References

Remington: The Science and Practice of Pharmacy, 20th Edition, 2000.

Pharmaceutical Dosage Forms and Drug Delivery Systems, Howard C.

Ansel, Nicholas G. Popovich, and Loyd V. Allen, 7th Ed., Lippincott
Williams & Wilkins 1999.

Chapter 8, Coarse Dispersions, in: Physical pharmacy by Alfred Martin,

Pilar Bustamante, and A.H.C. Chun, 4th Ed., Lea & Febiger, 1993

Ch.28 (Suspensions) and Ch.29 (Liquid Emulsions), in: A practical guide

to contemporary pharmacy practice, Judith E. Thompson, Williams &
Wilkins,1998

DISPERSE SYSTEMS
The

term "Disperse System" refers to a system

in which one substance (The Dispersed Phase)
is distributed, in discrete units, throughout a
second substance (the continuous Phase or
vehicle).

Each

phase can exist in solid, liquid, or

gaseous state

Dispersed Systems

Two phase systems

Emulsions -> Liquid in a liquid

Suspension -> Solid in a liquid
Foam -> air in a liquid

Dispersed Systems

Physical stability

Settling & Creaming

Stokes Law

v
Stability
Particles need to come into contact
(collide) to coalesce
Therefore, higher concentrations (via
creaming/settling) promote coalescence or
caking

DISPERSE SYSTEMS

Another important factor is DENSITY.

It is possible to manipulate the density of the
dispersion medium by adding nonionic
substances.
e.g. SORBITOL
PVP (polyvinyl pyrolidone)
GLYCERIN
SUGAR
PEG (polyethylene glycol)

Calculations

Determine the absolute viscosity of syrup using a

ball of radius of 0.2 cm. The density of the ball is
2.33g/cc and the density of the syrup is 1.33 g/cc at
250 C. The rate of falling is 4.35 cm/sec.

Determine the velocity of settling of sulfur in water.

The average particle radius is 5.5 m. The density
of sulfur and water at 250 C. is 1.96 and 0.997
g/c.c., respectively. The viscosity of water at 250 C.
is 0.00895 poise.

Calculations

If the height of the bottle is 10 cm how long will it

take to completely settle?

Particle

size determination:

From the previous example, calculate the average

particle size of sulfur.

What is the necessary viscosity to reduce the

sedimentation rate from 0.0071 cm/sec to 0.00071
cm/sec?

Physical Stability -> Phase Separation

Phases separation starts with growth in particle size

Physical contact -> first step in coalescence
Flocculation and aggregation

Coalescence

Come together but do not fuse

No disruption of interface
Surfactants slow process
Fusion of particles -> next step
Come together & fuse
Disruption of interface
Surfactants slow process

Phase separation (final endpoint)

Result of continued coalescence

Dosing uniformity

Importance

Aerosols (emulsion or suspension)

Multiple dose
Multiple use - if don't deliver uniform dose get an
enrichment or reduction in concentration with each dose
Single dose -> same process but less important
Results in over- or under- dosing
Example
Steroids like Betamethasone can lead to side effects or
ineffective therapy

Dispersion

What is a dispersion at molecular level?

What makes them physically stable?
Interfacial Phenomena

Coarse dispersion 10 to 50 m
Fine dispersion 0.5 to 10 m
Colloidal 1 nm to 0.5 m

What happens at interface is critical!!

Suspensions

Pharmaceutical suspensions are uniform dispersions of solid drug

particles in a vehicle in which the drug has minimum solubility.

Colloidal suspension 1 nm to 0.5 m

Coarse suspension 1 to 100 m

May be for oral, ophthalmic, parenteral, or topical use

Oral suspensions may be aqueous preparations with flavored,

sweetened vehicles or powder products for oral suspension

Marketed preparations:

ready-to-use
dry powders which must be reconstituted before administration

SUSPENSIONS

Examples of Pharmaceutical Suspensions:

1. Antacid oral suspensions

2. Antibacterial oral suspension
3. Dry powders for oral suspension (antibiotic)
4. Analgesic oral suspension
5. Anthelmentic oral suspension
6. Anticonvulsant oral suspension
7. Antifungal oral suspension

Suspensions: Advantages

Many patients prefer a liquid form over a solid form

Suspensions provide greater flexibility in the administration of

doses

A suspension can better mask the taste of a drug as compared to

a solution

Some drugs are chemically unstable when in solution but stable

when suspended

Desired features in a pharmaceutical suspension

1. Therapeutic efficacy - if the drug does not exert pharmacological activity after
administration, it has failed in its purpose.
2. Chemical stability - no degradation or decomposition of vital components within the
formulation during processing, storage, handling or administration.
3. Physical stability - the suspension should not settle too quickly and should be readily
redispersed on gentle shaking.
4. The particle size should remain fairly constant throughout the shelf-life of the product.
You don't want dissolution or aggregation of the particles within the suspension.
5. The suspension should pour easily and evenly from the container.
6. The formulation should be aesthetically pleasing to the eye, nose and mouth. The
appearance, viscosity, texture and any other properties detected by the senses must
be considered.

Desirable Features

particles should settle slowly

formulation should allow the easy redispersion of
sedimented particles
a flocculated suspension is desirable than a
deflloculated suspension
a suspension should not be too viscous to reduce
the sedimentation rate

Settling and Aggregation

The suspension shall form

loose networks of flocks that
settle rapidly, do not form
cakes and are easy to
resuspend.

Settling and aggregation may

result in formation of cakes
(suspension) that is difficult
to resuspend or phase
separation (emulsion)

flock

cake

Pemisahan Zat-zat Terdispersi

Sedimentasi

Bila konsentrasi zat terdispersi 0,5 2 % Hk. Stokes

berlaku
Bila konsentrasi zat terdispersi 5 10 % Hk. Stokes tak
berlaku (partiekel saling mempengaruhi sehingga cepat
terjadi pengendapan

Flokulasi

Susunan yang terbentuk merupakan ikatan yang lemah

(Van der Waals)
Cepat memisah kembali apabila dikocok perlahan
Mudah membentuk suspensi yang homogen kembali
Tidak membentuk caking

Pemisahan Zat-zat Terdispersi (lanjutan)

Deflokulasi

Agglomerasi

Susunan yang terbentuk merupakan ikatan yang kuat

Tidak mudah memisah dari endapannya apabila dikocok
Sulit tersuspensi kembali
Dapat membentuk caking
gumpalan dengan ikatan yang kuat

Caking

Gumpalan yang mengendap dengan masa yang keras

Sedimentation (Settling) rates

The well known Stokes relation describes the sedimentation

velocity of a particle in suspension:

2r 2 ( d1 d 2 ) g D 2 ( d1 d 2 ) g
v

9
18

where v = velocity of the sedimentation or rate of settling in

cm/sec;
r = particle radius;
D = particle diameter in cm;
d1 and d2 = density of the particle and the liquid, respectively, in
(g/cm3);
g = acceleration due to gravity (gravitational constant) = 980.7
cm/sec2;
= the viscosity of the medium in poises.

Sedimentation (Settling) rates

The various parameters influencing the rate of settling are

contained in the Stokes equation. These parameters lead to
several manufacturing considerations as well as to the inclusion
of certain additives to oral suspension formulations:

Reduction of particle size (Recall, however, that reducing the

particle size may also promote caking.)

Solid content - recall that Stokes equation is based on a dilute

suspension because the presence of other particles hinders settling

Increasing the density of the vehicle (additive)

Increasing the viscosity of the vehicle (within limits since the

increase in viscosity also affects flow from the bottle) (additive:
suspending agent or viscosity modifier)

Prevention of aggregation/caking (additives: surfactants and

flocculating agents)

Sedimentation (Settling) rates

(A) -Particle size
reduction:

This is usually accomplished by dry milling prior to

incorporating the dispersed phase into the vehicle:

1.

Micropulverizers are the high-speed equipment that can rapidly,

conveniently and inexpensively produce fine powders in the
diameter range 10 to 50 m.

2.

To achieve particles less than 10 m in diameter requires a

process called jet-milling or micronizing. The particles are
carried into compressed air streams where they collide with one
another due to the violent turbulence and high velocities
present in these systems. These collisions result in
fragmentation and the resultant decrease in particle size.

3.

Particles of extremely small dimensions can be produced by

spray drying.

Sedimentation (Settling) rates

(A) -Viscosity Modifiers:

Carboxymethylcellulose (CMC), methylcellulose, xanthan gum,

and bentonite have been used to thicken the continuous phase
and help to support the physical stability of the suspension. These
agents are poorly absorbed from the GI tract and essentially pass
through unchanged.

When polymeric substances and hydrophilic colloids are used as

suspending agents, appropriate testing must be performed to
ascertain that the substance does not interfere with the absorption
of the drug. The usual mechanism is adsorption or sequestering of
the drug which interferes with the rate and extent of absorption.

To determine if the product is too viscous, the study of flow

characteristics, or rheology, comes into play. Viscometers are
employed which measure the relative ease or difficulty in rotating
spindles (with or without baffles or flanges on them) through the
sample medium.

Theory of Sedimentation

The factors involved in the rate of velocity of settling of the

particles in a suspension are best expressed in the equation
of the Stokes law

Stokes equation applies to uniform, perfectly spherical

particles settling in a very dilute suspension with no
hindrance or turbulance

FACTORS TO BE CONSIDERED
Particle size
Density of the vehicle

-polyethylene glycol
-polyvinyl pyrolidone
-glycerin
-sorbitol
-sugar.

State

Rate of settling

Sedimentation
volume

Nature

Flocculated

Fast

High

Porous, easy to
redisperse

Deflocculated

Slow

Low

Compact, difficult
to redisperse

Sedimentation Volume
V = Vu /V0 ; ideally, V should be equal to 1.0

Thixotropic suspension
A

thixotropic suspension is the one which is

viscous during storage but loses consistency
and become fluid upon shaking.

well-formulated thixotropic suspension

would remain fluid long enough for the easy
dispense of a dose but would slowly regain
its original viscosity within a short time.

Formulation of suspension

component of suspending system

wetting agent
dispersants
flocculating agent
thickeners

component of the suspending agent

pH control agent
osmotic agent
coloring agents
preservatives to control microbial growth
liquid vehicles

METHODS OF PREPARATION
(1)

use of controlled flocculation

(2)

use of structured vehicle

Wetting of dispersed particles -Alcohol, glycerin, and propylene glycol

-Mineral oil
Hydrophilic and hydrophobic particles-

Wetting agent

Controlled flocculation

Most frequently used flocculating agents are electrolytes.

The flocculating power increases with the valency of the ions. As for
example, calcium ions are more powerful than sodium ions because
the velency of calcium is two whereas sodium has valency of one.

Other substances which initiate flocculation are combination of ionic

and nonionic surface active agents and lyophilic polymers. These
polymers form a bridge between particles and initiate flocculation.

Structured vehicle

Structured vehicles are the aqueous solutions of

natural and synthetic gums.

Methyl cellulose, carboxymethyl cellulose,

sodium carboxymethyl cellulose, acacia, and
tragacanth are the most commonly used structured
vehicle in the pharmaceutical suspensions

Preparation & Storage of Suspensions

Small scale mortar & pestle
Industrial scale colloid mill
Particle size 1-50 m
Package in wide mouth containers with adequate air
space shake before use

Examples :
Antacid oral suspensions
Antibiotics for oral suspension
Parenteral penicillin suspension

Fig. The four basic types of size reduction

equipment used to produce fine solid particles.

(a)
(b)
(c)
(d)

crushers and
shredders
hammer mills
colloid mills
fluid energy mills

A typical suspension formula..

Drug
Suspending agent
Wetting agent
Buffer
Preservative
Also, coloring, sweetening, and flavoring agents

Suspending Agent

Akasia/Gom Arab (2,5 %)

Tragacanth (1 2 %)
Tragacanth + air 20 x dicampur homogen
Na Alginat (1 2 %)
Metilselulosa (0,5 2 %)
Metilselulossa + air panas 10 x aduk selama 2 jam, + sisa air
Na CMC (0,25 2 %)
Na CMC + air panas 20 X biarkan 15 menit

Bentonit (2 5 %), untuk eksternal

Veegum (0,5 2,5 %)
Veegum + air 16 kalinya
Sering dikombinasi dengan CMC 1 % dan veegum 0,5 %
CMC (0,5 2 %)

Wetting Agent

Tween 80
Span
Alkohol
Propilenglikol
Dioktil Na Sulfosuksinat
Na Lauril Sulfat

untuk sediaan
oral

untuk obat
luar

Preservative

Metil paraben (Nipagin)

: 0,12 0,18 % (antibakteri)

Propil paraben (Nipasol) : 0,05 % (antijamur)

Asam benzoat

Na benzoat

: 0,1 %
: 0,1 %

Compounding of Suspensions

Solid dosage forms can be used

Check literature & reference books
Selected vehicles are commercially available
A smooth, nongritty product should be prepared
Neonatal formulations should not contain
preservatives, colorings, flavorings, and alcohol
Use manufactured liquid product, if available

Desain Pengembangan Formula

Karakter zat aktif : tidak larut dalam sejumlah air

yang dibutuhkan
Tujuan formulasi : mendapatkan suspensi yang
stabil, yaitu :
mudah terdispersi saat pengocokan dan saat
terbentuk endapan
Pengendapan terkendali
Mudah dituang

Desain Pengembangan Formula (lanjutan )

Teknik untuk mendapatkan suspensi yang stabil :

Memperkecil ukuran partikel

- suspending agent
- penggerusan
- wetting agent
Menaikkan viscosita medium dispersi, yaitu :
- suspending agent
- pengental
Menurunkan tegangan permukaan
- suspending agent
- wetting agent
Pengendalian sedimentasi
- pengental

EVALUATION OF SUSPENSIONS

Sedimentation volumeF = Vsed/Vtot

The value of F normally lies between 0 to 1 for

any pharmaceutical suspension.

The value of F provides a qualitive knowledge

about the physical stability of the suspension.

Degree of flocculation = Ffloc/Fdefloc

(Vsed/Vtot)floc
=------------------(Vsed/Vtot)defloc

When the total volume of both the flocculated and the

deflocculated suspensions are same, as for example,
100 ml in the Figure; the degree of flocculation,
= (Vsed)floc/(Vsed)defloc

Evaluasi sediaan
Parameter

Hal yg hrs diperhatikan

Viskositas

Disesuaikan sehingga tidak mudah

memisah tapi masih cukup mudah untuk
dituang

pH

dlm range pH stabilita

Stabilita fisik

T40 selama 3 bulan penampilan masih baik

Stabilita kadar

T40 selama 3 bulan, masih memenuhi

syarat

Evaluasi sediaan

Penampilan : bentuk, bau, rasa

Penentuan rekonstitusi

Penentuan pH sediaan
Penentuan volume sedimentasi

Suspensi kering dalam botol, tambahkan air sampai batas

kocok dengan normal, amati apakah sediaan mudah
direkonstitusi

Sediaan dimasukkan kedalam gelas ukur, diamkan

Volume sedimentasi merupakan volume endapan setelah
pendiaman dibagi volume sediaan awal

Pemeriksaan ukuran partikel

Penentuan viscositas dan sifat aliran

Evaluasi sediaan
Parameter yang diperhatikan formulasi dry sirup
Parameter

Hal yg hrs diperhatikan

Flow granul/serbuk

baik

Homogenitas

Perbedaan ukuran partikel antara zat aktif

& zat tambahan tidak terlalu besar
sehingga kemungkinan terjadi
pemisahan/segresi kecil

Stabilita fisik/kadar

T40 slm 3 bulan msh memenuhi (diterima)

Setelah rekonstitusi

sampai

pemakaian yang tertera pada

label, penampilan & kadar masih baik
saat rekonstitusi jml pelarut yang
ditmbhkan harus = label

Packaging and Storage of Suspensions:

1) Should be packaged in wide mouth containers
having adequate air space above the liquid.

2) Should be stored in tight containers protected

from: freezing and excessive heat & light
3) Label: "Shake Before Use" to ensure uniform
distribution of solid particles and thereby uniform
and proper dosage.

Administration and Counseling for Oral Suspensions

Most oral suspensions are administered by teaspoon or

tablespoon. Make certain that you counsel the patient regarding
which to use.

Reconstituted products are usually suspensions and an oversized

bottle is necessary to allow a headspace to shake the suspension
into for adequate redispersion.

Make clear to the patient that the headspace is not because they
have been cheated of drug, but rather to allow room to shake the
mixture.

Administration and Counseling for Oral Suspensions

Some patients don't understand that the medication is

for oral administration. For example, make clear to the patient that
the oral antibiotic suspension to treat a middle ear infection is to
be taken by mouth and not placed in the ear canal.

If the medication states that the product should be refrigerated,

counsel the patient to store it in the refrigerator. Some suspension
and emulsion products do not require refrigeration during storage.
It probably is dependent on the level of preservative present in the
formulation.

Administration and Counseling for Oral Suspensions

Some suspensions can interfere with the bioavailability of other

oral drugs.

Examples are: Cholestyramine suspension has been shown to

decrease the bioavailability of warfarin,
digitoxin and thyroid hormones, probably by adsorption of the drug
to the suspensoid particles.

Advise the patient to stagger the administration of their oral drugs

by several hours when interferences have been reported.

Acetaminophen Oral Suspension

MANUFACTURING DIRECTIONS
1.

2.
3.
4.

5.

6.

Acetaminophen dispersion should be uniformly mixed or levigated.

If acetaminophen dispersion is either added to hot syrup base or
homogenized for a long time, flocculation may appear. While
handling the syrup, mucilage, or drug dispersion, the handling loss
should not be more than 1%. If the loss exceeds 1%, it may give
poor suspension.
Add 180 g of item 13 to the mixer and heat to 90.C.
Dissolve items 3 and item 4 while mixing. Add and dissolve item 2
while mixing. Cool down to about 50. to 55.C.
Add and dissolve item 5 while mixing. Filter the syrup through T
1500 filters washed with item 13. Collect the syrup in clean
stainless steel tank.
Disperse item 9 in item 6 in a separate stainless steel container.
Add 40 g of hot item 13 (90.C) at once while mixing. Mix for 20
minutes to make a homogeneous smooth mucilage.
Mix item 7 in 10 g of item 13 (25.C) in a separate stainless steel
container. Add item 1 while mixing with stirrer. Mix for 25 minutes to
make uniform suspension.

Cont
7.

8.

9.
10.
11.
12.
13.
14.
15.
16.

Add sugar syrup and mucilage to the mixer. Rinse the container of mucilage
with 15 g of item 13 and add the rinsings to the mixer. Cool to 25.C while
mixing.
Add item 1 dispersion to the mixer. Rinse the container of dispersion with
15 g of item 13 and add rinsings to the mixer. Check the suspension for
uniformity of dispersion.
Mix for additional 5 minutes at 18 rpm, vacuum 0.5 bar if required.
Add item 8 to the mixer and mix for 10 minutes. Dissolve item 10 in 7 g of
item 13 and add to the mixer.
Disperse item 11 in 7 g of item 13 and add to the mixer. Add item 12 to the
mixer.
Add cold item 13 (25.C) to make up the volume up to 1.0 L.
Homogenize for 5 minutes at low speed under vacuum 0.5 bar, 18 rpm,
temperature 25.C.
Check the dispersion for uniformity.
Check the pH. Limit 5.7 0.5 at 25.C. If required adjust the pH with 20%
solution of Citric Acid or Sodium Citrate.
Transfer the suspension through 630 micron sieve after mixing for 5
minutes at 18-20 rpm, temperature NMT 25.C, to the stainless steel storage
tank.

Acetaminophen Suspension

1.

Prepare the solution of dextrose in water and add the other

solid ingredients with stirring in the following sequence:
citric acid, sodium citrate, orange flavor, Kollidon CL-M, and
acetaminophen.

2.

A white, homogeneous suspension is obtained.

Acetaminophen Syrup for Children

1.
2.

Dissolve Kollidon in water, add acetaminophen and

cyclamate, heat to 50.C, and stir to obtain a clear solution.
Dissolve the flavors and mix with glycerol. The obtained
syrup is a viscous, clear, sweet, and only slightly bitter
liquid.

Amoxacillin Powder for Suspension

1.
2.
3.
4.
5.
6.

Charge items 3 and 2 in a mixer and mix for 2 minutes.

Add item 4 and items 6 to 11 and mix for 5 minutes.
Pass through Fitz Mill, impact forward at high speed using sieve
24228.
In a separate mixer, charge items 5 and 1 and mix well, passing
through a sifter.
Add to step 3 and mix for 20 minutes.
Fill 65.00 g for 100 mL and 39 g for 60-mL pack size.

References

Remington: The Science and Practice of Pharmacy, 20 th Edition,

2000.

Pharmaceutical Dosage Forms and Drug Delivery Systems,

Howard C. Ansel, Nicholas G. Popovich, and Loyd V. Allen, 7th
Ed., Lippincott Williams & Wilkins 1999.

Chapter 8, Coarse Dispersions, in: Physical pharmacy by Alfred

Martin, Pilar Bustamante, and A.H.C. Chun, 4th Ed., Lea &
Febiger, 1993

Ch.28 (Suspensions) and Ch.29 (Liquid Emulsions), in: A

practical guide to contemporary pharmacy practice, Judith E.
Thompson, Williams & Wilkins,1998

Emulsions

Dispersed system - two immiscible liquid phases,

one of which is dispersed as globules in the other
o/w - oleaginous internal phase and an aqueous
external phase
w/o - aqueous internal and an oleaginous external
phase

Microemulsion: Droplets size range 0.01 to 0.1 m

Macroemulsion: Droplets size range approximately
5 m.

Definition
An emulsion is a dispersion in which the
dispersed phase
is composed of small globules of a liquid
distributed
throughout a vehicle in which it is immiscible.
dispersion

B phase

A phase

Emulsion

solution

Types
Types of
of emulsions
emulsions
Basic types

O/W

W/O

multiple

W/O/W

InternalExterna InternalExterna
phase l phase phase l phase
oil-in-water

water-inoil

O/W/O

Water inoil-inwaterOil-in-waterin-oil

Types of Emulsion
m
Water
Oil

Oil-in-water emulsion

Water-in-oil emulsion

Multiple Emulsions
m
Water
Oil

Water-in-oil-in-water emulsion

Oil-in-water-in-oil emulsion

Emulsion Size
0.5 m
0.5-1.5 m
1.5-3 m
>3 m
<

Fig.1 Mineral oil in water emulsion

How can the emulsion be

stabilized?
Reductionofthesurfacetensionisthekeytoavoidthe
coagulationoftheemulsion.
Substanceswhichreducethesurfacetensionarecalledsurfactants.
Thenumberofsurfactants(emulsifiers)isenormousand
theyaredividedupintoseveralgroupsaccordingtotheir
properties.
BesideO/WorW/Oemulsifiersurfactantsarealsousedas
antifoamingagent,wettingagent,dispersingagentand
solubilisator.

Surfactants and Micelles

Surface active agents have a certain affinity for both polar &
nonpolar solvents
Amphiphilic nature adsorb at interfaces
At a concentration that is characteristic of each amphiphile, these
molecules will aggregate to produce micelles

Working principle of emulsifier

water

water

oil

oil

W/O

O/W
Hydrophil head
Lipophil chain

emulsifier
The basic requirements for emulsifier
Types of emulsifier
Emulsifying mechanism

Properties supplied by the

emulsifier
Reduction of the surface energy
Generation of steric and electrostatic inhibitions
(inhibition of coalescence of the drops)
Inner phase is dispersed under high shear force to
achieve a homogeny monodispers mixture of the drops.
Thedropsizeofemulsionsistypicalinarangebetween
1and10m(upto25m).

Type of emusifier

1. high molecular
compound
2. surfactants
3. solid powder

1. high molecular compound

acacia
tragacanth
gelatin
lecithin
almond
cholesterol
others

2 . surfactants
anionic
anionic surfactants
surfactants
Active
part -
Na

polarity
hydrophili
c

Nonpolarity
hydrophobic

General topical used emulsions

nonionic
nonionic
surfactants
surfactants
Sorbitan W/O type
span20 40 60 80
Polyoxyethylene sorbitan monolaurate O/W
type
tween20 40 60 80
Polyxyethylene fatty acid ester
Myrij O/W type
Myrij 45 49 52

3. Solid power surfactants

Finely
Finely divided
divided solids
solids
can
can be
be aggregated
aggregated at
at
surface
surface between
between oil
oil and
and water
water to
to form
formsolid
solid
particle
particle membrane
membrane
contact
contact angle
angle of
of solid
solid powder
powder with
with water
water phase
phase
determine
determine the
the types
types of
of emulsions
emulsions
<90
<90 O/W
O/W

>90W/O
>90W/O

Emulsification

Emulsifier

EMULSIONS

Theories of Emulsification:
1) Surface Tension Theory:
- lowering of interfacial tension.
2) Oriented-Wedge Theory:
- mono molecular layers of emulsifying agents are
curved around a droplet of the internal phase of the
emulsion.
3) Interfacial film theory:
- A film of emulsifying agent prevents the contact and
coslescing of the dispersed phase.

Emulsifying Agents:

1) Carbohydrate Materials:
- Acacia, Tragacanth, Agar, Pectin. o/w emulsion.
2) Protein Substances:
-Gelatin, Egg yolk, Caesin o/w emulsion.
3) High Molecular Weight Alcohols:
- Stearyl Alcohol, Cetyl Alcohol, Glyceryl Mono stearate o/w emulsion,
cholesterol w/o emulsion.
4) Wetting Agents:
Anionic, Cationic, Nonionic
o/w emulsion
w/o emulsion
5) Finely divided solids:
Bentonite, Magnesium Hydroxide,
Aluminum Hydroxide o/w
emulsion

Additives of emulsions
1. coemulsifier
2 preservatives
3 antioxidants
4. sweeting agent

Formula Umum Emulsi

zat aktif (fase minyak), dan atau larut air

Emulgator
Antioksidan (bila perlu)
Pemanis, pengawet, aroma
Pewarna (bila perlu)

Tujuan formulasi

Pemilihan dan modifikasi emulgator

HLB ?

Cara Menentukan HLB

Metoda Aligasi

R/ Parafin cair
Setilalkohol
Emulgator
Pengawet
Air ad

25
20
2
0,2
100

Fase minyak % HLB

HLB butuh

Parafin cair

25

25/45 x 8 = 4,5

Setilalkohol

20 15

20/45 x 15 = 6,7

Jumlah

45

11,2

Mis. Emulgator yang digunakan :

Span 60 (HLB 4,7)
Tween 60 (HLB 14,9)
Jumlah emulgator yang digunakan :
Span 60 yg dipakai : 3,7/10,2 x 2 g
Tween 60 14,9
6,5
= 0,72g
11,2
Tween 60 yg dipakai : 6,5/10,2 x 2 g
Span 60 4,7
3,7
= 1,28 g

Methods
Methods of
of emulsion
emulsion preparation
preparation

Prescription laying for emulsions

Drug addition
Preparation method
emulsification facilities
The influcing factors on emulsification
examples

Preparation of Emulsions

High speed impellers in mixing tanks

Small scale extemporaneous preparation (See
Ansel)
Continental or dry gum method

4 (oil): 2 (water): 1 (gum)

English or wet gum method

Bottle or Forbes bottle method
In-situ soap method

Preparation method
1 hand-made method
1 dry gum
method

water

oil emulsifer
2 wet gum method
oil

water emusifier

direct
mixture
method
oil3water
emulsifer

emulsio
n

emulsio
n
emulsion

Methods of Manufacture
Recall

goal

Increase surface area

Requires energy to create surface

Overcome

surface tension
Add energy by creating shear gradient within
the liquid

Shear gradient

Emulsions:
Different ways of production
Hot/HotProcess

Both,fatandwaterphaseareheatupseparatelytoacertain
temp.(7085C).Thehotoilphaseandthehotwaterphase
werecombinedundervacuumatthehightemperatureand
emulsified.Emulsificationisdonebytherotorstatorsystem.
Subsequentlytheproductiscooleddown.

Hot/ColdProcess

Thefatphaseisheatuptoatemp.(app.10Cabovethehighest
meltingpointoftheingredients).Thehotfatphaseandthecold
waterphasewerecombinedundervacuumandemulsifiedatthe
mixingtemperature.Subsequentlytheproductiscooleddown.
Advantage:shortercoolingtimes,savingofenergy

Basic Methods
Mechanical

stirrers
Homogenizers
Colloid mills or Rotor-stator
Ultrasonifiers

Mechanical Stirrers

Not very efficient -> limits particle size

Especially viscous liquids

Advantages
Large scale - 1000 gal
Fusion manufacturing of emulsion
Keep mixed upon cooling

Homogenization

Compress liquids to high pressure -> spring

loaded orifice lets escape creating high shear
Develop pressures 500-5000 psi
Very high energy -> small particle size
2nd pass -> fine particle size
Hand homogenizer & glass syringe used for small scale
Use in Compounding Rx
Second most common method besides elbow grease
Hard to scale up -> orifice critical in particle size

Ultrasonic Homogenizer

Vacuum Homogenizer

Colloid Mills
1000-20000

rpm
High sheer rates
Heat build up a problem

Colloid Mill is suitable for Homogenising,

Emulsifying, Dispersing mixing.

Ultrasonification
Sound

energy produces holes in solution

then collapses very high shear
Hard to scale up
Film Formation

The emulsifier must be adsorbed quickly around

the dispersed drops and condensed film that
prevents coalescence

Process Diagram Of W/O - Cream Production On Dinex

Scraper: 30rpm Agitator: 30rpm for the whole process

Heating of fat phase onto 75 C,

then feed in Main vessel, run homogenizer
600rpm and keep on temperature

Preparation of water phase

Feed water phase slightly in Main vessel

Vacuum 700mbar
Homogenizer 3000 rpm

Homogenization 3000 rpm;

Vacuum 700mbar

Cooling downto 40 C
Homogenizer interval: Run 1500rpm 30s
Pause 150s

Preparation of additives, parfume

Feed additives + parfume,

Temperature 40C; Vacuum 700mbar
Homogenizer 3000 rpm

Homogenization 3000 rpm; 60s

Temperature 40 C; Vacuum 700mbar

Deaeration;
Temperature 40 C; Vacuum 50 mbar

Discharge;
Temperature 40 C
Homogenizer 1000 rpm

Physical stability of emulsions

Creaming
Aggregates of globules of the internal phase have a
greater tendency than do individual particles to rise
to the top of the emulsion or fall to the bottom
The difference in the density between the phases

Flocculation
The association of particles within an emulsion to
form large aggregates, which can be easily be
redispersed upon shaking.

O /W

phase
inversion
O/W type

O/W type W/O

W/O type
type

The
The reason
reason for
for phase
phase inversion
inversion

property of emulsifier
phase volume ratio
W/O type50%~60%
O/W type90%

W/O

Coalescence and breaking

irreversible
irreversible

coalescence
the mechanical of electrical barrier is insufficient
to prevent the formation of progressively larger
droplets.
breaking or creaking
The coalescence of the globules of the internal
phase and the seperation of that phase into a layer
Coalescence and breaking are irreversible

EMULSIONS

Stability of Emulsion:
An emulsion is considered to be physically unstable if :
a) The internal phase tends to form aggregates of globules.
b) Large globules or aggregates of globules rise to the top or
fall to the bottom of the emulsion to form a concentrated
layer of the internal phase.
c) If all or part of the liquid of the internal phase becomes
"unemulsified on the top or bottom of the emulsion.

Emulsion stability

Stokes law use to optimize

Shake well label
Preservatives
desired partition coefficient
incompatibilities/ionization status acacia
based emulsions parabens

Special Emulsion Systems

Multiple

emulsions

w/o/w
stability issues

Microemulsions

surfactant & cosurfactant spontaneous

formation
homogeneous, transparent & stable
< 0.2 microns dispersed phase

Multiple Emulsions
Emulsions

of emulsions and consist of more

than one dispersed phase, usually oil or water
droplets not identical with the continuous
phase.

The

term multiple emulsion has been used

to describe emulsion system in which drops of
the dispersed phases contain smaller droplets
that have the same composition as the
external phase

Preperation

The primary emulsion can then be emulsified with a

hydrophilic,high HLB surfactant, using lower shear
to produce a W/O/W emulsion of reasonable stability

The reverse procedure could be followed to prepare

an O/W/O emulsion.

The most promising use of multiple emulsions is in

the area of sustained-release drug formulations,
since the oil layer between two aqueous phases can
behave like a membrane controlling solute release

MICROEMULSIONS

Microemulsions are thermodynamically stable,

transparent (or translucent) dispersions of oil and
water that are stabilized by an interfacial film of
surfactant molecules.

The surfactant may be pure, a mixture, or combined

with a cosurfactant such as a medium-chain alcohol
(e.g., butanol, pentanol).

These homogeneous systems, which can be

prepared over a wide range of surfactant
concentrations and oil to water ratios (2080%), are
all fluids of low viscosity.

 Microemulsions are readily distinguished from normal

emulsions by their transparency, their low viscosity, and
more fundamentally their thermodynamic stability and
ability to form spontaneously.
Emulsions and microemulsions may be differentiated on
the basis of particle size.
Microemulsions contain particles at least an order of magnitude
smaller (i.e 10 100 nm) than those in conventional emulsions
that contain particle at the upper end of the colloidal size range
(100 100.000 nm)
Conventional emulsions are termed coarse emulsions or
macroemulsions when contrasted with micromulsions

Ternary phase diagram for oil, water, and surfactant mixtures

showing micellar, microemulsion, and multiphase macroemulsion
regions with schematic representations of various structures.

Pharmaceutical Applications
of Microemulsions
the ability to concentrate and localize significant
amounts of both oil and water-soluble materials
the rate of absorption of cyclosporin is more rapid and
less variable than it is with the conventional oily
dispersion.
Microemulsions have also been used for topical
delivery where they increase drug absorption.
For example, cetyl alcohol, which is commonly used as an
emulsifier in lotions and creams, is absorbed faster and
deeper into the skin when formulated as a component of a
microemulsion.

Formulation and Preparation of

Microemulsions
As microemulsions are thermodynamically
stable, they can be prepared simply by blending
oil, water, surfactant, and cosurfactant with mild
agitation.

Evaluasi Sediaan Emulsi

Pemerian

1.

2.
3.

4.
5.
6.
7.

Warna, bau, rasa

Pemeriksaan pH sediaan
Pemeriksaan tipe emulsi
Pengenceran
Pewarnaan
Fluoresensi
Daya hantar listrik

Pemeriksaan BJ sediaan
Pemeriksaan ukuran partikel
Penentuan viskositas dan sifat alir
Volume sedimentasi

EMULSIONS

Separation of the internal phase from the external

phase is called BREAKING of the emulsion. This
is irreversible.
Protect emulsions against the extremes of cold
and heat.
Emulsions may be adversely affected by
microbial contamination.

Eucalyptus and Mint Emulsion

1.
2.
3.

Heat item 1 to 71.C.

Combine rest of the ingredients in another
container and heat to 71.C as well.
Slowly add water at 71.C and mix for 1 hour.
Cool the mixture to 35. to 45.C and fill.

A solution is a homogeneous mixture that is prepared by

dissolving a solid, liquid or gas in another liquid.
Molecular solutions include:
water solutions
aromatic waters
syrups
tincture
spirits
Glycerins

Water Solutions
A solution is formed in water as a solvent
Preparation of Solutions
Weigh the sample
Dissolve the sample
filtrate
quality test
package

Aromatic Waters
Aromatic Waters are saturated solutions (unless otherwise
specified) of volatile oils or other aromatic or volatile
substances in distilled water.
Preparation method of Aromatic Waters
1. Distillation
2. Solution
3.Dilution

Syrups

Concentrated aqueous solution of sugar

Alcohol free
Flavoring mask bad taste

Simple syrup just sugar

Cherry, cocoa, orange, raspberry
Ora-Sweet & Ora-Sweet SF (sugar free)
Paddock Laboratories

Components

Sugar, antimicrobial preservative, flavorant & Colorant

Syrup Components Cont.

Sugar

Sucrose most popular

Dextrose
Non-sucrose
Sorbitol, glycerin, propylene glycol
Glycogenetic all above
i.e. - Converted into glucose in body
Non-glycogenetic
Methylcellulose & hydroxyethylcellulose

Ora-Sweet plus

Not absorbed
Has syrup like and feel
Good for diabetic patients

Simple Syrup, Syrup NF

85 g sucrose qs 100 mL
No preservatives needed
High osmotic pressure like honey
Sucrose solubility 1 g in 0.5 mL water

Syrup NF not saturated may store in fridge

See text for methods of preparation

Rx dilute, not all syrups concentrated

Diluted syrup could be used to grow stuff in micro lab be
careful!!
Is why
Dont give honey to infants
Put nitrates in caned hams with honey

Syrup Preservation
Three

Maintain high sucrose Conc.

Methods

Not less than 85 g sucrose in 100 mL water

Store at low temp

Antimicrobial preservative

Benzoic acid: 0.1 to 0.2%

Na benzoate 0.1 to 0.2%
Methyl-, propyl-parabens total 0.1%
Alcohol 10 to 15%

Components Cont.

Flavorant

Synthetic and naturally

Volatile oils
E.g. orange oil, vanillin, etc.
May add with alcohol for solubility

Colorant

To make more appealing

E.g.
Green with mint
Brown with chocolate