FORMULASI dan TEKNOLOGI LIKUIDA

Kuliah 5-6:

Dispersed System:
EMULSION
Dr. Rendra Pranadipa Tofani, Apt.
2017
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 TYPES of LIQUID Dosage Forms

Monophasic (Solutions) Polyphasic

Suspensions

Aqueous Solutions Colloids

Non-Aqueous Solutions Emulsion

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 Materi Kuliah
• Definition of Pharmaceutical Emulsion
• Why Emulsion?
• Types of Emulsion
• Why emulsions are thermodynamically unstable
• Stability problems in emulsions & What to do?
• What are Emulsifiers & Types of Emulsifier
• How emulsifier stabilises emulsion
• Advantages & Disadvantages of Emulsion
• Preparation of Emulsion

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 DISPERSE SYSTEM
• Consists of particulate matter (dispersed phase),
dispersed in a continuous medium (dispersion
medium)

Classification based on particle size:

• Molecular dispersion < 1 nm True Solution

• Colloidal dispersion 1 nm – 0,5µm Colloid

microemulsion

• Coarse dispersion > 0,5µm suspension

& emulsion
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 DEFINITION of Emulsion
• BI-PHASIC Liquid Dosage Form: consisting of one
liquid phase dispersed as GLOBULES / DROPLETS
in a immiscible liquid phase (continuous phase /
external phase)
• Thermodynamically META-STABLE  because
immiscible
• Stabilised by Emulsifier  Reduce interfacial
surface tension
Dispersed phase

Continuous phase
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 Theory of Emulsification
• When 2 immiscible liquids are mixed:
One of the liquids is dispersed as small droplets in the other.
But after a short while:
The liquids separate rapidly into
two clearly defined layers

why?
• A fine dispersion of oil and water leads to an enormous
increase in the interfacial area.
• This is associated by an increase in the interfacial free
energy also known as surface free energy.
• This phenomenon leads to the system is thermodynamically
unstable.
• The high interfacial free energy favors a reduction of
interfacial area by causing droplets to coalesce. Therefore
separation of phases takes place. 6
 Surface Free Energy

• The greater “A” of interfacial contact  the

greater the “G”
• G is equivalent to γ
• To reduce G  reduce γ  add surfactants /
emulsifying agents
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8
EMULSIFIER

Stabilisation mechanisms of emulsifier:

1. Reduction of interfacial tension
2. Formation of a rigid interfacial film: steric
stabilisation
3. Formation of electric double-layer: electrostatic
stabilisation
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 How Emulsifiers Work…
1. Reduction of interfacial tension
∆E = SL * ∆A
2. Steric barrier – rigid interfacial film-mechanical
barrier  prevent coalescence
If the concentration of the emulsifier is high enough, it forms a
rigid film between the immiscible phases, which hinders
mechanically the coalescence of the emulsion droplets.

3. Electrostatic barrier – electric double-layer

In case of an ionic surfactant, the hydrocarbon
++
+ +
tail is dissolved in the oil droplet, while the ionic + +
+ +
heads are facing the continuous aqueous phase. +++
+ +
As a result, the surface of the droplet is charged. ++
This creates a repulsive effect between the oil
droplets and thus hinders coalescence.
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Emulsion STABILISATION

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 CLASSIFICATION of Emulsions
Based on nature of dispersed phase
Oil in Water (O/W): Oil droplets dispersed in water.
Water in Oil (W/O): Water droplets dispersed in oil.
Based on size of dispersed phase /droplets.
 >1000 nm Macroemulsions
 100 – 1000 nm Microemulsions
 < 100 nm Nanoemulsions
Based on Number of dispersed phase: Multiple emulsion
W/o/w (water in oil in water): Small water droplets are
enclosed within larger oil droplets which are dispersed in water
O/w/o (oil in water in oil): Small oil droplets are enclosed
within larger water droplets which are themselves then
dispersed in oil phase 13
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 OIL in WATER Emulsions (O/W)
• Dispersed phase / Internal phase = OIL
• Dispersion medium/ continuous phase /External phase = WATER
• Advantages
– Easiest to formulate
– disperses more easily
– has consistent pH
– Least expensive
– Best feel – cooling effect
• Disadvantages
– Less oil delivered
– Not as effective for dry skin
– Not water-resistant
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 WATER in OIL (W/O)
Dispersed phase / Internal phase = WATER
Dispersion medium/ continuous phase /External phase=WATER
• Advantages
– Waterproofing possible
– Most effective for dry skin
– Better stability
• Disadvantages
– Oily, tacky feel
– More expensive
Examples: COLD CREAMS

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 Multiple Emulsions

• Multiple phases
– Oil in Water in Oil (O/W/O)
– Water in Oil in Water (W/O/W)
• Advantages
– More effective than Oil in Water
– Less greasy than Water in oil
– Time release, active delivery
possible
• Disadvantages
– Difficult to manufacture
– Not always stable

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 Pharmaceutical APPLICATIONs of Emulsion
 Masking of unpleasant taste:
Most important application of emulsion is for masking the
disagreeable taste of oily liquids by formulating them as o/w
emulsions. For e.g. some vitamins.
 Increase the absorption:
Emulsions of oils like liquid paraffin and olive oil enhance the
rate and extent of their absorption from the alimentary canal
due to fine state of subdivisions.
 Topically applied:
 Medicinal agents that are irritating to the skin are less
– irritating if present in the internal phase of emulsion.
 Cold cream and vanishing creams are a emulsion which
are used externally.
 More acceptable than greasy products (ointments).
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Parenteral administrations
Emulsions have been used for the intravenous administrations
of lipid nutrients.
w/o emulsions have been employed to disperse water soluble
antigenic materials in mineral oil for intramuscular depot injection.
Aerosol
Emulsification is used in aerosol to produce foams
Prolonged Action
These products can also be used for the prolonged release of
drugs that are incorporated into the internal aqueous phase.

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 FORMULATION of Emulsion

• Formula Components
– Oil Phase
• Hydrophobic materials: Oils, fats, lipids
• Affects viscosity, spread,
– Aqueous phase
• Extracts, colorants
• Humectants
• Thickeners
– Emulsifiers
• Holds it all together

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 Types of Emulsifying Agents
A. Synthetic
– Surface active agents
( Monomolecular
films)
B. Semi synthetic and
natural
– Hydrophilic colloids (
Multimolecular films)
C. Finely divided solid
particles ( Particulate
film)
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 A. Synthetic / SURFace ACTive AgeNTs
Description :
• Reduce interfacial tension and make the emulsion
thermodynamically more stable.
• Form protective monomolecular film

Oil

Rule of Bancroft : Type of emulsion is a function of relative solubility of

surfactant . The phase in which it is soluble becomes the continuous
phase
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• Combination of Emulsifiers:

Oil

Sodium cetyl sulphate

Cholesterol

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 Types of SURFACTANTS
1. Anionic Surfactants
- Long anion chain, while cation is inactive
- External preparation: bitter taste & irritant on mucosa
 Soaps
 Mono-valent
 K, Na, NH4 salt of lauric & oleic acid
 Soluble in water & good o/w emulsifier
 Bitter taste & irritating to GIT (external only)
 High pH  precipitated below pH 10 (unionized fatty acids: low
solubility)
 These emulsion NOT stable at pH less than 10
 Polyvalent: Ca, Mg, Al salts of fatty acids
 Water Insoluble & give w/o emulsion
 Organic: Triethanolamine soaps of fatty acids: o/w (pH up to 8)
 Sulphates
 Neutralised esters of sulfuric acid & fatty alcohols (SLS)
 Sulphonates (CH3(CH2)n CH2SO3 – Na+)
 E.g. dioctyl sulphosuccinate
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2. Cationic Surfactants
• Positive charge produced on dissociation
• Combined with secondary emulsifying agents
• Quarternary ammonium: cetrimide, benzalkonium
chloride, benzetonium chloride

Cetrimide: cetyl trimethyl ammonium bromide

• Bactericidal activity
• Emulsion pH range 4-6
• Weak emulsifying agent  combine with other
• Incompatible with anionic surfactants
• Cetrmide emulsifying wax ( 10% cetrimide + 90%
cetosterylalcohol) produces a stable emulsion
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3. Nonionic Surfactants
• Most non-ionic surfactants are based on:
 A fatty acid or alcohol (usually with 12-18 carbon atoms), the
hydrocarbon chain of which provides the hydrophobic part.

 An alcohol (-OH) and/or ethylene oxide group (-OCH2CH2-) which

provide the hydrophilic part of the molecule.

• Advantages : They are not effected by pH change and presence of

electrolytes.
• They also show low irritancy as compared to other surfactants.
Most commonly used nonionics are
• glyceryl esters (auxillary E.A)
• sorbitan fatty acid esters (spans) w/o
• polyoxyethylene derivatives of sorbitan fatty acid esters (Tweens or
polysorbates) o/w
• Polyoxyethylene / polyoxypropylene block polymers (Macrogol) o/w
emulsions used for IV 28
• Sorbitan esters of fatty acids (Spans)
 Sorbitan is esterified with lauric, palmitic, stearic or oleic fatty acid.
 Variations in the type of fatty acid produce different Spans:
Span 20 with lauric acid (sorbitan monolaurate)
Span 40 with Palmitic acid (sorbitan monopalmitate)
Span 60 with stearic acid (sorbitan monostearate)
Span 80 with oleic acid (sorbitan monooleate)

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• Polysorbates (Tweens)
 Polyethylene glycol derivatives of the sorbitan esters (Polyoxtethylene
sorbitan ester of fatty acids).
 Variations in the type of fatty acid produce different tweens chain with
different oil and water solubility, (Tween 20, 40, 60 and 80).
 Advantages of tweens:
o Compatible with other types of surfactants.
o Stable to heat, pH change and electrolytes.
o Low toxicity, for oral and parenteral preparations.
 Disadvantages:
o Unpleasant taste.
o Inactivate some preservatives as paraben by complexation

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B. Semi-synthetic/Natural Emls.: HYDROCOLLOID
- Provide a protective layer (Multimolecular films)
around the droplets
- Swell to increase the viscosity of the system (so
that droplets are less likely to change)

1. Semi-synthetic:
- Methyl cellulose
- Carboxy methyl cellulose
They are used for formulating o/w type of
emulsions. They primarily act by increasing the
viscosity of the system.
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2. Natural origin:
Plant origin: Polysaccharides ( Acacia, tragacanth,
agar, pectin, lecithin)  o/w emulsions.

From animal origin

 Proteins ( Gelatin) o/w emulsions.
 Lecithin, o/w i/v emulsion
 Cholesterol. w/o
 Wool fat, w/o

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Accacia: (o/w)
Best E.A for oral emulsions, they have low viscocity, so creaming
occurs, addition of Tragacanth can improve the stability.

Tragacanth
High viscocity, used as emulsions stabilizer

Agar
Extract from sea weed, used as emulsion stabilizer
Soluble in boiling water, on cooling it forms gel.
Low conc is used if the product is to be poured (oral)

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Lecithin
They are used for formulating o/w emulsions. Purified lecithin from
soy or egg yolk is used for i/v emulsions.

cholesterol :
It forms w/o emulsion.

Wool fat
It is mainly used in w/o emulsions meant for external use. It is also
used as eye ointment base

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 C. Finely DIVIDED SOLIDs
Description :
Finely divided solid particles that are wetted to some degree by
both oil and water act as emulsifying agents. This results from
their being concentrated at interface, where they produce a
particulate film around the dispersed droplets to prevent
coalescence.

 Colloidal Clays
• Bentonite,( Al2O3.4SiO2.H2O),
• Veegum ( Magnesium Aluminium silicate) ,
• Magnesium trisilicate.
 Metallic hydroxides
• Magnesium hydroxide,
• Aluminium hydroxide,
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Bentonite:
• gray, odorless and tasteless powder which swells in the
presence of water to form a suspension with a pH of about 9
• Depend on the order of mixing, both o/w or w/o emulsion
can be formed with bentonite. For o/w emulsion, bentonite is
first dispersed in water and allowed to hydrate to form
magma. Then oil phase is gradually added with constant
agitation. To prepare w/o emulsion, bentonite is first
dispersed in oil and then water is added gradually.
Veegum :
• Used as stabilizer in concentration of 1% for cosmetic lotions
and creams. Prepared with anionic or non ionic emulsifying
agents.
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 Co-Emulsifier
• Auxiliary (Secondary) emulsifying agents include those compounds
that are normally incapable themselves of forming stable
emulsion. Their main value lies in their ability to function as
thickening agents and thereby help stabilize the emulsion.

• E.g Stearic acid, Methyl cellulose

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 Emulsifiers / Surfactants are characterized according to the "balance"
between the hydrophilic ("water-loving") and lipophilic ("oil-loving")
portions of their molecules.
 The hydrophilic-lipophilic balance (HLB) number indicates the polarity of
the molecules in a range of 1-40, with the most commonly used
emulsifiers having a value between 1 and 20.
 The HLB number increases with increasing hydrophilicity.
 According to the HLB number, surfactants may be utilized for different
purposes:

Function HLB Range

Antifoaming agent 1-3
Emulsifier, (w /o) 3-6
Wetting agent 7-9
Emulsifier, (o/ w) 8-18
Detergent 13-15
Solubilizer 15-18 38
• HLB tells about varying degrees of non-polar & polar character.
Less polar
(low HLB)

More Polar
(High HLB)
– Specific oils need emulsifier with specific HLB (polar/non-polar
character) to be effectively emulsified.
– Emulsifiers should have similar HLB values to that of the respective
oils in order to achieve maximum stabilization.

Common Oils used and

the HLB needed to
Create an emulsion

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 The desired HLB numbers can also be achieved by mixing lipophilic
and hydrophilic surfactants.
 William Griffin devised HLB System to calculated amount of
emulsifier to get the desired HLB.

 Advantage of HLB system:

 Gives stable emulsion.
 Works best with nonionic surfactants.
 Disadvantage:
 HLB is only a good approximation.
 Doesn’t always work. 40
• WHAT ARE OTHER ADDITIVES IN EMULSIONS?
Preservatives
Antioxidants
Humectants
Density modifiers
Buffers
Flavors and sweetening agents

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 Preservatives
 Low o/w partition coefficient.
 Free from toxicity, color, odor and taste.
 Effective in present of other ingredients and in wide range
of pH and temperature.

Types of preservative
 Parahydroxybenzoic acid esters:
• Methyl, ethyl, propyl, butyl esters are effective at pH 7-9.
 Organic mercurial compounds:
• Phenyl mercuric nitrate and acetate effective in emulsions
• containing non-ionic emulgents.
 Organic acids:
• Used in acidic pH (Benzoic and Sorbic acids).
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 Quaternary ammonium compounds:
• Cetrimide Emulsifying and preservative agent ineffective
against gram –ve bacteria and bacterial spores.
 Chlorocresol:
• For external preparations, its activity reduce at pH and in
• presence of vegetable oils.

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 Humectants

• Propylene glycol, glycerol and sorbitol (5%).

• Reduce the evaporation of water from
opened package or from the skin.
• At high concentration they cause dehydration
and remove moisture from the skin.

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 Antioxidants
Oxidation of vegetable oils cause its rancidity with unpleasant odor
and appearance
Classification:
 True Antioxidants (oil soluble)
• E.g. Butylated hydroxy anisole, Butylated hydroxy toluene,
• L-tocopherol (Vitamin E).
• they capable of involvement in free radical process, protecting the
• oil from involvement.
 Reducing agents:
• E.g. Sodium metabisulfate, Cystein HCl , Ascorbic acid (Vitamin C).
• EDTA as chelating agent retard the oxidation reaction as it
chelate metal ions that catalyze oxidation process.
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 Manufacture of Emulsion
On a small scale, emulsions may be prepared using:
• A dry porcelain mortar and pestle.
• A mechanical blender or mixer.
• A simple prescription bottle.

On a large scale
Mechanical stirrer
High speed impeller in large volume mixing
tanks may be used to form the coarse
emulsion.
Homogenizers
The dispersion of two liquid is achieved by
forcing their mixture through a small inlet
orifice at high pressure.
colloid mill
Colloid mill operate on the principle of high
shear, which is generated between the rotor
and the stator of the mill. 46
 Lab methods used by community pharmacists
1- The continental or dry gum method
the emulsifying agent (usually acacia) is mixed with the oil before the
addition of water.
2- The English or wet gum method
the emulsifying agent is added to the water. (In which It Is soluble)
to form a mucilage, and then the oil is slowly incorporated to form
the emulsion
3- The bottle or the Forbes bottle method
The bottle method is reserved for volatile oils or less viscous oils.
Powdered acacia + 2 part of oil are placed in a dry bottle and the
mixture is thoroughly shaken.
A volume of water approximately equal to the oil is then added in
portions, the mixture being thoroughly shaken after each addition the
primary emulsion thus formed may be diluted to the proper volume
with water. 47
Bancroft's rule:
• Emulsion type depends more on the nature of the emulsifier
than on the relative proportions of oil or water present or the
methodology of preparing emulsion.

The phase in which an emulsifier is more soluble

constitutes the continuous phase
• In O/W emulsions – emulsifying agents are more soluble in
water than in oil (High HLB surfactants).
• In W/O emulsions – emulsifying agents are more soluble in
oil than in water (Low HLB surfactants).
The order of addition of the phases
• W O + emulsifier W/O
• O W + emulsifier O/W.

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MULTIPLE EMULSION

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50
 Test for Identification of Emulsion Type
Miscibility tests with oil or water
The emulsion will only be miscible with liquids that are miscible
with its continuous phase.

Conductivity measurements
Systems with aqueous continuous phases will readily conduct
electricity, whereas systems with oily continuous phases will not
since most oils are poor conductors

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Staining tests
• If a water-soluble dyes is added in an o/w emulsion the emulsion
takes up the color uniformity, phase is continuous phase.

• Conversely if the emulsion is w/o type and dye being soluble in

water, the emulsion takes up the color only in the dispersed phase
and the emulsion is not uniformly colored.

O/W emulsion W /O emulsion

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Fluorescence Method
Many oils fluoresce under ultraviolet
light. Thus, if the whole field
fluoresces under fluorescent light
microscope, the emulsion is wl o, if,
on the other hand, only a few
fluorescent dots are evident, the
emulsion is o/w. O/W emulsion W /O emulsion
Wetting of Filter Paper Method
This method depends on the respective abilities of oil and water to
wet filter paper. A drop of the emulsion is placed on a piece of filter
paper; if the liquid spreads rapidly, leaving a small drop at the center,
the emulsion is o/w. If no spreading occurs, the emulsion is w/o.
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 Stability of Emulsion
Characteristics of Stable Emulsion:
• dispersed globules retain their initial character
• and remain uniformly distributed throughout the
continuous phase.

Thus:
• Change in number of dispersed globules
• Change in size of globules
• Change in globule size distribution (polydispersity
index)
• and change in viscosity means unstable emulsions.
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1. PHYSICAL Instability of Emulsions

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 Instability: Creaming and Sedimentation
• This process results from external forces, usually
gravitational or centrifugal.
• When such forces exceed the thermal motion of the
droplets (Brownian motion), a concentration
gradient builds up in the system such that the larger
droplets move more rapidly either to the top
resulting in CREAMING (if their density is less than
that of the medium)
• or to the bottom resulting in SEDIMENTATION (if
their density is greater than that of the medium) of
the container.

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Creaming and sedimentation results temporary changes of emulsion into
two regions, one of which is richer in the disperse phase than the other e.g.
the creaming of milk, when fat globules slowly rise to the top of the
product.
Creaming and sedimentation are reversible process.
Velocity of the creaming and sedimentation is governed by Stokes’ law

2 r2 ( - o) g
V=
9

g = gravity constant
r = radius of the dispersed globules
 = viscosity of the external phase
 = density of the internal phase
o= density of the external phase
v = velocity of sedimentation of the dispersed spherical particles
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 Instability: Coalescence (Breaking, Cracking)
Process of thinning and disruption of the liquid
film between the droplets, with the result that
fusion of two or more droplets occurs to form
larger droplets.
Cracking or coalescence of an emulsion leads
to the separation of dispersed phase as a layer.
Cracking is a irreversible process (permanent loss) .

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 Preventing Coalescence
The coalescence of oil globules in an o/w emulsion is
resisted by the presence, of a mechanically strong
adsorbed layer of emulsifier around each globule.

This is achieved by the presence of either a

condensed mixed monolayer of lipophilic and
hydrophilic emulgents, or a multimolecular film of a
hydrophilic material.

59
 Instability: Flocculation and Ostwald Ripening
• Flocculation : Aggregation of the droplets (without
any change in primary droplet size) into larger units.
• Flocculation occurs when there is not sufficient
repulsion to keep the droplets apart at distances
where the van der Waals attraction is weak.
• Ostwald Ripening (Disproportionation) :
Aggregation of the droplets with change in primary
droplet size.
• With emulsions which are usually polydisperse, the
smaller droplets will have a greater solubility when
compared to larger droplets (due to curvature
effects).
• With time, the smaller droplets disappear and their
molecules diffuse to the bulk and become deposited
on the larger droplets. 60
 Instability: Phase Inversion
O/W W/O
• Nature of emulsifier: Making the emulsifier more oil soluble tends
to produce a W/O emulsion and vice versa. (Bancroft's rule)

• Phase volume ratio

Oil/Water ratio  W/O emulsion and vice versa.

• Temperature of the system:  Temperature of O/W makes the

emulsifier more hydrophobic and the emulsion may invert to
W/O.

• Addition of electrolytes and other additives: Addition of Strong

electrolytes to O/W (stabilized by ionic surfactants) may invert to
W/O

Example: Inversion of O/W emulsion (stabilized by sodium cetyl

sulfate and cholesterol) to a W/O type upon addition of polyvalent Ca. 61
 2. CHEMICAL Instability of Emulsion
A. Chemical incompatibility of the emulsifier system with the active
agent and with the other emulsion ingredients
• Ionic emulsifying agents are usually incompatible with materials of
opposite charge. i. e. anionic and cationic surfactants.
• Addition of electrolyte may cause salting out of the emulsifying
agent or phase inversion e.g. sodium soap stabilize o/w emulsion
so when a divalent electrolyte such as CaCl2 is added it may form
the calcium soap, which stabilize a w/o emulsion.
• Emulsifier may also be precipitated by the addition of materials in
which they are insoluble e.g. precipitation of hydrophilic colloids by
the addition of alcohol.
• Changes in pH may also lead to the breaking of emulsions. Sodium
soaps may react with acids and produce the free fatty acid and the
sodium salt of the acid. Soap-stabilized emulsions are therefore
usually formulated at an alkaline pH.
62
B. Oxidation

Many of the oils and fats used in emulsion formulation are of

animal or vegetable origin and can be susceptible to oxidation
by:
 Atmospheric oxygen or .
 By the action of microorganisms.

The resulting rancidity is manifested by the formation of

degradation products of unpleasant odour and taste.

This can be controlled by the use of:

 Antioxidants.
 Antimicrobial preservatives.
63
C. Microbiological Contamination may cause:
Gas production.
 Colour and odour changes.
 Hydrolysis of fats and oils.
 pH changes in the aqueous phase.
 Breaking of the emulsion.
Why it happens?
 Some of the hydrophilic colloids (emulsifying agents) may provide a suitable
nutritive medium for microorganisms.
 Most fungi and many bacteria will multiply readily in the aqueous phase of
an emulsion.
 o/w emulsions tend to be more susceptible to microbial spoilage than w/o
products, why? In w/o emulsions the continuous oil phase acts as a barrier
to the spread of microorganisms throughout the product, and the less water
there is present the less growth there is likely to be.
 Therefore an antimicrobial agent must be added. 64
D. Adverse Storage Conditions
Increase in temperature will causes:
• An increase in the rate of creaming, due to a fall in apparent
viscosity of the continuous phase.

• Increased kinetic motion of the dispersed droplets thus the

number of collisions between globules will increase

• The emulsifying agent at the oil/water interface will result in a

more expanded monolayer, and so coalescence is more likely.

• Certain macromolecular emulsifying agents may be coagulated.

Decrease in temperature may cause:

• Precipitation of certain emulgents.

65
 Stability Testing of Emulsion
1. Macroscopic Examination
Examination of the degree of creaming or coalescence occurring over
a period of time.
This is carried out by calculating the ratio of the volume of the
creamed or separated part of the emulsion and the total volume.
2. Globule Size Analysis
Microscopic examination - Coulter counter - laser diffraction sizing are
most widely used to determine the mean globule size as an increase
with time is a sign for coalescence.
3. Viscosity Changes
Any variation in globule size or number or in the orientation or
migration of emulsifier over a period of time may be detected by a
change in apparent viscosity.
In order to compare the relative stabilities of similar products it is
often necessary to speed up the processes of creaming and
coalescence by temperature cycling or centrifugation. 66
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Any Questions ??

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