An emulsion is liquid preparation containing two immiscible liquids, one of which is dispersed as globules (dispersed phase = internal phase)

in the other liquid (continuous phase = external phase).

(ontinuous phase Dispersed phase

Microemulsion: Droplets si e range !.!" to !." m Macroemulsion: Droplets si e range approximatel# $ m.

3o stabili e these droplets, emulsif#ing agent should be added

General Types of Pharmaceutical Emulsions: ") %otions &) %iniments ') (reams )) *intments $) +itamin drops Primary and secondary emulsion: ,rimar# emulsion containing one internal phase, for example, oil-in-water emulsion (o.w) and *il 4ater water-in-oil emulsion (w.o). /econdar# emulsion= multiple-emulsion: it contains two internal phase, for instance, o.w.o or w.o.w. 0t can be used to dela# release or to increase the stabilit# of the acti1e compounds.
O/W W/O *il 4ater

4ater *il *il W/O/W 4ater

*il 4ater

O/W/O

Emulsion Type and Means of Detection: using of na2ed e#e, it is 1er# difficult to differentiate between o.w or w.o emulsions. 3hus, the four following methods ha1e been used to identif# the t#pe if emulsions. 1) Dilution Test: based on the solubilit# of external phase of emulsion. - o.w emulsion can be diluted with water. - w.o emulsion can be diluted with oil.

"

8ew drops of water

4ater distribute uniforml#

*.4 emulsion

8ew drops of emulsion

4ater separate out as la#er

4.* emulsion

&) Conducti ity Test: water is good conductor of electricit# whereas oil is non-conductor. 3herefore, continuous phase of water runs electricit# more than continuous phase of oil.

6ulb

5lectrode 5mulsion

= 6ulb glows with *.4 = 6ulb doesn7t glow with 4.*

') Dye!"olu#ility Test: - 4ater-soluble d#e will dissol1e in the aqueous phase. - *il-soluble d#e will dissol1e in the oil phase.

4hat is loo2 li2e under the microscope after mixing with suitable d#e

*il-soluble d#e (e.g. /carlet)

4ater-soluble d#e (e.g. Amaranth d#e)

4.*

*.4

*.4

4.*

&

$!%luorescence test: oils gi1e fluorescence under 9+ light, while water doesn7t. 3herefore, *.4 emulsion shows spott# pattern while 4.* emulsion fluoresces.

,harmaceutical applications of emulsions:

". &. '. 3o mas2 the taste *.4 is con1enient means of orall# administration of water-insoluble liquids *.4 emulsion facilitates the absorption of water-insoluble compounds comparing to their oil# solution preparations (e.g. 1itamins) *il-soluble drugs can be gi1en parentrall# in form of oil-in water emulsion. (e.g 3axol) 5mulsion can be used for external application in cosmetic and therapeutic uses.

). $.

Theories of Emulsification:

0ncase of two immiscible liquids

*il *il 4ater Agitation 4ater *il 4ater

/eparate rapidl# into two clear defined la#ers An explanation of this phenomenon is because of cohesi1e force between the molecules of each
separate liquid exceeds adhesi1e force between two liquids. 3his is manifested as interfacial energ# or tension at boundar# between the liquids.

/mall droplet

/urface area

0nterfacial tension /#stem is thermod#namicall# unstable : high energ#;

'

/#stem tends to separate in two la#er to reduce the surface area

3herefore, to pre1ent the coalescence and separation, emulsif#ing agents ha1e been used. 3#pes of emulsif#ing agents : ". /urface acti1e agent: adsorbed at oil.water interface to form monomolecular film to reduce the interfacial tension <#drophilic colloids: forming a multimolecular film around the dispersed droplet 8inel# di1ided solid particles: the# are adsorbed at the interface between two immiscible liquid phases to form particulate film

&. '.

&!Monomolecular adsorption

4= . A /
/urface area /urface free energ#

0nterfacial tension

0n emulsion, the surface area is high to maintain the dispersion of the droplets. 3hus, based on the abo1e equation surface free energ# becomes high consequentl#. 3he onl# wa# to 2eep it low is to reduce the interfacial tension. /urface acti1e agent (/AA) is molecule which ha1e two parts, one is h#drophilic and the other is h#drophobic. 9pon the addition of /AA, the# tend to form monola#er film at the oil.water interface.

<#drophilic head <#drophobic tail

4ater
8orm monomolecular film

*il
3he functions of surface acti1e agents to pro1ide stabilit# to dispersed droplets are as following: i. =eduction of the interfacial tension

ii. 8orm coherent monola#er to pre1ent the coalescence of two droplet when the# approach each other iii. ,ro1ide surface charge which cause repulsion between ad>ust particles

(ombination of surface-acti1e agents is used most frequentl#. 3he combination should form film that closel# pac2ed and condensed

3his figures shows schematic of oil droplets in an oilwater emulsion. ?ou can see the orientation of a 3ween and a /pan molecule at the interface 8igure (a) shows good combination, which forms excellent emulsion. 8igure (b) and (c) show poor emulsion due to lac2 of closel# pac2ed or lac2 of complexation, respecti1el#.

(lassification of surface-acti1e agents:

Aote that: Anionic /AA are mainl# used for external used. (ationic /AA are used for external used. 3he# ha1e, also, good antimicrobial acti1it# (e.g. 6en al2onium chloride) Aonionic /AA are stable o1er wide range of p<. 3he# are not affected b# change in p< or addition of electrol#tes. 3he# are less toxic and main function to pro1ide steric repulsion

'!Multimolecular adsorption

,ol#saccharides

Amphoterics

/#nthetic or semi-s#nthetic pol#mers (arbomer resins (ellulose ethers (arbox#meth#l chitin ,5B-n (eth#lene oxide pol#mer)

Acacia Agar Alginic acid (arrageenan Buar gum Carra#a gum 3ragacanth

Belatin

colloids

<#drophilic colloids form multimolecular adsorption at the oil. water interface. 3he# ha1e low effect on the surface tension. 3heir main function as emulsion stabili ers is b# ma2ing coherent multi-molecular film. 3his film is strong and resists the coalescence. 3he# ha1e, also, an auxiliar# effect b# increasing the 1iscosit# of dispersion medium. Most of the h#drophilic colloids form oil-in-water emulsions. /ome of them can pro1ide electrostatic repulsion li2e acacia, which contains Arabic acid and proteins ((**< and A<')

C!"olid particle adsorption 8inel# di1ided solid particles are adsorbed at the surface of emulsion droplet to stabili e them. 3hose particles are wetted b# both oil and water (but not dissol1ed) and the concentration of these particles form a particulate film that pre1ent the coalescence.

,articles that are wetted preferentiall# b# water from o.w emulsion, whereas those wetted more b# oil form w.o emulsion Aote that the# are 1er# rare to use and can affect rheolog# of the final product /i e of the particle is 1er# important, larger particles can lead to coalescence

8inel# di1ided solids

6entonite <ectorite Caolin Magnesium aluminum silicate Montmorillonite Aluminum h#droxide Magesium h#droxide /ilica

Other emulsifyin( a(ents Aatural emulsif#ing agents: ". &. '. ). 5gg #ol2: it contains phospholipids and cholesterol. 3he main withdraw bac2 is that spoils quic2l#E therefore, it can7t be used in industr#. 0t is used for extemporaneous preparation. 4ool fat: anh#drous lanolin, it is used to prepare w.o emulsion for external uses. /tarch: it forms starch mucilage and it is restricted for enemas preparation. (holesterol: it has stabili ing actionE therefore, another emulsifier should be included. )o* to control emulsion type durin( formulation+ a. b. +olume of internal and external phases controls the t#pe of emulsion. 3he smaller 1olume will be for the internal phase and the larger 1olume will be for external phase. 0n some cases, internal phases can be more than $!F of the total 1olume (see the following section) Dominance of polar and non-polar characteristic of emulsif#ing agents (relati1e solubilit# of emulsif#ing agent in water and oil). Dominance of polar part results in formation of o.w emulsion and dominance of non-polar part results in formation of w.o emulsion. Aote that polar groups are better barriers than non-polarE therefore, o.w emulsion can be prepared with more than $! F of oil phase : internal phase;. What the factors that affect the choice of emulsion type+ 3he choice of emulsion depends on (")-properties and uses of final products (&)- the other material required to be present. *il-soluble drug is prepared in o.w emulsion due its solubilit# and its taste can be mas2ed b# adding fla1oring agents 8or intra1enous in>ection : i.1.; o.w emulsion is the onl# t#pe could be used. 8or intramuscular in>ection :i.m.; both o.w and w.o t#pes of emulsion could be used. 4atersoluble drug can be prepared in w.o emulsion to get prolonged action (depot therap#) 3opical application: o /emisolid emulsions are called creams and lotions Oil in water emulsion Water in oil emulsion

8or insoluble drug 8or local effect 5asil# to wash from s2in Doesn7t ha1e greas# texture of oil# preparation Acceptable b# consumer

8or water soluble drug (an be use to h#drate the upper la#er of stratum corneum (moisturi ing cream) (an increase the absorption of G drug from these formulation (an be used to clean s2in from dirt Aot acceptable b# consumer

Methods for preparation of emulsion: 0n small scales such as in pharmac#-hospital labs, mortar and pestle are the needed equipments. 0n large scale such as in pharmaceutical industr#, different machines are used:

1, Mixer or mechanical stirring: the emulsion is prepared b# agitation of emulsion

ingredient

-, (olloid mills

.,

5mulsif#ing Agents: ") (arboh#drate Materials: Acacia, 3ragacanth, Agar, ,ectin. o.w emulsion. &) ,rotein /ubstances: Belatin, 5gg #ol2, (aesin o.w emulsion. ') <igh Molecular 4eight Alcohols: /tear#l Alcohol, (et#l Alcohol, Bl#cer#l Mono stearate-----------o.w emulsion. cholesterol------------------------------------------------------- w.o emulsion )) 4etting Agents: Anionic, (ationic, Aonionic o.w emulsion w.o emulsion

$) 8inel# di1ided solids: 6entonite, Magnesium <#droxide, Aluminum <#droxide o.w emulsion. Phase /n ersion: 3he relati1e 1olume of internal and external phases of an emulsion is important. (increase) internal concentration (increase) 1iscosit# up to a certain point. +iscosit# will decrease after that point. At this point the emulsion has undergone in1ersion i.e. it has changed from an o.w to a w.o, or 1ice 1ersa. 0n practice, emulsions ma# be prepared without in1ersion with as much as about D$F of the 1ol. of the product being internal phase. Methods of Preparation of Emulsions: ") (ontinental or Dr# Bum Method: I):&:"I Method ) parts (1olumes) of oil JAnsel. Dth ed. page '@HK & parts of water " part of gum Acacia or other o.w emulsifier is triturated with oil in a perfectl# dr# 4edgwood or porcelain mortar until thoroughl# mixed. Blass mortar has too smooth a surface to produce the proper si e reduction of the internal phase (Do not use glass mortar). After the oil and gum ha1e been mixed, the two parts of water are then added all at once and the mixture is triturated immediatel#. &) 5nglish or wet Bum Method: /ame proportion of oil, water and gum are used as in the continental or dr# gum method but the order of mixing is different. Mucilage of the gum is prepared b# triturating acacia (or other emulsifier) with water. 3he oil is then added slowl# in portions, and the mixture is triturated to emulsif# the oil. /hould the mixture become too thic2 during the process, additional water ma# be blended into the mixture before another successi1e portion of oil is added. ') 6ottle or 8orbes 6ottle Method: 9seful for5xtemporaneous preparation of emulsion from 1olatile oils or oleaginous substance of low 1iscosit#. put powdered acacia in a dr# bottle Add & parts of oil

"!

3horoughl# sha2e the mixture in the capped bottle. A 1olume of water approximatel# equal to the oil is then added in portions, the mixture being thoroughl# sha2en after each addition. 3his method is not suitable for 1iscous oils (i.e. high 1iscosit# oil). "ta#ility of Emulsion: An emulsion is considered to be ph#sicall# unstable if : a) 3he internal phase tends to form aggregates of globules. b) %arge globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to form a concentrated la#er of the internal phase. c) 0f all or part of the liquid of the internal phase becomes Iunemulsified on the top or bottom of the emulsion. /eparation of the internal phase from the external phase is called 6=5AC0AB of the emulsion. 3his is irre1ersible. -,rotect emulsions against the extremes of cold and heat. -5mulsions ma# be ad1ersel# affected b# microbial contamination. Bels and Magmas: Bels are defined as semisolid s#stems consisting of dispersions made up of either small inorganic particles or large organic molecules enclosing or interpenetrated b# a liquid. Magmas or Mil2s are gels consisted of floccules of small distinct particles. Bels and Magmas are considered colloids because the# contain particles within the range of colloidal dispersions. 5xamples of Magmas L Bels: 6entonite Magma, A8: ,reparation of $F bentonite, a nati1e, colloidal h#drated aluminum silicate, in purified water. Aluminum <#droxide Bel, 9/,: 3his is an aqueous suspension of a gelatinous precipitate composed of insoluble aluminum h#droxide and h#drated aluminum oxide, equi1alent to about )F of aluminum oxide. Mil2 of Magnesia, 9/,: 3his is a preparation containing between D and G.$F of Magnesium h#droxide.

""

A.

Water-soluble polymers 3he water-soluble or h#drophilic pol#mers ma# be grouped either b# their origin or on the basis of their electrical charge (4).

". a. b.

6ased on their origin, there are three classes of water-soluble pol#mers: natural pol#mers, deri1ati1es of cellulose, and s#nthetic h#drophilic pol#mers. 3he natural pol#mers include pol#saccharides, such as acacia, agar, pectin, sodium alginate, xanthan gum, and tragacanth, and pol#peptides, such as casein and gelatin. 3he cellulose deri1ati1es are semis#nthetic products, made b# chemical modification of cellulose to #ield soluble pol#mers. 5xamples include meth#lcellulose, sodium carbox#meth#lcellulose, h#promellose, and h#drox#eth#l and h#drox#prop#l cellulose.

c.
gl#cols.

3he s#nthetic water-soluble pol#mers include 1in#l pol#mers such as pol#1in#l alcohol and po1idone (pol#1in#lp#rrolidone), carbomer (which is a copol#mer of acr#lic acid), and pol#eth#lene

&. a.

6ased on electrical charge, the h#drophilic pol#mers are either uncharged or anionicE cationic pol#mers are uncommon. 5xamples of the nonionic or uncharged pol#mers include meth#lcellulose and eth#lcellulose, h#promellose, h#drox#eth#l and h#drox#prop#l cellulose, p#rox#lin, pol#eth#lene oxide, pol#1in#l alcohol, and po1idone (pol#1in#lp#rrolidone),

b.
carbox#meth#lcellulose.

5xamples of anionic pol#mers include acacia, alginic acid, pectin, tragacanth, xanthan gum, and carbomer at a p< fa1oring the ionic form of the acid group, and sodium alginate and sodium

'. a. b.
surface acti1it#.

4ater-soluble pol#mers ha1e the following characteristics in common: 3he# fa1or o.w emulsions. 3he# ha1e the ad1antage of being 1iscosit#-building agents in addition to ha1ing

c.

4ith the exception of some of the natural gums, most of the water-soluble pol#mers are used as auxiliar# emulsif#ing agents.

"&

).

*ther properties of the water-soluble pol#mers depend on the particular chemical structure of the pol#mer. 3hese agents are discussed in detail in (hapter "H, Viscosity-Inducing Agents. Information is given on their individual properties, solubilities, incompatibilities, formulation methods, and uses.

6. ". a.
+

Anionic soaps and detergents /oft soaps 3hese are salts of fatt# acids in which the positi1e ion is uni1alent, such as Aa +, , and !"#+. $he most common fatty acids are stearic %&-'(), oleic %&-'(, consisting mainly of %* )-H-

octadecenoic acid), palmitic ((-"@), and lauric ((-"&).

b.

*ften the emulsifier is formed at the time of emulsification b# adding an al2ali base (e.g., Aa*<, C*<, A<#O", sodium borate) or an organic amine base %e.g., triethanolamine) to a fi+ed oil that contains a sufficient amount of fatty acid. ,or this reason, these are often called nascent (which means :ha1ing recentl# come into exisitence;) soap emulsifiers.

". &. c. d. ". &.

/oaps with an organic amine as the cation are more balanced and less h#drophilic and form more stable emulsions than the al2ali soap emulsifiers (5). 5mulsions made with al2ali soap emulsif#ing agents sometimes require the addition of auxiliar# emulsifiers for stable emulsions. /oft soaps are water-soluble and.or water-dispersible. 3he# usuall# form o.w emulsions. 3he classic 1anishing creams and other water-washable creams of this t#pe are o/*emulsions that use soft-soap emulsifiers. 3wo exceptions are =ose 4ater *intment and (old (ream. 3hese are */o emulsions formed when a solution of sodium borate (borax) is added to melted white and cet#l ester waxes, which contain sufficient fatt# acids for the formation of a soap emulsifier.

e. ".
most stable above p" '- %5).

/oft soaps gi1e emulsions with a p< in the basic range. 3he al2ali soap emulsions ha1e a p< in the range of G to "! (9) and are

&. f.

3he organic bases gi1e soaps that ha1e a lower neutralit# point (about p< G), with the p< of the emulsions nearer to neutralit# and more stable to changes in p< (5). /oap emulsifiers are wea2 electrol#tes (salts of a carbox#lic acid J=-(**./, a wea0 acid) and re1uire this ionic center for their surface activity. $his means that any drug or other ingredient that neutrali2es that ionic center will destroy an emulsion stabili2ed by these emulsifiers. 3roblematic

"'

ingredients include drugs or additives that are acids or that produce an acid p" %e.g., phenol, salicylic acid), because lowering the p" shifts the e1uilibrium in favor of the wea0ly dissociated, oil-soluble 4-&OO" form.

g.

/oft soaps are incompatible with multi1alent cations (Mg++, &a++) because these replace the univalent ion, forming the multiple hydrocarbon chain soap of the multivalent ion. $his shifts the hydrophilic-lipophilic balance of the molecule in favor of the lipophilic type. $his new emulsifier favors the opposite type of emulsion %w5o) and may cause the emulsion to 6crac07 or coalesce.

h.

/oaps are also incompatible with high concentrations of electrol#tes and with high-molecular-weight cations such as the preser1ati1es ben al2onium chloride and ben ethonium chloride ( 9). $he anionic portion of the soap binds these preservatives and renders them inactive.

i. &. a.

/oft soaps are unsuitable emulsifiers for internal-use emulsions because of their soap# taste and laxati1e action (5). <ard soaps 3hese are salts of fatt# acids in which the positi1e ion is di1alent or tri1alent ((a+8, 9g+8, *n+8, Al+:). $he most common hard soap is calcium oleate. $his is formed by reacting calcium hydro+ide in &alcium "ydro+ide $opical ;olution %also 0nown as lime water) with oleic acid found in oli1e oil and certain other fixed oils.

b. c. d.

<ard soaps are oil-soluble and water-insoluble. 3he# form w.o emulsions. %i2e soft soaps, these are salts of a carbox#lic acid (=-(**.), a wea0 acid, which gives the wea0ly dissociated 4-&OO" form on addition of drugs or other ingredients that are acids or that produce an acid p". "ard soaps are particularly sensitive to acid ingredients %5).

e. f. '. a.

3he =-(**.groups of hard soaps may interact with and bind high-molecularweight cations li0e ben2al0onium chloride. <ard soaps are unsuitable for internal-use emulsions. Detergents 3hese are salts of al2#l sulfates, sulfonates, phosphates, and sulfosuccinates. 3wo examples of detergents from this group that are commonl# used in pharmaceuticals are sodium laur#l sulfate and dioct#l sodium sulfosuccinate (docusate sodium).

b. c. d.

Detergents are 1er# h#drophilic and are soluble in water. 3he# alwa#s form o.w emulsions. As strong electrol#tes, the# are more stable to acids, such as phenolic compounds and salic#lic acid, and are not sensiti1e to high concentrations of electrol#tes.

")

e.
such as cet#l or stear#l alcohol.

6ecause their ionic centers strongl# repel each other, detergents do not form firm, intact barriers. 3hese surfactants are most often used in con>unction with secondar# non-ionic emulsifiers

f.
soap# taste and laxati1e action.

%i2e soaps, detergents are unsuitable for internal-use emulsions because of their

(. ". &. '. D. ".

Cationic surfactants 3he cationic surfactants are quaternar# ammonium compounds such as ben al2onium

chloride, ben ethonium chloride, and cet#lp#ridinium chloride. 3he# are 1er# h#drophilic and are 1er# soluble in water. (ationic surfactants do not ma2e good emulsifiers but are useful as antimicrobial agents. 3heir properties and uses as antimicrobial agents are discussed in (hapter "@, Antimicrobial 3reservatives. Finely divided solids 3hese are usuall# finel# di1ided h#drophilic inorganic solids. 4hen these solids are in a 1er# fine state of subdi1ision, the# tend not to be easil# wetted b# liquids, and the# orient at interfaces, forming a barrier to coalescence. 3he most common examples of this t#pe include the colloidal cla#s bentonite and +eegum and metallic h#droxides, such as magnesium oxide and inc oxide.

&.

%arge quantities of finel# di1ided solids, which are in a product formulation for therapeutic purposes, ma# function as emulsifiers if an appropriate order of mixing is used. An example is the emulsification of &$F mineral oil with D$F magnesia magma (<ale#7s M-*).

'.

3he finel# di1ided solids are not usuall# used b# themsel1es but are useful as auxiliar# emulsifiers. An exception is the magnesia magmaMmineral oil emulsion mentioned pre1iousl#. <ere, the finel# di1ided magnesium oxide of magnesia magma ser1es as the sole emulsifier agent for the mineral oil ( 9).

).

<#drophilic solids fa1or o.w emulsions and are used most often as auxiliar# emulsifier for this emulsion t#pe. 3here are, howe1er, examples of h#drophilic solids present in w.o formulations. An example is the presence of the h#drophilic solids calamine and inc oxide in (alamine %iniment A8 0N, a w.o emulsion that has calcium oleate as the primar# emulsif#ing agent.

$.

8inel# di1ided h#drophobic solids fa1or the formation of w.o emulsions. 0f a large quantit# of a h#drophobic solid is added to a s#stem with the primar# emulsifier fa1oring an o.w emulsion, the final emulsion t#pe is difficult to predict. An example is the formulation of an oral o.w emulsion of the waterinsoluble h#drophobic drug sulfadia ine, with a non-ionic emulsif#ing s#stem that fa1ors an o.w emulsion. Depending on the exact conditions, the result ma# be either a w.o or an o.w emulsion. 6ecause o.w emulsions

"$

are preferred for oral products, the formation of a w.o emulsion in this case ma# create a compounding problem.

5. ".

Natural non-ionic surfactants 3hese include fatt# acid alcohols, such as stear#l alcohol and cet#l alcohol, wool fat or

wool wax and its deri1ati1es, wool alcohols and cholesterol, and deri1ati1es of other natural waxes, such as spermaceti and cet#l esters wax (s#nthetic spermaceti). 3hese are a1ailable as fractions of the natural products or their s#nthetic 1ersions.

&.

/ome of the natural waxes, such as wool wax, %anolin 9/, (wool fat, the waxli2e substance from the wool of sheep, that has been cleaned, decolori ed, and deodori ed), Modified %anolin 9/, (wool fat that has been processed to reduce the contents of free lanolin alcohols and detergent and pesticide residues), and h#drous lanolin (h#drous wool fat) and its s#nthetic 1ersion <#drophilic ,etrolatum 9/, are complex mixtures of oils, waxes, and emulsifiers (6). $he purified emulsifying agents in "ydrophilic 3etrolatum are the non-ionic emulsifiers stearyl alcohol and cholesterol. <anolin and hydrous lanolin contain mi+tures of similar natural emulsifiers. All are capable of absorbing water to form w5o emulsions. $hese are discussed in more detail in (hapter &', Ointment =ases.

'.

Although the purified fractions and their s#nthetic counterparts ma# be used to produce w.o emulsions, the# are also commonl# used as auxiliar# emulsifiers to stabili e o.w emulsions when a powerful o.w emulsif#ing agent, such as a detergent, is present as the primar# emulsifier. An example of such a s#stem is the o.w cream <#drophilic *intment 9/, (6). In this product, sodium lauryl sulfate is the primary emulsifier, with stearyl alcohol as the au+iliary emulsifying agent.

8. ".

Synthetic non-ionic surfactants 3hese are complex esters and ester-ethers, deri1ed from pol#ols, al2#lene oxides, fatt#

acids, and fatt# alcohols. 3he h#drophilic portion of these molecules consists of free h#drox#l and ox#eth#lene groups. 3he lipophilic part has long-chain h#drocarbons of fatt# acids and fatt# alcohols. Although the# are gi1en a chemical designation based on the primar# component, these are actuall# complex mixtures of closel# related deri1ati1es. 8or example, sorbitan monooleate, also 2nown as ;pan (-, is a mixture, but the primar# component is sorbitan monooleate. ,ol#sorbate G! (3ween G!) is pol#ox#eth#lene &! sorbitan monooleateE the &! indicates that there are approximatel# &! moles of eth#lene oxide for each mole of sorbitol and sorbitol anh#dride. (ommonl# used non-ionic surfactants include 1arious /pans, 3weens, Arlacels, and M#r>s.

&. a.

Aon-ionic surfactants ha1e the following characteristics in common: 3he# are neutral compounds that are stable o1er a wide p< range.

"@

b.
electrol#tes.

3he# are relati1el# insensiti1e to the presence of high concentrations of

c. d.

3he# are heat stable. 6ecause these compounds do not possess significant innate abilit# as 1iscosit#inducing agents, depending on the waterMoil phase ratio and the melting point of the oil phase, emulsions made with these agents ma# require auxiliar# 1iscosit#-inducing agents or a 1iscous 1ehicle for the external phase.

e.

Aon-ionic surfactants are mixed in 1arious proportions to gi1e either w.o or o.w emulsions. 3he appropriate amounts of indi1idual emulsifiers needed to form a specific emulsion t#pe can be determined using a mathematic s#stem called the "<= system. 3his s#stem assigns numeric 1alues to fats and oils and to emulsifiers based on the relati1e amounts of h#drophilic and lipophilic portions present in these molecules. 5xamples of the calculation and use of the <%6 s#stem can be found in (hapter &H, <i1uid >mulsions.

B. ".

Amphoteric or zwitterionic surfactants 3hese surfactants can be anionic, cationic, or non-ionic in solution, depending on the

acidit# or p< of the water. 3he# are usuall# mild, ma2ing some of them particularl# suited for use in pharmaceutical products and preparations.

&.

An amphoteric surfactant frequentl# used in pharmaceutical dosage forms is %ecithin A8, a complex mixture of phosphatides, mainl# phosphatid#l choline (8). $wo ma?or sources of the phosphatides are egg yol0s and soya beans. <ecithins are mainly used as dispersing, elmulsifying, and stabili2ing agents % 10). <ecithin is often included in in?ectable products, especially parenteral nutrition solutions. $herapeutically, lecithin and derivatives have been used as pulmonary surfactants. <ecithin also forms a component of the bilayers of liposomes %3).

'.

%ecithin is a ma>or component of ,luronic (poloxamer) lecithin organogel (,%* gel). 3his transdermal 1ehicle is used b# compounding pharmacists to administer medications through the s2in when the medication is to be absorbed through the s2in for almost immediate effect. 3his use is illustrated with /ample ,rescription '!.D i

Synthetic Emulsifying Agents Cationic, e.g., benzalkonium chloride, benzethonium chloride Anionic, e.g., alkali soaps (sodium or potassium oleate); amine soaps (triethanolamine stearate); detergents (sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sodium docusate). Nonionic, e.g., sorbitan esters (Spans ), polyo!yethylene deri"ati"es of sorbitan esters (#$eens ), or glyceryl esters

"D

Cationic and anionic surfactants are generally limited to use in topical, o%$ emulsions. Cationic agents (&uarternary ammonium salts) are incompatible $ith organic anions and are infre&uently used as emulsifiers. Soaps are sub'ect to hydrolysis and may be less desirable than the more stable detergents.

Emulsions are stabilized by adding an emulsifier or emulsifying agents. These agents have both a hydrophilic and a lipophilic part in their chemical structure. All emulsifying agents concentrate at and are adsorbed onto the oil:water interface to provide a protective barrier around the dispersed droplets. In addition to this protective barrier, emulsifiers stabilize the emulsion by reducing the interfacial tension of the system. ome agents enhance stability by imparting a charge on the droplet surface thus reducing the physical contact between the droplets and decreasing the potential for coalescence. ome commonly used emulsifying agents include tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polymers !nown as the pans" and Tweens". Emulsifying agents can be classified according to: #$ chemical structure% or &$ mechanism of action. 'lasses according to chemical structure are synthetic, natural, finely dispersed solids, and au(iliary agents. 'lasses according to mechanism of action are monomolecular, multimolecular, and solid particle films. )egardless of their classification, all emulsifying agents must be chemically stable in the system, inert and chemically non*reactive with other emulsion components, and nonto(ic and nonirritant. They should also be reasonably odorless and not cost prohibitive. Synthetic Emulsifying Agents (ationic, e.g., ben al2onium chloride, ben ethonium chloride Anionic, e.g., al2ali soaps (sodium or potassium oleate)E amine soaps (triethanolamine stearate)E detergents (sodium laur#l sulfate, sodium dioct#l sulfosuccinate, sodium docusate). Aonionic, e.g., sorbitan esters (/pansO), pol#ox#eth#lene deri1ati1es of sorbitan esters (3weensO), or gl#cer#l esters 'ationic and anionic surfactants are generally limited to use in topical, o+w emulsions. 'ationic agents ,-uarternary ammonium salts$ are incompatible with organic anions and are infre-uently used as emulsifiers. oaps are sub.ect to hydrolysis and may be less desirable than the more stable detergents. Natural Emulsifying Agents A variety of emulsifiers are natural products derived from plant or animal tissue. /ost of the emulsifiers form hydrated lyophilic colloids ,called hydrocolloids$ that form multimolecular layers around emulsion droplets. 0ydrocolloid type emulsifiers have little or no effect on interfacial tension, but e(ert a protective colloid effect, reducing the potential for coalescence, by: pro1iding a protecti1e sheath around the droplets imparting a charge to the dispersed droplets (so that the# repel each other) swelling to increase the 1iscosit# of the s#stem (so that droplets are less li2el# to merge) 0ydrocolloid emulsifiers may be classified as: 1egetable deri1ati1es, e.g., acacia, tragacanth, agar, pectin, carrageenan, lecithin

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animal deri1ati1es, e.g., gelatin, lanolin, cholesterol /emi-s#nthetic agents, e.g., meth#lcellulose, carbox#meth#lcellulose /#nthetic agents, e.g., (arbopolsO 1aturally occurring plant hydrocolloids have the advantages of being ine(pensive, easy to handle, and nonto(ic. Their disadvantages are that they re-uire relatively large -uantities to be effective as emulsifiers, and they are sub.ect to microbial growth and thus their formulations re-uire a preservative. 2egetable derivatives are generally limited to use as o+w emulsifiers. The animal derivatives general form w+o emulsions. 3ecithin and cholesterol form a monomolecular layer around the emulsion droplet instead of the typically multimolecular layers. 'holesterol is a ma.or constituent of wool alcohols and it gives lanolin the capacity to absorb water and form a w+o emulsion. 3ecithin ,a phospholipid derived from egg yol!$ produces o+w emulsions because of its strong hydrophilic character. Animal derivatives are more li!ely to cause allergic reactions and are sub.ect to microbial growth and rancidity. Their advantage is in their ability to support formation of w+o emulsions. emi*synthetic agents are stronger emulsifiers, are nonto(ic, and are less sub.ect to microbial growth. ynthetic hydrocolloids are the strongest emulsifiers, are nonto(ic, and do not support microbial growth. 0owever, their cost may be prohibitive. These synthetic agents are generally limited to use as o+w emulsifiers. Finely Divided or Finely Dispersed Solid Particle Emulsifiers These agents form a particulate layer around dispersed particles. /ost will swell in the dispersion medium to increase viscosity and reduce the interaction between dispersed droplets. /ost commonly they support the formation of o+w emulsions, but some may support w+o emulsions. These agents include bentonite, veegum, hectorite, magnesium hydro(ide, aluminum hydro(ide and magnesium trisilicate. Auxiliary Emulsifying Agents A variety of fatty acids ,e.g., stearic acid$, fatty alcohols ,e.g., stearyl or cetyl alcohol$, and fatty esters ,e.g., glyceryl monostearate$ serve to stabilize emulsions through their ability to thic!en the emulsion. 4ecause these agents have only wea! emulsifying properties, they are always use in combination with other emulsifiers. P

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Aatural 3#pes a)+egetable source

examples Acacia,trgac anth,pectin,d eri1ati1es of cellulose

/#nthetic a)Anionic

examples a.")al2ali soap (sodium ,potassium and ammonium salts of fatt# acids)eg-cal oleate a.&)soaps of di.tri1alent metal, a')amine soaps,a)) sulfated and sulfonated compounds eg sodium laur#l sulphonate b) cet#ltr#meth#l ammonium bromide(cetrimide) and ben al2onium chloride c) tweens(pol#eth#lene fatt# acid ester) and span(sorpitan fatt# acid ester) d)betaines a.")promote w.o emulsion

8ine /olid

particles
6entonite

b)Animal source

Belatin, cholesterol, wool fat

b)(ationic(quarte ner# ammonium compounds) c)Aon ionic d)Amphoteric a) for external use, form o.w emulsion d) (harge depend on ph of the s#stem (low ph cationic and high ph anionic) b) anti bacterial and anti infecti1e properties c) low toxicit# and irritanc# and high degree of compatibilit#and les sensiti1e to ph change and addition of electrol#tes b) toxicit# and irritanc#,uns table at high ph .

8eatures

a&) produce o.w emulsion, neutral p< a') stable o1er high p< range,o.w emulsions

0f the particles are preferentall# wetted b# oil phase-forms w.o emulsion

Ad1antage

Aon Mtoxic and relati1el# inexpensi1e

8orming a coherent film which pre1ents the coalescence of the dispersed molecules

Disad1antage

=eadil# support microbial growth shows batch to batch 1ariation susceptible to alcohol and electrol#tes

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