INTRODUCTION:

Surfactants are compounds that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid.

Surfactants may act as:

· Detergents,

· Wetting agents,

· Emulsifiers,

· Foaming agents,

· Dispersants.¹

The word “catanionic mixture” is self-explanatory; it means a mixture of a cation and an anion. However, what the term fails to indicate is that both of the components additionally possess surface-active properties. Hence, there are two forces driving the formation of catanionic aggregates, arising from electrostatic and hydrophobic interactions.

Figure 1. Schematic of the catanionic mixture, where formation of (A) vesicles And (B) spherical, elongated and branched micelles can occur.

Composition and Structure:¹

Surfactants are usually organic compounds that are amphiphilic, meaning they contain both hydrophobic groups (their tails) and hydrophilic groups (their heads). Therefore, a surfactant contains both a water-insoluble (or oil-soluble) component and a water-soluble component. Surfactants will diffuse in water and adsorb at interfaces between air and water or at the interface between oil and water, in the case where water is mixed with oil. The water-insoluble hydrophobic group may extend out of the bulk water phase, into the air or into the oil phase, while the water-soluble head group remains in the water phase.

Structure of surfactant phases in water:¹

In the bulk aqueous phase, surfactants form aggregates, such as micelles, where the hydrophobic tails form the core of the aggregate and the hydrophilic heads are in contact with the surrounding liquid. Other types of aggregates can also be formed, such as spherical or cylindrical micelles or lipid bilayers. The shape of the aggregates depends on the chemical structure of the surfactants, namely the balance in size between hydrophilic head and hydrophobic tail. A measure of this is the HLB, Hydrophilic-lipophilic balance. Surfactants reduce the surface tension of water by adsorbing at the liquid-air interface. The relation that links the surface tension and the surface excess is known as the Gibbs isotherm.

Dynamics of Surfactants at Interfaces:¹

The dynamics of surfactant adsorption is of great importance for practical applications such as in foaming, emulsifying or coating processes, where bubbles or drops are rapidly generated and need to be stabilized. The dynamics of adsorption depend on the diffusion coefficient of the surfactant. As the interface is created, the adsorption is limited by the diffusion of the surfactant to the interface. In some cases, there can exist an energetic barrier to adsorption or desorption of the surfactant. If such a barrier limits the adsorption rate, the dynamics are said to be ‘kinetically limited'. Such energy barriers can be due to steric or electrostatic repulsions. The surface rheology of surfactant layers, including the elasticity and viscosity of the layer, play an important role in the stability of foams and emulsions.

Classification of surfactants:¹

The "tail" of most surfactants is fairly similar, consisting of a hydrocarbon chain, which can be branched, linear, or aromatic. Fluor surfactants have fluorocarbon chains. Siloxane surfactants have siloxane chains. Many important surfactants include a polyether chain terminating in a highly polar anionic group. The polyether groups often comprise ethoxylated (polyethylene oxide-like) sequences inserted to increase the hydrophilic character of a surfactant. Polypropylene oxides conversely, may be inserted to increase the lipophilic character of a surfactant. Surfactant molecules have either one tail or two; those with two tails are said to be double-chained. Surfactant classification according to the composition of their head: nonionic, anionic, cationic, amphoteric.

Most commonly, surfactants are classified according to polar head group. A non-ionic surfactant has no charged groups in its head. The head of an ionic surfactant carries a net positive, or negetive charge. If the charge is negative, the surfactant is more specifically called anionic; if the charge is positive, it is called cationic. If a surfactant contains a head with two oppositely charged groups, it is termed zwitterionic. Commonly encountered surfactants of each type include:

Anionic Sulfate, sulfonate, and phosphate esters:

Anionic surfactants contain anionic functional groups at their head, such as sulfate, sulfonate, phosphate, and carboxylates. Prominent alkyl sulfates include ammonium lauryl sulfate, sodium lauryl sulfate (SDS, sodium dodecyl sulfate, another name for the compound) and the related alkyl-ether sulfates sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES), and sodium myreth sulfate. Docusates: dioctyl sodium sulfosuccinate, perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, linear alkylbenzene sulfonates (LABs). These include alkyl-aryl ether phosphates and the alkyl ether phosphate.

Carboxylates:

These are the most common surfactants and comprise the alkyl carboxylates (soaps), such as sodium stearate. More specialized species include sodium lauroyl sarcosinate and carboxylate-based fluorosurfactants such as perfluorononanoate, perfluorooctanoate (PFOA or PFO).

Cationic head groups:

· pH-dependent primary, secondary, or tertiary amines: Primary and secondary amines become positively charged at pH < 10

· Octenidine dihydrochloride;

Permanently charged quaternary ammonium cation:

· Alkyltrimethylammonium salts: cetyl trimethyl ammonium bromide (CTAB) a.k.a. hexadecyl trimethyl ammonium bromide, cetyltrimethyl ammonium chloride (CTAC)

· Cetylpyridinium chloride (CPC)

· Benzalkonium chloride (BAC)

· Benzethonium chloride (BZT)

· 5-Bromo-5-nitro-1,3-dioxane

· Dimethyldioctadecylammonium chloride

· Cetrimonium bromide

· Dioctadecyldimethylammonium bromide (DODAB)

Zwitterionic surfactants:

Zwitterionic (amphoteric) surfactants have both cationic and anionic centers attached to the same molecule. The cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations. The anionic part can be more variable and include sulfonates, as in the sultaines CHAPS (3-[(3-Cholamidopropyl) dimethylammonio]-1-propanesulfonate) and cocamido propyl hydroxysultaine. Betaines such as cocamidopropyl betaine have a carboxylate with the ammonium. The most common biological zwitterionic surfactants have a phosphate anion with an amine or ammonium, such as the phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.

Nonionic surfactant:

Many long chain alcohols exhibit some surfactant properties. Prominent among these are the fatty alcohols, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol (consisting predominantly of cetyl and stearyl alcohols), and oleyl alcohol.

Ø Polyoxyethylene glycol alkyl ethers (Brij): CH3–(CH2)10–16–(O-C2H4)1–25–OH:

· Octaethylene glycol monododecyl ether

· Pentaethylene glycol monododecyl ether

Ø Polyoxypropylene glycol alkyl ethers: CH3–(CH2)10–16–(O-C3H6)1–25–OH

Ø Glucoside alkyl ethers: CH3–(CH2)10–16–(O-Glucoside)1–3–OH:

· Decyl glucoside,

· Lauryl glucoside

· Octyl glucoside

Ø Polyoxyethylene glycol octylphenol ethers: C8H17–(C6H4)–(O-C2H4)1–25–OH:

· Triton X-100

Ø Polyoxyethylene glycol alkylphenol ethers: C9H19–(C6H4)–(O-C2H4)1–25–OH:

· Nonoxynol-9

Ø Glycerol alkyl esters:

· Glyceryl laurate

Ø Polyoxyethylene glycol sorbitan alkyl esters: Polysorbate

Ø Sorbitan alkyl esters: Spans

Ø Cocamide MEA, cocamide DEA

Ø Dodecyldimethylamine oxide

Ø Block copolymers of polyethylene glycol and polypropylene glycol: Poloxamers

Ø Polyethoxylated tallow amine (POEA).

What are Cationic Surfactants?²

Cationic surfactants are basically soaps or detergents, in which the hydrophilic, or water-loving, end contains a positively-charged ion, or cation. Typical examples are trimethyl alkylammonium chlorides, and the chlorides or bromides of benzalkonium and alkylpyridinium ions. All are examples of quats, so named because they all contain a quaternary ammonium ion.

All soaps or surfactants, short for surface active agents, work by the same basic principle, based on the fact that most substances in nature are either hydrophilic, or water-loving, or lipophilic, or fat-loving. Hydrophilic substances dissolve readily in water, and lipophilic substances dissolve in hydrocarbons, which are organic compounds containing a lot of carbon and hydrogen. The usual job of these soaps or detergents is to make lipophilic substances — like oils, fats, and greases — soluble in water, so they can be washed away. Since water easily dissolves ionic substances, or materials that contain one or more charged atoms, and hydrocarbons dissolve oils, fats, and greases, a detergent molecule has a hydrocarbon end and an ionic end. The hydrocarbon end of the soap molecule dissolves in a particle of grease or oil, leaving the ionic end exposed to the water.

When enough soap molecules have embedded their hydrocarbon ends in the particle, the surrounding water molecules attract the ionic ends of the surfactant. The particle then becomes emulsified, or suspended in water. In this form, it can be rinsed away.

The hydrophilic portion of a surfactant can be one of four types. It may be be nonionic but still very water soluble; zwitterionic, meaning it contains both positive and negative charges; anionic, or negatively charged; or cationic, which is positively charged. The charge on the ionic portion significantly affects the properties of the surfactant.

Soaps, strictly defined, are always anionic, so the charged end has a negative charge. They are very good at emulsifying oily dirt and keeping it suspended in water, and has good sudsing properties. They may, however, react with metal ions present in hard water, such as calcium and magnesium, to form insoluble soap scums.

Cationic surfactants are almost all man-made, and their ionic portion is positively charged. They are good emulsifying agents too, and do not form insoluble scums with positively-charged hard-water ions. These surfactants have also been found to be good bactericides and some find use as topical antiseptics. Their germicidal properties make them especially useful in bathroom and hand sanitizers.

Furthermore, cationic surfactants are attracted to negatively-charged sites that occur naturally on most fabrics. They can bind to these sites and provide the fabric with a soft, luxurious feel. For this reason, they are often used as fabric softeners.

Mechanism of Action of Surfactant:³

Surfactants can work in three different ways:

· Roll-up,

· Emulsification

· Solubilization.

(a) Roll-up mechanism:

The surfactant lowers the oil/solution and fabric/solution interfacial tensions and in this way lifts the stain of the fabric.

(b) Emulsification:

The surfactant lowers the oil solution interfacial tension and makes easy emulsification of the oil.

(c) Solubilization:

Through interaction with the micelles of a surfactant in a solvent (water), a substance spontaneously dissolves to form a stable and clear solution.

Pharmaceutical Application of surfactants:^3-9

(a) Surfactants as enhancers for percutaneous absorption:

The transport of molecules through the skin can be increased by the use of certain adjuvant known as enhancers. Ionic surfactants enhance transdermal absorption by disordering the lipid layer of the stratum corneum and by denaturation of keratin. Enhancers may increase drud penetration by causing the stratum corneum to swell and/or leach out some of the structural components, thus reducing the diffusional resistance and increasing the permeability of the skin. Nishihata et al proposed a mechanism for the enhancing the effect of reducing agents such as ascorbate and dithiothreitol. The poor permeability of the skin is due to the ordered layer of intercellular lipids and to low water content. Proteins in keratinized tissue are rich in cysteine residues, and the strong disulfide bonds may be the reason for the insoluble nature of this protein. The reducing agents causes a decrease in the number of disulfide bridges, thus increasing the hydration of the proteins, which results in increased skin permeability. Azone is one of the most efficient enhancers of percutaneous absorption. It greatly improves the penetration of hydrophilic and hydrophobic compounds, the latter to a small degree. A possible mechanism of azone is its fluidization of the intercellular lipid lamellar region of the stratum corneum. Azone is a very nonpolar molecule which enters the lipid bilayers and disrupts their structure. In contrast, a strongly dipolar solvent, dimethyl sulfoxide (DMSO), enters the aqueous region and interacts with the lipid polar heads to form a large solvation shell and expands the hydrophilic region between the polar heads. As a result, both azone and DMSO increases the lipid fluidity, thus reducing the resistance of lipid barrier to the diffusion of drugs. Alcohol derivatives of N, N disubstituted amino acids and hexamethylene lauramine also enhance the permeability of drugs.

(b) Surfactants as flocculating agents:

A suspending agent is frequently added to retard sedimentation of the floccules. Such agents are carboxy methyl cellulose, carbopol 934, veegum, tragacanth, or bentonite which is employed either alone or in combination. This may lead to incompatibilities, depending on the initial particle charge and the charge carried by the flocculating agent and the suspending agent. Flocculating a positively charged particles are done by the addition an anionic electrolyte such as

monobasic potassium phosphate.

(c) Surfactants in mouth washes:

Mouthwashes are aqueous solutions often in concentrated form containing one or more active ingredients or excipients. They are used by swirling the liquid in the oral cavity. Mouthwashes can be used for two purposes. They are therapeutic and cosmetic. Therapeutic mouth rinses or washes can be formulated in order to reduce plaque, gingivitis, dental caries, and stomatitis. Cosmetic mouthwashes may be formulated to reduce bad breath through the use of antimicrobial and/or flavouring agents. Surfactants are used because they aid in the solubilization of flavours and in the removal of debris by providing foaming action.

(d) Surfactants in respiratory distress therapy:

Surfactant preparations are used as replacement therapy for the treatment of premature infants suffering from neonatal respiratory distress syndrome (also known as hyaline membrane disease). This pulmonary condition occurs in approximately 20% of the 250,000 premature babies born in the US each year and accounts 5000 deaths annually. A substantial deficiency in the endogenous lung surfactant is the principal factors contributing to the pathology of respiratory distress syndrome. The lung surfactant preparations are used in combination with supplemental oxygen and mechanical Ventilation to facilitate gas exchange for either prophylactic or rescue treatment of neonatal respiratory distress syndrome. The exogenous surfactants are either derived from animals or synthesized.

(e) Surfatants in suppository bases:

Several nonionic surface active agents, closely related chemically to the polyethylene glycols, have been developed as suppository vehicles 16. Many of these bases can be used for formulating both water soluble and oil soluble drugs. The surfactants most commonly used in suppository formulations are the polyoxyethylene sorbitan fatty acid esters (tween), polyoxyethylene stearates (Myrj), and the sorbitan fatty acid esters (Span and Arlacel). Caution must be exercised in the use of surfactants with drugs. There are reports indicating increased rate of drug absorption, and other reports showing interaction of these surface active agents with drugs and consequent decrease in therapeutic activity. Each formulation must be tested in vivo to evaluate its medicinal effectiveness, as well as safety. Gross and Becker recommended a water dispersible, high melting point (500C) suppository base consisting of polyoxyethylene 30 stearate (Myrj 51), water, white wax, and dioctyl sodium sulfosuccinate (Aerosol OT). The use of aerosol OT in the formula was claimed to lend synergism to the surfactant and thus aid in rapid disintegration of suppository. The drugs studied were Phenobarbital, quinine hydrochloride, tannic acid, and chloramphenicol. Ward reports on several polyoxyethylene sorbitan derivatives (Tweens), which are designed to melt at body temperature into liquids that disperse readily in the body fluids.

(f) Surfactants in suspension aerosols:

The addition of surfactants to aerosol suspensions has been most successful. These surfactants exert their activity by coating each of the particles in suspension and orients at the solid-liquid interface. Agglomeration is reduced, thereby increasing stability by providing a physical barrier. According to the investigations carried out by Young, Thiel, and Laursen nonionic surfactants were found to be most effective than the other type of surfactants. Those surfactants having an HLB less than 10, such as sorbiton trioleate, could be utilized for aerosol dispersions. Other agents that were found to be useful are sorbiton monolaurate, sorbiton monooleate, and sorbiton sesqioleate.

(g) Surfactants in water based aerosols:

Relatively large amounts of water can be used to replace all or part of the nonaqueous solvents used in aerosols. These products are generally referred to as water-based aerosols and depending on the formulation they are emitted as a spray or foam. To produce a spray, the formulation must consist of a dispersion of active ingredients and other solvents in an emulsion system in which the propellant is in the external phase. In this way, when the product is dispensed, the propellant vaporizes and disperses the active ingredients into minute particles. Since propellant and water are not miscible, a three phase aerosol forms (propellent phase, water phase and vapor phase). Surfactants have been used to a large extent to produce a satisfactory homogeneous dispersion. Surfactants that possess low water solubility and high solubility in nonpolar solvents have been found to be most useful. Long chain fatty acid esters of polyhydroxylic compounds including glycols, glycerol, and sorbitol esters of oleic, stearic, palmitic, and lauric acid exemplify this series. In general, about 0.5% to 2.0% of surfactant is used. The propellent content varies from 25to60%, but can be as low as 5%, depending on the nature of the product.

(h) Surfactants for contact lens cleaning:

Surfactants act as cleansers, which emulsify accumulated oils, lipids and inorganic compounds over contact lenses. Surfactant agents are utilized either with in a mechanical washing device or by placing several drops of the solution on the lens surface and gently rubbing the lens back and forth with the thumb and fore finger or by placing the lens in the palm of the hand and rubbing gently with a finger tip (about 20 to 30 seconds). The ingredients in these cleansers usually include a nonionic detergent, wetting agent, buffers, and preservatives.

(i) Surfactants in hard gelatin capsules:

Aguiar et al measured the dissolution of poorly soluble benzoic acid presented as a loose powder, and the same powder filled into a size 00 and a size 1 capsule. The slowest dissolution rate was obtained with the size 1 capsule in which the powder is most tightly packed. They overcome this problem by adding 0.5% of polyol surfactant into the formulation. This greatly improved the dissolution rate which they showed was due to an increase in the deaggregation rate of the material. If hydrophobic compounds have to be included in formulations because of filling machine requirements, their deleterious effect on drug release can be overcome by the addition of wetting agents, surfactants at levels of 0.1-0.5%.

(j) Surfactants as emulsifying agents:

In surfactants, the lipophilic protein of the molecule generally accounting for the surface activity of the molecule. Owing to their opposing ionic charges, anionic and cationic agents tend to neutralize each other if present in the same system and are thus considered incompatible with one another. Depending upon their individual nature certain members of these groups form o/w emulsions and others w/o emulsions. Anionic emulsifiers include various monovalent, poplyvalent, and organic soaps such as triethanolamine oleate and sulfonate such as sodium lauryl sulfate, benzalkonium type of emulsifier. Agents of the nonionic type include sorbiton esters and the polyoxtetylene derivatives. The ionic nature of the surfactant is of prime consideration in the selection of a surfactant to utilize in forming an emulsion. Non ionic surfactants are effective over Ph range 3 to 10, cationic surfactants are effective over pH range 3 to 7, and anionic surfactants require a pH of greater than 8. A hydrophilic Tween can be combined with a lipophilic Span surfactant at varying proportions so as to produce the desired o/w or w/o emulsion .Boyd et al discussed the molecular association of Tween 40 and Span 80 in stabilizing the emulsions. If the hydrocarbon portion of the Span 80 (sorbiton mono oleate) molecule lies in the oil globule the sorbiton radical lies in the aqueous phase. The bulky sorbiton heads of the Span molecule prevent the hydrocarbon tails from associating closely in the oil phase. When Tween 40 (polyoxyethylene sorbiton monopalmitate) is added, it orients at the interface such that part of its hydrocarbon tail is in the oil phase, and the reminder of the chain, together with the sorbiton ring and the polyoxyethylene chains, is located in the water phase. It is observed that the hydrocarbon chain of the Tween 40 molecule is situated in the oil globule between the Span 80 chains, and this orientation results in effective van der waals attraction. In this manner the interfacial film is strengthened and the stability of the o/w emulsion is increased against particle coalescence.

(k) Surfactants as cerumen removing solutions:

Cerumen is a combination of the secretions of sweat and sebaceous glands of the external auditory canal. The secretions, if allowed to dry, form a sticky semisolid which holds shredded epithelial cells, fallen hair dust and other foreign bodies that make their way into the ear canal. Excessive accumulation of cerumen in the ear may cause itching, pain, impaired hearing and is a deterrent to otologic examination Through the years, light mineral oil, and hydrogen peroxide have been commonly used agents to soften impacted cerumen for its removal. Recently, solutions of synthetic surfactants have been developed for their cerumenolytic activity in the removal of ear wax. One of these agents are tri ethanolamine polypeptide oleate-condensate, commercially formulated in propylene glycol, is used to emulsify the cerumen thereby facilitating its removal (Cerumenex drops). Another commercial product utilizes carbamide peroxide in glycerin/propylene glycol (Debrox drops). On contact with the cerumen, the carbamide peroxide releases oxygen which disrupts the integrity of the impacted wax, allowing its easy removal.

(l) Surfactant influencing drug absorption:

Surfactants in general cannot be assumed to be inert excipients since they have been shown to be capable of increasing, decreasing or exerting no effect on the transfer of drugs across biological membranes. In addition, surfactants might also produce significant changes in the biological activity of drugs by exerting an influence on drug metabolizing enzymes or on the binding of drugs to receptor proteins. Surfactants influences drug absorption from the gastrointestinal tract in humans. Surfactant monomers can potentially disrupt the integrity and function of a membrane. Hence, such a membrane disrupting effect would tend to enhance drug penetration and hence absorption across the gastrointestinal barrier. Inhibition of drug absorption may occur as a consequence of a drug being incorporated into surfactant micelles. If such surfactant micelles are not absorbed, which appears to be usually the case, and then solubilisation of drug may result in a reduction of the concentration of free drug in solution in the gastro intestinal fluids which is available for absorption. Inhibition of drug absorption in the presence of micellar concentrations of surfactant would be expected to occur in the case of drugs which are normally soluble in the gastrointestinal fluid, in the absence of surfactant. However, in the case of poorly soluble drugs whose absorption is dissolution rate limited, the increase in saturation solubility of the drug by solubilization in surfactant micelles could result in more rapid rates of drug dissolution and hence absorption. Very high concentrations of surfactant in excess of that required to solubilize the drug could decrease drug absorption by decreasing the chemical potential of the drug. Release of poorly soluble drugs from tablets and hard gelatin capsules may be increased by the inclusion of surfactants in their formulations. The ability of a surfactant to reduce the solid/liquid interfacial tension will permit the gastrointestinal fluids to wet more effectively and to come into more intimate contact with the solid dosage forms. This wetting effect may thus aid the penetration of gastrointestinal fluids into the mass of capsule contents which often remains when the hard gelatin shell has dissolved and/or reduce the tendency of poorly soluble drug particles to aggregate in the gastrointestinal fluids. In each case the resulting increase in total effective surface area of the drug in contact with gastrointestinal fluids would tend to increase the dissolution and absorption rates of the drugs.

PROPERTIES OF SURFACTANT¹⁰

• Wetting of Solids

• Solubilization

• Emulsification

• Dispersion of solid in solution

• Micellization

• Detergency

CONCLUSION:

Cationic surfactants are basically soaps or detergents, in which the hydrophilic, or water-loving, end contains a positively-charged ion, or cation. Most commonly, surfactants are classified according to polar head group. A non-ionic surfactant has no charged groups in its head. The head of an ionic surfactant carries a net positive, or negative charge. If the charge is negative, the surfactant is more specifically called anionic; if the charge is positive, it is called cationic. If a surfactant contains a head with two oppositely charged groups, it is termed zwitterionic.

REFERENCE:

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4. Reddy, I and M. Ganesan , Ocular therapeutics and drug delivery: an overview, in Ocular therapeutics and drug delivery, I. Reddy, Editor., Technomic: Lancaster. p. 3-29.

5. Larson RG : The structure and rheology of complex fluids. Oxford University Press, New York.

6. Jung, H.T. et al., The origins of stability of spontaneous vesicles. P. Natl. Acad. Sci. USA,. 98(4): p. 1353-1357.

7. Kaler EW, et al., Spontaneous Vesicle Formation in Aqueous Mixtures of Single-Tailed Surfactants. Science,. 245(4924): p. 1371-1374.

8. Kaler, E.W. et al., Phase-Behavior and Structures of Mixtures of Anionic and Cationic Surfactants. J. Phys. Chem. 96(16): p. 6698-6707.

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10. http://www.pharmatutor.org/articles/surfactants-and-its-applications-in-pharmaceuticals-overview?page=0,0

Received on 01.10.2015 Modified on 16.10.2015

Res. J. Pharm. Dosage Form. and Tech. 7(4): Oct.-Dec., 2015; Page 294-300

DOI: 10.5958/0975-4377.2015.00041.5