1. INTRODUCTION:

The insurmountable issue of modern medication renders the creation of drug delivery systems very difficult. Almost 40% of the freshly created capsules have limited aqueous solubility1. Extreme bioavailability results from the limited solubility and, ultimately, limited discharging capacity of the tablets in gastrointestinal fluids.

Several strategies can be used to improve bioavailability, including the use of surfactants, salts, micro pulverization, reduction of particle size, high dispersion, liposomes, microemulsion, complexation, nanoparticles, nano/microspheres, prodrugs, and penetration enhancers. Lipid formulations, which have gained popularity lately, are used to enhance the oral bioavailability of poorly soluble medications. There are two types of self-dispersible lipid formulations:

· Self-emulsifying drug shipment system (SEDDS) and

· Self-microemulsifying drug shipment device (SMEEDS)7

Figure 1: Capsule dosage form containing microemulsion

The term SMEDDS 6Y (Type III B structures) refers to an isotropic mixture consisting of natural or synthetic oils, liquid or solid surfactants, or one or more hydrophilic solvents and co-solvents/surfactants which on mixing and dilution with aqueous fluid (GI fluid) yield acceptable oil-in-water (o/w) microemulsions with minimal agitation. The systems are prepared using the liposome supplier that would facilitate enhanced GI absorption of the poorly water-soluble capsules; protect the drug from enzymatic degradation; be easily prepared, thermodynamically stable, and appropriate for oral drug delivery. The oil component in this type of system helps solubilize the hydrophobic drugs so as to enhance drug loading and improve its bioavailability. As a result, oral administration of drugs is much easier, cheaper, and non-invasive compared to other modes of drug administration. Therefore, the drugs should have some aqueous as well as lipid solubility when considering their administration orally. In case the chemical entity under consideration has no aqueous solubility, oral administration cannot be an ideal way of delivering the drug to the body. Oral administration of poorly water-soluble drugs This is among the new ways of overcoming the aforementioned challenges.

Formulation strategies such as enhancing the rate of dissolution or dissolving the drug in solution form and maintaining it in that form within the intestine may be used to improve the bioavailability of drugs in class II. Through careful consideration of formulation, bioavailability for drugs in class IV may be improved. Although the bioavailability of class IV drugs may be hampered by the low permeability of the membrane, formulation may still help improve bioavailability. A drug belonging to class II whose absorption profile resembles that of a drug belonging to class I can be achieved if the drug remains solubilized in the gut lumen. Formulations may not help in the absorption of drugs in classes IV and III^1.

Table 1: Representative Drug Examples for BCS Classes

Class I	Class II	Class III	Class IV
Amiloride	Artemether	Abacavir	Albendazole
Abacavir	Dapsone	Allopurinol	Indinavir
Diazepam	Folic acid	Biperiden	Furosemide
Diltiazem	Ibuprofen	Captopril	Mesylate
Ethambutol	Itraconazole	Metformin.HCL	Nelfinavir

Figure 2: Typical representation of biopharmaceutical classification system

2. History:

The term "microemulsion" was introduced by chemistry professors Hoar and Shulman from Cambridge University back in 1943. Microemulsions are formed by:

1. Reducing the interfacial tension at the oil/water interface to a very low value, and

2. Providing maximum flexibility and fluidity in the interfacial layer.

A simple addition of a "co-surfactant" that contributes to the flexibility of the oil/water interface and precise proportioning of the mixture of components usually suffices in ensuring the above conditions are met. In such cases, it results in the formation of the most thermodynamically favorable structure that remains stable relative to normal emulsions without requiring any large input of energy for its creation (in the form of agitating). Microemulsions are transparent, and the structure of microemulsion cannot be observed through optical microscopy since the particles involved have sizes much smaller than the wavelength of light ^[2]
.

3. Why Sedds Are Needed:

SEDDS is a technique that can deliver poor solubility drugs through oral route. SEDDS can be prepared by putting the drug in solution state before filling the formulation in capsule form. SEDDS could be useful in administering oral hydrophobic drugs. The key benefit of using SEDDS lies in its ability to bypass the first rate limiting step of particle dissolution in aqueous environment of the GI tract. However, during dispersion in the GI tract, there exists the possibility of drug precipitation. The use of hydrophilic solvent, such as polyethylene glycol, will increase the likelihood of drug precipitation. Fewer drug precipitates will occur when using a lipophilic solvent for drug delivery due to partition kinetics that favours retention of drug molecules in lipid droplets.^3.

4. Self Micro Emulsifying Drug Delivery Systems:

In cases where agitation under mild conditions followed by dilution in aqueous environments, such as GI fluids, occurs, SMEDDS can be referred to as isotropic blends of natural and/or synthetic oils, solid and/or liquid surfactants, or alternatively, hydrophilic solvents in combination with either or both co-solvent(s) or surfactant(s). The gastric and intestinal motility serves as agitation in self-emulsification for SMEDDS, hence making the process easy for SMEDDS to get distributed throughout the GI tract. Self-emulsifying drug delivery systems (SEDDS), which are alternatively referred to as self-emulsifying oil formulation (SEOF), are different from SMEDDS in that SMEDDS gives rise to transparent microemulsion with droplet size below 50 nm whereas SEDDS form opaque emulsions with droplet sizes varying from 100-300 nm. Also, SMEDDS contain lower amount of oil (20%), while SEDDS contain higher amounts of oil (40%-80%). Emulsions are metastable and susceptible dispersions while SMEDDS are stable to manufacture. Therefore, these systems have the potential to improve rate and extent of absorption rate and produce more consistent blood-time profiles of lipophilic drugs, which have rate limiting absorption due to their dissolution limits.⁴

5. Types of Smedds/Microemulsion:

Winsor identified four distinct types of microemulsion phases that are present in an equilibrium; these phases are known as Winsor phases. What they are is:

1. Winsor 1: in two phases, the upper excess oil phase is in equilibrium with the lower (o/w) microemulsion phases.

2. Winsor 2: containing two phases, the upper (w/o) phases being microemulsion phases in balance with less liquid surplus.

3. Winsor 3: this three-phase system has equilibrium between upper and lower excess oil and water, with the middle microemulsion phases (o/w plus w/o, or bicontinuous).

4. Winsor 4: With oil, water, and surfactant thoroughly combined in single phases ⁵

6. Formulation/Composition of Smedds:

Despite numerous oils and surfactants available as constituents of microemulsion formulation, the application of such ingredients is highly constrained due to their possible toxicity and ability to cause irritations, as well as unknown mechanisms of their action. The creation of gentle and non-aggressive microemulsions requires using appropriate concentration and quality of emulsifiers, that should be biocompatible, non-toxic, and approved for clinical applications. It was discovered early that the nature of the oil/surfactant combination, concentration and oil/surfactant ratio, concentration and composition of co-surfactant and surfactant/co-surfactant ratio, as well as temperature of self-microemulsification reaction are all specific factors influencing the formation of self-microemulsion system. The fact that only certain excipients combinations allow obtaining effective self-microemulsifying formulations has significantly strengthened this discovery.

Table 2: Comparison of microemulsion with conventional Emulsion

S. No	Property	Microemulsion	Emulsion
1	Appearance	Transparent (Translucent)	Cloudy
2	Optical isotropy	Isotropic	Anisotropic
3	Interfacial tension	Ultra low	High
4	Microstructure	Dynamic (interface is continuously and spontaneously fluctuating)	Static
5	Droplet size	20-200nm	>500nm
6	Stability	Thermodynamically stable, long shelf life	Thermodynamically unstable & kinetically stable
7	Phases	Monophasic	Biphasic

SMEDDS Formulation Contains Following Components: Table

1. Oil phase

2. Surfactant

3. Secondary surfactant (co-surfactant/co-solvent)

4. Active agent (Drug)

1. Oils:

The choice of the triglyceride molecule determines the type of oil that is one of the key elements of the SMEDDS formula because the oil can facilitate self-emulsification and dissolve the amount of the lipophilic medication required while enhancing the transportation of the drug by the intestine lymphatic system. Self-emulsifying formulations can be developed with either short or medium chain triglyceride (MCT) oils with different levels of saturation. Due to their inability to dissolve many lipophilic medications, edible oils are not preferred. Hydrolyzed or modified vegetable oils are commonly applied because they act as good emulsifiers with many surfactants that are allowed to use orally with high solubility. Semi-synthetic or amphiphilic derivatives of the medium chain are slowly replacing the traditional medium chain triglyceride oils in SMEDDS. According to Deckelbaum (1990), MCT exhibits more mobility and solubility at the interface between the lipid/water than LCT, resulting in a higher rate of MCT hydrolysis compared to LCT. In general, the application of LCT rather than MCT requires a higher dosage of cremophor RH40 to develop microemulsions.

2. Surfactants:

There are several classes of surfactants based on the hydrophilic group present in the molecule. As pointed out by Khoo (1998), there are four types of surfactants, namely,

i. Anionic Surfactants:

In cases where the hydrophilic group, such as carboxyl (RCOO-), sulphonate (RSO3-), or sulphate (RO-SO3-), is negatively charged. Two examples are sodium lauryl sulphate and potassium laurate.

ii. Cationic Surfactants:

In this case, the hydrophilic group carries a positive charge Ammonium halide, for example, is a quaternary compound.

iii. Ampholytic surfactants (also known as zwitterionic surfactants)

In this type, the hydrophilic group carries both positive and negative charges. Sulphobetaines, for instance.

iv. Non-ionic surfactants:

If the hydrophilic group is highly polar and charge-free, the water solubility of such compounds can be provided by highly polar groups, such as hydrox-yl or polyoxyethylene (OCH2CH2O). Illustrative examples are polysorbates and sorbitan esters. Nonionic surfactants with high hydrophilic-lipophil

3. Co-surfactant and co-solvent:

The addition of co-surfactant can help decrease the amount of surfactant needed to make an optimal SMEDDS. In general, there must be greater than 30% w/w surfactant. The role of the co-surfactant together with the surfactant is to decrease the interfacial tension to a minimum or even to a negative value. Under this condition, the interfacial tension would expand itself and form small droplets. Then the droplets would take up additional surfactant and surfactant/co-surfactant until such time that the bulk properties become low enough to bring back the interfacial tension to a positive value ^6.

4. Active Ingredient:

For SMEDDS to keep the API in its dissolved state, the API should dissolve in the oil phase. This makes SMEDDS difficult to work with when dealing with drugs that have poor solubility in lipids or water. If the drug does not have very good solubility in either the oil phase or any other component of SMEDDS, then it cannot be used for formulations, especially in high doses. The API should ideally have a log p value greater than 2 ⁷

7. Drug Incorporation In SMEDDS:

Since they are highly hydrophobic in nature and thus unable to dissolve in most solvent solutions, there is difficulty in formulating poorly aqueous soluble drugs due to their inability to be dissolved in solvents. Drugs that are insoluble will have higher dissolution in new synthetic hydrophilic oils compared to natural vegetable oils. Introduction of other solvents such as propylene glycol (PG), polyethylene glycol (PEG), and ethanol might increase the solubility of the drug in the lipid system. This depends on the physicochemical compatibility of the two. The optimal oil/surfactant ratio is normally modified due to the partial inhibition of the self-emulsification process by the drug. Complex formation between the drug molecule and one of the mixture components via interaction with the LC phase or absorption into the interfacial monolayer of the surfactant are two possible routes for modification of the performance of SMEDDS. It is possible that there will be a modification in the droplet size distribution that differs according to the concentration of the drug molecule, resulting from the inhibition of self-emulsification processes by the drug molecule. In complex systems where small oil droplets are present in the emulsion, the presence of the drug molecule results in modifications.⁸

8. Method of Preparation:

8.1 Phase Titration Method:

Spontaneous emulsification technique (or phase titration method) is employed for the formation of microemulsions, which may be demonstrated through the use of phase diagrams. During the process of mixing different compounds, the complicated network of reactions may be examined by constructing phase diagrams. Apart from microemulsions, various association formations like emulsion, micelles, lamellar, hexagonal, cubic, and numerous gel and oily dispersions are created in response to the nature and composition of different components. The understanding of their phase equilibria and determination of phase boundaries are essential elements of the experiment. As the preparation of quaternary phase diagrams (four-component systems) is complicated and time-consuming, the pseudo ternary phase diagrams are prepared in order to determine the different regions, including the microemulsion region, in which each corner of the graph indicates the presence of 100 percent of the particular component. It may simply be differentiated between w/o and o/w microemulsions by looking at the composition or whether it is oil or water-rich.

8.2 Phase Inversion Method:

Phase inversion of microemulsions occurs due to excessive use of the dispersed phase or changes in temperature conditions. Physical properties such as particle size and others observed during phase inversion can influence the process of drug release both in vitro and in vivo. These processes occur by modifying the spontaneous curvature of the surfactant. An o/w microemulsion will be made to transition to w/o microemulsion by varying the temperature of the system with regard to the non-ionic surfactants. In order to aid in forming fine oil droplets, the system passes through a region of zero spontaneous curvature and low surface tension as it undergoes cooling. This method is termed as phase inversion temperature (PIT). Other parameters apart from temperature may be considered, including pH and salt content. Changing the spontaneous radius of curvature can be attained through varying water volume fraction in the mixture. In this case, the water is gradually introduced into oil to create water droplets in an unvarying oil phase. Initially, the water volume fraction is used to stabilize a w/o microemulsion. However, changing the spontaneous curvature of the surfactant, an o/w microemulsion can be obtained at the inversion locus.⁹

9. Formulation Design:

The formulation design of SMEDDS requires the following procedures.

· Excipient screening.

· Pseudoternary phase diagram development.

· SMEDDS preparation.

· SMEDDS characterization.

9.1. Excipient Screening:

9.1.1. Solubility Studies:

Such studies facilitate the prediction of in vivo drug precipitation and will mainly help in selecting appropriate excipients for SMEDDS formulations In this regard, it is necessary to determine the drug's solubility in various oils, surfactants, and cosurfactants Such solubility studies are usually conducted using the shake flask approach and require the addition of a large excess of the drug to the excipient followed by shaking for 48 hours at room temperature using an air oscillator or water bath shaker. This should further be followed by drug content determination through centrifugation of the solution, followed by filtration of the solution through a 0.45 μm filter. The main objective in such solubility studies is usually to determine the surfactants and cosurfactants that will solubilize the drug effectively and oils that dissolve well with the drug.

9.1.2. Selection of Surfactants and Cosurfactants for Their Self-Emulsification Properties:

The determination of the self-emulsifying properties of surfactants may be achieved by mixing equal volumes of the selected oil and surfactant. After homogenizing, the mixture may then be added to distilled water to establish the degree of ease at which the formation of the emulsion occurs.

9.2. Construction of Pseudoternary Phase Diagram:

Depending on the composition, the following diagram illustrates the behavior of the phase within the system. In order to study the phase behavior of three components, a ternary phase diagram is used. For SEDDS, it refers to the three-component system consisting of water, oil, and surfactant. But in SMEDDS, the common addition would be the cosurfactant or cosolvent. The three vertices in the ternary diagram indicate that the component could accommodate 100% of its capacity. When there is a fourth component in the system, then it may be considered a Pseudoternary phase diagram since one of the corners indicates the combination of two components, for example, cosurfactant and surfactant.

Figure 1: Pseudo ternary phase diagram

Mixtures having differing ratios of the components used in microemulsion formation should be checked for their emulsification efficacy, which helps in drawing up Pseudoternary phase diagrams Phase diagrams help in knowing the extent of formation of various structures like emulsions, microemulsions, micelles, inverted micelles or otherwise. This phase diagram also helps to assess the extent of dilatability and also helps to know about various composition leading to a monophasic system Two of the four ratios of the components used are kept constant in case of Pseudoternary diagrams and along with the remaining two components; these ratios become the three sides of the phase diagram Normally, the mixture of surfactant and cosurfactant makes the ratio fixed, but sometimes oil and surfactant mixture ratio becomes constant In addition to this ratio, one more component like oil or cosurfactant in required proportion is taken. Finally, the fifth component which normally will be water is added little by little and then solution is checked for clarity, fluidity, self-emulsification time and dispersibility Each mixture must contain all its components at 100% concentration

Next, you can use the right software for plotting the Pseudoternary diagram. On the phase diagram, proper symbols can be used to mark the sample points that have made a homogeneous solution. This will give an area that represents the present area of the monophasic microemulsion If there is a large area, then the emulsification efficiency is high.

9.2.1. Interpretation of a Ternary Diagram (Figure 3):

The following guidelines may be helpful to interpret ternary diagrams easily.

In a conventional ternary diagram, three materials, A, B, and C, are represented by three vertices. An increase in the percentage of A from zero percent concentration (B point) to one hundred percent concentration (A point) is shown by an arrow pointing towards BA, an increase in the percentage of C from zero percent concentration (A point) to one hundred percent concentration (C point) is shown by an arrow pointing towards AC, and an increase in the percentage of B from zero percent concentration (C point) to one hundred percent concentration (B point) is shown by an arrow pointing towards CB.

The composition at point “O” will be determined using the below information.

(i) A line can be drawn from point O to AB such that it will be parallel to CB. Percent composition of A at point O (X) will be identified by the intersection of the line on AB.

(ii) Using another line that is parallel to AC towards BC will help determine the percentage composition of B at point O. Point O (Y) percent composition of B will be shown by the intersection of this line on BC.

(iii) Similarly, a line parallel to AB towards AC (Z) can be used to identify the concentration of C at point O.

9.3. Preparation of SMEDDS:

The drug can be added into a blend of oil, surfactant, and cosurfactant and mixed by means of vortexing In certain cases, the drug will be dissolved in an excipient, and the drug solution will be subsequently mixed with other excipients. The solution must now be well-mixed and analysed for signs of turbidity. If necessary, the solution will have to be heated so that a clear solution can be formed after 48 hours of equilibration.

9.4. Evaluation/Characterization of SMEDDS:

9.4.1 Visual Assessment:

Visual inspection of the process of self-emulsification permits evaluation. If, on visual inspection, the resultant diluted SMEDDS is clear, isotropic, and transparent upon dilution with water, it means that microemulsion has been formed. The formation of macroemulsion is indicated by its opaque and milky white nature.

9.4.2 Droplet Size Analysis:

Droplet size in SMEDDS depends primarily on the type and amount of surfactant used. The formation of a microemulsion through the dilution process results in very narrowly distributed droplets to ensure the effective drug delivery and stability in vivo. Droplet size analysis may be performed using photon correlation spectroscopy techniques and microscopic techniques. Droplet size may also be analysed using the dynamic light scattering technique using the Zetasizer.

9.4.3 Measurement of Zeta Potential:

There are two main devices that have been used for measuring the zeta potential, namely, zeta potential analysers and zeta meters after the correct dilution process, the zeta potential will reveal the stability of the emulsion. The higher the zeta potential, the greater the stability. The zeta potential is generally negative because of free fatty acid presence; however, a positive charge is attained when using a cationic lipid such as oleylamine there is an expectation of high adhesion and increased absorption due to the positively charged droplets interacting effectively with the GIT lining.

9.4.4 Self-Emulsification Time:

The dissolution test method USP type II, which entails dripping the formulation into the basket filled with water and observing the appearance of a transparent solution as the paddle rotates at 50 rpm, may be used for estimating generally the time needed for self-emulsification of the formulation. The assessment of self-emulsification helps determine the level of self-emulsification of the formulation.

9.4.5 Viscosity Measurements:

Generally, a rheometer device such as the rotating spindle Brookfield viscometer or the Brookfield cone and plate rheometer with cone spindle attachment is used for measurement of viscosity in dilutions of SMEDDS that form microemulsions. Creation of a microemulsion of O/W type from W/O microemulsion through bicontinuous phase is demonstrated through initial increase then subsequent decrease in viscosity as a function of water amount due to water percolation threshold effect Plot of shear stress against shear rate gives an idea about rheology of a microemulsion. Spherical droplets are seen in this case because of Newtonian behaviour of the liquid.

9.4.6 Dilution Studies:

Dilution of the microemulsion preconcentrate to several levels that mimic the physiological conditions of the stomach and in several diluents including double distilled water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) enables evaluation of the effect of dilution on the clarity of the microemulsion. The absence of variation in type of diluent and clarity in high dilution suggests that there is no precipitation of drugs. Diluting SMEDDS 100 times with the above diluents reproduces in vivo conditions Dilution of SMEDDS with a number of solvents including buffer pH 1.2, buffer pH 6.8, etc., along with distilled water can be employed to determine the effect of pH of the dilution media.

9.4.7 Refractive Index:

Refractive index is the property that is used to investigate isotropic behavior of diluted SMEDDS, or microemulsion. After analysing refractive index values of optimized formulation at temperatures 4°C and 25°C up to six hours in different time intervals, Karamustafa and Ćelebi concluded that there was no any change in refractive index of the formulation; therefore, microemulsion structure was stable Stability of microemulsion structure thermodynamically is confirmed by constant refractive index value Refractometer is used for determination of the refractive index value. There are two parameters that influence on refractive index: cosurfactant content and globule size. Increasing globule size increases the refractive index, while increasing cosurfactant concentration decreases it because of the decreasing microemulsion rigidity.

9.4.8 Percent Transmittance:

This test determines the transparency of the diluted SMEDDS formulation. It is determined by spectrophotometry with the diluted formulation in water that serves as a blank. The higher the value closer to 100%, the clearer and more transparent the microemulsion will be.

9.4.9 Transmission Electron Microscopy (TEM) Experiment:

Its main purpose is to analyse the morphology and structure of the produced microemulsions via the dilution of SMEDDS. The analysis is made via diffraction methods with bright-field visualization at magnifications. Morphology can be assessed by diluting SMEDDS on a holey carbon film.

The authors of and stained their samples for TEM investigation. In both experiments, one drop of diluted formulation was placed on a copper grid, stained, for example, with uranyl acetate, dried, and the size and morphology of the droplets were investigated. Moreover, other stains can be used, including, for example, 1% phosphotungstic acid and 1% methylamine vanadate solution Also, TEM can be used to investigate the homogeneity of droplet size distribution.

9.4.10 Differential Scanning Colorimetry:

This technique is mostly used for characterizing microemulsions that are prepared from diluted SMEDDS through water-equivalent peaks. This peak gives information regarding the state of water, either free or bound With pure water serving as a control sample, the freezing point is represented by an intense peak around -17°C. Bound water is contained within microemulsions; it may be bounded by surfactants. According to the DSC analysis performed by Podlogar et al. on the water-Tween 40/Imwitor 308-isopropyl myristate microemulsion system, they detected peaks representing water at temperatures below that of pure water (approximately at -45°C at 15% w/w). Any increase in water concentration beyond this will result in increased temperatures. Based on their thermal behavior of water, they concluded that O/W microemulsions are formed when there is high water content (>35% W/W).

9.4.11 Techniques of NMR:

It can be applied in determining the structure of the microemulsion that arises because of the process of diluting SMEDDS. The Fourier transforms pulsed gradient spin-echo (PGSE) approach can be used for studying the diffusion of microemulsion composition. The PGSE-NMR technique is utilized for determining the effects that arise due to dilution from the microemulsion stage to the bicontinuous phase. It is possible to measure the droplet size of the microemulsion through 129xe NMR, where there is a shift towards the high field that corresponds to the increase in the droplet size. The self-diffusion NMR technique is useful in determining the kind of microemulsion formed. They are also utilized to determine transitions such as W/O to bicontinuous and bicontinuous to O/W as the concentration increases gradually. The diffusion coefficient of different microemulsions is determined by comparing the value obtained with the diffusion coefficient of pure components. If one component diffuses at a slower rate compared to the diffusion of the pure component, then the formation of O/W or W/O drops occurs. The surfactant and cosurfactant also diffuse slowly since they form a membrane around the drops. In a case where the diffusion coefficients of both the oil and water phases are fast and similar to the pure components, bicontinuous microemulsion exists.

9.4.12 In vitro Release Pattern:

The dialysis method at 37±0.5°C or the USP XXIII dissolution apparatus I at 100rpm or the USP XXIII dissolution apparatus II at 50rpm can be used for evaluating the drug release pattern from the formulation before its filling into hard gelatine capsules. To evaluate the amount of drug release and compare it with that of the controls, sampling needs to be done at appropriate intervals. The polarity of the oil droplets influences the amount of medication released by the dilute SMEDDS formulation. Drug release occurs faster from the oil droplets into the aqueous environment the higher the polarity. The main factors that determine polarity include the hydrophilic-lipophilic balance of the surfactant, concentration of its hydrophilic moiety, molecular weight, and unsaturation of fatty acid residues.

Comparison of Drug Release from Paddle Type Apparatus and Reciprocatory Cylinder Apparatus has been made in a study conducted by Jantratid et al. It was found that the USP apparatus 3, which consists of the reciprocating cylinder (Bio-Dis), is more suitable than the paddle method for drug release studies for liquid lipid-based formulations, including SMEDDS. Moreover, the results have been found to be reproducible for this method of drug release determination. According to the study, this type of response was due to the uniform break-up of the oil layer using mesh inserts.

9.4.13 Thermodynamic Stability Tests:

The effect of temperature variations on the formulation can be determined through these tests. Following dilution with an aqueous medium, the formulation is subjected to centrifugation at 15,000rpm for 15 minutes or 3500rpm for 30 minutes Formulations that do not exhibit phase separation undergo freezing and thawing processes at temperatures of -20°C and 40°C, respectively. The appearance of the formulation remains unaltered in case of thermodynamically stable formulations.¹⁰

10. Mechanism of Emulsification:

Several techniques have been discussed in the literature. The mechanism of formation of microemulsions cannot be described through one theory. Droplets of emulsions are formed due to the film being formed as a result of interaction of surfactant and co-surfactant at the oil-water interface. From the point of thermodynamics, emulsification takes place when free energy required for increasing the surface area of both oil and aqueous phases is lesser than entropy required for favoring dispersion. Free energy (G) will be changed during the process of emulsification and can be mathematically represented as under: G = ∑N φ r2 where G is free energy of the process (excluding free energy of mixing), N is the number of droplets, r is the droplet radius and G is the interfacial energy with time. In order to minimize the interfacial area and hence reduce the free energy, normally two phases of emulsions exist independent of each other. As such, emulsifying agents act to stabilize the emulsions forming monolayer of droplets and eventually reducing the interfacial energy¹¹.

Oral administration of SMEDDS

11. Dosage Form Development of S-SMEDDS:

11.1 Dry Emulsions:

Dry emulsions can be defined as powders which are capable of forming an emulsion either in the body or when mixed with an aqueous solution. Dry emulsions are useful in the preparation of tablets and capsules. O/W type of emulsion is preferred for dry emulsion formulation. In this process, O/W emulsions can be prepared by methods such as rotary evaporation 28, freeze-drying 29 or spray drying 30, 31 using a solid carrier (e.g. lactose, maltodextrin) in the aqueous phase. By using rotary evaporation technique, Myers and Shively successfully made solid glass emulsions in dry "foam" form using sucrose and heavy mineral oil. An advantage with the emulsifiable glasses is that it does not require any surfactant. It has been observed that for freeze-drying method of stabilization, slow freezing rate and presence of amorphous cryoprotectant are required whereas heating before thawing decreases stabilization effect. In case of dry emulsion formation, spray drying is preferred technique 32. Preparation of O/W emulsion followed by elimination of aqueous phase by spray drying process. The recent development in this field appears to be enteric coated dry emulsion.

A formulation has been developed that can be used for oral delivery of protein and peptide drugs. In this regard, a pH-sensitive polymer, along with a vegetable oil and a surfactant, were lyophilized to develop the formulation.

11.2 Self-Micron Emulsifying Capsules:

Microemulsions are formed when capsules containing conventional liquid SME formulation are administered; thereafter, microemulsion droplets are dispersed in the GI tract to attain absorption. Nevertheless, it cannot be predicted whether an improvement in the drug's absorption profile will occur in case there is irreversible phase separation of the microemulsion. To tackle this problem, SME formulation 33 is designed by incorporating sodium dodecyl sulphate in it. Supersaturable SMEDDS was prepared for the same purpose where a little bit of HPMC (or other polymers) was included in the formulation in order to develop supersaturated state in vivo and prevent drug precipitation 34, 35. It is also possible to fill capsules with liquid SE compositions in a solid or semi-solid state using solid carriers (absorbents, polymers, and so on). For example, a solid matrix of PEG can be chosen. Upon contact with water, the solid PEG did not impact the dissolution characteristics of the drug and self-emulsifying process 36, 37. The SME capsules taken by mouth have proven to enhance patients' compliance as opposed to the parenteral method that was used before. For example, low molecular weight heparin (LMWH) was available in clinical use solely via a parenteral administration, and it was used for the treatment of venous thromboembolism. So, the development of the oral LMWH treatment in hard capsules was considered. The dispersing of LMWH in SMEDDS was followed by the solidifying of the resulting mixture into powder form using three types of absorbents: silicon dioxide, magnesium aluminium silicate, and microporous calcium silicate. Eventually, the SME hard capsules were filled with those solids 38. Similarly, other absorbents were used in the preparation of SME tablets containing gentamicin. This antibiotic was only administrated topically or injectively in clinics.

11.3 Self-Micron Emulsifying Sustained / Controlled Release Tablets:

Many studies have been conducted in order to study the possibility of the utilization of lipids and surfactants in the preparation of SME tablets. In order to reduce significantly the amount of solidifying agents in making SEDDS solid dosage form, gelled SMEDDS was developed. Colloidal silicon dioxide (Aerosil 200) was used as a gelling agent in the oily system. The drug release rate was reduced while at the same time reducing the required solidifying agents. For example, the use of SE tablets can increase the effectiveness of penetration through the GI mucosal membrane thus avoiding GI bleeding. SE tablets are extremely useful in preventing adverse effects. During the same time period, the SME tablets sustained significantly high concentrations of the active drug in the bloodstream compared to a non-emulsifying tablet 39. An SME osmotic pump tablet, which represents the latest innovation in the field of SME tablet studies, utilizes the primary osmotic pump technology as a carrier. Unlike commercially available carvedilol tablets 40, the advantages of the system include stable plasma concentrations and regulated drug release, leading to increased bioavailability of 156.78%. available online at: www.ijpsr.com 3556 International Journal of Pharmaceutical Sciences and Research (IJPSR), Volume 3(10), pp. 3550-3558, Yetukuri and Sudheer, ISSN: 0975-8232, 2012. available online at: www.ijpsr.com 3557

11.4 Self-Micro Emulsifying Drug Delivery System (SME):

Pellets provide several advantages over conventional solid dosage forms as a dosage form, such as reduced variability in plasma profiles between subjects, reduced gastrointestinal irritation without any compromise to drug absorption, and manufacturing advantages. Therefore, it becomes necessary that SME pellets combine the advantages of SMEDDS and pellets together.

11.5 Self- Micron Emulsifying Solid Dispersions:

Solid dispersions have the potential to improve the bioavailability and rate of dissolution of poorly water-soluble medications; however, there are issues with stability and manufacturing. Excipients can be added to PEG solid dispersions to improve the absorption of poorly water-soluble medications. They can also be melted and poured straight into hard gelatine capsules, eliminating the need to first mill and blend before filling. TPGS (tocopherol polyethylene glycol 1000 succinate), Labrasol1, Gelucire1 44/14, Gelucire150/02, and other SME excipients have been extensively utilized in this field 42–45.

11.6 Self-Micron Emulsifying Suppositories:

According to a few studies, apart from GI absorption, SME can also improve adsorption in the rectal/vaginal areas 46. For example, the compound glycyrrhizin, which is taken orally and very rarely attains therapeutic plasma levels, can be delivered using vaginal/rectal SME suppositories to ensure sufficient therapeutic levels for the treatment of chronic liver ailments.

11.7 Self-Micron Emulsifying Implants:

The study of SME implants has greatly enhanced both the utility and efficiency of S-SMEDDS. For instance, 1,3 bis (2 chloroethyl)-1 nitrosourea is used as a chemotherapeutic agent for malignant brain tumours. Its inefficiency could be attributed to its short half-life. It was improved compared to that delivered by poly (d, l lactide co glycoside) (PLGA) wafers by creating SMES 47.¹²

12. Benefits and Drawbacks:

12.1 Benefits:

1. Bioavailability enhancement within the oral cavity Several drugs with poor solubility in water display low bioavailability primarily because of their slow dissolution rate-dependent absorption process. Enhanced bioavailability is realized through improved drug transport across the intestinal aqueous phase and the absorptive brush border membrane due to the ability of SMEDDS to dissolve the drug in the GIT as well as increase its specific surface area in a micro emulsified state (1-100nm globules).

2. SMEDDS: Manufacturing and Scaling-up Easier One of the advantages that makes SMEDDS unique from all other drug delivery systems like solid dispersions, liposomes, nanoparticles, etc., which aim at improving the bioavailability, is the fact that SMEDDS can be easily manufactured and scaled up. For large-scale manufacturing, the only requirement for SMEDDS is the use of very minimal and inexpensive manufacturing setup, such as a basic mixing apparatus with stirrer and volumetric filling equipment.

3. Diminishing the intra- and inter-subject variability and the effect of the food There is considerable variation in the intra- and inter-subject variability for many drugs that may lead to poor compliance and decreased efficacy. The efficacy of many drugs may be affected by the presence of food. One of the benefits of such drugs is SMEDDS. There have been several publications regarding the reproducibility of plasma profile of SMEDDS.

4. Presence of peptides which are susceptible to GIT enzymatic hydrolysis One of the outstanding advantages which makes SMEDDS stand out among other drug delivery systems is their capability of delivering macromolecules including peptides, hormones, enzymes, and inhibitors while also protecting them from any enzymatic hydrolysis. Using Polysorbate 20 in the preparation of microemulsions prevents the hydrolysis of prodrugs by cholinesterase within the intestine they are also suitable for heat-labile drugs like peptides and are spontaneously formed without requiring any form of energy or heating. In addition, they allow higher drug loading ability and do not affect the digestion of lipids.

Advantages of SMEDDS in Comparison to Emulsion:

1. Apart from having the advantages associated with emulsions, including enhancing solubility of lipophilic drugs, SMEDDS also address the challenge of emulsion layering during long periods of storage. This is due to the fact that SMEDDS constitute thermodynamically stable systems and hence easier to store.

2. The SMEDDS produce microemulsions that are highly optically transparent and have high thermodynamic stability. The difference between the two is determined by the size of their droplets. Ordinary emulsions' droplets range in size from 0.2 to 10μm, whereas those formed by SMEDDS in the microemulsion form range between 2 and 100nm (known as nano-particles' droplets). The reason why the droplets formed by SMEDDS are easily absorbed into the body through gastrointestinal tract is due to the fact that their total surface area for absorption is relatively large compared to a solid dosage form.

3. SMEDDS offer several ways to deliver the medication, like soft or loaded gelatine capsules and tablets, whereas emulsions can be used orally only as solutions.

12.2 Limitations:

1. Inability to develop any reliable in vitro predictive model for formulation studies is among the limitations that hinder the development of SMEDDS formulations.

2. Conventional dissolution techniques are not effective since the drug dissolution depends on digestion first.

3. Before making an evaluation about how powerful this in vitro model is, further studies need to be done.

4. Because the next phase of study depends upon correlations between in vitro and in vivo studies, different types of lipid-based prototype formulations should be made and tested in vivo through suitable animal experiments.

5. There are certain disadvantages associated with this system, including the chemical instability of the drug, along with high concentrations of surfactants (about 30–60%) that cause irritation in the digestive tract.

6. Moreover, the lipophilic drugs precipitate due to the migration of the volatile co-solvent from the conventional S.M.E.D.s into the shell of either hard or soft gelatine capsules.

7. Dilution with a hydrophilic solvent causes increased precipitation of the drug.

8. Validation is relatively difficult in multi-component systems.¹³

13. Factors Affecting Smeeds:

13.1 Solubility of the drug:

The solubility of the drug in the oil phase plays a vital role in maintaining the dissolved condition of the drug for the formation of SMEDDS. Since SMEDDS is diluted, there might be a problem with precipitation due to a decrease in the solvation capability of the surfactant or co-surfactant.

13.2 Polarity of lipid phase:

The other factor that affects the release of the drug from the micro-emulsion is the polarity of the lipid phase. Factors such as the HLB value, length and unsaturation of the fatty acid chain, molecular weight of hydrophilic moiety and concentration of the emulsifier affect the polarity of the droplet. Polarity shows the type of forces acting and affinity of the drug for the solvent, water or oil. Based on the type of forces, high polarity helps the drug to dissolve easily in solvent, water or oil. High polarity allows faster release of the drug into aqueous phase due to the faster dissolution process. It was observed that the rate of release of idebenone from SMEDDS depended on the polarity of oil phase. The maximum release occurred in formulation with the maximum polarity of oil phase.

13.3 Emulsion droplet charge:

In contrast to the luminal mucosal solution, the apical potential of absorptive and other bodily cells is negatively charged as shown by several physiologic experiments. It was shown by Gershan and Benita that positive charges carried by emulsion droplets generated by mixing oleyl amine with SMEDDS interacted with the caco2 monolayer and the luminal surface of the exercised rat small intestine. The formulation showed an increase in the oral bioavailability of progesterone in young rats. Benzoic acid could perform two functions through the formation of positively charged emulsion: to improve the self-emulsifying and self-micro emulsification of the oily phase within SEDDS in 0.1 HCL.

13.4 Equilibrium solubility:

Solubility in Gut equilibrium can be used to assess the probability of precipitation. As reported in the Plutons experiment, five days may be required for this formulation to achieve equilibrium, while it can remain supersaturated for up to twenty-four hours after the first emulsification event.

13.5 Nature and dosage of the drug:

The use of high dosages in the SMEEDS formulation is not suitable. They have adequate solubility in the hydrophobic phase among the best SMEEDS ingredients. The solubility of the drug in water and lipids is very low. This poses a challenge in retaining the drug in the dissolved state. The drug solubility in the lipid phase affects the retention of the drug in the dissolved state. The dilution of SMEDDS will cause a reduction in the solubilizing ability of the surfactants.¹⁴

14.CHALLENGES TO SMEDDS:

Figure 4: Challenges

14.1 Precipitation of drug:

Precipitation of drug within the body is a result of administration of the SMEDDS formulation. In vivo drug precipitation occurs when the solubility capability of the drug formulation drops down. As per the findings of Porter et al. (2007) and Dai (2010), there are different factors like the sudden change in pH, dilution of the drug with bodily fluids or digestion of the drug from solubilized excipients that lead to the in vivo precipitation of the drug. It is common for drug precipitation to reduce the drug concentration in the aqueous phase, and thereby delay or lower its effectiveness (Hoener & Benet, 2002). The separation of drug formulation in the form of oil/water emulsion in the GI tract after diluting the drug with aqueous media is important to ensure effectiveness. In the study conducted by Mohsin et al. (2008), a very slow precipitation of 3–7% of the total dose of fenofibrate was observed in case of turbid emulsions following SEDDS aqueous dispersion.

14.1.1 Mechanism for Preventing Drug Crystallization:

The exact mechanism by which these drugs act against crystal formation is unclear; however, the following aspects are some of the probable mechanisms that could explain the action. A. Lattice formation: There have been studies conducted on the possibility of producing a super-saturated mixture of HPMC with the supersaturated SMEDDS formulation by forming a lattice structure with cellulosic polymers. This lattice formation is composed of bundles of cellulose polymers, which are formed in aqueous solutions of HPMC, where HPMC chains form a fragile lattice with bulky clusters of hydrophobic groups surrounded by structured water shells.

SMEDDS products in the market are available in soft gelatine capsule form. There are not many disadvantages with gelatine capsules, though. Some of the issues associated with gelatine capsules are cross-linking of gelatine, crystallization of solubilized materials, loss of mechanical integrity of shells, movement of solutes from the shell to the fill, TSEs (transmissible spongiform encephalopathies), and religion/consumer preference.

14.2 Problems associated with handling and storage of liquid SMEDDS:

SMEDDS are generally delivered in hard or soft gelatine capsules, which makes them very viscous in nature. They can cause interactions between the capsule shell and the liquid mixture of lipids and lead to their leaching out. Especially when stored at low temperatures, this can lead to brittleness or softness of the shell and precipitation of the drug and other excipients inside the shell. Efforts have been made to modify liquid SMEDDS to solid SMEDDS in order to solve these problems (Tang et al., 2008).

14.3 Limited lymphatic uptake of SMEDDS:

With regard to lipophilic drugs administration orally, intestinal lymphatic transfer has been known as one of the ways through which drug absorption occurs. Lipophilic drugs undergo diffusion and adsorption through the intestinal entero-cyte before they can diffuse on secret able enterocyte lipoprotein chylomicron. Lymph is described as the filtrate of blood that is made up of fluid and protein (blood plasma). As per Alexandera et al. (2010) and Yanez et al. (2011), the lymphatic systems' ducts lead to the spleen, lymph nodes, bone marrow, and thymus gland. With respect to lymphatic uptake and absorption of particles, lymphatic capillaries are key. Capillary lymphatics' walls consist of one layer of widely spaced nonpenetrated endothelial cells giving rise to many clefts and pores (Charman et al., 1986; Porter & Charman, 2001). It is at the point when the intraluminal lymphatic pressure is lower than interstitial pressure, macromolecules diffuse into the capillary lumen through the pores. There exist several factors affecting the uptake of particles into lymphatic system.¹⁵

Figure 5: Inhibiting drug precipitation

15. Use of SMEDDS:

1. Stabilizing solubility and bioavailability:

Improving the solubility and rate of dissolution of BCS Class II compounds to multiple times its bioavailability.

2. Lipolysis Independent:

As the main contribution to self-emulsification in the definition comes from pancreatic lipase and bile salts, the lipolysis has no impact on the drug delivery system, meaning that this type of drug delivery is independent of lipolysis because it does not involve the effect of pancreatic lipase and bile salts, which facilitate self-emulsification.

3. Polymerization of SMEDDS:

The inclusion of polymer in the SMEDDS formulation helps in providing controlled release of the drug.

4. Protection from Biodegradation:

As the drug is very close to a change in the pH level, many drug combinations become inactive in physiological fluids and systems due to the acidic pH level of the stomach, resulting in hydrolysis or enzymatic breakdown; hence, the LC layer acts as a barrier between the drug and this breakdown.

5. Medication Stacking Limit Improvement:

High medication stacking limits in detailing occur due to definition excipients, giving high solvency power to the medication^16.

16. Recent Advances in SMEDDS:

Self-emulsifying tablets for controlled and sustained drug delivery:

There is considerable information available on self-emulsifying tablets. The use of lipids along with surfactants promises well in this regard.

1. Auto-Emulsifying pills

The micro emulsion droplets develop post-administration of the capsules that contain the conventional liquid SE formulations, spreading out through the GI system until they reach the absorption sites. Nevertheless, one cannot predict whether there will be an increase in the absorption rate of the drug since phase separation is inevitable once it occurs. The SE formulation was thus modified to incorporate sodium dodecyl sulphate to counteract this problem. 56 In a similar way, the super-saturable SEDDS was designed to maintain a super saturated condition in vivo by incorporating a little amount of hydroxypropyl methylcellulose (or any polymer). It prevents precipitation.

2. Self-emulsifying suppositories:

Some scientists have shown that Solid-SEDDS may also enhance the absorption of the medication in the rectum/vagina as well as the GI system.61 For instance, glycyrrhizin may be administered using vaginal or rectal SE suppositories to provide therapeutic levels for treating chronic liver disease, although the drug rarely achieves therapeutic plasma concentrations upon oral administration.

3. Drug Delivery Through Microemulsion:

It has been found that dioctyl sodium sulfosuccinate or Aerosol OT can enhance the absorption of several drugs through the intestines.60,64 Although numerous studies have explored the possible role of aerosol OT microemulsion in delivering medicines topically, further studies are needed to establish whether aerosol OT can be used as an oral microemulsion drug delivery vehicle.

4. Pellets having controlled release or sustained emulsification:

The design and development of SEDDS were based on certain essential criteria such as particle size, drug solubility, safety, compatibility, and self-emulsification. In contrast to other conventional solid dose formulations, there are many advantages of using pellets as a multiple-unit dose drug carrier compared to other solid doses, including decreased intra- and inter-individual variation of plasma concentration, greater manufacturing flexibility, and reduced gastric irritation without compromising the drug’s bioavailability. It appears logical to explore the feasibility of SE pellets, thus integrating the advantages of pellets and SEDDS ^17.

17. CONCLUSION:

The concept of SMEDDS, otherwise known as self-micro emulsifying drug delivery systems, is a relatively new but promising approach toward enhancing the efficacy and pharmacokinetic performance of poorly soluble medicines. The use of SMEDDS in pharmaceutical product development is highly advantageous due to its ability to facilitate the quick formation of microemulsions upon interaction with gastrointestinal fluids, resulting in increased solubility and absorption rates. Another positive feature about SMEDDS lies in its ability to accommodate various active pharmaceutical ingredients.

It is important to resolve the challenges of stability, scaling, and regulatory issues that can arise when it comes to the successful launch of the product in the market. Future work related to the use of SMEDDS for clinical practice must focus on further refinement of the technology itself through research into new excipients as well as testing in vivo experiments. Overall, future research in the development of self-micro emulsifying systems could make great strides within the scope of medicine delivery.

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Received on 28.05.2026 Revised on 16.06.2026

Accepted on 01.07.2026 Published on 07.07.2026

Available online from July 10, 2026

Res. J. Pharma. Dosage Forms and Tech.2026; 18(3):265-277.

DOI: 10.52711/0975-4377.2026.00038

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