Advances in SNEDDS Tablets: Marketed Formulations and Emerging Technologies for Precision Drug Delivery

The oral administration of drugs is the most common way to achieve pharmacological effects for adequate disease treatment. It has high patient acceptance and convenience because of its painless application route. (1 to 3) A highly challenging feature of many orally administered drugs is their poor aqueous solubility, which can be responsible for limited as well as strongly variable drug absorption. (3 to 11). The oral delivery of drugs may also be associated with precipitation, food and drug interactions, susceptibility to degradation, and first-pass metabolism, leading to low oral bioavailability. According to the BCS (Biopharmaceutical Classification System), most of the drugs discovered thus far are classified into class II (low solubility, high permeability) and class IV (low solubility, low permeability). Following their oral administration, these compounds exhibited low oral bioavailability due to their low solubility or membrane permeability. Therefore, there is an urgent need to develop new drug carriers for their oral delivery. The oral absorption of poorly water-soluble drugs could be improved with food rich in lipids, which has led to the use of lipid-based formulations to improve the drug solubility and absorption following oral administration (12). Lipid-based formulations tend to improve solubility, enhance GI tract absorption, inconsistent dissolution, enzymatic degradation, and erratic intestinal absorption.The Biopharmaceutics Classification System (BCS), implemented by Gordon Amidon in 1995, categorizes drugs according to their expected bioavailability. The concept is based on the principle that the oral bioavailability of a drug is essentially determined by its solubility and its permeation properties. Class II includes drugs that exhibit a low solubility and high permeability, whereas Class IV involves drugs that are poorly soluble as well as poorly permeable (Figure 1). Hence, drugs assigned to Class II or IV are attractive drug candidates for solubility improvement in 7 studies, especially drugs assigned to Class II, as they are often subjected to dissolution rate-limited absorption.

FIG :1

Generally, self-emulsifying formulations are categorized as self-emulsifying (SEDDS), self-microemulsifying (SMEDDS), and self-nanoemulsifying drug delivery systems (SNEDDSs). SEDDS, SMEDDS, and SNEDDS can be differentiated basically according to their size of globules upon aqueous dispersion. A lipid formulation classification system (LFCS) based on the composition was developed, which categorized the LBF into four different types. The self-nano-emulsifying drug delivery system (SNEDDS) stands at the forefront of contemporary pharmaceutics as a pivotal nanocarrier system. The marvellous feature of SNEDDS is its proficiency in producing a precisely structured, homogenous oil-in-water nano-emulsion liquid. This is attained through a harmonized formulation integrating an oil base, surfactant, co-surfactant, and the target active pharmaceutical ingredient (API). (1).

FIGURE 2

The comparatively low free energy and a minimum interfacial tension of the instantaneously forming, optically translucent nano-emulsifying systems are responsible for the pronounced stability of SEDDS (10, 11, 25, 34). Compared to conventional dosage forms (e.g., tablets), additional benefits of SEDDS include the omission of a dissolution step for solid drugs before drug absorption in the intestine, as the drug is already dissolved in a water-free preconcentrate. Furthermore, the droplet sizes obtained after dispersion in an aqueous fluid fall within the lower nanometre range, which may facilitate intestinal drug absorption. (22, 23, 35, 36

Different techniques for the production of Nanoemulsions[12]

1. High-energy emulsification methods.

1. Ultrasonication.
2. High-pressure homogenization

2. Low-energy emulsification methods.

1. Phase inversion temperature method.
2. Solvent displacement method
3. Phase inversion composition

With increasing interest in patient-centric formulations and personalized medicine, solid SEDDS (S-SNEDDS) tablets are gaining commercial traction. This review provides a comparative analysis of marketed SNEDDS tablets and examines cutting-edge technologies shaping the future of this delivery platform.

Advantages of SNEDDS Compared to Conventional Emulsions

Self-emulsifying drug delivery systems (SNEDDS) offer multiple benefits over traditional emulsions, particularly in terms of formulation ease, stability, and patient usability.

1. Simplified Formulation Process
   Unlike conventional emulsions that require high shear mixing and specialized machinery, SEDDS are prepared through a straightforward method involving the dissolution of the drug in oil, followed by blending with surfactants and co-surfactants. This makes the development and scaling-up process less complicated and more cost-effective.
2. Superior Physical Stability
   Traditional emulsions are often prone to physical instabilities such as phase separation, creaming, or coalescence. SEDDS, however, are thermodynamically stable and form isotropic systems, which maintain their uniformity even when subjected to minor temperature variations.
3. Enhanced Patient Convenience
   SEDDS are commonly delivered in soft or hard gelatin capsules, providing a convenient and easily portable dosage form. These capsule-based formulations also support unit dosing and are compatible with standard pharmaceutical packaging, improving patient adherence compared to bulkier emulsion containers.
4. Cost-Effective Manufacturing
   Preparing conventional emulsions generally requires expensive, high-energy equipment to control critical process variables. In contrast, the manufacturing of SEDDS can be achieved with simpler, less costly setups, making them more accessible and easier to produce in different industrial settings.
5. Improved Dose Uniformity and Portability
   One of the major challenges with emulsions is the potential for non-uniform distribution of the drug due to droplet instability. SEDDS overcomes this by forming uniform nanoemulsions upon contact with gastrointestinal fluids, ensuring consistent drug delivery. Their capsule presentation also improves portability and dosage accuracy(5).

FIGURE 3

Excipient Selection in SEDDS Formulation

The development of Self-Emulsifying Drug Delivery Systems (SEDDS) relies heavily on the careful and strategic selection of excipients. Excipients are non-active substances that serve as the carrier or medium for the active pharmaceutical ingredient (API). In the case of SEDDS, excipients not only aid in drug solubilization but also play a critical role in the formation, stability, and bioavailability of the nano-emulsion formed upon dilution in gastrointestinal (GI) fluids. These excipients typically include oils, surfactants, and cosurfactants, each selected based on the solubility profile of the drug and the intended delivery characteristics of the formulation.

1. Role of Drug Solubility in Excipient Selection

The solubility of the drug in various excipients is the foundational criterion for formulating a successful SEDDS. Since many new chemical entities (NCEs) are lipophilic and poorly water-soluble, the excipients must enhance their solubility to improve oral absorption and bioavailability. Solubility studies are conducted early in the formulation design to identify the oil, surfactant, and cosurfactant in which the drug shows maximum solubility. This ensures that the drug remains in solution throughout the formulation and after dispersion in the GI tract.

2. Oils

Oils are the core component of SEDDS and significantly influence the drug's solubilization, emulsification efficiency, and lymphatic transport. They act as the primary solubilizing vehicle for lipophilic drugs and facilitate their absorption through the intestinal lymphatic system. The choice of oil determines not only the loading capacity of the drug but also the overall efficiency of the self-emulsification process.

Types of Oils Used:

• Natural Oils: These include vegetable oils like corn oil, peanut oil, soybean oil, and olive oil. While these oils are biocompatible, they may have variable composition and stability.
• Synthetic and Semi-Synthetic Oils: Examples include medium-chain triglycerides (MCTs), long-chain triglycerides (LCTs), and structured lipids. These offer consistent composition and better emulsification properties.
• Other Lipidic Substances: Fatty acid esters, mineral oil, lanolin, fatty alcohols, silicon oil, and refined animal fats are also used based on the formulation needs.

The use of medium- and long-chain triglycerides supports drug solubilization and helps trigger bile salt and lipase secretion in the GI tract. These endogenous agents facilitate the formation of micelles, which aid in lymphatic transport and avoid hepatic first-pass metabolism, thereby enhancing bioavailability.

3. Surfactants

Surfactants are amphiphilic compounds that reduce the interfacial tension between oil and water phases, promoting spontaneous emulsification upon mild agitation in GI fluids. They play a key role in stabilizing the emulsion formed during the self-emulsification process. The selection of an appropriate surfactant is critical for achieving a stable, uniform, and finely dispersed system.

Hydrophilic-Lipophilic Balance (HLB):
Surfactants used in SEDDS generally possess a high HLB value (typically >10), which is ideal for forming oil-in-water (O/W) emulsions. A high HLB surfactant facilitates the formation of small droplet sizes, leading to a larger surface area for drug release and absorption.

Commonly Used Surfactants:

• Polysorbates: Tween 80 (Polyoxyethylene sorbitan monooleate), Tween 20
• Sorbitan Esters: Span 80
• Polyoxyls: Cremophor RH40 (Polyoxyl 40 hydrogenated castor oil), Cremophor EL

Surfactants are typically used in concentrations ranging from 30% to 60% w/w in the formulation. An optimal amount ensures effective emulsification and maintains the physical stability of the emulsion over time. However, the excessive use of surfactants can lead to gastrointestinal irritation and potential toxicity, which necessitates the inclusion of cosurfactants.

4. Cosurfactants

Cosurfactants are low molecular weight compounds that work synergistically with surfactants to reduce the interfacial tension further and stabilize the emulsion. They enhance the flexibility of the interfacial film surrounding the oil droplets, which is crucial for forming fine and thermodynamically stable emulsions.

Functions of Cosurfactants:

• Lower the interfacial tension to a smaller or even negative value.
• Reduce the amount of surfactant required for emulsification.
• Improve the penetration of dispersion media into oil globules.
• Enhance the self-emulsification rate and reduce the shear required for dispersion.
• Minimize gastrointestinal distress caused by high surfactant content.

Common Cosurfactants:

• Glycerin
• Propylene glycol
• Polyethylene glycol
• Ethanol

The choice of cosurfactant depends on its compatibility with the surfactant and the oil phase. For example, ethanol and propylene glycol are commonly used due to their ability to improve the solubility of hydrophobic drugs and support the formation of micro/nano emulsions with smaller globule sizes.

5. Importance of Compatibility and Miscibility

The success of a SEDDS formulation depends not only on the individual solubilization capacity of the excipients but also on their mutual miscibility and compatibility. A clear and stable isotropic mixture of oil, surfactant, and cosurfactant must be formed before emulsification. The phase behavior of these excipients is typically studied using pseudo-ternary phase diagrams to determine the optimal ratios that yield a stable and efficient self-emulsifying region.

6. Effect on Bioavailability

Excipients in SEDDS enhance the bioavailability of poorly water-soluble drugs through multiple mechanisms:

• Improved solubilization and dissolution in GI fluids.
• Enhanced permeability and absorption via the lymphatic system.
• Protection of the drug from degradation in the harsh GI environment.
• Avoidance of first-pass metabolism for lipophilic drugs transported via lymphatics.

7. Safety and Regulatory Considerations

While selecting excipients, formulators must consider not only efficacy but also safety and regulatory compliance. All excipients used should be Generally Recognized as Safe (GRAS) or approved for pharmaceutical use by regulatory authorities like the FDA or EMA. The potential for hypersensitivity, GI irritation, and long-term toxicity must be evaluated, especially for surfactants and cosurfactants used at higher concentrations. [ 6,4,7,8]

FIGURE 4

MARKETED PRODUCTS OF SNEDDS

There are several marketed products of SNEDDS available in the market . Many of them have addressed the biovailability problems faced by the formulations . Self – Emulsifying systems prove to be beneficial in addressing problems related to solubility, Bioavailbility, and others . They have been several attempts to the problems related to the stability issues of this formulation. Converting into solid forms is a an wonderful solution to the problem . Here is a comparative study of SNEDDS with its  Brand name ,Company , Dosage form ,Excipients , Droplet size ,Bioavailabilty comparison, and approval .

FIGURE 5AND 6: NEORAL AND TAGRETIN

FIG 7,8,9 AND 10: FORTOVASE, NORVIR, GENGRAF, LIPIREX

COMPARATIVE BIOAVAILABILITY STUDIES IN LITERATURE

1. Ehab Taha,  Dalia Ghorab,  Abdel-azim Zaghlou of College of Clinical Pharmacy, King Faisal University, Al-Hasaa, Saudi Arabia;  Faculty of Pharmacy, Cairo University, Cairo, Egypt; Faculty of Pharmacy, Kuwait University, Kuwait studied Bioavailability Assessment of Vitamin A Self-Nanoemulsified Drug Delivery Systems in Rats: found that Vitamin A SNEDD-filled capsules and compressed tablets showed a significant increase in the rate and extent of drug absorption and the bioavailability compared to the capsule filled with an oily solution of vitamin A.
2. Alhasani KF, Kazi M, Ibrahim MA, Shahba AA, Alanazi FK studied Self-nanoemulsifying ramipril tablets: a novel delivery system for the enhancement of drug dissolution and stability found that for Ramipril, a poorly soluble antihypertensive drug, researchers prepared a solid SNEDDS using Labrafil M2125 CS, Cremophor RH40, and PEG 400. The formulation demonstrated a twofold increase in dissolution rate compared to the pure drug and remained stable under accelerated stability conditions.
3. Khan AW, Kotta S, Ansari SH, Sharma RK, Ali J.  studied the Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble carbamazepine: formulation and evaluation found that Carbamazepine, an antiepileptic drug with low bioavailability, was formulated into a SNEDDS using oleic acid, Tween 80, and Transcutol HP. The formulation resulted in uniform nano-sized droplets and improved plasma concentration profiles, leading to more predictable and consistent therapeutic levels.
4. Garg V, Singh H, Bimbrawh S, Kumar S, Sharma PK. Studied on Development and characterization of SNEDDS of lopinavir for oral delivery, found that Lopinavir, a protease inhibitor used in HIV treatment, was developed into a SNEDDS using castor oil, Cremophor EL, and PEG 600. This lipid-based system significantly enhanced lymphatic transport and oral bioavailability compared to conventional formulations.
5. Bandyopadhyay S, Katare OP, Singh B. studied on Development of self-nanoemulsifying drug delivery system (SNEDDS) of valsartan for improvement of oral bioavailability found that Valsartan, a drug with poor aqueous solubility, was incorporated into a solid SNEDDS with Labrafac Lipophile WL, Kolliphor RH40, and propylene glycol. The optimized formulation resulted in a nearly threefold increase in bioavailability, highlighting the system's potential for improving therapeutic outcomes in cardiovascular diseases.

Hot-Melt Extrusion and Polymer Innovation in S-SNEDDS Development: A Novel Strategy for Enhancing Drug Solubility and Stability

The development of solid self-nanoemulsifying drug delivery systems (S-SNEDDS) marks a significant advancement in addressing the solubility challenges of poorly water-soluble drugs. Traditional techniques such as adsorption onto solid carriers (e.g., mesoporous alumina and microcrystalline cellulose) have demonstrated adequate storage stability under ICH intermediate conditions (30°C/65% RH for three months), with formulations maintaining visual integrity and drug release variation <3%. However, limitations in adsorption-based systems led to the exploration of hot melt extrusion (HME) as a novel approach to solidify liquid SNEDDS (L-SNEDDS). Initial HME trials incorporating L-SNEDDS with commercially available thermoplastic polymers (e.g., EUDRAGIT® E PO, Soluplus®, Kollidon®) revealed technical challenges, including poor melt viscosity, extruder clogging, and insufficient mechanical strength of the extrudates. To overcome these issues, a customized copolymer, ModE (dimethylaminopropyl methacrylamide-butyl methacrylate-methyl methacrylate), was synthesized via radical polymerization by structurally modifying EUDRAGIT® E PO. This novel aminomethacrylate-based polymer demonstrated improved glass transition temperature (Tg), melt processability, and L-SNEDDS binding capacity. Drug release studies using three model drugs (celecoxib, efavirenz, and fenofibrate) confirmed that S-SNEDDS prepared with ModE showed superior dissolution performance compared to both conventional polymers and analogous amorphous solid dispersions (ASDs). Notably, lower molecular weight (Mw) and Tg variants of ModE correlated with higher drug release, emphasizing the role of polymer flexibility and solubilizing capacity. In conclusion, the integration of HME and tailored polymers such as ModE presents a promising direction for the scalable and efficient manufacture of S-SNEDDS, offering enhanced drug loading, solubility, and stability—key parameters for advancing oral delivery of BCS Class II drugs.75, 77,78, 79,80

3D-Printed SNEDDS for Personalized Drug Delivery

The integration of three-dimensional (3D) printing with self-nanoemulsifying drug delivery systems (SNEDDS) marks a significant advance in personalized medicine. Recent research has demonstrated the utility of 3D printing in fabricating customized SNEDDS-based dosage forms for both local and systemic drug delivery.

Integrating SNEDDS with 3D printing technologies offers a unique opportunity to resolve these issues by customizing solidified dosage forms that preserve the nanoemulsion advantages.

3D-Printed Lidocaine SNEDDS Suppositories: A Localized Approach

Chatzitaki et al. [3] developed a novel SNEDDS-based suppository using PAM 3D printing to deliver lidocaine (LID), a local anesthetic. The lipid base consisted of refined soybean oil and Geloil™ SC, while the Smix phase included glyceryl distearate and polyglyceryl-3 dioleate. The resultant SNEDDS showed droplet sizes between 31–42 nm, indicating successful nanoemulsification. A major advantage of this formulation was the ability to print different dosage forms (1%, 2%, 5% w/w LID) for patient-specific therapy, such as for those undergoing prostate biopsy. Mechanical tests showed that all formulations met European Pharmacopoeia standards for suppositories. Furthermore, in vitro drug release studies revealed delayed release in higher LID concentration suppositories, a valuable characteristic for sustained local anesthetic action.

This method allowed for the direct incorporation of SNEDDS into semi-solid, patient-tailored suppositories without additional solidifying excipients, making it a promising platform for personalized rectal or vaginal drug delivery.

3D-Printed Cyclosporine SNEDDS Capsule Shells: A Systemic Approach

In contrast, Algahtani et al. [4] addressed the need for personalized systemic dosing through FDM 3D printing of capsule shells filled with cyclosporine A (CsA)-loaded SNEDDS. CsA is a lipophilic immunosuppressant with poor water solubility and high inter-subject variability. The SNEDDS formulation used caproyl 90 and octanoic acid as the oil phase and cremophor EL with PEG 400 as the Smix. To convert the liquid SNEDDS to a solid form, PEG 6000 was used. The printed capsule had a dome-shaped shell with a top opening, allowing simple filling of molten SNEDDS using a pipette or syringe. This approach eliminates the need for precision printing of the drug itself—only the capsule is printed, making it more feasible for in-clinic or pharmacy-level use. Characterization techniques (FTIR, DSC, SEM/EDX) confirmed formulation integrity, and in vitro studies demonstrated complete CsA release within 60 minutes, following Korsmeyer-Peppas kinetics. Importantly, variations in shell design or drug load did not significantly impact release, highlighting the robustness of the delivery system 7 (a tob)

FIGURE 11

FIGURE12

3D printing of SNEDDS offers a transformative approach to overcoming solubility, dosing, and patient-specific challenges. From rectal lidocaine suppositories to oral cyclosporine capsules, these innovative systems exemplify the adaptability of 3D printed drug delivery. As technology matures and regulatory frameworks evolve, 3D printed SNEDDS hold immense promise for the future of personalized medicine.

Role of Formulation AI in SNEDDS Optimization

The development of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) is a complex and multifactorial process that involves the careful selection and optimization of formulation components such as oils, surfactants, co-surfactants, and active pharmaceutical ingredients (APIs). Traditional formulation methods rely on trial-and-error approaches, which are time-consuming, resource-intensive, and often lack predictive power. Formulation Artificial Intelligence (Formulation AI), particularly techniques such as Artificial Neural Networks (ANN), Genetic Algorithms (GA), and Design of Experiments (DoE)-based AI modeling, has emerged as a powerful tool for optimizing SNEDDS by providing a more efficient, accurate, and data-driven formulation pathway.

OPTIMISATION OF SNEDDS USING ANN.

Giang Thi Thu Vu et. al studied the Application of the artificial neural network to optimize the formulation of self-nanoemulsifying drug delivery systems containing rosuvastatin formulation.   Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) are a promising strategy for enhancing the solubility and bioavailability of poorly water-soluble drugs such as rosuvastatin (Ros). In this study, the effect of key formulation excipients on the physicochemical characteristics of Ros-SNEDDS was systematically investigated using artificial neural network (ANN) modeling. The components under evaluation included Cremophor RH40 (surfactant), PEG 400 (co-surfactant), and Capryol 90 (oil phase), with special emphasis on how these ingredients affected the droplet size, polydispersity index (PDI), and drug entrapment efficiency.

Experimental Approach and Design

The formulation optimization was guided by a design of experiments (DoE) approach, incorporating ANN-based modeling. The independent variables were the proportions of Cremophor RH40, PEG 400, Capryol 90, and the percentage of rosuvastatin incorporated in the SNEDDS. The dependent variables included droplet size, PDI, and drug entrapment efficiency. A pseudoternary phase diagram was initially constructed to identify the nanoemulsion region and suitable ratios of oil, surfactant, and co-surfactant. Once the preliminary screening identified feasible regions of emulsification, various formulations were created and evaluated. The ANN model, trained using JMP 15 software, was used to predict and optimize outcomes based on experimental data. A three-node, one-hidden-layer neural network with a hyperbolic tangent (TanH) activation function was employed, validated using 5-fold cross-validation to ensure model robustness. The resulting R-square values (>0.87 for both training and validation sets) demonstrated excellent model fit and predictive capability.

Effect of Excipients on Droplet Size

Droplet size is a critical parameter that influences the stability, absorption, and bioavailability of SNEDDS formulations. The study found that the droplet size of the resulting nanoemulsions was strongly influenced by the proportions of Capryol 90 and Cremophor RH40. Specifically, an increase in Capryol 90 concentration led to a proportional increase in droplet size. This is expected as oils with higher viscosity can result in larger emulsion droplets upon emulsification. Conversely, higher amounts of Cremophor RH40 tended to reduce droplet size. Cremophor RH40 is a non-ionic surfactant with good emulsification capacity, and its presence helps stabilize smaller droplets by reducing interfacial tension. PEG 400 had a more moderate effect, where its influence became more prominent depending on its combination with the other two excipients [6]. Contour plots constructed from the ANN model provided visual confirmation of these relationships, particularly at a fixed rosuvastatin concentration of 10%. The interplay of excipients could thus be mapped to predict the optimal formulation zone for minimal droplet size.

Effect on Polydispersity Index (PDI)

PDI is a measure of the uniformity of droplet size distribution. Lower values (<0.3) indicate a more homogeneous nanoemulsion system. Two optimal zones were identified for achieving low PDI values:

• Zone 1: PEG 400 (0.10–0.20), Capryol 90 (0.35–0.50), Cremophor RH40 (0.37–0.45).
• Zone 2: PEG 400 (0.31–0.60), Capryol 90 (0.10–0.30), Cremophor RH40 (0.23–0.45).

Within these zones, PDI showed different trends. In Zone 1, increasing PEG 400 tended to increase the PDI, indicating a broader size distribution, whereas increasing Capryol 90 resulted in a more uniform emulsion. These findings highlight the delicate balance required in SNEDDS formulation to ensure optimal emulsification.

Effect on Drug Entrapment Efficiency

Drug entrapment efficiency is a vital parameter that determines the therapeutic efficacy of SNEDDS. It was observed that drug entrapment was inversely proportional to the amount of Cremophor RH40 and directly proportional to the amount of Capryol 90. High levels of surfactant can lead to micellar solubilization of the drug in the aqueous phase rather than encapsulation within the oil droplets, thereby reducing entrapment efficiency. The entrapment efficiency was particularly high (up to 97%) in a specific formulation window: PEG 400 (0.22–0.25), Capryol 90 (0.32–0.41), and Cremophor RH40 (0.38–0.45). These findings support the notion that the oil phase plays a crucial role in encapsulating hydrophobic drugs like rosuvastatin, while excessive surfactant may dilute this effect.

Impact of Rosuvastatin Concentration

The concentration of rosuvastatin itself was another critical factor influencing SNEDDS behavior. As the drug loading increased from 8% to 12%, a nonlinear trend in droplet size, PDI, and drug entrapment was observed. Initially, increasing the drug load from 8% to 9% caused a decrease in entrapment efficiency, possibly due to drug saturation in the oil phase. However, further increase to 12% led to a proportional rise in entrapment, suggesting enhanced solubilization at higher drug concentrations, potentially due to better accommodation in the lipid matrix. In contrast, both droplet size and PDI increased with drug concentration, likely due to the viscosity increase and altered interfacial film stability caused by higher drug content.

Design Space and Optimization

The design space for optimal SNEDDS formulations was defined based on overlapping contour plots for all three response variables (droplet size, PDI, and entrapment efficiency). As the percentage of rosuvastatin increased, the viable design space narrowed, reflecting the increasing difficulty of achieving optimal performance at higher drug loadings [1].

• At 8% Ros: Broader design space. Cremophor RH40 (0.20–0.45), Capryol 90 (0.10–0.43 and 0.48–0.50), PEG 400 (0.28–0.60).
• At 10% Ros: Moderate design space. Cremophor RH40 (0.25–0.45), Capryol 90 (0.10–0.31 and 0.37–0.50), PEG 400 (0.10–0.20 and 0.31–0.60).
• At 12% Ros: Narrowest design space. Cremophor RH40 (0.33–0.45), Capryol 90 (0.10–0.18 and 0.37–0.50), PEG 400 (0.37–0.53).

This progressive restriction emphasizes the challenge of balancing solubilization, stability, and uniformity at high drug loading levels.                                                                                              

FIGURE 1