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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)
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Suspensions
Colloids:
Particle size: 1 nm - 1 mm
No sedimentation by Brownian movement
Suspensions:
Particle size: > 1mmSedimentation
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Suspensions
Pharmaceutical suspensions are uniform dispersions
of solid drug particles in a vehicle in which the drughas 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 withflavored, sweetened vehicles or powder productsfor oralsuspension
Marketed preparations: ready-to-use dry powders which must be reconstituted before
administration
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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
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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
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B. Amsden CHEE 440
Electrical Properties
particles may become charged byadsorption of ionic species present in soln or
preferential adsorption of OH-
ionization of -COOH or -NH2 group
-----
-solid
+++++
+ hydroxyl ion
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B. Amsden CHEE 440
Electric Double Layer
--
----
++
++++
+
-+
+-
+ --
++
-
+-- ++ -
+
+
gegenion
Nernst potential
zeta potential
tightly
bounddiffuse
electroneutralbulk
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Electrical Double Layer
Surface charge
----
-
---+
+
++
Stern layer (fixed)Zeta potential
Nernst potential
Electroneutral solution
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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
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What are colloids? Colloids are particles of a few mm 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
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If all the particles have a
large negative or positivezeta potential, they willrepel each other becauseof electrostatic repulsionforces -- stable dispersion
Negativezeta potential
Positivezeta potential
+30 mV
-30 mV
0 mV
STABLE
STABLE
NOT STABLE
Zeta Potential and Dispersion Stability
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Zeta Potential & Dispersion Stability
If all the particles have a large negative orpositive zeta potential, they will repel each other
because of electrostatic repulsion force ----
stable dispersion
In general, the higher the zeta potential, the morestable the particle dispersion. The dividing lines
for aqueous dispersion is considered to be
>+30mV or
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Desirable Features
particles should settle slowly
formulation should allow the easyredispersion of sedimented particles
a flocculated suspension is desirablethan a deflloculated suspension
a suspension should not be too viscousto reduce the sedimentation rate
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Well Formulated Suspension
Resuspend easily upon shaking
Settle slowly after shaking
Homogeneous mix of drugPhysicallyand chemically stable during its shelf
life
Sterile (parenteral, ocular) Gets into syringe (parenteral, ocular)
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Untuk cairan obat luar :
Produk tersebut harus cukup cair sehingga dapattersebar dengan mudah ke seluruh daerah yangsedang diobati tapi juga tidak boleh sedemikianmudah bergerak sehingga gampang hilang dari
permukaan dimana obat tersebut digunakan Cairan tersebut harus dapat kering dengan cepat
dan membentuk suatu lapisan pelindung yangelastis sehingga tidak akan mudah terhapus
Mempunyai warna dan bau yang nyaman
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Untuk tujuan farmasi :
Kestabilan fisik suspensi didefinisikan sebagaitidak menggumpal tetap terdistribusi merata diseluruh system.
Karena kondisi ini jarang terjadi maka dapatdikatakan, jika partikel-partikel tersebutmengendap, maka partikel-partikel tersebut harusmudah disuspensi kembali dengan sedikit
pengocokan.
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Pengendapan dalam suspensi
Physical stability
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Theory of Sedimentation
The factors involved in the rate of velocity of settlingof the particles in a suspension are best expressed inthe equation of the Stokes law
Stokes equation applies to uniform, perfectly
spherical particles settling in a very dilute suspensionwith no hindrance or turbulance
FACTORS TO BE CONSIDERED Particle size
Density of the vehicle- -polyethylene glycol -polyvinyl pyrolidone -glycerin -sorbitol -sugar.
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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
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Stokes Law
= kecepatan akhir
(cm/dt)
d= diameter partikel sdano= kerapatan
fase terdisper danmedium pendispersi
o= viskositas medium
pendispersi (poise)
v Stability
Particles need to comeinto contact (collide) to
coalesce Therefore, higher
concentrations (viasettling) promotecoalescence or caking
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External Forces Acting onParticles
V(-o)g
2-5 mm
Gravity Brownian Movement
Sedimentationequilibrium:Gravity isneutralized byBrownian movement
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Calculations
Determine the absolute viscosity of syrupusing a ball of radius of 0.2 cm. The densityof the ball is 2.33g/cc and the density of thesyrup is 1.33 g/cc at 250 C. The rate of fallingis 4.35 cm/sec.
Determine the velocity of settling of sulfur inwater. The average particle radius is 5.5 m.The density of sulfur and water at 250 C. is1.96 and 0.997 g/c.c., respectively. Theviscosity of water at 250 C. is 0.00895 poise.
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Calculations
If the height of the bottle is 10 cm how longwill 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 thesedimentation rate from 0.0071 cm/sec to0.00071 cm/sec?
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State Rate of settling Sedimentation
volume
Nature
Flocculated Fast High Porous, easy toredisperse
Deflocculated Slow Low Compact, difficultto redisperse
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Deflocculated suspension Flocculated suspension
- Low sedimentation rate
- Liquid above sediment
remains turbid (particles of< 1 mm 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 mm sediment)
- Sedimentation is build up
from the top
- Loose sediment easy to
redisperse
Deflocculated is also referred to as peptised
Sedimentation behavior
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Deflocculated suspension Flocculated suspension
Structures sediment
o
u
V
VF==Degree of sedimentation:
Original volume
Volume sediment
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Settling and Aggregation
The suspension shall formloose networks offlocksthat settle rapidly, do not
form cakes and are easyto resuspend.
Settling and aggregation
may result in formation ofcakes(suspension) that isdifficult to resuspend orphase separation
(emulsion)
flock
cake
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Sedimentation Volume
V = Vu /V0 ; ideally, V should be equal to 1.0
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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
18d2(s - f)g
v =
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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 combineabove
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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
ll d l l
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B. Amsden CHEE 440
Controlled Flocculation
polymers
adsorb to particle surface
bridging
viscosity, thixotropy
protective colloid action
most effective
S d hi l
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B. Amsden CHEE 440
Structured Vehicles
pseudoplastic or plastic dispersion
medium
examples
methylcellulose, bentonitenegatively charged
increase viscosity
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B. Amsden CHEE 440
Combined Approach
possibility of incompatibilities of
suspending agent and flocculatingagent
structured vehicles have negativecharge
incompatible if particle carries anegative charge
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Pertimbangan Rheologi
Prinsip rheologi bisa diterapkan untukpenyelidikan dari factor-faktor berikut :
viskositas dari suatu suspensi apabilamempengaruhi pengendapan dari partikel-partikel zat terdispersi
perubahan dalam sifat-sifat aliran dalamsuspensi bila wadahnya dikocok dan dituangdari botol
kualitas penyebaran dari cairan (lotio) biladigunakan untuk suatu bagian permukaanyang akan diobati
pembuatan suspensi
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Emulsions
Dispersed system - two immiscible liquid phases,one of which is dispersed as globules in theother o/w - oleaginous internal phase and an aqueous
external phase
w/o - aqueous internal and an oleaginous externalphase
Microemulsion: Droplets size range 0.01 to 0.1m
Macroemulsion: Droplets size rangeapproximately 5 m.
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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.
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O/W W/O
Types of emulsions
W/O/W O/W/O
Internalphase
Externalphase
oil-in-water water-in-oil
Water in-oil-in-water
Oil-in-water-
in-oil
Internalphase
Externalphase
Basic types multiple
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Types of Emulsion
Oil-in-water emulsion Water-in-oil emulsion
Water
Oil
mm
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Multiple Emulsions
Water-in-oil-in-water emulsion Oil-in-water-in-oil emulsion
Water
Oil
mm
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Instability emulsions
Sedimentation Floating
Combined with coalescence
cracking of breaking
Possibly combined with floccu-
lation (secondary minimum)
Sedimentation Creaming
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Settling & Creaming
Stokes Law
v Stability
Particles need to come into contact(collide) to coalesce
Therefore, higher concentrations(via settling) promote coalescenceor caking
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Schematic of the emulsion breakdownprocesses.
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Contoh Soal
Suatu emulsi o/w mangandung minyakmineral dengan BJ 0,9 terdispers dalam suatufase air yang mempunyai BJ 1,05. Jikapartikel minyak mempunyai diameter rata-
rata 5 m, fase luar mempunyai viskositas0,5 poise berapakah kecepatan creamingdalam cm per hari ?
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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
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Surfactants adsorb at interfaces Interfacial energy decreases(interfacial energy: energy required to create new interface)
Improvement stability emulsions
hydrophobic
hydrophilic
oil
water
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Emulsification
Emulsifier
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Theories of Emulsification:
1) Surface Tension Theory:- lowering of interfacial tension.
2) Oriented-Wedge Theory:
- mono molecular layers of emulsifying agentsare curved around a droplet of the internalphase of the emulsion.
3) Interfacial film theory:
- A film of emulsifying agent prevents thecontact and coslescing of the dispersedphase.
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Surfactants and Micelles
Surface active agents have a certain affinity for bothpolar & nonpolar solvents
Amphiphilic nature adsorb at interfaces
At a concentration that is characteristic of eachamphiphile, these molecules will aggregate to producemicelles
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Viscositas dari fase luar dapat ditingkatkan tanpamelewati batas-batas konsistensi yang dapat diterimadengan menambah suatu zat pengental (viscosityimprover atau thickening agent)
Ukuran partikel dari bola-bola bisa dikurangi denganmenghomogenkannya.
Ini merupakan dasar untuk kestabilan terhadap creamingdari corpus yang homogen.
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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 perbandingandengan penambahan volume fase internal.
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Sifat Rheologi Emulsi
Kebanyakan emulsi, kecuali emulsi encer,menunjukkan aliran Non Newton
Faktor-faktor prinsip yang mempengaruhi sifat-sifataliran dari emulsi adalah sifat viskositas yangberhubungan dengan fase terdispers, fase kontinu
dan zat pengemulsi
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Pengurangan ukuran partikel rata-rata akanmenaikkan viskositas.
Makin luas distribusi ukuran partikel, makin rendahviskositasnya jika dibandingkan dengan system yangmemiliki ukuran partikel rata-rata serupa tetapi dengandistribusi ukuran partikel yang lebih sempit.
Makin tinggi konsentrasi zat pengemulsi, akan makintinggi pula viskositas produk tersebut.
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Example:
Determine the absolute viscosity of syrup using a
ball of radius of 0.2 cm. The density of the ball is2.33g/cc and the density of the syrup is 1.33 g/cc at250 C. The rate of falling is 4.35 cm/sec.
v = 2r2 (D - d) g/9n
n= 2r2 (D - d) g/9v
= 2 (0.2)(0.2) [2.33 - 1.33] 980/9(4.35)
= 2.0 poise
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If the height of the bottle is 10 cmhow long will it take to completelysettle?
1/x = 7.1*10-3/10
x = 1408 sec = 23.5 appprox. 24minutes
It sediment too fast. Increase viscosityto reduce the sedimentation.
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Particle size determination:
From the previous example, calculate theaverage particle size of sulfur.
v = 2r2 (D - d) g/9n
r2= 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
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What is the necessary viscosity to reduce thesedimentation rate from 0.0071 cm/sec to0.00071 cm/sec?
v = 2r2 (D - d) g/9n
= 2r2 (D - d)g/9v
= 2 (5.5*10-4)2 (1.96 - 0.997)(980)/9(0.00071)
= 0.0894 poise