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!!
Disperse systems
Definition:
- A substance, the disperse (discontinuous) phase, is
dispersed as particles over the dispersion medium
(continuous phase)
- Phases can be solids, liquids or gasses
Disperse phase
(discontinuous phase)
Dispersie medium
(continuous phase)
Suspensions
Colloids:
Particle size: 1 nm - 1 m
No sedimentation by Brownian movement
Suspensions:
Particle size: > 1m
Sedimentation
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
B. Amsden CHEE 440
Interfacial Phenomena
flocculation or caking
determined by forces of attraction (van der Waals)
versus forces of repulsion (electrostatic)

deflocculated
repulsion> attraction
affected by [electrolytes]

flocculated
attraction > repulsion

B. Amsden CHEE 440
Electrical Properties
particles may become charged by
adsorption of ionic species present in soln or
preferential adsorption of OH
-

ionization of -COOH or -NH
2
group

-
-
-
-
-
-
solid
+
+
+
+
+
+
hydroxyl ion
B. Amsden CHEE 440
Electric Double Layer
-
-
-
-
-
-
+
+
+
+
+
+
+
-
+
+
-
+
-
-
+
+
-
+
-
-
+
+ -
+
+
gegenion
Nernst potential
zeta potential
tightly
bound
diffuse
electroneutral
bulk
Electrical Double Layer
Surface charge
-
-
-
-
-
-
-
-
+
+
+
+
Stern layer (fixed)
Zeta potential
Nernst potential
Electroneutral solution
B. Amsden CHEE 440
Electrical Props contd
Nernst potential
potential difference between the actual
solid surface and the electroneutral bulk

Zeta potential
potential difference between the tightly
bound layer and the bulk
governs electrostatic force of repulsion
between solid particles
What are colloids?
Colloids are particles of a few m or smaller suspended in
a liquid
Colloids have high surface areas/mass
When working with colloidal systems it is necessary to control:
Stability controlled by:
Surface charges on the particles
pH and/or ionic strength of the dispersing media
Selective adsorption of ions
Particle size
Colloidal Systems
If all the particles have a
large negative or positive
zeta potential, they will
repel each other because
of electrostatic repulsion
forces -- stable dispersion
Negative
zeta potential
Positive
zeta potential
+30 mV
-30 mV
0 mV
STABLE
STABLE
NOT STABLE
Zeta Potential and Dispersion Stability
Zeta Potential & Dispersion Stability
If all the particles have a large negative or
positive zeta potential, they will repel each other
because of electrostatic repulsion force ----
stable dispersion
In general, the higher the zeta potential, the more
stable the particle dispersion. The dividing lines
for aqueous dispersion is considered to be
>+30mV or <-30mV
So, if all the particles have a zeta potential which
is more negative than -30mV or more positive
than +30mV the dispersion should remain stable
no guarantee though
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

Well Formulated Suspension
Resuspend easily upon shaking
Settle slowly after shaking
Homogeneous mix of drugPhysically
and chemically stable during its shelf
life
Sterile (parenteral, ocular)
Gets into syringe (parenteral, ocular)
Untuk cairan obat luar :
Produk tersebut harus cukup cair sehingga dapat
tersebar dengan mudah ke seluruh daerah yang
sedang diobati tapi juga tidak boleh sedemikian
mudah bergerak sehingga gampang hilang dari
permukaan dimana obat tersebut digunakan
Cairan tersebut harus dapat kering dengan cepat
dan membentuk suatu lapisan pelindung yang
elastis sehingga tidak akan mudah terhapus
Mempunyai warna dan bau yang nyaman
Untuk tujuan farmasi :
Kestabilan fisik suspensi didefinisikan sebagai
tidak menggumpal tetap terdistribusi merata di
seluruh system.

Karena kondisi ini jarang terjadi maka dapat
dikatakan, jika partikel-partikel tersebut
mengendap, maka partikel-partikel tersebut harus
mudah disuspensi kembali dengan sedikit
pengocokan.
Pengendapan dalam suspensi
Physical stability

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.

Sedimentation rate (1)
Three forces acting on the falling particle:
- gravity (constant, +)
- upwards forces (constant, |)
- friction (increases with increasing speed, |)
Equilibrium of forces constant speed
Stokes Law





v = kecepatan akhir
(cm/dt)
d = diameter partikel
s dan o = kerapatan
fase terdisper dan
medium pendispersi
qo = viskositas medium
pendispersi (poise)
v
Stability
Particles need to come
into contact (collide) to
coalesce
Therefore, higher
concentrations (via
settling) promote
coalescence or caking
External Forces Acting on
Particles
V(-
o
)g
2-5 m
Gravity
Brownian Movement
Sedimentation
equilibrium: Gravity is
neutralized by
Brownian movement
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?

State Rate of settling Sedimentation
volume
Nature
Flocculated Fast High Porous, easy to
redisperse
Deflocculated Slow Low Compact, difficult
to redisperse
Deflocculated suspension Flocculated suspension
- Low sedimentation rate
- Liquid above sediment
remains turbid (particles of
< 1 m do not sediment due
to Brownian movement)
- Sedimentation is build up
from the bottom
- Compact sediment
difficult to redisperse
- High sedimentation rate
- Liquid above sediment is
clear (also particles
< 1 m sediment)
- Sedimentation is build up
from the top
- Loose sediment easy to
redisperse

Deflocculated is also referred to as peptised
Sedimentation behavior
Deflocculated suspension Flocculated suspension
Structures sediment
o
u
V
V
F
= = Degree of sedimentation:
Original volume
Volume sediment
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
Sedimentation Volume
V = Vu /V0 ; ideally, V should be equal to 1.0
Sedimentation
Stokes law:
Take care:
- Wetting particles (contact angle)
- Shape of the particles (compare: parachute)
- High particle concentration
- Non-Newtonian liquids (yield stress)
- Convection by differences in temperature
18q
d
2
(
s
-
f
)g
v =
Improvement of stability
- Decreasing particle size, d
- Decreasing difference in density,|
s
-
f
|

- Increasing viscosity, q
Stokes law:
18q
d
2
(
s
-
f
)g
v =
B. Amsden CHEE 440
Formulation of Suspensions
2 common approaches :
1.use of a structured vehicle
caking still a problem
2.flocculation
no cake formation

less common approach is to combine
above
B. Amsden CHEE 440
Controlled Flocculation
electrolytes
most widely used
reduce zeta potential
decrease force of repulsion
change pH
bridge formation
alcohol
reduction in zeta potential
surfactants
form adsorbed monolayers on particle surface
efficacy is dependent on charge, concentration
B. Amsden CHEE 440
Controlled Flocculation
polymers
adsorb to particle surface
bridging
viscosity, thixotropy
protective colloid action
most effective
B. Amsden CHEE 440
Structured Vehicles
pseudoplastic or plastic dispersion
medium
examples
methylcellulose, bentonite
negatively charged
increase viscosity
B. Amsden CHEE 440
Combined Approach
possibility of incompatibilities of
suspending agent and flocculating
agent
structured vehicles have negative
charge
incompatible if particle carries a
negative charge

B. Amsden CHEE 440
Preparation of Suspensions
reduce drug powder to desired size
add drug and wetting agent to solution
prepare solution of suspending agent
add other ingredients
electrolytes, color, flavor
homogenize medium
package
Pertimbangan Rheologi
Prinsip rheologi bisa diterapkan untuk
penyelidikan dari factor-faktor berikut :
viskositas dari suatu suspensi apabila
mempengaruhi pengendapan dari partikel-
partikel zat terdispersi
perubahan dalam sifat-sifat aliran dalam
suspensi bila wadahnya dikocok dan dituang
dari botol
kualitas penyebaran dari cairan (lotio) bila
digunakan untuk suatu bagian permukaan
yang akan diobati
pembuatan suspensi
Thixotropic suspension
A thixotropic suspension is the one which is viscous
during storage but loses consistency and become
fluid upon shaking.
A 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.
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
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.

dispersion
B phase
A phase Emulsion solution
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.
O/W
W/O
Types of emulsions
W/O/W O/W/O
Internal
phase
External
phase
oil-in-water water-in-oil
Water in-
oil-in-water
Oil-in-water-
in-oil
Internal
phase
External
phase
Basic types
multiple
Types of Emulsion
Oil-in-water emulsion
Water-in-oil emulsion
Water
Oil
m
Multiple Emulsions
Water-in-oil-in-water emulsion Oil-in-water-in-oil emulsion
Water
Oil
m
Instability emulsions
Sedimentation Floating
Combined with coalescence
cracking of breaking
Possibly combined with floccu-
lation (secondary minimum)
Sedimentation Creaming
Settling & Creaming
Stokes Law





v
Stability
Particles need to come into contact
(collide) to coalesce
Therefore, higher concentrations
(via settling) promote coalescence
or caking
Schematic of the emulsion breakdown
processes.
Contoh Soal
Suatu emulsi o/w mangandung minyak
mineral dengan BJ 0,9 terdispers dalam suatu
fase air yang mempunyai BJ 1,05. Jika
partikel minyak mempunyai diameter rata-
rata 5 m, fase luar mempunyai viskositas
0,5 poise berapakah kecepatan creaming
dalam cm per hari ?
Physical Stability -> Phase Separation

Phases separation starts with growth in particle size
Physical contact -> first step in coalescence
Flocculation and aggregation
Come together but do not fuse
No disruption of interface
Surfactants slow process
Fusion of particles -> next step

Coalescence
Come together & fuse
Disruption of interface
Surfactants slow process

Phase separation (final endpoint)
Result of continued coalescence
Surfactants adsorb at interfaces Interfacial energy decreases
(interfacial energy: energy required to create new interface)
Improvement stability emulsions
hydrophobic
hydrophilic
oil
water
Emulsification
Emulsifier
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.

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
Viscositas dari fase luar dapat ditingkatkan tanpa
melewati batas-batas konsistensi yang dapat diterima
dengan menambah suatu zat pengental (viscosity
improver atau thickening agent)

Ukuran partikel dari bola-bola bisa dikurangi dengan
menghomogenkannya.
Ini merupakan dasar untuk kestabilan terhadap creaming
dari corpus yang homogen.
Stability
Phase Inversion O/W W/O
Change water washable, etc.
E.g. divalent salts Ca++, Mg++ in hard water









Inversi juga bisa dihasilkan dengan mengubah perbandingan
dengan penambahan volume fase internal.

Sifat Rheologi Emulsi
Kebanyakan emulsi, kecuali emulsi encer,
menunjukkan aliran Non Newton

Faktor-faktor prinsip yang mempengaruhi sifat-sifat
aliran dari emulsi adalah sifat viskositas yang
berhubungan dengan fase terdispers, fase kontinu
dan zat pengemulsi


Faktor-faktor yang berhubungan dengan fase terdispers :
perbandingan volume fase
distribusi ukuran globul
viskositas dari fase dalam itu sendiri

Jika konsentrasi volume fase terdispers rendah (< 0,05), system
tersebut adalah Newton.

Dengan naiknya konsentrasi volume, system tersebut menjadi
lebih tahan terhadap aliran dan menunjukkan karakteristik
aliran pseuodoplastik.

Pada konsentrasi yang cukup tinggi, terjadi aliran plastis.

Jika konsentrasi volume mendekati 0,74 mungkin terjadi inversi
dengan berubahnya viskositas secara nyata.
Pengurangan ukuran partikel rata-rata akan
menaikkan viskositas.
Makin luas distribusi ukuran partikel, makin rendah
viskositasnya jika dibandingkan dengan system yang
memiliki ukuran partikel rata-rata serupa tetapi dengan
distribusi ukuran partikel yang lebih sempit.

Makin tinggi konsentrasi zat pengemulsi, akan makin
tinggi pula viskositas produk tersebut.
Example:
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.
v = 2r
2
(D - d) g/9n
n= 2r
2
(D - d) g/9v
= 2 (0.2)(0.2) [2.33 - 1.33] 980/9(4.35)
= 2.0 poise

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.
v = 2r
2

(D - d) g/9n
= 2 (5.5*10
-4
)(5.5*10
-4
)(1.96 - 0.977)
*980/9(0.00895)
= 7.1*10
-3
cm/sec.

If the height of the bottle is 10 cm
how long will it take to completely
settle?
1/x = 7.1*10
-3
/10
x = 1408 sec = 23.5 appprox. 24
minutes
It sediment too fast. Increase viscosity
to reduce the sedimentation.
Particle size determination:
From the previous example, calculate the
average particle size of sulfur.
v = 2r
2
(D - d) g/9n
r
2
= v9n /2 (D - d) g
= (0.0071)(9)(0.00895)/2(1.96 -
0.997)980
r = 5.5*10
-4
cm
diameter = 11*10
-4
cm
What is the necessary viscosity to reduce the
sedimentation rate from 0.0071 cm/sec to
0.00071 cm/sec?
v = 2r
2
(D - d) g/9n
= 2r
2
(D - d)g/9v
= 2 (5.5*10
-4
)
2
(1.96 - 0.997)(980)
/9(0.00071)
= 0.0894 poise