Nanoemulsions: A Comprehensive Review of Drug Delivery Systems

Technical Review Article | Open Access | Published 2nd April 2025

Nanoemulsions: A Comprehensive Review of Drug Delivery Systems

Sumeet Dwivedi*, Kalyani Makode, Priya Mourya, Pravin Kumar Sharma, G.N. Darwhekar | EJPPS | 301 (2025) https://doi.org/10.37521/ejpps30108 | Click to download

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Abstract

An amphiphilic surfactant stabilizes the droplets of water as well as oil in nanoemulsions. Medication administration may benefit from the use of ultrafine dispersions with different drug loading, viscoelastic qualities, and better attributes. For nanoemulsions, a droplet size range of 20–500 nanometers have been defined. The surface characteristics and droplet diameter of a nanoemulsion formulation have a significant impact on its biological behaviour. Because small droplet sizes produce transparent emulsions, adding an oil phase has little impact on theappearance of product.A layer of surfactant and cosurfactant particles with droplet sizes of less than 100 nm forms an interfacial layer that stabilizes transparent or translucent oils in water dispersions, sometimes referred to as nanoemulsions.Oswald ripening makes nanoemulsions vulnerable to flocculation, creaming, and other emulsion-related physical instability issues. Despite this, because of their minuscule sizes, they can remain stable (metastable) for extended periods of time provided that sufficient surfactants are applied. The use of cutting-edge nanoscience-based technologies to enhance food quality, safety, and nutrition is growing in popularity. In this market, nanoemulsions are quite popular since they are simple to make using modern food components and technology. Small oil droplets dispersed in water, known as food nanoemulsions, are being employed as vehicles for a range of hydrophobic substances, including as antioxidants, antimicrobial agents, nutraceuticals, and nutrients.

Keywords: Nanoemulsions, Surfactants, Ostwald ripening, thermodynamic stability, physical stability, shelf life.

Introduction

Nanoemulsions are dispersions of two immiscible fluids that are either water-in-oil (w/o) or oil-in-water (o/w). The right amphiphilic emulsifiers or emulsifiers are added to stabilize these 20–200 nm droplets. Thus, nanoemulsions are sometimes referred to as mini emulsions. Unlike microemulsions (ME), nanoemulsions (NE) have kinetic stability, which makes them stable on heterogeneous systems. Nanoemulsions, often referred to as "potential thermodynamic stability" because of their prolonged physical consistency, are distinct from other materials since they do not seem to agglomerate or flocculate.

Researchers initially started working with colloidal systems in the early 20th century, which is when the history of nanoemulsions began. While early studies focused on macroemulsions and microemulsions, they also laid the groundwork for the development of nanoemulsions. In the 1990s, nanoemulsions as a unique class of emulsions attracted a lot of attention. This time period saw a change in perspective toward the possible uses of nanoemulsions, especially in the food and pharmaceutical sectors. The production of nanoemulsions for various drug delivery modalities offers a plethora of benefits and notable advantages that contribute to the increased efficacy and versatility of pharmaceutical formulations. As an example of a non-nanoemulsion formulation that significantly improves medication bioavailability over nanoemulsion-based formulations is transdermal gel. Nanoemulsions, which are characterized by their nanoscale droplets, provide a high interfacial area for drug dissolution and enhanced solubility for drugs with limited water solubility. Higher drug-loading capacities have this advantage, which makes it possible to provide a greater variety of therapeutic drugs. When applied topically, nanoemulsions can accelerate the absorption of medicine in transdermal gels, leading to more rapid onset of action and improved therapeutic outcomes. Moreover, the exceptional stability of nanoemulsions prevents medication degradation and increases the shelf life of medications. This feature is especially significant

when talking about transdermal gels because the formulation's durability over time is what ensures constant drug delivery.¹⁻⁵

Nanoemulsion types depending on composition

Oil in Water (O/W) nanoemulsions: in the continuous aqueous phase, beads are dispersed within the oil.

Water in Oil (W/O) nanoemulsions: in the continuous oil phase, beads are dispersed inside the water.

Bi-continuous nanoemulsions, in which the framework contains small-scale gaps filled with both water and oil.

W/O/W (Water-in-Oil-in-Water)

O/W/O, or oil in water in oil.⁶

Advantages of Nanoemulsions over other dosage forms

Removes absorption variability.

Quickens the absorption rate.

Assists in solvating lipophilic medication.

Gives medications that are water insoluble an aqueous dose form.

Makes material more bioavailable.

The substance can be administered by oral, intravenous, and topical methods.

The medication molecule penetrates quickly and effectively.

Aids in disguising flavour.

Provides protection against hydrolysis and oxidation when the medication is in the oil phase of an o/w emulsion.

Lower energy consumption.

Patient compliance is increased by liquid dosage forms.

Because of their thermodynamic stability, nanoemulsions can self-emulsify, allowing for system characteristics that are independent of the technique used.

Both lipophilic and hydrophilic substances are carried by nanoemulsions.

Using nanoemulsion as a delivery mechanism increases a drug's effectiveness, enabling a reduction in the overall dosage and decreasing adverse effects.⁷

Fig. 2. Unique Characteristics of Nanoemulsion ⁷

Disadvantages of Nanoemulsion Based Systems

a) A high concentration of cosurfactant and surfactant is utilized to stabilize the nanodroplets.

b) Limited capacity to dissolve substances with elevated melting points.

c) For medicinal applications, the surfactant needs to be nontoxic.

d) Temperature and pH levels in the environment can affect the stability of nanoemulsions. These metrics change after patients get nanoemulsion.⁷

Components of Nanoemulsion

Here are some essential chemical needs and typical chemicals used in nanoemulsion formulations: Creating an oral nanoemulsion entails choosing elements that can stabilize the emulsion, boost solubility, improve bioavailability, and assure safety for oral consumption.

a) Surfactants: In nanoemulsions, surfactants are essential for maintaining the interface between the water and oil phases. They inhibit droplet coalescence and lessen interfacial tension.

Examples of non-ionic surfactants are members of the Tween and Span families,
Ionic surfactants, such as sodium dodecyl sulphate,
Zwitterionic surfactants, such as lecithin.

b) Co-surfactants: To further improve stability and lower interfacial tension, co-surfactants are frequently utilized with surfactants. Typical co-surfactants are

Glycerol,
propylene glycol,
polyethylene glycol (PEG).

c) Oils: Acting as the centre of the nanoemulsion, oils aid in the solubilization of lipophilic medications. They ought to be digested and biocompatible. Examples consist of

Soybean oil,
Medium-chain triglycerides (MCTs),
Triglycerides of caprylic/capric acid.

d) Solvents: To help the emulsion develop, solvents are utilized to dissolve lipophilic components. It should be okay to eat them orally. Typical solvents consist of:

Ethanol,
Polyethylene glycol (PEG),
Propylene glycol.

e) Co-solvents: useful tool for improving stability and solubility. They are frequently used in conjunction with other solvents. Examples consist of:

Glycerol,
Ethanol,
propylene glycol.

f) Stabilizers: In order to increase the physical stability of nanoemulsions, stabilizers are gradually introduced. They stop the coalescence and agglomeration of droplets.

Hydrocolloids (such as xanthan gum, guar gum),
polymers (such as polyvinyl alcohol, polyvinylpyrrolidone),
proteins (such as gelatin, casein) are examples of common stabilizers.

g) Antioxidants: When a formulation comprises unsaturated oils, antioxidants are included to prevent oxidation of sensitive components.

Vitamin E (α-tocopherol),
butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT).

h) Preservatives: To stop microbiological development and guarantee the formulation's stability while being stored, preservatives could be required. Typical preservatives consist of: Parabens, such as

Propylparaben,
methylparaben,
benzalkonium chloride,
Sodium benzoate⁸.

METHODS OF PREPARATION

Techniques using High Energy

High pressure Homogenization Method

The method produces NEs with very fine particle sizes (up to 1 nm) using a high-pressure homogenizer and piston homogenizer. Two liquids (the oily phase and the aqueous phase) are forced through a tiny intake hole at a very high pressure using a high-pressure homogenizer in order to create dispersion.⁹

Fig. 3. High-pressure homogenization techniques¹⁰

Microfluidization

A device known as a microfluidizer is used in the Microfluidization process, which is a mixing technique at the microscale level. High pressure (between 500 and 20,000 psi) is applied to the fluids as they are driven through the microchannels during the microfludization process. In general, microchannels are tiny channels that permit mixing at the microscale. After mixing, the aqueous and oil phases of the macroemulsion are run through a microfluidizer. The macroemulsion enters the interaction chamber through the microchannels under high pressure¹¹ . Two fast-moving macroemulsion streams collide in the interaction chamber. Shearing, cavitation, and impact forces produced by this collision result in stable nanoemulsions¹².

Ultrasonication

When it comes to cleaning and operation, ultrasonication outperforms other high energy methods. During ultrasonic emulsifications, ultrasonic waves create cavitation forces that lead the macroemulsion to break into a nanoemulsion. Ultrasonicators are ultrasonic wave-producing probes used in this operation. The ultrasonic energy input and duration may be adjusted to achieve the desired particle size and stability of the nanoemulsion.The primary source of physical shear in ultrasonic emulsification is the acoustic cavitation process.The process of microbubble production, development, and collapse known as cavitation is brought on by variations in the sonic wave's pressure.The collapse of microbubbles produces intense turbulence that results in nanosized droplets ¹⁴.

Techniques using Low Energy

Phase Inversion Method

This method achieves fine dispersion by using the chemical energy that arises from phase shifts that take place during the emulsification process. Based on the idea that a polyoxyethylene-type surfactant's solubility varies with temperature, Shinoda et al. created the phase inversion temperature (PIT) approach. Either a composition changes at constant temperature or a temperature change at constant composition results in appropriate phase transitions. The polymer chain's dehydration causes the surfactant to become lipophilic as the temperature rises. The micellar solution phase becomes inflated with oil at low temperatures due to the significant positive spontaneous curvature of the surfactant monolayer. ¹⁵

Fig. 6. Phase inversion emulsification techniques ¹⁶.

Spontaneous Emulsification

It involves three main phases.

a) Hydrophilic surfactant, oil and lipophilic surfactant, and water miscible solvent combine to form a homogeneous organic solution.

b) After injecting the organic phase into the aqueous phase while swirling magnetically, an o/w emulsion is created.

c) Evaporation at lower pressure eliminates the water-miscible solvent.

A low energy approach for creating nanoemulsions is membrane emulsification. Surfactant is used relatively little in this process, which results in an emulsion with a restricted size distribution range. A dispersed phase that transforms into a continuous phase by way of a membrane is formed throughout this process. One of the method's drawbacks is its modest distributed phase flow across the membrane, which might cause problems when scaling up ¹⁷.

Solvent Evaporation Technique

This technique prepares an O/W emulsion by mixing a mixed medication with an organic solvent in a consistent phase, while using an acceptable surfactant. Subsequently, the organic solvent is evaporated using a vacuum, heating, or ambient conditions to produce drug-filled microspheres. This is followed by filtering or centrifugation ¹⁸.

Hydrogel Technique

This approach bears similarities to the solvent evaporation technique. To create a drug-solvent nanoemulsion that is miscible with the drug antisolvent, high shear forces are employed. Greater force strength inhibits the formation of gem crystals and Ostwald maturation ¹⁹.

Evaluation Parameters

Visual appearance

A transparent or calibrated glass cylinder can be used to analyze the appearance's uniformity and color at equilibrium.²⁰.

Viscosity

The viscosity of the formulations was tested to ascertain their rheological characteristics. This was accomplished using a CPE 61 spindle rotating at 30 rpm and a Brookfield Rheometer viscometer at 30°C. The three acquired findings were averaged and considered. ²⁰.

pH is a crucial component of nanoemulsions. The final preparation's pH and, thus, the administration route are determined by the constituents employed in the formulation. The preparation's stability may be impacted by the formulation's zeta potential, which may be impacted by a pH shift. The pH of the formulations was measured with a digital pH meter. It was determined by averaging the three sets of results. ²¹.

Determination of encapsulation efficiency

A specific amount of drug encapsulated in the formulation is extracted into an appropriate buffer after a weighed quantity of the formulation is ultrasonically dispersed in an organic solvent to release the drug.To determine the drug concentration, the extraction is diluted appropriately and compared to a suitable blank before being submitted to spectrophotometric examination at the drug's λmax.These formulas can be used to calculate the drug's entrapment efficiency (EE) and loading efficiency (LE)²⁷. High-performance liquid chromatography (HPLC) methods in the reverse phase might potentially be used to determine the drug content²².

Determination of zeta potential

The zeta potential is a method for figuring out the surface charge of a particle in a liquid. The physicochemical properties of the drug, polymer, and medium, as well as the presence and adsorption of electrolytes, all affect the value of the zeta potential, which is a helpful tool for predicting dispersion stability. It is measured using the Malvern Zetasizer apparatus. Zeta potential is calculated by diluting the nanoemulsion and using the electrophoretic mobility of the oil droplets to estimate its value. Zeta potential of ±30 mV is considered sufficient to ensure the physical stability of the nanoemulsion. ²³.

Dilution tests

For the o/w and w/o formulations, the maximum amount of water and oil were added, respectively, and the formulations were examined visually to ensure phase separation and clarity. Here, using water dilution, the formulation was visually examined 50 and 100 times for phase separation and clarity. The outcomes were measured in triplicate, and the average was used. ²⁴.

Centrifugation:

Verifying this characteristic's physical stability was the reason for its characterization. The nanoemulsion system was centrifuged for 10 minutes at 5000 rpm to look for signs of phase separation or creaming. The visual appeal of the system was evaluated.²⁵ .

Stability of Drug Nanoemulsion

The ampoules containing drug nanoemulsion formulation samples were stored in stability chambers at two different temperatures for a period of two months: ambient temperature (250C) and accelerated temperature (40±20C). At 0, 1, and 2 months, duplicate samples were taken out to assess their chemical and physical stabilities. Once the body had been diluted with water, the mean globule size and zeta potential were determined using a globule size analyzer. The stability of the body was evaluated visually for any physical changes (such as phase separation and drug precipitation). Chemical stability was defined as the drug's content as measured at 257 nm by UV visible spectroscopy²⁶ .

In vitro drug release

In vitro drug release for the nanoemulsion formulation should be carried out in order to evaluate and determine which formulation releases the greatest amount of drug release.The USP Dissolution apparatus Type II was used to conduct this test in 500 cc of phosphate buffer ph7.4 at 75 rpm and 37+0.5 0C. Two millilitres of a nanoemulsion formulation carrying ten milligrams of medication as a single dosage were added to a Himedia dialysis membrane 150 bag. At regular intervals of 0, 0.5, 1, 1.5, 2, 4, 6, and 8 hours, samples (5 mL) were removed, and an aliquot of phosphate buffer was added. The drug release from the nanoemulsion formulation was contrasted with that of the pure drug solution and the traditional tablet formulation. The UV-Visible spectrophotometer was used to measure the drug content of the samples at given lmax ²⁷.

APPLICATIONS OF NANOEMULSIONS

Nanoemulsions are often used to ensure that active pharmaceutical components are distributed appropriately across a range of routes, including as oral, parenteral, topical, ophthalmic, and transdermal. ²⁸

Fig. 7: Shows applications of Nanoemulsion

In Cosmetics

The potential use of nanoemulsions as carriers for controlled cosmetic delivery and ideal dispersion of active ingredients in targeted skin layers is growing in significance. Nanoemulsions are a better choice than liposomes for the transport of lipophilic compounds because of their lipophilic core. Certain properties of macroemulsions, including intrinsic creaming, sedimentation, flocculation, or coalescence, are absent from nanoemulsions and make them appropriate for use in cosmetic applications. With high-energy equipment, it is often feasible to avoid introducing potentially irritating surfactants during production. The use of nanoemulsions in personal care products has garnered a lot of attention lately as a way to distribute active chemicals in certain skin layers and administer cosmetics in a regulated manner.²⁹

In Transdermal Delivery

Many diseases and disorders, including depression, anxiety, Parkinson's and Alzheimer's diseases, cardiovascular conditions, etc., have attracted a lot of interest in this field because of the ease with which drugs can be delivered via the skin to the systemic circulation for a variety of clinical conditions.Products for transdermal medications have been developed.Nanoemulsion is quickly absorbed through skin pores and enters the systemic circulation, where it is channeled for efficient distribution ³⁰. Caffeine has been used orally for the treatment of many cancers. For transdermal medication administration, formulations containing oil and water nanoemulsion have been created. The permeability characteristics for the drugs added to the nanoemulsion significantly increased when the in vitro skin penetration profile of these and aqueous caffeine solutions was investigated. ³¹.

In Targeted Drug Delivery

To transport to the target region, the majority of nanosystems, including liposomes, dendrimers, nanoemulsions, nanoparticles, micelles, and nanocapsules, are being investigated in this instance. One benefit of nanoemulsion is that it allows for targeted medication distribution. On the other hand, targeted administration through certain cellular markers may boost medicinal agent efficacy and lower toxicity. Research is being done on nanoemulsions for the treatment, diagnosis, and prevention of cancer³².

Parenteral Delivery

Because of the stringent requirements for formulations whose droplet size is less than one micrometer for the intravenous route, nanoemulsions are advantageous. Parenteral, or injectable, nanoemulsion administration is utilized for nutrition (fats, carbs, vitamins, etc.), among other uses. A lot of research has been done on lipid nanoemulsion for parenteral drug delivery. Compared to coarse particle emulsion, nanoemulsion clears more slowly. and thusremain within the body for an extended length of time. Parenteral administration can be done with O/W and W/O nanoemulsions.¹⁸.

Topical Delivery

One of the main benefits of using topical medicine administration over other delivery methods is that the drug's hepatic first pass metabolism and its accompanying side effects may be avoided. Next, the drug's targetability and direct delivery to the affected skin or eyes. Only systemic antibiotics have been able to attain the amount of topical antibacterial activity that the nanoemulsion can. The broad-spectrum action of the nanoemulsion against bacteria and fungus ³³.

In Oral Drug Delivery

Peptides and proteins are components of several pharmaceutical drugs, which gives them incredibly potent and targeted physiological effects. These medicines can be protected from the digestive enzyme by being added to an oil matrix using a nanoemulsion. ³⁴.

In Ocular Delivery

The lacrimal secretion and nasolacrimal discharge in the eyes cause limited absorption and pharmacological efficacy when conventional eye drops are used to administer ophthalmic medications. When it comes to ocular administration, dilutable nanoemulsions provide a number of advantages over conventional drug delivery techniques, such as a longer impact and a high ability to reach deeper layers of the ocular tissue and aqueous humor. One way to address the problem of drug solubility in ocular medicine administration is to apply nanoemulsion. Catalytic nanoemulsions are ideal drug delivery vehicles for ophthalmic applications because they interact with negatively charged corneal cells to promote medicine absorption. ³⁵.

In Biotechnology

Enzymatic catalysis is used in nanoemulsions for a variety of purposes, such as steroid transformation, acetal synthesis of peptides and sugars, transesterification, and other hydrolysis reactions. ³⁶.

Compatibility of Different Components of Nanoemulsions

Nanoemulsions are complex systems where the compatibility of different components is essential for stability, functionality, and bioavailability. The key components of nanoemulsions include the oil phase, aqueous phase, surfactants, cosurfactants, and additives, and their compatibility affects the overall performance of the formulation. Below is an overview of the compatibility considerations for each component:

Oil Phase Compatibility

The choice of oil influences solubilization of active ingredients and stability.
Oils should be compatible with the surfactant and should not cause phase separation.
Examples:
- Medium-chain triglycerides (MCT) are commonly used due to their good emulsification properties.
- Essential oils and lipophilic drugs should be checked for solubility and potential interactions with surfactants

Aqueous Phase Compatibility

Typically water-based, but can include buffers, hydrophilic active ingredients, and preservatives.
Should not destabilize the surfactant layer or induce osmotic stress that leads to phase separation.
Electrolytes or pH-sensitive compounds may require additional stabilizers.

Surfactant and Cosurfactant Compatibility

Surfactant selection is crucial for emulsion stability and reduction of interfacial tension.
Surfactants must be compatible with both oil and aqueous phases.
Hydrophilic-lipophilic balance (HLB) value determines compatibility:
- High HLB (e.g., Tween 80) for oil-in-water (O/W) emulsions.
- Low HLB (e.g., Span 80) for water-in-oil (W/O) emulsions.
Cosurfactants (e.g., ethanol, propylene glycol) improve interfacial properties but should not cause destabilization by excessive solubilization.

Additives Compatibility

Preservatives (e.g., parabens, benzyl alcohol) must be soluble in one of the phases without affecting the nanoemulsion’s stability.
pH modifiers (e.g., citric acid, sodium hydroxide) should be used carefully to avoid disrupting surfactant structure.
Polymers or stabilizers (e.g., Xanthan gum, PEG derivatives) must not lead to coalescence or flocculation.

Overall Compatibility Considerations

Droplet Size & Zeta Potential: Should be monitored to avoid aggregation.
Thermodynamic Stability: Avoid phase separation, Ostwald ripening, or creaming.
Temperature & Storage Conditions: Some components may degrade at high temperatures.

Some Examples of Pharmaceutical Nanoemulsions:

Example 1: Cannabidiol (CBD) Nanoemulsion

Oil Phase: Medium-chain triglycerides (MCT) oil
Surfactant: Polysorbate 80 (Tween 80)
Cosurfactant: Ethanol (5–10%)
Aqueous Phase: Water + glycerin
Additives: Sodium benzoate (preservative), citric acid (pH adjuster)
Compatibility Notes:
- MCT oil has good solubility for CBD and works well with Tween 80.
- Ethanol enhances solubility but should be optimized to avoid phase separation.
- Citric acid ensures stability at pH ~4–6.

Example 2: Curcumin Nanoemulsion

Oil Phase: Caprylic/capric triglycerides
Surfactant: Soy lecithin
Cosurfactant: PEG-40 hydrogenated castor oil
Aqueous Phase: Phosphate-buffered saline (PBS)
Additives: Ascorbic acid (antioxidant)
Compatibility Notes:
- Lecithin stabilizes the system and enhances bioavailability.
- PEG-40 hydrogenated castor oil prevents droplet aggregation.
- Ascorbic acid protects curcumin from oxidative degradation.

Food-Grade Nanoemulsions:

Example 3: Essential Oil Nanoemulsion (e.g., Lemon Oil)

Oil Phase: Lemon essential oil
Surfactant: Sodium caseinate
Cosurfactant: Maltodextrin
Aqueous Phase: Water
Additives: Xanthan gum (stabilizer)
Compatibility Notes:
- Sodium caseinate stabilizes the essential oil droplets.
- Maltodextrin improves dispersion.
- Xanthan gum prevents phase separation and increases viscosity.

Example 4: β-Carotene Nanoemulsion

Oil Phase: Corn oil
Surfactant: Tween 20
Cosurfactant: Glycerol
Aqueous Phase: Water
Additives: Sodium citrate (pH buffer)
Compatibility Notes:
- Corn oil provides excellent solubility for β-carotene.
- Tween 20 ensures small droplet size.
- Glycerol prevents excessive coalescence.

Cosmetic & Skincare Nanoemulsions:

Example 5: Vitamin E Nanoemulsion

Oil Phase: Tocopherol (Vitamin E) in Jojoba oil
Surfactant: Polyglyceryl-10 oleate
Cosurfactant: Propylene glycol
Aqueous Phase: Aloe vera extract
Additives: Hyaluronic acid (moisturizer)
Compatibility Notes
- Jojoba oil mimics skin lipids, enhancing bioavailability.
- Polyglyceryl-10 oleate ensures mild, skin-friendly emulsification.
- Aloe vera extract hydrates the skin without destabilizing the nanoemulsion.

Example 6: Sunscreen Nanoemulsion

Oil Phase: Octyl methoxycinnamate (UV filter) in coconut oil
Surfactant: Sodium lauryl sulfate (SLS)
Cosurfactant: Ethanol
Aqueous Phase: Water
Additives: Titanium dioxide nanoparticles (UV-blocking agent)
Compatibility Notes:
- Octyl methoxycinnamate dissolves well in coconut oil.
- Ethanol enhances solubilization but should be used in controlled amounts.
- Titanium dioxide disperses effectively in the aqueous phase.

Conclusion

Nanoemulsions are transparent, isotropic, thermodynamically stable liquid mixtures of water, oil, surfactant, and co-surfactant. They are the most effective dosage form for safeguarding labile drugs, regulating drug release, boosting the solubility of weakly water-soluble drugs, increasing bioavailability, and reducing patient variability. These days, nanoemulsions can be made for a variety of delivery methods. For the administration of medications, nanoemulsion formulation can be considered an effective, safe, and patient-compliant formulation. This can be achieved by controlling variables like the type and quantity of cosurfactant and surfactant, the type of oil phase, the techniques used, process variables, and additives.

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