INTRODUCTION:

Today, up to 90% of new chemical entities in development are said to fall under either Biopharmaceutics Classification System (BCS) Class II (70%) or Class IV (20%). In other words, the bioavailability of the vast majority of drug candidates is expected to be low and/or variable because of their poor solubility in physiological (aqueous) media.¹

Biopharmaceutical Classification System:

Model List of Essential Medicines of the World Health Organization (WHO) has assigned BCS (Biopharmaceutical Classification System) on the basis of data available in the public domain. Out of 130 orally administered drugs on the WHO list, could be classified with certainty.

· 84% of the drugs belong to Class I (Highly soluble ,Highly permeable)

· 17% to Class II (Poorly Soluble, Highly Permeable)

· 39% to Class III (Highly Soluble, Poorly Permeable)

· 10% to Class IV (Poorly Soluble, Poorly permeability)

A drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption and a drug with poor membrane permeability will typically exhibit permeation rate limited absorption.²

Figure No.-1 Classification of BCS class of drug.³

The oral-based drug delivery system is the most common way to deliver drugs into the bloodstream. In general, water-soluble drugs can diffuse freely and easily into the gastrointestinal tract with high bioavailability.⁴ Enhancement of bioavailability of poorly water soluble drugs becomes farthest challenge for pharmaceutical scientist. (Most of new drug candidates reveal low solubility in water, which leads to poor oral bioavailability, high intra- and inter-subject variability and lack of dose proportionality.⁵ Different techniques have been reported in the literature to achieve better drug dissolution rates.

Lipid Formulation Classification System⁶:

The different lipid drug delivery systems available include lipid emulsion, lipid solution, microemulsion, dry emulsion etc all these different systems and due to large number of possible excipient combinations that may be used to assemble it in a single lipid-based formulations, self-emulsifying systems in particular a classification systems known as lipid formulation classification system (LFCS).

Type I This systems consist of formulations which comprise drug in solution in triglycerides and/or mixed glycerides or in an oil-in water emulsion stabilized by low concentrations of emulsifiers such as 1% (w/v) polysorbate 60 and 1.2% (w/v) lecithin.

Type II Self-emulsification is generally obtained at surfactant contents above 25% (w/w). The progress of emulsification may be compromised by the formation of viscous liquid crystalline gels at the oil/water interface.

Type II lipid-based formulations provide the advantage of overcoming the slow dissolution.

Type III Type III formulations can be further segregated into Type IIIA and Type III B formulations in order to identify more hydrophilic systems (Type IIIB) where the content of hydrophilic surfactants and co-solvents increases and the lipid content reduces.

Type IV Type IV formulations do not contain natural lipids and represent the most hydrophilic formulations.

Self Micro Emulsifying Drug Delivery System (SMEDDS):

In recent years, much attention has been focused on oral dosage forms using a self-micro emulsifying drug delivery system (SMEDDS) for the purpose of improving the solubility and absorption of poorly water-soluble drugs.⁷ Self micro emulsifying drug delivery system (SMEDDS) are defined as an isotropic mixtures of natural or synthetic oils, solid or liquid surfactants, or alternatively, one or more hydrophilic solvents and co-solvents/co-surfactants that have a unique ability of forming fine oil-in water (o/w) micro emulsions upon mild agitation followed by dilution in aqueous media, such as GI fluids. SMEDDS consists of a mixture of drugs, oils, surfactants and/or other additives. Gentle mixing of these ingredients in aqueous media generates micro-emulsions with a droplet size in a range of 10-100 nm. Both systems, SEDDS (droplet sizes of 200 nm-5 mm) and SMEDDS (droplet size <100 nm) are associated with the generation of large surface area dispersions that provide optimum conditions for the increased absorption of poorly soluble drugs.⁸ SEFs are prepared using surfactants of HLB < 12 while self-micro emulsifying formulations (SMEFs) and self nano-emulsifying formulations (SNEFs) with surfactants of HLB >12.⁹ SMEDDS has been shown to improve absorption of drugs by rapid self-micro emulsification in the stomach, with the micro-emulsion droplets subsequently dispersing in the gastrointestinal tract to reach sites of absorption . The resultant small droplet size from SMEDDS provides a large interfacial surface area for drug release and absorption, and the specific components of SMEDDS promote the intestinal lymphatic transport of drugs. Oral absorption of several drugs has been enhanced by SMEDDS.¹⁰

Need of SMEDDS:

Oral delivery of poorly water-soluble compounds is to pre-dissolve the compound in a suitable solvent and fill the formulation into capsules. The main benefit of this approach is that pre-dissolving the compound overcomes the initial rate limiting step of particulate dissolution in the aqueous environment within the GI tract. However, a potential problem is that the drug may precipitate out of solution when the formulation disperses in the GI tract, particularly if a hydrophilic solvent is used (e.g. polyethylene glycol). If the drug can be dissolved in a lipid vehicle there is less potential for precipitation on dilution in the GI tract, as partitioning kinetics will favor the drug remaining in the lipid droplets. Another strategy for poorly soluble drugs is to formulate in a solid solution using a water-soluble polymer to aid solubility of the drug compound. For example, polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG 6000) have been used for preparing solid solutions with poorly soluble drugs. One potential problem with this type of formulation is that the drug may favor a more thermodynamically stable state, which can result in the compound crystallizing in the polymer matrix. Therefore the physical stability of such formulations needs to be assessed using techniques such as differential scanning calorimetric analysis or X-ray crystallography. Self-micro emulsifying drug delivery system is a novel approach and is being extensively used to enhance the solubility and bioavailability of poorly water soluble drugs. In addition to this, the formulated SMEDDS will also prevent the drug from hostile gastric environment which will further help in better systemic absorption.¹¹

Potential Advantages of Self micro-emulsifying Drug Delivery System^8,12:

1. Enhanced oral bioavailability enabling reduction in dose.

2. More consistent temporal profiles of drug absorption.

3. Selective targeting of drug(s) toward specific absorption window in GIT.¹³

4. Protection of drug(s) from the hostile environment in gut.

5. Control of delivery profiles e.g. Paclitaxel.¹⁴

6. Reduced variability including food effects.

7. Protective of sensitive drug substances.

8. High drug payloads.

9. Liquid or solid dosage forms.

10. Greater bioavailability.¹⁵

11. Less drug need to be used.

12. For many drug taken by the mouth.

13. Faster release rates and it improve the drug acceptance by consumers. These systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood time profiles.¹⁶

Disadvantages of SMEDDS^17,18:

1. One of the obstacles for the development of SMEDDS and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulations.

2. Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug.

3. This in vitro model needs further development and validation before its strength can be evaluated.

4. Further development will be based on in vitro - in vivo correlations and therefore different prototype lipid based formulations needs to be developed and tested in vivo in a suitable animal model.

5. The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) which irritate GIT.¹⁹

6. Moreover, volatile co solvents in the conventional self-microemulsifying formulations are known to transfer into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs.

7. The precipitation tendency of the drug on dilution may be higher due to the dilution effect of the hydrophilic solvent.

8. Formulations containing several components become more challenging to validate

Advantages of SMEDDS over Emulsion^7,10

1. SMEDDS not only offer the same advantages of emulsions of facilitating the solubility of hydrophobic drugs, but also overcomes the drawback of the layering of emulsions after sitting for a long time. It can be easily stored since it belongs to a thermodynamics stable system formed by the SMEDDS exhibit good thermodynamics stability and optical transparency.

2. Droplets of microemulsion formed by the SMEDDS generally ranges between 2 and 100 nm. Since the particle size is small, the total surface area for absorption and dispersion is significantly larger than that of solid dosage form and it can easily penetrate the gastrointestinal tract and be absorbed. The bioavailability of the drug is therefore improved.

3. SMEDDS offer numerous delivery options like can be filled in hard gelatin capsules or soft gelatin capsules or can be formulated into tablets whereas emulsions can only be given as oral solutions.

4. Emulsion cannot be autoclaved as they have phase inversion temperature, while SMEDDS can be autoclaved.

S-SMEDDS Overcoming the Need of Liquid SMEDDS²⁰

1. S-SMEDDS form is more preferred than liquid SMEDDS form.

2. S-SMEDDS (solid microemulsion preconcentrate) readily forms microemulsion when comes in contact with water.

3. Need for outsourcing of soft gelatin capsule manufacturing at the early stage of drug product development may be avoided.

4. S-SMEDDS remain solid at room temperature, yet maintains all the advantages of liquid SMEDDS.

5. S-SMEDDS can be filled into hard gelatin capsules.

6. S-SMEDDS is highly stable and reproducible than liquid SMEDDS.

7. S-SMEDDS may even be incorporated into other solid dosage forms (e.g., fast dissolving tablets, films etc

Biopharmaceutical Aspects of SMEDDS in Improving Absorption²¹

a Alteration (reduction) in gastric transit.

b Increase in effective luminal drug solubility.

c Stimulation of intestinal lymphatic transport.

d Change in biochemical barrier function of GI tract.

e Change in the physical barrier function of the GI tract.

Table No.1- Difference and Similarities Between SEDDS and SMEDDS^21-,23

SEDDS	SMEDDS
DIFFERENCE
Can be a simple binary formulation with the drug And a lipid excipients able to self-emulsify in Contact with GIF OR A system comprising drug, surfactant, oil.	Are composed of the drug compound, surfactant, and oil.
Lipid droplet size in the dispersion ranges From 200nm-5μm providing large surface area absorption. The dispersion has a turbid appearance.	Lipid droplet size in the dispersion is <200nm. The dispersion has an optically clear to translucent appearance.
SEDDS system is not thermodynamically Stable in water or physiological condition.	SMEDDS system is thermodynamically Stable.
SIMILARITIES
Form fine oil-in-water dispersion in contact with GIF.

The emulsification process:

Self-emulsification is a phenomenon which has been widely exploited commercially in formulations of emulsifiable concentrates of herbicides and pesticides. Concentrates of crop-sprays are to be diluted by the user, such as farmers or house-hold gardeners, allowing very hydrophobic compounds to be transported efficiently. In contrast, SMEDDS, using excipients acceptable for oral administration to humans, have not been widely exploited and knowledge about their physicochemical principles is therefore limited.³

Mechanism of Self-Emulsification^7,14,24,25

Self-emulsification process is related to the free energy. According to Reiss (1975), the theory of formation of microemulsion shows that emulsification occurs when the entropy change that favors dispersion is greater than energy required to increase the surface area of the dispersion and the free energy (ΔG) is negative. The free energy in the microemulsion formation, is directly proportional to the energy required to create new surface between the two desired phases^8,12,26 and can be described by the equation (1)

ΔG = Σ N π r2 σ ………. (1)

Where, ΔG is the free energy associated with the process, N is the number of droplets of radius r and σ represents the interfacial energy.^[27]After a certain time, the two phases of the emulsion tend to separate to reduce the interfacial area, and subsequently, the free energy of the system decreases. To stabilize emulsions, emulsifying agents are added which reduces the interfacial energy, as well as provide a barrier to prevent coalescence.

Formulation Design of SMEDDS:

Pre-formulation studies are carried out for the selection of oil, surfactant and co-surfactant as these are specific for a particular SMEDDS. First we determine solubility of drug in various oils and surfactant/co-surfactant then prepare a series of SMEDDS containing drug in various oil and surfactant/co-surfactant. These formulations are analysed for self-emulsification properties and droplet size upon addition to water under mild agitation (in- vitro) studied. By constructing the pseudo-ternary phase diagram we identify the efficient self-emulsification region. So by doing such studies an optimized formulation is selected and its bioavailability also compared with a reference formulation.

Parameters taken into consideration while formulating SMEDDS

• Solubility of drug in formulation as such and upon dispersion

• The rate of digestion (for digestion susceptible formulation)

• The solubilisation capacity of the digested formulation²⁸

Formulation components of SMEDDS^7,29:

• Drug

• Oil

• Surfactant

• Co-surfactant

• Co-solvent

The components are selected with objectives, such as:

• To achieve maximal drug loading.

• To achieve minimal self-emulsification time and droplet size in the gastric milieu for maximal absorption.

• To reduce variation in the emulsion droplet size as a function of pH and electrolyte content of the aqueous medium.

• To prevent/minimize drug degradation/metabolism in physiological milieu.

The components of the SMEDDS are as follows:

Drug:

Poorly water soluble drugs are a broad class of drugs that differ significantly in physicochemical properties, so it would be useful if there were practical guidelines to help identify the most appropriate formulation for specific drugs. High melting point drugs with log P values of about 2 are poorly suited to SEMDDS. At the other end of the spectrum, lipophilic drugs, such as cinnarizine with log P values greater than 5, are good candidate for SMEDDS.

Oil:

Oils are the most important excipient because oil can solubilise the lipophilic drug in a specific amount and it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract.^19,21 Long chain triglyceride and medium chain triglyceride oils with different degree of saturation have been used in the design of SMEDDS.³⁰ Unmodified edible oils provide the most natural basis for lipid vehicles, but their poor ability to dissolve large amounts of hydrophobic drugs and their relative difficulty in efficient self-micro emulsification markedly reduces their use in SMEDDS. Recently medium chain triglycerides are replaced by novel semi synthetic medium chain triglycerides containing compound such as gelucire, other suitable oil phases are digestible or nondigestible oils and fats such as olive oil, corn oil, soya bean oil, palm oil and animal fats etc.

Surfactant:

Nonionic surfactants with high Hydrophilic Lipophilic Balance (HLB) values are used in formulation of SMEDDS (e.g. Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). The usual surfactant strength ranges between 30–60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules.

Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule.

The four main groups of surfactants are defined as follows:

Anionic Surfactants:

where the hydrophilic group carries a negative charge such as carboxyl (RCOO-), sulphonate (RSO3-) or sulphate (ROSO3-).

Examples: Potassium laurate, sodium lauryl sulphate.

Cationic surfactants:

where the hydrophilic group carries a positive charge.

Example: quaternary ammonium halide.

Ampholytic surfactants:

(also called zwitterionic surfactants) contain both a negative and apositivecharge. Example: sulfobetaines

Nonionic surfactants:

where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O). Examples: Sorbitanesters (Spans), polysorbates (Tweens).²⁶

The surfactants used in these formulations are known to improve the bioavailability by various mechanisms including: improved drug dissolution, increased intestinal epithelial permeability, increased tight junction permeability and decreased/inhibited p-glycoprotein drug efflux.

Co-Surfactant:

Co-surfactant is used with surfactant together to decrease the interfacial tension to a very small even transient negative value. At this value the interface would expand to form fine dispersed droplets, and subsequently adsorb more surfactant until their bulk condition is depleted enough to make interfacial tension positive again. This process known as “spontaneous emulsification” forms the microemulsion.³¹ In SMEDDS, generally co-surfactant of HLB value 10-14 is used. Hydrophilic co-surfactants are preferably alcohols of intermediate chain length such as hexanol, pentanol and octanol which are known to reduce the oil water interface and allow the spontaneous formulation of micro emulsion.

Co-Solvent:

Organic solvents are suitable for oral administration. Examples are ethanol, propylene glycol, and polyethylene glycol,³² which may help to dissolve large amounts of hydrophilic surfactant or drug in liquid base. Addition of an aqueous solvent such as Triacetin, (an acetylated derivative of glycerol) for example glyceryl triacetate or other suitable solvents that act as co-solvents.

Construction of Ternary Phase Diagrams¹⁸:

Ternary phase diagram is useful to identify best emulsification region of Oil, Surfactant and Co-Surfactant combinations. Ternary phase diagram of surfactant, co-surfactant and oil will plot; each of them, representing an apex of the triangle. The methods are used to plot Ternary phase diagrams are namely Dilution method and Water Titration method.

Dilution Method:

Ternary mixtures with varying compositions of surfactant, co-surfactant and oil will be equipped. The surfactant concentration will diverge from 30 to 75% (w/w), oil concentration will diverge from 25 to 75% and co-surfactant concentration will diverge from 0 to 30% (w/w). For any mixture, the total of surfactant, co-surfactant and oil concentrations always added to 100%. For example, in the experiment, first mixture consisted of 75% of surfactant, 25% of the oily phase and 0% of co-surfactant. Further, the co-surfactant was increased by 5% for each composition, oily phase concentration will keep constant and the surfactant concentration will adjust to make a total of 100%. Forty-two such mixtures with varying surfactant, co-surfactant and oil concentrations will prepare. The percentage of surfactant, co-surfactant and oil used herein will decide on the basis of the requirements. Compositions are evaluated for nanoemulsion formation by diluting appropriate amount of mixtures with appropriate double distilled water. Globule size of the resulting dispersions will be determined by using spectroscopy technique. Dispersions, having globule size 200 nm or below will consider desirable. The area of nanoemulsion formation in Ternary phase diagram will identified for the respective system in which nanoemulsions with desire globule size were obtain.

Water Titration Method:

The pseudo-ternary phase diagrams were also constructed by titration of homogenous liquid mixtures of oil, surfactant and co-surfactant with water at room temperature. Oil phase, Surfactant and the co-surfactant (surfactant: co-surfactant ratio) were prepared varied from 9:1 to 1:9 and weighed in the same screw-cap glass tubes and were vortexed. Each mixture was then slowly titrated with aliquots of distilled water and stirred at room temperature to attain equilibrium. The mixture was visually examined for transparency. After equilibrium was reached, the mixtures were further titrated with aliquots of distilled water until they showed the turbidity. Clear and isotropic samples were deemed to be within the microemulsion region. No attempts were made to completely identify the other regions of the phase diagrams. Based on the results, appropriate percentage of oil, surfactant and co-surfactant was selected, correlated in the phase diagram and were used for preparation of SMEDDS.

Figure No.2- Ternary Phase Diagram³⁴

Solidification techniques for transforming liquid/ semisolid SMEDDS to S-SMEDDS

1. Capsule filling with liquid and semisolid self-emulsifying formulations:

Capsule filling is the simplest and the most common technology for the encapsulation of liquid or semisolid SE formulations for the oral route. For semisolid formulations, it is a four-step process: (i) heating of the semisolid excipient to at least 20˚C above its melting point; (ii) incorporation of the active substances (with stirring); (iii) capsule filling with the molten mixture and (iv) cooling to room temperature. For liquid formulations, it involves a two-step process: filling of the formulation into the capsules followed by sealing of the body and cap of the capsule, either by banding or by micro spray sealing. The advantages of capsule filling are simplicity of manufacturing; suitability for low-dose highly potent drugs and high drug loading potential (up to 50% (w/w).⁸

2. Spray drying:

Essentially, this technique involves the preparation of a formulation by mixing lipids, surfactants, drug, solid carriers, and solubilization of the mixture before spray drying. The solubilized liquid formulation is then atomized into a spray of droplets. The droplets are introduced into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporates, forming dry particles under controlled temperature and airflow conditions. Such particles can be further prepared into tablets or capsules. The atomizer, the temperature, the most suitable airflow pattern and the drying chamber design are selected according to the drying characteristics of the product and powder specification.³⁵

Figure No.3– It shows spray drying technique.

3. Adsorption to solid carriers:

Free flowing powders may be obtained from liquid SE formulations by adsorption to solid carriers. The adsorption process is simple and just involves addition of the liquid formulation onto carriers by mixing in a blender. The resulting powder may then be filled directly into capsules or, alternatively, mixed with suitable excipients before compression into tablets. A significant benefit of the adsorption technique is good content uniformity. SEDDS/SMEDDS can be adsorbed at high levels [up to 70% (w/w)] onto suitable carriers. Solid carrier can be microporous substances, high surface area colloidal inorganic adsorbent substances, cross-linked polymers or nanoparticle adsorbent, for example, silica, silicates, magnesium trisilicate, magnesium hydroxide, talcum, crospovidone.²⁵

4. Spray cooling:

The technique spray cooling is also known as spray congealing, where, the molten formulation is sprayed into a cooling chamber. When this molten mixture comes in contact with cooling air, the molten droplets congeal and recrystallize into spherical solid particles which collect into the bottom of the chamber as fine powder. The fine powder may then be used for development of solid dosage from such as capsules, tablets etc. To atomize the liquid mixture and to generate droplets, different atomizers can be used but ultrasonic atomizer is most preferred. The excipients used with this technique are polyoxyl glycerides specially steroyl polyoxyl glycerides, gelucire 50/13. Praziquantel and diclofenac SEDDS have been prepared by using spray cooling technique.^3,36

5. Melt granulation:

Melt granulation is a one step process, where, powder agglomerates are obtained by adding binder that melts or softens at low temperature. Melt granulation is also known as “thermoplastic pelletization.” It is used for those excipients that exhibit thermoplastic properties. A large range of solid and semi-solid lipid can be used as a binder for solid dispersions prepared by melt granulation whereas, lipids with a low HLB and high melting point are suitable for sustained release formulations. Semi-solids with high HLB are used for immediate release and bioavailability enhancement. Gelucire, a lipid based excipient, is able to further increase the dissolution rate as compared to polyethylene glycol because of its self emulsifying ability. Gelucire 44/14 has high HLB value of 14 and possesses good self emulsifier property. Other lipid based excipients used for solid SES are lecithin, partial glycerides and polysorbates (tweens). Melt Granulation process is used for adsorbing SES into solid carriers like silica and magnesium alumino meta-silicate. The parameters that control granulation process are the impeller speed, mixing time, viscosity and particle size of binder.³⁷

6. Melt extrusion/extrusion spheronization: Extrusion Spheronization technique is based on the property of materials which can be easily extruded and spheronized. These techniques do not require liquid excipients although constant temperature and pressure has to be maintained to achieve high drug loading. Melt extrusion ensures content uniformity and is widely used method for preparing pellets and granules. In extrusion, raw materials with plastic properties are converted into uniform pellets of varying size which depend on size of extruder aperture. Self nanoemulsifying formulation of ubiquinone has been formulated by using extrusion Spheronization technique. The bioavailability of propranolol has also been improved by using this technique. Self emulsifying pellets and bilayered cohesive self emulsifying pellets of diazepam have also been prepared by extrusion spheronization technique.^3,36,37

Dosage form development of S-SMEDDS^7,9,31,38,39

1. Dry emulsions

2. Self- micro emulsifying capsules

3. Self-emulsifying tablet

4. Self- micro emulsifying sustained/controlled-release tablets

5. Self- micro emulsifying sustained/controlled-release pellets

6. Self- micro emulsifying solid dispersions

7. Self- micro emulsifying suppositories

8. Self- micro emulsifying implants

9. Self-Emulsifying Beads Supersaturable Self-Emulsifying System

10. Gelled Self-Emulsifying System For Extended Release

11. Self-Emulsifying Microsphere

12. Self-Emulsifying Liposphere

13. Self-Emulsifying Nanoparticles

Evaluation of SMEDDS^{9,12,14,26,29,40,41}

A. Thermodynamic stability studies:

The physical stability of a lipid –based formulation is also crucial to its performance, which can be adversely affected by precipitation of the drug in the excipient matrix. In addition, poor formulation physical stability can lead to phase separation of the excipient, affecting not only formulation performance, but visual appearance as well. In addition, incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drug.

a) Heating cooling cycle:

Six cycles between refrigerator temperature (4ºC) and 45ºC with storage at each temperature of not less than 48 hr is studied. Those formulations, which are stable at these temperatures, are subjected to centrifugation test.

b) Centrifugation:

Passed formulations are centrifuged thaw cycles between 21 ºC and +25 ºC with storage at temperature for not less than 48s hr is done at 3500 rpm for 30 min. Those formulations that does not show any phase separation are taken for the freeze thaw stress test.

c) Freeze thaw cycle:

Three freeze for the formulations. Those formulations passed this test showed good stability with no phase separation, creaming, or cracking.⁴²

B. Dispersibility test:

The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus 2. One milliliter of each formulation was added to 500 mL of water at 37 ± 0.5 0C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation. The in vitro performance of the formulations is visually assessed using the following

Grading system:

Grade A: Rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance.

Grade B: Rapidly forming, slightly less clear emulsion, having a bluish white appearance.

Grade C: Fine milky emulsion that formed within 2 min.

Grade D: Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer than 2 min).

Grade E: Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface.

Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While formulation falling in Grade C could be recommend for SEDDS formulation.²⁸

C. Turbidimetric Evaluation:

Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of Self emulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic plate at ambient temperature, and the increase in turbidity is measured using a turbidimeter. However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification).³³

D. Viscosity Determination:

The SEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it can be easily pourable into capsules and such system should not too thick to create a problem. The rheological properties of the micro emulsion are evaluated by Brookfield viscometer. This viscosities determination conform whether the system is w/o or o/w. If system has low viscosity then it is o/w type of the system and if high viscosities then it are w/o type of the system.²³

E. Droplet Size Analysis Particle Size Measurements: The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to measure sizes between 10 and 5000 nm. Light scattering is monitored at 25°C at a 90° angle, after external standardization with spherical polystyrene beads. The nanometric size range of the particle is retained even after 100 times dilution with water which proves the system’s compatibility with excess water.³⁰

F. Refractive Index and Percent Transmittance: Refractive index and percent transmittance proved the transparency of formulation. The percent transmittance of the system is measured at particular wavelength using UV-spectrophotometer keeping distilled water as blank.

G. Drug content:

Drug from pre-weighed SEDDS is extracted by dissolving in suitable solvent. Drug content in the solvent extract is analyzed by suitable analytical method against the standard solvent solution of drug.^43,44

H. Zeta potential measurement:

Zeta potential measurement can be carried out using zeta potential analyzer or zetameter.^44,45SMEDDS formulation containing 10 mg of drug was diluted to 20 mL with distilled water in a flask and was mixed gently by inverting the flask. The particle size so formed was determined by dynamic light scattering (DLS) technique using Zetasizer.⁷

Characterization of Solid SMEDDS:

The characterization of solid SMEDDS was carried out for reconstitution properties (visual observation and particle size determination), yield of spray dried product, powder flow properties (including angle of repose, bulk density, tapped density, Carr’s compressibility index and Hausner ratio), weight variation test for capsules, drug content determination and in-vitro dissolution test. Solid state characterization includes Differential scanning calorimetry, Scanning electron microscopy and Powder X-ray diffraction.⁴⁶

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Received on 23.05.2016 Accepted on 30.06.2016

Asian J. Pharm. Tech. 2016; 6 (3): 159-168.

DOI: 10.5958/2231-5713.2016.00023.4

DRUG NAME	COMPOUND	DOSAGE FORM	COMPANY
Neoral®	Cyclosporine A/I	Soft gelatin capsule	Novartis
Norvir	Ritonavir®	Soft gelatin capsule	Abbott Laboratories
Fortovase®	Saquinavir	Soft gelatin capsule	Hoffmann-La Roche inc.
Agenerase®	Amprenavir	Soft gelatin capsule	Glaxo Smithkline
Targretin®	Bexarotene	Soft gelatin capsule	Ligand
Rocaltrol®	Calcitriol	Soft gelatin capsule	Roche
Convulex®	Valproic acid	Soft gelatin capsule	Pharmacia
Lipirex®	Fenofibrate	Hard gelatin Capsule	Genus
Sandimmune®	Cyclosporine A/II	Soft gelatin capsule	Novartis
Gengraf®	Cyclosporine A/III	Hard gelatin Capsule	Abbott Laboratories
Vesanoid®	Tretinoine	soft gelatine capsule	Roche
Accutane®	Isotretionine	soft gelatine capsule	Roche
Kaletra®	Lopinavir and Ritonavir	oral solution	Abbott
Aptivus®	Tipranavite	soft gelatine capsule	Boehringer Ingelheim