (since the GI tract is an aqueous environment) (44, 49). Therefore, surfactants with HLB above 10 are used to produce more stable oil-in-water nano-emulsions. A drawback of the SNEDDS excipient combination is its poor palatability and irritating smell, which can be unattractive to some patients.

When considering solid SNEDDS as the end goal, initial excipients used should be carefully selected based on the conversion method and specific desired solid dosage form. Non-ionic, amphiphilic surfactants are preferred for the formulation of solid SNEDDS as they do not cause significant charge interactions with excipients (especially with adsorbers), making them ideal for solid-state stabilization (50). Surfactant concentration can also be reduced in solid SNEDDS, which offers less toxicity for long-term use than the liquid counterpart. Additionally, conversion to solid SNEDDS can contribute to masking the irritating smell often perceived in liquid SNEDDS. The conversion method of SNEDDS usually involves the incorporation of porous carriers such as crosslinked porous silicon dioxide, magnesium trisilicate, magnesium aluminometasilicate, talcum, crosslinked sodium carboxymethyl cellulose, cross-linked polymethyl methacrylate, and crospovidone (7, 51,52,53,54,55). According to our literature search, adsorbents form the simplest and most extensively used method for liquid-to-solid SNEDDS conversion. However, a high concentration of adsorbents may be needed to obtain excellent flowability of solid SNEDDS. This increases the volume dose and may affect patient acceptability and compliance. Additionally, adsorbents increase the adhesion capacity of solid SNEDDS particles, which may lead to poor disintegration (26). To combat these challenges, solid SNEDDS are often filled into hard gelatin capsules and more recently, one study reported the formulation of SNEDDS into orally disintegrating tablets (26, 56, 57). Solid carriers for SNEDDS are selected based on their ability to absorb and retain a high amount of liquid SNEDDS without compromising flowability. Some commonly used carriers and their specific properties for solid SNEDDS conversion are listed in Table I.

Table I Examples of Carriers Used in Solid SNEDDS and Their Distinct Properties

In de novo SNEDDS designed without a liquid intermediate, drug, solid lipids, and surfactants are melted and processed into granules or extrudates that self-nano-emulsify upon dispersion. Instead of using porous carriers, solid surfactants like sodium lauryl sulfate or poloxamers can form the base, eliminating the need for a prior liquid formulation. Amphiphilic polymers such as hydroxypropyl methylcellulose acetate succinate, (HPMC-AS), Soluplus® and copovidone, combined with solid/semi-solid lipids create de novo solid matrices that have both solubilization and self-emulsifying capacity (37, 69,70,71). The lipid and surfactant selection in de novo SNEDDS is usually based on their solid properties and melting points. The melting point of the chosen excipients is critical: it should be high enough to maintain formulation stability at room temperature, but low enough to allow processing methods such as melt granulation or hot melt extrusion without degrading the drug. Gelucires and poloxamers are the most common semi-solid surfactant bases due to their amphiphilic character and low melting points that enable processing. Solid lipids such as Compritol, Precirol, and stearic acid contribute to stability and allow solid dosage development, though they have lower solubilizing capacity (72, 73).

Tanga, S., Ramburrun, P. & Aucamp, M. From Liquid SNEDDS to Solid SNEDDS: A Comprehensive Review of Their Development and Pharmaceutical Applications. AAPS J 28, 10 (2026). https://doi.org/10.1208/s12248-025-01167-x