Solubility:

Solubility is defined as concentration of the dissolved solid (the solute) in the solvent medium, which becomes saturated with solute and is in equilibrium with the solute at a defined pH, temperature and pressure. (27) Solubilisation of solute in a given solvent can also be described in terms of free energy change of the system. Solubility at constant temperature and pressure involves free energy of the solid (GsolidT,P) and free energy of molecules in solution (G solution T,P). At saturation equilibrium solubility, the free energy of the solid equals the free energy of the molecules in the solution, as denoted in following Eq.,

Gsolid T, P=Gsolution T, P (N saturation)

Where, G is the free energy.

Classification of solubility as per usp norms:

Table no.2: Classification system of solubility

Descriptive term	Approximate volume of solvent in milliliters per garm of solute
Very soluble	Less than 1
Freely soluble	From 1 to 10
Soluble	From 1 to 10
Sparingly soluble	From 30 to 100
Slightly soluble	From 30 to 100
Very slightly soluble	From 30 to 100
Insoluble or practically insoluble	More than 10,000

Types of lipid formulation classification:

The different lipid drug delivery system available includes lipid solution, lipid emulsion, microemulsion, dry emulsion. To get a clear picture of all these different systems and due to large number of possible excipient combination that may be used to assemble these lipid-based formulations, self emulsifying systems in particular a classification systems have been established called as lipid formulation classification system (LFCS). LFCS was established by Pouton in 2000 and recently updated in 2006. The LFCS are classified into four classes are as follows; (5,17,39,40,41)

Type I:

This system consist of formulation which comparise drug in solution 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. (41)

Type II:

Lipid formulation constitutes SEDDS. Self-emulsification is generally obtained at surfactant contents above 25% (w/w). However, at higher surfactant contents (greater than 50-60% (w/w/) depending on the materials) the progress of emulsification may be compromised by the formation of viscous liquid crystalline gels at the oil/water interface. (17)

Type III:

Type III formulation can be further segregated into Type III A and Type IIIB formulation in order to identify more hydrophilic systems (Type IIIB) where the content of hydrophilic surfactants and co-solvents increases and the lipid content reduces. (41)

Type IV:

In order to capture the recent trends towards formulation which contain predominantly hydrophilic surfactants and co-solvents, this category was recently added. Type IV formulations do not contain natural lipids and represent the most hydrophilic formulation. These formulations commonly offer increased drug payloads when compared to formulation containing simple glyceride lipids and also produce very fine dispersions when introduced in aqueous media.(17)

Self micro-emulsifying drug delivery system:

Self micro-emulsifying drug delivery system (SMEDDS) is isotropic mixture of oil, hydrophilic surfactant and/or a co-surfactant and a solubilised drug. They can be encapsulated in hard gelatin or soft gelatin capsule or can be converted into solid state (solid SEDDS/SMEDDS). These formulations spontaneously form a fine oil-in-water microemulsion upon dilution with water. In the GI tract, they are readily dispersed, where the motility of the stomach and small intestine provides the gentle agitation necessary for emulsification. (3,10)

Following are the basic difference of SMEDDS, SNEDDS AND SEDDS, Table no.3.

Need of self micro-emulsifying drug delivery system:

Most of (up to 40 %) the new chemical entities discovered by the pharmaceutical industry today are form BCS class II i.e. low soluble and high permeable and associated with poor bioavailability. The solubility issue not only complicating the delivery of these new drugs but also affect the delivery of many exciting drugs. 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. 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. 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. (11)

Difference between sedds, smedds and snedds:

Table no. 3: Basic difference of SEDDS-SMEDDS-SNEDDS.

Characteristic	SEDDS	SMEDDS	SNEDDS
Appearance	Turbid, opaque (white)	Clear , transparent	Colloidal dispersion
Optical isotropy	Anisotropic	Isotropic	Isotropic
Microstructure	Static	Dynamic	Dynamic
Droplet size	100-300 nm	<50 nm	1-100 nm
Droplet shape	Roughly spherical	Various structure ranging from droplet like swollen micelles to bicontinuous structure	Spherical (small sized droplet)
Molecular Packing	Inefficient	Efficient	Efficient
HLB	< 12	>12	>12-14
Phase	Biphasic	Monophasic	Monophasic
Viscosity	High	Low	Low
Interfacial tension	High	Ultralow	Low
Oil concentration	40-80 %	<20 %	-
Surfactant concentration	20-60 %	20-50 %	0-20%
Stability	Thermodynamically unstable	Thermodynamically stable	Thermodynamically stable

Mechanism of self- emulsification

The theory of formation of microemulsion shows that emulsification occurs when the entropy change for 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 and can be described by Eq.,

ΔG = Σ N π r2 σ

Where, N --- number of droplets,

r --- radius of droplets,

σ --- Interfacial energy

ΔG --- free energy associated with the process,

Conventional emulsions are formed by mixing two immiscible liquids namely water and oil stabilized by an emulsifying agent. When an emulsion is formed surface area expansion is created between the two phases. The emulsion is stabilized by the surfactant molecules that form a film around the internal phase droplet. In conventional emulsion formation, the excess surface free energy is dependent on the droplet size and the interfacial tension. If the emulsion is not stabilized using surfactants, the two phases will separate reducing the interfacial tension and the free energy. (5,6,9,10,30)

ADVANTAGES OF SMEDDS

1. Improvement In Oral Bioavailability:

Dissolution rate dependent absorption is a major factor that limits the bioavailability of numerous poorly water soluble drugs. The ability of SMEDDS to present the drug to GIT in solubilized and micro emulsified form (globule size between 1-100 nm) and subsequent increase in specific surface area enable more efficient drug transport through the intestinal aqueous boundary layer and through the absorptive brush border membrane leading to improved bioavailability.

2. Ease Of Manufacture And Scale-Up:

Ease of manufacture and scale-up is one of the most important advantage that makes SMEDDS unique when compared to other drug delivery systems like solid dispersions, liposomes, nanoparticles, etc., dealing with improvement of bio-availability. SEDDS require very simple and economical manufacturing facilities like simple mixer with agitator and volumetric liquid filling equipment for large-scale manufacturing. This explains the interest of industry in the SMEDDS.

3. Reduction In Inter-Subject And Intra-Subject Variability And Food Effects:

There are several drugs which show large inter-subject and intra-subject variation in absorption leading to decreased performance of drug and patient non-compliance. Food is a major factor affecting the therapeutic performance of the drug in the body. SMEDDS are a benefit for such drugs. Several research papers specifying that, the performance of SMEDDS is independent of food and, SMEDDS offer reproducibility of plasma profile are available.

4. No Influence Of Lipid Digestion Process:

Unlike the other lipid-based drug delivery systems, the performance of SMEDDS is not influenced by the lipolysis, emulsification by the bile salts, action of pancreatic lipases and mixed micelle formation.

5. Ability To Deliver Peptides That Are Prone To Enzymatic Hydrolysis In Git:

One unique property that makes SMEDDS superior as compared to the other drug delivery systems is their ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and their ability to offer protection from enzymatic hydrolysis. The intestinal hydrolysis of prodrug by cholinesterase can be protected if polysorbate 20 is emulsifier in micro emulsion formulation.

6. Increased Drug Loading Capacity:

Selective targeting of drugs towards specific absorption window in GIT. SMEDDS also provide the advantage of increased drug loading capacity when compared with conventional lipid solution as the solubility of poorly water soluble drugs with intermediate partition coefficient (2<log P>4) are typically low in natural lipids and much greater in amphilic surfactants, cosurfactants and co-solvents.

7. Control Of Delivery Profile:

It can be achieved by incorporating suitable polymer. (3, 4,6,7,9,12,17)

DISADVANTAGES:

1. 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. The large quantity of surfactant in self‐emulsifying formulations (30‐60%) irritates GIT. Consequently, the safety aspect of the surfactant vehicle had to be considered.

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. Chemical instabilities of drugs and high surfactant concentrations. (5,10,11,14)

FORMULATION COMPONENT:

The formation of self micro-emulsifying drug delivery system usually involves a combination of three to five components, namely, oil, surfactant, co-surfactant, drug and water. The micro-structural state of SMEDDS may be affected by the presence of additives. The tendency towards a W/O or an O/W microemulsion is dependent on the properties of oil, surfactant, co-surfactant and water-to-oil ratio and temperature. The type associated structures formed from these component at a particular temperature depends not only on the chemical nature of each component but also on their relative concentration.

Self micro-emulsifying process is specific to following studies;

The selection of formulation Self Microemulsifying drug delivery system is specific to following parameter studies such as Nature of oil, Surfactant ,Concentration of surfactant, Oil/surfactant ratio, Concentration and nature of the co-surfactant, Surfactant/co-surfactant ratio, Temperature at which microemulsion forms. (19,22,32,39,43)

a. Active Pharmaceutical Ingredient:

Active pharmaceutical agent should be soluble in oil phase as this influence the ability of SMEDDS to maintain the API in solubilised form. Drugs which have low solubility in water or lipids are difficult to deliver through SMEDDS. Drugs which are administered in very high dose are not suitable for formulation unless they have extremely good solubility in at least one of the components of SMEDDS, preferably oil phase. High melting point drugs with log P values of about 2 are poorly suitable for SMEDDS. While, lipophilic drugs having log P values greater than 5, are good candidate for SMEDDS. (3,5)

The development of o/w or w/o microemulsion because of its ;

Improved drug solubilization, Long shelf life, Ease of preparation, Modified drug release characteristics, Improvement of bioavailability, To allow slow release of drug, To show prolong effects, To avoided high concentration in blood.

b. Oil

Lipids are the important component of SMEDDs, as solubilization and access of the drug to the lymphatic circulation of poor water soluble drugs depend on the type and concentration of oil used in the formulation. Lipids are generally insoluble in water and are often identified by their fatty acid composition. Lipid with high HLB are suitable for immediate release and bioavailability enhancements and lipid low HLB and high melting point are suitable for sustained release. Both long and medium chain triglyceride (LCT and MCT) oils with different degrees of saturation have been used for the design of self-emulsifying formulations. The lipid concentration of oil in SMEDDS are used as less than only 20 %. e.g. Capmul MCM, Maisine 35-1, Capryol 90. Labrafil M 1944 CS, Labrafil M 2125 CS.

c. Surfactant:

Surfactant is surface active molecules which concentrate at the oil-water interface and stabilize the internal phase in an emulsion. Surfactant is critical components of SMEDDS systems since they are responsible for forming a stable emulsion upon aqueous dilution. Non-ionic surfactants are commonly used in this type of formulation. Proper selection of the surfactant is based on its Hydrophilic Lipophilic Balance (HLB) value and safety consideration. (43)They are classified on an empirical scale known as Hydrophilic-Lipophilic Balance (HLB), which runs from 1 to 20. In general, water dispersed in oil (w/o) microemulsion are formed using surfactant, which have HLBs in the range of about 3-6, whereas oil dispersed in water (o/w) microemulsion are formed using surfactants, which have HLB values in the range of about 8-18. The main role of surfactant is to lower the oil-water interfacial tension by way of their interfacial absorption. (22) Surfactant used in these formulations is also known to improve bioavailability by various mechanisms, including the following: Improved drug dissolution, Increased intestinal epithelial permeability, Increased tight junction permeability, Inhibition of p-glycoprotein efflux. e.g. Tween (20,40,60,80), Span (20,40,60,80), Labrasol, Cremophore RH 40, Capmul MCM.

d. Co-Surfactant:

For the production of an optimum SMEDDS, high concentration of surfactant is required in order to reduce interfacial tension sufficiently, which can be harmful, so co-surfactants are used to reduce the concentration of surfactants. Co-surfactants like diethyl-glycol-monoethyl ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate etc, may help to dissolve large amount of hydrophilic surfactants or hydrophobic drug in the lipid base. These solvents sometimes play role of co-surfactant in microemulsion systems. Co-surfactants with HLB value 10-14 is used along with surfactant for lowering the interfacial tension, interface would expand to form fine dispersed droplets. Fluid interfacial film is achieved by the addition of a cosurfactant. Co-surfactant will enhance the fluidity of the interface and thereby increasing the entropy of the system. (11,15,16) E.g. PEG (300,400,600), Transcutol P, Propylene glycol.

General scheme of smedds preparation:

First, SMEDDS are prepared by blending of oil, water, surfactant and co-surfactant upon mild agitation or mild heat system to form a clear microemulsion. Second, in case of AOT microemulsion ‘o’ surfactant is absent. So it has prepared by dissolving the ‘s’ in the ‘o’ to form a solution. This solution is added to water with gentle shaking. In case of non-ionic surfactant was dissolved first in water, then solution become rapidly translucent and after few seconds it forms a optically clear microemulsion. Third, the formation of o/w or w/o microemulsion by using surface active agent (SAA), it may be used as base for preparation of SMEDDS. In this process the surface active agent is added by using stirring on magnetic stirrer. Then it forms cubic structure of mixture, but further addition of hydrophilic surface active agent to forms a w/o or o/w microemulsion (vice-versa). Then that system co-surfactant is added drop by drop by titration until clarity is obtained. (23,22)

METHODS:

Self emulsifying drug delivery system is prepared by using three method of preparation are as follows ;Phase titration method, Phase inversion temperature method, Constructing pseudo-ternary phase diagram. (16,23,22,21)

a. Phase Titration Method:

It involves the process of, first-dilution of an oil-surfactant mixture with water (w/o), second-dilution of an water-surfactant mixture with oil (o/w),and third-mixing of all components at once. In this system, the order of ingredient addition may determine whether the microemulsion forms or not. e.g. Soybean oil (oil) + sucrose (surfactant) + ethanol (co-surfactant) dilute with water to forms good microemulsion.(30)

b. Phase Inversion Temperature Technique:

The formation of o/w or w/o self microemulsifying drug delivery system is dependent on temperature ranges. The temperature ranges in which an o/w microemulsion phase inverts to w/o microemulsion phase (vice –versa). E.g. by using non-ionic surfactant: Polyoxyethylene are susceptible to temperature, surfactant solubility of oil – water strongly depends on temperature.

c. Construction Of Pseudo-Ternary Phase Diagram:

The micro emulsion existence region was determined by constructing pseudo ternary phase diagram. Pseudo-ternary phase diagrams of oil, surfactant/co-surfactant (smix), and water were developed using the water titration method. This diagram will be best suited for making different possible compositions of oils surfactant / co- surfactant and water. Pseudo-ternary phase diagram were constructed to examine the formation of O/W micro emulsion using four component oil, surfactant, co-surfactant, and aqueous phase system. [e.g. The four component consist of Labrafil M 1944 CS (oil), Tween 20 (surfactant), Transcutol P and PEG 600 (co-surfactant) and distilled water (aqueous phase)]. In water titration method, mixture of oil and surfactant/co-surfactant (S/CoS) at certain volume ratios was diluted with water in a drop wise manner. The ratios of surfactant /co-surfactant were prepared in specific manner, i.e. 1:1, 2:1, 3:1,and 4:1 (w/w). Each of these ratios was mixed with increasing percentage of oil, i.e., 10%, 20%, 30%, 40% and upto 90% to get phase diagram. These each mixture was titrated with water and agitation was provided by magnetic stirrer. After each addition the system was examined for appearance and flow property. The concentration of water at which turbidity-to-transparency and transparency –to-turbidity transitions occurred was derived friom the total weight measurements. These values of oil, surfactant , and co surfactant were use to determine the boundaries of emulsion region. After the identification of microemulsion region in the phase diagrams, selection of microemulsion region were selected at desired component ratios, selection of microemulsion region from phase diagram was based on the fact that solution remains clear even on infinite dilution.(1, 2,3,22,23,30,33,41)

Figure No. 1: Construction of Pseudoternary Phase Diagram

Characterization:

1. Particle Size:

The droplet size of the emulsion is a crucial factor because it determines the rate and extent of drug release as well as absorption. Photon correlation spectroscopy (PCS) is a useful method for determination of emulsion droplet size especially when the emulsion properties do not change upon infinite aqueous dilution, a necessary step in this method. (7)

2. Polarity:⁽¹⁾

Polarity of the lipid phase governs the drug release from the micro-emulsion it means polarity characterizing emulsification efficiency. Polarity of oil droplet is governed by some parameters such as, the HLB, chain length and degree of unsaturation of the fatty acids, molecular weight of the hydrophilic portion and concentration of the emulsifier. Polarity has an impact on affinity of the drug for oil and/or water, and the type of forces formed. Highest release will be obtained with the formulation that have oil phase with highest polarity.

3. Zeta Potential Measurement:

In disperse systems, electrical charges are developed by several mechanisms at the interface between the dispersed phase and the aqueous medium. The two most common mechanisms are the ionization of surface functional groups and the specific adsorption of ions. Theses electrical charges play an important role in determining the interaction between the particles of the dispersed phase and the resultant physical stability of the system, particularly for those in the colloidal size range. The potential between the tightly bound surface liquid layer (shear plane) of the particle and the bulk phase of the solution is called as zeta potential. The measurement of the zeta potential tells about the stability. For o/w emulsions with low electrolyte content in the aqueous phase, a zeta potential of 30 mV is found to be sufficient to establish an energy maximum to ensure emulsion stability. (14)

4. Drug Precipitation /Stability On Dilution:

The ability of SMEDDS to maintain the drug in solubilised form is greatly influenced by the solubility of the drug in oil phase. If the surfactant or co-surfactant is contributing to the greater extent in drug solubilisation then there could be a risk of precipitation, as dilution of SMEDDS will lead to lowering of solvent capacity of the surfactant or co-surfactant, hence it is very important to determine stability of the system after dilution. This is usually done by diluting a single dose of SMEDDS in 250ml of 0.1N HCl solution. This solution is observed for drug precipitation if any. Ideally SMEDDS should keep the drug solubilized for four to six hours assuming the gastric retention time of two hours. (7)

Evaluation of SMEDDS:

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. Furthermore, incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drug. (20)

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

· Centrifugation: Passed formulations are centrifuged thaw cycles between 21 ºC and +25 ºC with storage at each temperature for not less than 48 h 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.

· Freeze Thaw Cycle: Three freeze for the formulations. Those formulations passed this test showed good stability with no phase separation, creaming, or cracking. (7,24)

b. Dispersability Test:

The efficiency of self-emulsification of oral nano or micro emulsion is assessed by using a standard USP XXII dissolution apparatus 2 for dispersibility test. One milliliter of each formulation was added in 500 mL of water at 37 ± 10C. A standard stainless steel dissolution paddle is used with rotating speed of 50 rpm provided gentle agitation. The in vitro performance of the formulations is visually assessed using the following grading system: (2,4,7, 9, 20, 24,25,28,33)

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 nano emulsion when dispersed in GIT. While formulation falling in Grade C could be recommend for SMEDDS formulation. (1,2,10,25,29,33)

c. Turbidimetric Evaluation:

Nephelo-turbidimetric 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 hot plate at appropriate temperature, and the increase in turbidity is measured, by using a turbid meter. 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). (10,25,28,30,33)

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. (25,33)

e. Droplet Size And Particle Size Measurement:

The particle size of the microemulsion is determined by photon correlation spectroscopy or SEM (Scanning Electron Microscopy) which can measure sizes between 10 and 5000 nm. The nanometric size range of the particle is retained even after 100 or 1000 times diluted with distill water, which proves the system’s compatible with excess water. (13,25,28,33)

f. Refractive Index And Percent Transmittance:

Refractive index and percent transmittance proved the transparency of formulation. The refractive index of the system is measured by refractometer by placing drop of solution on slide and it compare with water (1.333). The percent transmittance of the system is measured at particular wavelength using UV-spectrophotometer keeping distilled water as blank. If refractive index of system is similar to the refractive index of water(1.333) and formulation have percent transmittance > 99 percent, then formulation have transparent nature.(2,25,33)

g. Electro Conductivity Test:

This test is performed for measurement of the electro conductive nature of system. The electro conductivity of resultant system is measured by electro conductometer. In conventional SMEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids. (1,2,33)

h. In Vitro Release:

The quantitative in vitro release test was performed in 900 ml purified distilled water, which was based on USP 24 method. SMEDDS was placed in dialysis bag during the release period to compare the release profile with conventional tablet. 10 ml of sample solution was withdrawn at predetermined time intervals, filtered through a 0.45 μ membrane filter, dilute suitably and analyzed spectrophotometrically. Equal amount of fresh dissolution medium was replaced immediately after withdrawal of the test sample. Percent drug dissolved at different time intervals was calculated using the Beer Lambert’s equation.

i. Drug Content:

Drug from pre-weighed SEDDS is extracted by dissolving in suitable solvent. Drug content in the solvent extract was analyzed by suitable analytical method against the standard solvent solution of drug. (2,20,33).

j. Droplet Polarity And Droplet Size Of Emulsion

Polarity of oil droplets is governed by the HLB value of oil, chain length and degree of unsaturation of the fatty acids, the molecular weight of the hydrophilic portion and concentration of the emulsifier. A combination of small droplets and their appropriate polarity (lower partition coefficient o/w of the drug) permit acceptable rate of release of the drug. Polarity of the oil droplets is also estimated by the oil/water partition coefficient of the lipophillic drug. (33)Size of the emulsion droplet is very important factor in self emulsification / dispersion performance, since it determine the rate and extent of drug release and absorption. The Coulter nanosizer, which automatically performs photon correlation analysis on scattered light, can be used to provide comparative measure of mean particle size for such system. This instrument detects dynamic changes in laser light scattering intensity, which occurs when particle oscillates due to Brownian movement. This technique is used when particle size range is less than 3μm; a size range for a SMEDDS is 10 to 200 nm. (2)

Recent advancement in smedds to form solid-smedds:

SMEDDS can exist in either liquid or solid state. SMEDDS are usually, however, limited to liquid dosage forms, because many excipients used in SMEDDS are not solid at room temperature. Given advantages of solid dosage forms, S-SMEDDS have been extensively exploited in recent years, as they frequently represent more effective alternative to conventional liquid SMEDDS. S-SMEDDS focus on the incorporation of liquid/semisolid self emulsifying (SME) ingredients into powders/nanoparticles by different solidification techniques. (19,9,18)

1. Spray Drying

In this technique, formulation preparation involves by mixing lipids, surfactants, drug, solid carriers, and solublization of mixtures before spray drying. The solublized liquid formulation is then atomized into a spray of droplets. The volatile phase (e:g the water contained in an emulsion) evaporates as the droplets introduced in a drying chamber, forming dry particles under controlled temperature and airflow conditions. A variety of solid carriers have been used for preparation of S-SMEDDS e:g Dextran 40 (water soluble solid carrier, Aerosil®200 (non-porous and hydrophilic solid carrier). (18,31,32)

Critical parameters of spray drying system includes

· Inlet temperature of air, Outlet temperature of air, Viscocity, Solid content, Surface tension

· Feed temperature, Volatility of solvent, Nozzle material.

2. Adsorption to Solid Carriers

These solid carriers have property to absorb liquid/semisolid formulation as self emulsifying system (SES). It is a simple procedure, where SES is incorporated into a free flowing powder material adsorbed by mixing in a blender. This solid mixture is filled into capsule or added to more excipient before compression into tablets.(34) The above mixture was solidified to powder forms using three kinds of adsorbents: microporous calcium silicate (FloriteTM RE); magnesium aluminum silicate (NeusilinTMUS2) and silicon dioxide (SylysiaTM 320).(14,35)

3. Encapsulation Of Liquid And Semisolid Smedds

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 200C 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 microspray sealing.(36) In parallel with the advances in capsule technology proceeding, liquid-oros technology has been designed for controlled delivery of insoluble drug substances or peptides. This system is based on osmotic principles and is a liquid SME formulation system. It consists of an osmotic layer, which expands after coming into contact with water and pumps the drug formulation through an orifice in the hard or soft capsule. A primary consideration in capsule filling is the compatibility of the excipients with the capsule shell. The advantages of capsule filling are simplicity of manufacturing; suitability for low-dose highly potent drugs and high drug loading (up to 50% (w/w)) potential. (18,37)

4. Melt Granulation:

Melt granulation is a process in which powder agglomeration is obtained through the addition of a binder that melts or softens at relatively low temperatures. As a ‘one-step’ operation, melt granulation offers several advantages compared with conventional wet granulation, since the liquid addition and the subsequent drying phase are omitted. The main parameters that control the granulation process are impeller speed, mixing time, binder particle size, and the viscosity of the binder. A wide range of solid and semisolid lipids can be applied as meltable binders.Gelucire1, a family of vehicles derived from the mixtures of mono-/di-/tri-glycerides and polyethylene glycols (PEG) esters of fatty acids, is able to further increase the dissolution rate compared with PEG usually used before, probably owing to its SME property.Other lipid based excipients evaluated for melt granulation to create solid SMES include lecithin, partial glycerides, or polysorbates. The melt granulation process was usually used for adsorbing SMES (lipids, surfactants, and drugs) onto solid neutral carriers (mainly silica and magnesium alumina meta silicate). (5,18,37,38)

5. Melt Extrusion/ Extrusion Spheronization

1. Melt extrusion is a solvent-free process that allows high drug loading approximately 60%. Extrusion is a procedure of converting a raw material with plastic properties into a product of uniform shape and density, by forcing through a die under controlled temperature, product flow, and pressure conditions.

2. The extrusion spheronization process is commonly used in the pharmaceutical industry to make uniformly sized pellets. This process requires the following steps: Mix dry active ingredients and excipients to form a homogeneous powder; wet massing with binder; extrusion into a spaghetti like extrudate; spheronization from the extrudate to pheroids uniform size; drying; sifting to achieve the desired size distribution. Applying this technique, self emulsifying pellets of diazepam and progesterone has been prepared to provide a good in vitro drug release (100% within 30 min, T50% at 13 min) and bi-layered cohesive self emulsifying pellets have also been prepared. (8)

Characterization of solid-SMEDDS :

A. Characterization Of Solid Smedds:

Reconstituted power properties, Yield of spray dried product, Powder flow properties, Drug content, In-Vitro Dissolution study.

B. Solid State Characterization Of S-Smedds Powder:

Differential Scanning Calorimetry, Scanning electron microscopy, Powder X-ray Diffraction.

C. Stability Study (Three Month):

At- 20°, At- 25°, At- 40°.

Application/solid dosage forms of SMEDDS :

1. Dry emulsion

2. Self-emulsifying capsule

3. Self-emulsifying sustained/controlled-release tablets

4. Self-emulsifying sustained/controlled-release pellets

5. Self-emulsifying solid dispersion

6. Self-emulsifying beads

7. Self-emulsifying sustained-release microspheres

8. Self-emulsifying nanoparticles

9. Self-emulsifying suppositories

10. Self-emulsifying implants (9,18, 42,13)

Marketed formulation:

Table no.4: Available marketed Microemulsion formulation

Brand name	Composition	Manufactured by
Neoral	Cyclosporine A	Novartis
Norvir	Ritonavir	Abbott Laboratories
Fortovase	Saquinavir	Hoffmann La Roche Inc
Agenerase	Amprenavir	Glaxosmithkline
Lipirex	Fenofibrate	Sanofi-Aventis
Convulex	Valproic acid	Pharmacia
Solufen	Ibuprofen	Sanofi-Aventis (20, 21)

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Received on 18.07.2016 Modified on 20.09.2016

Research J. Pharm. and Tech. 2017; 10(4): 1215-1224.

DOI: 10.5958/0974-360X.2017.00218.9

Class	Solubility	Permeability	IVIVC Expectation	Example	Problems
I	High	High	IVIVC if dissolution rate is slower than the gastric emptying rate, otherwise limited or no correlation	Metoprolol, Diltiazem, Verapmil, Propranolol.	Enzymatic degradation, gut wall efflux
II	Low	High	IVIVC expected if the in vitro dissolution rate is similar to the in vivo dissolution rate, unless the dose is very high	Phenytoin, danazol, Ketoconazole Mefenamic acid, Nifedipine.	Solubilization and bioavailability
III	High	Low	High Low Absorption (permeability) is rate determining and limited or no IVIVC with dissolution rate	Cimetidine, Acyclovir, Neomycin, Captopril.	Enzymatic degradation, gut wall efflux, Bioavailability
IV	Low	Low	Limited or no IVIVC expected	Taxol, Griseofulvin, Neomycin, furesimide.	Solubilization, enzymatic degradation, gut wall efflux and bioavailability