Surfactants and their applications in pharmaceutical Dosage forms

* Surfactants Surfactants are termed as surface-active agents also wetting agents,

emulsifying agents or suspending agents depending on its properties and use.

Surface-active agents are substances which, at low concentrations, adsorb

onto

the surfaces or interfaces of a system and alter the surface or interfacial free

energy and the surface or interfacial tension.

Surfactants are monomers, it has a characteristic structure possessing both

hydrophobic groups / non-polar regions (their "tails") usually contain a C12–

C18 hydrocarbon chain and hydrophilic groups / Polar Regions(their "heads").

Therefore, they are soluble in both organic solvents and water, so they called

amphiphilic.

(Martin Alfred. Physical Pharmacy-Physical Chemical principles in Pharmaceutical Sciences.). (Perkins Warren S. )

Fig.no.1. Surfactant (Monomer) Head - Polar, Hydrophilic

Tail - Non polar, Hydrophobic

Hydrophilic headHydrophobic tail

Sodium dodecyl sulphate .The polar "head" has affinity for water and the "tail" has affinity for oil

Mechanism of ActionSurfactants can work in three different ways:

Roll-up, Emulsification and 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.

Fig. Surfactant mechanism of action in stain removal from fabric

Classification of surfactants:

Surfactant can be classified based on charge groups present in their head. A

nonionic surfactant do not have any charge groups over its head. The head of an

ionic surfactant carries a net charge. If the charge is negative, the surfactant is more

specifically called anionic and if the charge is positive, it is called cationic.

If a surfactant contains a head with two oppositely charged groups, it is termed

zwitterion.

1. Anionic surfactants2. Cationic surfactants3. Non-ionic surfactants4. Zwitterionic/ amphoteric surfactants

(a)Anionic surfactants:

In solution, the head is negatively charged.

These surfactants are the most widely used

type of surfactant for preparing shampoos

because of its excellent cleaning properties

and high hair conditioning effects. Anionic

surfactants are particularly effective at oil

cleaning and oil/clay suspension.

The most commonly used anionic surfactants are alkyl sulphates, alkyl

ethoxylate sulphates and soaps. Most of the anionic surfactants are

carboxylate ,sulfate and sulfonate ions .(ARG Remington ,The science and practice of

pharmacy ,19th edn ,Vol 1) . The straight

chain is a saturated /unsaturated C12-C18 aliphatic group. The water

solubility potential of the surfactant is determined by the presence of

double bonds . (G.Zagrafti .The science and practice of pharmacy)

(b) Cationic Surfactants:

In solution, the head of the cationic surfactant is positively charged. Cationic

surfactants are quaternary ammonium compounds and they are mostly used for

their disinfectant and preservative properties as they have good bactericidal

properties. They are used on skin for cleansing wounds or burns. Mostly used

cationic surfactants are cetrimide which has tetradecyl trimethyl ammonium

bromide with minimum amount of dodecyl and hexadecyl compounds . Other

cationic surfactants are benzalkonium chloride,cetylpyridinium chloride etc.

(c) Non-Ionic Surfactants:

Those surfactants do not have any electrical charge, which makes them resistant to

water hardness deactivation.

They are less irritant than other anionic or cationic surfactants.

The hydrophilic part contains the polyoxyethylene ,polyoxypropylene or polyol

derivatives.

The hydrophobic part contains saturated or unsaturated fatty acids or fatty alcohols

They are excellent grease/oil removers and emulsifiers.

The non ionic surfactant can be classified as

• Polyol esters ,

• polyoxyethylene esters ,

• poloxamers .

The Polyol esters includes glycol and glycerol esters and sorbitan

derivatives.

Polyoxyethylene esters includes polyethylene glycol (PEG 40,PEG -

50 ,PEG- 55).

The most commonly used non-ionic surfactants are ethers of fatty

Alcohols.

(Zhang W, Dai X et al)

(d) Amphoteric/Zwitterionic Surfactants:

These surfactants are very mild, making them particularly suited for use in

personal care preparations over sensitive skins.

They can be anionic (negatively charged), cationic (positively charged) or

non-ionic (no charge) in solution, depending on the acidity or pH of the

water.

Those surfactants may contain two charged groups of different sign.

Whereas the positive charge is almost always ammonium but the source of

the negative charge may vary (carboxylate, sulphate, sulphonate).

These surfactants have excellent dermatological properties. They are

frequently used in shampoos and other cosmetic products, and also in hand

dishwashing liquids because of their high foaming properties.

(Zhang W, Dai X et al)

Amphoteric Surfactant

PROPERTIES OF SURFACTANT

• Wetting of Solids

• Solubilization

• Emulsification

• Dispersion of solid in solution

• Micellization

• Detergency

( Rawlins EA, editors. Bentley’s Text book of Pharmaceutics). (Faeder J et al)

• Micellization

Definition- A micelle is an aggregate of surfactant molecules dispersed in

a liquid colloid. The process of forming micelle is known as micellization.

Micelle formations in polar and non-polar solvent depend on the

concentration of the surfactant in the particular solvent.

If add surfactant (monomers) in solvent, at low concentration some

monomers dispersed in solvent or aggregate at the surface or interface until

all surface or interface saturated by surfactant.

Further addition of surfactant increase concentration of monomers and it

goes in solvent and start to form micelles. This concentration is called

CMC. [Critical micelle concentration]

CMC- The concentration of monomer at which the micelles are start to form in

solvent at particular temperature. Micelles form only when the concentration

of surfactant is greater than the critical micelle concentration (CMC). (Tanford C. The hydrophobic effect: Formation of micelles and biological

membranes.)

Wetting of Solidso A drop of liquid when placed on a flat, homogeneous solid surface comes

to equilibrium, assuming a shape which minimizes the total free energy of

the system.

o The angle between the liquid and the solid is called the contact angle (θ),

the angle being measured through the liquid.

o The contact angle may be calculated if the surface and interfacial tensions

are known from Young’s equation given in Eq. (1) or (2).

o γSA = γSL + γLA cos θ ______________________________(1)

Or

o Cosθ = γSA – γSL / γLA ______________________________(2)

Where γLA is the surface tension of the liquid, γSL is the interfacial tension

existing between the solid and liquid phases, and γSAis the surface tension (or

surface free energy) of the solid.

o The term ‘‘wetting agent’’ is applied to any substance that increases

the ability of water or an aqueous solution to displace air from a

liquid or solid surface.

o For good wetting, cosθ should be as close as possible to 1; that is, θ

should be as close as possible to 0.

If θ< 90, wetting of the solid is said to take place. If θ> 90, wetting

does not take place.

Fig.no.9. Contact angles of liquid on surface.

Emulsification This is the property of surfactants to form a stable emulsion of two or more

immiscible liquids.

When oil and water mixed together and agitated, droplets of varying size are

produced.

Tension exists at the interface because the two immiscible liquid phases tend to

have different attractive forces for a molecule at the interface.

Molecules of one phase are repelled by other phase due to greater interfacial

tension, but for dispersion of liquid necessary of reduction of interfacial

tension.

This is done by addition of surfactants and having following mechanisms.

• Reduction of interfacial tension – Thermodynamic stabilization.

• Formation of interfacial film – mechanical barrier to coalescence.

• Formation of electrical double layer – electrical barrier to approach of

particles.

♦ Interfacial Tension

Even though reduction of interfacial tension lowers the interfacial free energy

produced on dispersion. Surfactants are adsorbing on the interface of them,

because hydrophilic head have affinity towards water and hydrophobic tail towards

oil. This is responsible for reduction of interfacial tension and two immiscible

phases are become miscible.

♦ Interfacial Film

The formation of film by the emulsifier is similar to adsorption of surfactants at the

interface of an oil and water. If the concentration of emulsifier is high enough, it

forms a rigid film between the immiscible phases which act as a mechanical bar to

both adhesion and emulsifier of emulsion droplets. In O / W emulsions, the mixture

of sodium cetyl sulfate and cholesterol form more stable interfacial film.

♦ Electrical Repulsion / Electrical Double Layer

It has just been described how interfacial films significantly alter the

rate of coalescence of droplets by acting as barriers. In addition, the

same or similar film can produce repulsive electrical forces between

approaching droplets. Such repulsion is due to an electrical double

layer, which may arise from electrically charged groups oriented on

the surface of emulsified globules.

* Solubilization• Solubilization can be defined as ‘‘the preparation of a thermodynamically stable

isotropic solution of a substance normally insoluble or very slightly soluble in a

given solvent by the introduction of an additional amphiphilic component or

components.

• ’’ The amphiphilic components (surfactants) must be introduced at a

concentration at or above their critical micelle concentrations.

• Simple micellar systems (and reverse micellar) as well as liquid crystalline

phases and vesicles referred to above are all capable of solubilization.

• In liquid crystalline phases and vesicles, a ternary system is formed on

incorporation of the solubilizate and thus these anisotropic systems are not

strictly in accordance with the definition given above.

Solubilization by micelles

The location of a solubilized molecule in a micelle is

determined primarily by the chemical structure of the

solubilizate.

Solubilization can occur at a number of different sites in a

micelle:

Fig : In Aqueous Systems Solubilization Of Drugs At Diff. Positions Of Micelle.

1. On the surface, at the micelle–solvent interface,

2. At the surface and between the hydrophilic head groups,

3. In the palisades layer, i.e., between the hydrophilic groups and the first few

carbon atoms of the hydrophobic groups that comprises the outer regions of the

micelle core.

4. More deeply in the palisades layer, and in the micelle inner core.

( Loyd V Allen et al)

Examples

1. Polar alcohols are soluble in aqueous solution, so it located in solution / on

surface of micelle.

2. Phenol are having polar –OH group and non polar benzene ring. In which –OH

gr. Located in hydrophilic environment and benzene ring in hydrophobic

environment, so it located at the surface and between the hydrophilic head groups.

3. Semi polar materials, such as fatty acids are usually located in the palisades

layer, the depth of penetration depending on the ratio of polar to non-polar

structures in the solubilisate molecule.

4. Non-polar additives such as hydrocarbons tend to be intimately associated with

the hydrocarbon core of the micelle.

(Kwon GS, Kataoka K. Block copolymer micelles as long circulating drug vehicles.)

Pharmaceutical Examples of solubilization

• The solubilization of phenolic compounds such as cresol, chlorocresol,

chloroxylenol and thymol with soap to form clear solutions for use in

disinfection.

• Solubilized solutions of iodine in non-ionic surfactant micelles

(iodophors) for use in instrument sterilization.

• Solubilization of drugs (for example, steroids and water insoluble

vitamins), and essential oils by non-ionic surfactants (usually polysorbates or

polyoxyethylene sorbitan esters of fatty acids).

( Malmsten M. “Surfactants and polymers in drug delivery system”,)

Detergency

It is most important property of surface active agents. Surface active agents are

referred as detergents. The term Detergency is mostly used in the cleaning /

removing of grease, oil and dirt from the solid surface. The principle of detergency is

based on the formation of micelle.

The process needs many of the actions specific to surfactant molecules.

1. The surfactant requires good wetting properties to ensure good contact with the

solid surface.

2. It also has the ability to remove dirt into the bulk liquid.

This property is achieved by lowering the surface tension of the medium in

which surfactants is dissolved.

By lowering this interfacial tension between two media or interfaces (e.g.

air/water, water/stain, stain/fabric) the surfactant plays a key role in the

removal and suspension of dirt.

The lower surface tension of the water makes it easier to lift dirt and grease

off of dirty dishes, clothes and other surfaces, and help to keep them

suspended in the dirty water.

The water-loving or hydrophilic head remains in the water and it pulls the

stains towards the water, away from the fabric.

The surfactant molecules surround the stain particles, break them up and

force them away from the surface of the fabric.

They then suspend the stain particles in the wash water to remove them.

If the dirt is oily it may be emulsified or solubilized by the surfactant.

(Liberman et al, Lachaman et al, Allen Loyd V et al)

APPLICATION OF SURFACTANTS IN PHARMACEUTICALS

SOLID DOSAGE FORMS Surface-active agents have been widely shown to enhance drug dissolution

rates.

This may be due to wetting effects, resulting in increased surface area,

effects on solubility and effective diffusion coefficient or a combination of

effects.

Consequently surfactants have been included in tablet and capsule

formulations to improve wetting and deaggregation of drug particles and

thus increase the surface area of particles available for dissolution.

This wetting effect is found to be operative at concentrations below the

CMC.

However they also reduce the effective rate of drug diffusion as a

consequence of drug solubilization within micelles.

The effect of surfactants on the dissolution of solids is complex. In

addition to effects on the available surface area, surfactants in

concentrations above the CMC can increase drug solubility and hence the

effective concentration gradient.

I. Hard Gelatin Capsules and Tablets

Wetting agents : Surfactants are used in capsule and tablet formulations as wetting

agents to aid dissolution.

Lubricants, anti-adherents, and glidants.

The primary function of tablet lubricants is to reduce the friction arising at the

interface of tablet and die walls during compression and ejection.

Lubricants also possess antiadherent (prevention of sticking to the punch and,

to a lesser extent, to the die wall) and glidant (improvement of flow

characteristics of powders or granulates) characteristics and are useful in the

processing of hard gelatin capsules.

Magnesium stearate is used extensively as a lubricant in tablet manufacture. It

is an example of a ‘‘boundary lubricant,’’ that is, the polar regions of the

molecule adhere to the metal surface of the die wall (in tablet manufacture).

Lubricants may be classified as water-soluble or water-insoluble. The latter

are generally more effective than water-soluble lubricants and can be used at a

lower concentration.

Common water-insoluble lubricants (which are surfactants) include

magnesium stearate, calcium stearate, sodium stearate, and stearic acid;

water-soluble lubricants include sodium lauryl sulphate and magnesium

lauryl sulphate.

Sodium lauryl sulphate is used in the production of hard gelatin capsules

where it is added to the gelatin solution during the preparation stage.

Adsorption of magnesium stearate to the powder or granule surfaces also

prevents agglomeration of the feed material and aids flow.

II. Suppositories Several non-ionic surface-active materials have been developed as

suppositories vehicles.

Many of these bases, known as water-dispersible bases, can be used for

the formulation of both water-soluble and oil soluble drugs.

The surfactants most commonly used are the polyoxyethylene sorbitan

fatty acid esters (Tweens), the polyoxyethylene stearates, and the

sorbitan fatty acid esters (Spans).

The stainless steel molds are lubricated prior to dipping into the gelatin

solution and sodium lauryl sulphate is added to reduce the surface tension

of the mix and cause the mold pins to wet more uniformly.(Corrigan OI, Healy AM. Surfactants in Pharmaceutical Products and Systems.)

Surface-active agents are widely used in combination with other

suppository bases.

The inclusion of these agents in the formulation may improve the

wetting and water-absorption properties of the suppository. In

addition, emulsifying surfactants help to keep insoluble substances

suspended in a fatty base suppository.

The inclusion of a surfactant in the suppository formulation may

enhance the rectal absorption of drugs.

Corrigan OI, Healy AM. Surfactants in Pharmaceutical Products and Systems.

LIQUID SYSTEMS

Formulation of Solution

Surfactants used in Formulation of Solution as solubilizing agent, which

increase Drug solubility. It includes Sorbitan mono oleate and PEG. It used in

rang 0.05-0.5% to avoid toxicity.[26]

• Formulation of Suspension (Dispersants)

surfactants may be used in the formulation of suspension to aid dispersion

of the solid particles in the liquid.

This is particularly important if the powder is not readily wetted by the

liquid vehicle. Surfactants can reduce the interfacial tension between the

solid particles and the liquid vehicle.

The advancing contact angle is reduced, and wetting of the solid

particles promoted. Such a system is said to be deflocculated.

The inclusion of a surface-active agent to improve powder wettability

can often improve the bioavailability of the formulation.

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.

Reshad M, Nesbit M, Petrie A, Setchell D.Eur J Prosthodont Restor Dent. 2009

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.

• 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.

Brands in pakistanABBOWAX drops, CARBOWAX drops

(Dimmitt P.J Pediatr. Health Care. 2005 Sep-Oct;)

SEMISOLID SYSTEMS

Surfactants are major constituents of pharmaceutical, cosmetic, and food

semisolid formulations, many of which are emulsions, either oil in water (o/w)

or water in oil (w/o). They are included for their stabilizing, wetting,

solubilizing, detergent and penetration enhancing properties.

Emulsion formulation: Water-in-oil emulsions traditionally contain surfactants

of natural origin such as cholesterol, wool fat, wool alcohols, lanolin, divalent

salts of fatty acids soaps, calcium oleate and/or synthetic agents of low

hydrophilic-lipophilic balance (HLB) (indicating high lipophilicity), such as

Spans (fatty acid esters of sorbitan).

The water soluble surfactant may be anionic (e.g., sodium lauryl

sulphate), cationic (e.g., cetrimide), or non-ionic (e.g., cetomacrogol,

Tweens).

Mixed emulsifiers control the consistency of a cream by forming a

viscoelastic network throughout the continuous phase of the emulsion.

The network results from the interaction of the mixed emulsifier with

water, forming a liquid crystalline phase.

(Abramzom AA. REVIEWS-SURFACTANTS THEIR PROPERTIES AND USE)

Formulation of Ointments

Ointments are semisolid preparation meant for external application to skin or

mucous membrane; they usually contain medicaments or medicaments in

dissolved, suspended or emulsified in an ointment base. Sometimes in the

ointment preparation surfactants are useful for the easy removal from the skin

by washing with water & also for the consistency by reduction of surface

tension.

Surfactants are also used in formulation of cold cream, cleansing cream,

vanishing cream, shaving cream or any media.

(Corrigan OI, Healy AM. Surfactants in Pharmaceutical Products and Systems.)

Formulation of Shampoo

Shampoo is a hair care product used for the removal of oils, dirt, skin

particles, dandruff, environmental pollutants and other contaminant

particles that gradually build up in hair. The goal is to remove the

unwanted build-up without stripping out so much as to make hair

unmanageable.

Shampoo, when lathered with water, is a surfactant, which, while

cleaning the hair and scalp, can remove the natural oils (sebum) which

lubricate the hair shaft.

( Corrigan OI, Healy AM. Surfactants in Pharmaceutical Products and Systems.)

Formulation of Aerosols

Surfactants are found in both solution and suspension formulations of metered

dose inhalers (MDIs).

The most common surfactants found in pressurized aerosol preparations

include

sorbitan trioleate (Span 85),

oleic acid, and

Lecithin

These agents are non-volatile liquids which dissolve in the propellant blend.

Their function in the formulation is to provide lubrication for the metering

valves and, in the case of suspension formulations, to maintain the disperse

nature of the drug.

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