SUSPENSI

Teuku Nanda Saifullah Sulaiman

Laboratorium Teknologi Formulasi
Fakultas Farmasi UGM
 Definisi
• Suatu sediaan cair yang berisi suatu partikel solid
yang tidak larut dan terdispersi dalam suatu fase
cair.

• A Pharmaceutical suspension is a coarse

dispersion in which internal phase is dispersed
uniformly throughout the external phase.

• Suspensions are a class of dispersed system in

which a finely divided solid is dispersed
uniformly in a liquid dispersion medium (Nash
1988).
• The internal phase consisting of insoluble solid
particles having a specific range of size which is
maintained uniformly through out the suspending
vehicle with aid of single or combination of
suspending agent.

• The external phase (suspending medium) is generally

aqueous in some instance, may be an organic or oily
liquid for non oral use.

• Suspensions can be classified as coarse or colloidal

dispersion, depending on the size of particles.
• A wide variety of pharmaceutical preparations
have been used as suspensions, for example,
White Lotion, Magma of Bismuth, and
Compound Mixture of Opium and Glycyrrhiza
(Brown Mixture).
• In addition, several official ointments are
suspensions of solids in a semisolid base.
• A large number of suspensions are categorized
as mixtures in the United States Pharmacopeia
and the National Formulary.
Classification
1. Based On General Classes
– Oral suspension
– Externally applied suspension
– Parenteral suspension
2. Based On Proportion Of Solid Particles
– Dilute suspension (2 to10%w/v solid)
– Concentrated suspension (50%w/v solid)
3. Based On Electrokinetic Nature Of Solid Particles
– Flocculated suspension
– Deflocculated suspension
4. Based On Size Of Solid Particles
– Colloidal suspension (< 1 micron)
– Coarse suspension (>1 micron)
– Nano suspension (10 nm)
 Advantages And Disadvantages
Advantages
• Suspension can improve chemical stability of certain drug. E.g.Procaine penicillin G
• Drug in suspension exhibits higher rate of bioavailability than other dosage forms.
bioavailability is in following order,
Solution > Suspension > Capsule > Compressed Tablet > Coated tablet

• Duration and onset of action can be controlled. E.g.Protamine Zinc-Insulin

suspension
• Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol

Disadvantages
• Physical stability,sedimentation and compaction can causes problems.
• It is bulky sufficient care must be taken during handling and transport.
• It is difficult to formulate
• Uniform and accurate dose can not be achieved unless suspension are packed in
unit dosage form
 Features Desired In Pharmaceutical Suspensions
• The suspended particles should not settle rapidly and
sediment produced, must be easily re-suspended by the use
of moderate amount of shaking.
• It should be easy to pour yet not watery and no grittiness.
• It should have pleasing odour, colour and palatability.
• Good syringeability.
• It should be physically, chemically and microbiologically
stable.
• Parenteral/Ophthalmic suspension should be sterilizable.
The following can be the reasons for the formulation of
a pharmaceutical suspension:

– The drug is insoluble in the delivery vehicle.

– To mask the bitter taste of the drug.
– To increase drug stability.
– To achieve controlled/sustained drug release.
 Applications
• Suspension is usually applicable for drug which is
insoluble or poorly soluble. E.g.Prednisolone
suspension

• To prevent degradation of drug or to improve

stability of drug. E.g. Oxytetracycline suspension

• To mask the taste of bitter of unpleasant drug.

E.g. Chloramphenicol palmitate suspension
• Suspension of drug can be formulated for topical
application e.g. Calamine lotion

• Suspension can be formulated for parentral

application in order to control rate of drug
absorption.

• Vaccines as a immunizing agent are often

formulated as suspension.E.g. Cholera vaccine

• X-ray contrast agent are also formulated as

suspension. E.g. Barium sulphate for examination of
alimentary tract
 Berbagai bentuk sediaan suspensi untuk
penghantaran obat

• Suspensi konvensional
• Sustained Release Suspensions
• Emulsions
• Colloidal Dispersions
– Micelles
– Microemulsions
– Nanosuspensions
– Liposomes
– Nanoparticles
– Microspheres
• Velocity of sedimentation expressed by Stoke’s equation

Where, vsed. = sedimentation velocity in cm / sec

d = Diameterof particle
r = radius of particle
ρ s= density of disperse phase
ρ o= density of disperse media
g = acceleration due to gravity
η o = viscosity of disperse medium in poise
Pertimbangan-pertimbangan yang penting
dalam memformulasi suspensi
1. Nature of suspended material
– Particles that have low interfacial tension are
easily wetted by water and there fore can be
suspended easily.
– Particles of materials with high interfacial
tension, however, are not easily wetted.
2. Size of suspended particles
– The particle diameter in a suspension is usually greater
than 0.5 m.
– Reduction of particle size leads to a decrease in the rate
of sedimentation
– Particle size also affects rate and extent of absorption,
dissolution, and biodistribution of the drug
– reducing particle size beyond a certain limit may lead to
formation of a compact cake upon sedimentation.
– suspensions may have smaller particles than 0.5 m and
may show some characteristics typical to colloidal
dispersions, such as Brownian movement
3. Viscosity of the dispersion medium
– Greater viscosity of dispersion medium offers the
advantage of slower sedimentation
– it may compromise other desirable properties such as
syringability for parenteral suspensions, spreadability for
topical suspensions, ease of administration for oral
suspensions
 An ideal suspension formulation
• Insoluble particles should be uniformly dispersed.
• Suspension should redisperse uniformly in the continuous
phase, upon moderate shaking
• Correct amount of medication with minimal dose variation.
• The rate of settling can be decreased by using viscosity
improving agents,
• Ease of redispersibility can be controlled by using flocculating
agents.
• The suspended particles should be small, uniformly sized to
give a smooth elegant product free from grittiness.
 Interfacial Properties
• Surface Free Energy

Where
G = increase in surface free energy,
 A = increase in surface area,
 = interfacial tension between the solid articles and the dispersion medium.

The smaller the DG is, the more thermodynamically stable is

the suspension
• Therefore, a system with very fine particles is
thermodynamically unstable because of high total surface
area.

• Thus, the system tends to agglomerate in order to reduce the

surface area and thereby the excess free energy.

• When a wetting agent is added to the suspension formulation,

it is adsorbed at the interface. This will result in a reduction of
the interfacial tension, making the system more stable.
• Surface Potential
– Surface potential exists when dispersed solid particles in a
suspension possess charge in relation to their surrounding
liquid medium.

– Solid particles may become charged through different

ways

– the surface active agents, which are already adsorbed at

the solid–liquid interface, may ionize to give the particles
positive or negative charge.

– Sodium dodecyl sulfate (SDS), for example, is anionic in

aqueous medium.

– Solid particles can also be charged by ionization of

functional group of the particles.
Electric Double Layer
• When dispersed particles are in contact with an aqueous
solution of an electrolyte, the particles may selectively adsorb
one charge species.

• If the adsorbed species is an anion, the particles will be

overall negatively charged.

• The ions that give the particle its charge, anions in this case,
are called potential-determining ions or co-ions.

• Remaining ionic species in the solution are the rest of the

anions and the total number of cations added.

• This means, there will be excess cations than anions in the

dispersion medium. These cations having a charge opposite to
that of the potential-determining ions are known as counter-
ions or gegenions.
 Nernst and Zeta Potentials
• The electric double layer is formed in order to neutralize the
charged particles in a suspension.

• The difference in electric potential between the actual or true

surface of the particle and the electroneutral region is
referred to as the surface or electrothermodynamic or Nernst
potential (E)

• Hence, Nernst potential is controlled by the electrical

potential at the surface of the particle due to the potential
determining ions.

• The potential difference between the shear plane and the

electroneutral region is known as the electrokinetic or zeta (z)
potential
Variation in concentration of cations and anions with distance
from a negatively charged suspended particle
The relationship between Nernst and zeta potentials
• While Nernst potential has little influence in the
formulation of stable suspension, zeta potential has
significant effect on it

• Zeta potential governs the degree of repulsion

between adjacent, similarly charged solid dispersed
particles.
• If the zeta potential is reduced below a certain value,
which depends on the specific system under
investigation, the attractive forces between particles
due to van der Waals’ force, overcome the forces of
repulsion and the particles come together to form
floccules.
• This phenomenon is known as flocculation.
 Wetting
• Low adhesion of hydrophobic powders materials
occurs due to high interfacial tension between the
powders and the dispersion medium.

• Because of this tension, the contact angle between

the solid and liquid phases remains very high.

• By using surface active agents, the interfacial tension

can be lowered to decrease the contact angle,
resulting in good wetting.

• Wetting of solids can be determined by using Young’s

equation:
• Some insoluble solids are not easily wetted by
water and thus need wetting agents to be able
to disperse readily throughout the medium.

• Some wetting agents include surfactants,

hydrophilic colloids, and solvents.

• Surface active agents or surfactants

possessing HLB value between 7 and 9 are
suitable as wetting agents.
• Most surfactants are used at concentrations of 0.1%.

• For oral use Tweens and Spans are commonly used, while
sodium lauryl sulphate (SLS) is used for external
applications.

• Some wetting agents may cause foaming and formation of

deflocculated systems.

• Hydrophilic colloids like acacia, bentonite, tragacanth,

alginates, and cellulose derivatives function as a protective
colloid by coating the surface of the particles and thus
imparting hydrophilic character to the solid particles.

• Solvents such as alcohol, glycerol, and glycols are water-

miscible and reduce the liquid/air interfacial tension,
increasing wetting.
 DLVO Theory (Derjaguin,Landau, Verwey and Overbeek)
• Particle collision in a suspension preparation may occur due to
Brownian motion or differential sedimentation rates

• The consequence of collision would be either the formation

of aggregates or redispersion of the particles.

• zeta potential plays a very important role in suspension

stability.
• A minimum, known as the critical zeta potential, is required to
prepare a stable suspension.

• A system with low critical zeta potential indicates that only a

minute charge is required for stabilization
• The precipitation of suspension can be brought
about by adding electrolytes.

• The precipitating power increases rapidly with the

valence of the ions.

According to this theory, the potential energy of interaction

between particles, VT is the result of repulsion due to
electrical double layer, VR and attraction due to van der
Waals’ force, VA and can be shown by
•Peningkatan energi pada jarak dekat 
peningkatan daya tolak menolak
•Energi total positif  peningkatan daya tolak
menolak
•Energi total negatif  peningkatan daya tarik
menarik

Net energy of interaction between two particles as a function of

interparticulate distance 35
 • VR >> VA = the dispersion will be highly stable because of the
high net repulsive force.
• This dispersion is resistant to aggregation (i.e., flocculation or
coagulation) as long as the particles do not sediment under
gravity.
• VA >> VR = rapid aggregation

In addition to electric stabilization, steric stabilization can also be applied

to prepare a stable dispersion. Substances such as nonionic surfactants, when
adsorbed at the particle surface, can stabilize a dispersion, even when there is no
significant zeta potential.

VS = Steric stabilization
 Flocculation and Deflocculation
• Flocculated systems result in rapid rate of
settling because each individual unit is
composed of many particles and is therefore
larger.
• However, due to the loose packing of flocs
they are easily dispersible on shaking.
• Deflocculated systems on the other hand are
made up of smaller particles whose settling
rate is slower, but the settled particles tend to
form an irreversible compact and are difficult
to redisperse.
• This phenomenon is called caking
• For coarse suspensions, a deflocculated
suspension will have better uniformity of dose
but poorer stability due to formation of cake
• a stable suspension is obtained by preparing a
partially flocculated suspension with controlled
viscosity so that settling is minimal.
• Controlled flocculation is achieved by a
combination of particle size control,electrolytes
to control zeta-potential and by the addition of
polymers.
• Inorganic electrolytes, added to an aqueous
suspension alter the zeta-potential of the
dispersed particle.
Degree of flocculation (β)
• Lowering the zeta-potential sufficiently will result
in flocculation.
• Some of the commonly used electrolytes include
sodium salts of acetates, phosphates, and citrates
• Use of ionic surfactants may also result in
flocculation by neutralization of particle charges.
• Starch, alginates, tragacanth, and cellulose
derivatives are sometimes added to control the
degree of flocculation so that the suspension is in
a flocculated state and the sedimentation volume
is large.
• Suspensions should exhibit high viscosity at low
shear rate

• Also, the viscosity should be low enough to be

poured from the container but should spread
evenly, if it is intended for external application.

• Suspensions for injection should be able to

pass through hypodermic needles.
• Acacia gum is used as a thickening agent for
extemporaneously prepared suspensions.

• Tragacanth forms viscous aqueous solutions,

and its thixotropic and pseudoplastic
properties make it a better thickening agent
than acacia.

• Sodium alginate is used as a suspending agent

but is incompatible with cationic materials.
• Several cellulose derivatives, such as
methylcellulose (Celacol), hydroxyethylcellulose
(Natrasol 250), sodiumcarboxymethylcellulose,
and microcrystalline cellulose, disperse in water
to produce viscous colloidal solutions and are
suitable, as suspending agents.
• Buffers are included in suspensions to
maintain chemical stability and control
tonicity.
• Flavors, colors, and perfumes may be added to
improve palatability and appearance of the
product.
• Humectants like glycerol and propylene glycol
are added in concentrations of 5% for external
applications to prevent the product from
drying out after application to the skin.
• Addition of preservatives is important,
particularly when using naturally occuring
adjuvants.

• In some situations sweeteners may be added but

their affect on final product viscosity and degree
of flocculation should be well understood.
 METODE PEMBUATAN
• Suspensions are manufactured by:
– precipitation methods
– dispersed methods
• Suspensions are normally manufactured using
colloidal mills
PREPARATION OF SUSPENTION
(on laboratory or small pilot batch)
1. Drug dispersion
2. Preparation of structure vehicle and addition
of drug
3. Addition of other formula adjuncts
4. Deaeration, followed by making up to final
volume
5. Homogenization
6. In-process testing
7. Transfer and filling
1. Drug dispersion
Untuk memudahkan dispersi, bahan aktif ditambah
larutan pekat wetting agent dlm sedikit pembawa
gunakancolloid mill utk pembasahan optimal

Alkohol atau gliserin dapat digunakan pada tahap

awal pendispersian partikel untuk membantu penetrasi
pembawa kedalam massa serbuk

Atau bahan aktif didispersikan dgn cara menambahkan

perlahan-lahan kedalam air atau sistem air-gliserin
mengandung wetting agent
2. Preparation of structure vehicle and addition
of drug dispersion

structure vehicle : aqueous solution of suspending

agent ; hydrocolloid, polysaccharide, clay atau
kombinasinya
3 Addition of other formula adjunct :
Bahan tambahan lain spt chelating agent, antioxidant,
humectan, preservative, color, fragrance:
- Dapat langsung ditambahkan kedlm pembawa atau
- Dilakukan presolubilized dlm cosolvent yg tepat
Waktu dan suhu pencampuran tgt sifat fisika-kimia
Fragrance ditambahkan terakhir dan suhu sudah dingin
4. Deaeration, followed by making up to final
volume
Tiap bacth diproses melewati deaerating
equipment sblm diadkan.
Suspensi dgn udara yg terjebak dlm jumlah
besar tidak aseptabel secara farmasetik, dpt
mempengaruhi sifat reologi, dosis, warna, BJ,
volume
5. Homogenization
Terakhir, suspensi dilewatkan colloid mill atau
homogenizer untuk mengecilkan ukuran
partikel yang beraglomerasi

6. In-process testing
untuk menjamin kualitas produk pada setiap
langkah yang dilakukan
7. Transfer and filling

Sediaan dipindahkan ke storage /holding tank

untuk pengisian sesudah memenuhi in
process spesification.

Sediaan tidak boleh mengalami perubahan

kimia,fisika dan mikrobiologi setelah proses
pemindahan dan pengisian
 Kontrol kualitas
• Ukuran partikel dan distribusi ukuran partikel
• Homogenitas
• Viskositas
• pH
• Disolusi
• effectiveness of preservative
• Kecepatan pengendapan
• Kemudahan penuangan
• Redispersibilitas
• Sterilitas (untuk tujuan tertentu)
Sedimentation volume (F) or height (H) for flocculated
suspensions
F = V u / VO
Where,
Vu = final or ultimate volume of sediment
VO = original volume of suspension before settling.
Sedimentation volume is a ratio of the final or ultimate
volume of sediment (Vu) to the original volume of sediment
(VO) before settling.
Similarly when a measuring cylinder is used to measure the
volume
F= H u/ HO
Where,
Hu= final or ultimate height of sediment
H O = original height of suspension before settling
• Sedimentation volume can have values ranging from less
than 1 to greater than1; F is normally less than 1.
F=1, such product is said to be in flocculation equilibrium.
And show no clear Supernatant on standing Sedimentation
volume (F¥) for deflocculated suspension
F ¥ = V¥/ VO
Where,
F¥ = sedimentation volume of deflocculated suspension
V¥ = sediment volume of completely deflocculated
suspension.
(Sediment volume ultimate relatively small)
VO= original volume of suspension.