Pharmaceutical suspension

Delivered by Sabtanti Harimurti, Ph.D., Apt

Translation of Nahla S. Barakat, Ph.D ppt

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 Definition
• Suspensi Farmasi adalah dispersi kasar dimana fase internal
tersebar merata di seluruh fase eksternal.

• Fase internal terdiri dari partikel padat tidak larut. Memiliki

rentang ukuran tertentu dan seragam di seluruh
pembawanya (fase eksternal) dan terdistribusi merata
dengan bantuan zat pensuspensi tunggal atau kombinasi.

• Fase eksternal (pembawa/medium) umumnya berair,

contohnya, cairan organik atau minyak untuk penggunaan
non oral.
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 Classification
• Based On General Classes
Oral suspension
Externally applied suspension
Parenteral suspension
• Based On Proportion Of Solid Particles
Dilute suspension (2 to10%w/v solid)
Concentrated suspension (50%w/v solid)
• Based On Electrokinetic Nature Of Solid Particles
Flocculated suspension
Deflocculated suspension
• Based On Size Of Solid Particles
Colloidal suspension (< 1 micron)
Coarse suspension (>1 micron)
Nano suspension (10 ng)

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 Advantages

• Suspensi dapat meningkatkan stabilitas kimia obat tertentu. Misalnya

Penisilin prokain G (suspensi untuk IM long action).
• Obat dalam suspensi menunjukkan tingkat bioavailabilitas yang lebih
tinggi dibandingkan bentuk sediaan lainnya, urutan bioavailabilitas
sebagai berikut,
Solution > Suspension > Capsule > Compressed Tablet > Coated
tablet
Durasi dan onset kerja dapat dikendalikan. Misalnya Suspensi Protamine
Zinc-Insulin.
 Suspensi dapat menutupi rasa pahit obat. Misalnya kloramfenikol
palmitat

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 Disadvantages

• Stabilitas fisik, sedimentasi dan pemadatan dapat

menyebabkan masalah.
• Pengelolaan yang memadai harus dilakukan selama
penanganan dan transportasi.
• Sulit untuk diformulasikan.
• Dosis seragam dan akurat tidak dapat dicapai kecuali
suspensi dikemas dalam bentuk satuan dosis

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 Features Desired In Pharmaceutical Suspensions
• Partikel-partikel yang tersuspensi seharusnya tidak
mengendap dengan cepat dan menghasilkan sedimen, dan
harus mudah kembali pengojogan yang ringan.
• Mudah untuk dituang.
• Harus berbau dan berwarna yang baik.
• Good syringeability (bisa diinjeksikan  untuk sediaan
injeksi).
• Harus stabil secara fisika, kimia dan mikrombiologi.
• Untuk parental/ophthalmic suspension harus disterilkan.

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 Applications

 Suspensi biasanya berlaku untuk obat yang tidak larut atau sukar larut. Misalnya

prednisolon .

 Suspensi Untuk mencegah degradasi obat atau untuk meningkatkan stabilitas obat.

Misalnya suspensi oxytetracycline.

 Untuk menutupi rasa pahit obat tidak menyenangkan.? Misalnya Suspensi

Kloramfenikol palmitat .

 Suspensi obat yang diformulasikan untuk aplikasi topikal misalnya Calamine lotion.

 Suspensi dapat diformulsikan untuk aplikasi injeksi IM untuk mengontrol tingkat

penyerapan obat, Eg penisilin prokain.

 Vaksin sebagai agen imunisasi sering diformulasikan sebagai suspensi.? Misalnya

vaksin kolera.

 X-ray agen kontras juga diformulasikan sebagai suspensi.? Misalnya Barium sulfat
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untuk pemeriksaan saluran pencernaan
 Theory of Suspensions
 Sedimentation Behaviour
 Sedimentasi berarti pengendapan partikel atau floccules
yang disebabkan karena gaya gravitasi dalam bentuk sediaan
cair..
 Theory of Sedimentation
 Velocity of sedimentation expressed by Stoke’s
equation
 V= 2r2 (ρ s- ρ o ) g or V= d2 (ρ s- ρ o ) g
9 18

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 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 = viscosity of disperse medium in poise

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  Factors Affecting Sedimentation

 Particle size diameter (d)

Vαd2
 Sedimentation velocity (v) adalah berbanding lurus dengan kuadrat dari diameter particel..

 Density difference between dispersed phase and dispersion

media (ρs - ρo)
 V α (ρ s - ρo)
 Umumnya, berat jenis partikel lebih besar dari media pendispersi tetapi, dalam kasus-kasus
tertentu berat jenis partikel kurang dari fasa pendispersi, sehinggapartikel tersuspensi akan
mengapung & sulit untuk didispersikan secara merata dalam medium pendispersi.
 Jika berat jenis fase terdispersi dan pendispersi adalah sama, laju pengendapan menjadi nol.

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 • Viscosity of dispersion medium (η )
V α 1/ ηo
• Sedimentation velocity adalah berbanding terbalik kepada viscositas
medium pendispersi.
• Jadi peningkatan viskositas medium akan mengurangi pengendapan,
sehingga partikel mencapai sistem dispersi baik tetapi pada
peningkatan viscositas yang lebih besar akan menimbulkan masalah
seperti dalam penuangan, syringibility dan redispersibility dari
suspensi.

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 Advantages and Disadvantages due to viscosity of medium

Advantages
 High viscosity menghambat cristalisasi ( timbulnya kristal).
 High viscosity mencegah transformasi metastable crystal ke stable
crystal.
 High viscosity meningkatkan stabilitas fisika.

Disadvantages
 High viscosity menghambat re-dispersi dari sedimen
 High viscosity menghambat penyerapan obat.
 High viscosity menciptakan masalah dalam penanganan bahan selama
manufaktur.

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 Sedimentation Parameters

Two important parameters are considered:

 Sedimentation volume (F) or height (H) for flocculated

suspensions
 F = V u / VO -------------- (A)
 Where, Vu = final or ultimate volume of sediment
 VO = original volume of suspension before settling.
 Sedimentation volume (F) is a ratio of the final or
ultimate volume of sediment (Vu) to the original volume of sediment (VO) before
settling.
 Sedimentation volume can have values ranging from less than 1 to 1; F is normally less
than 1.
 F=1,such product is said to be in flocculation equilibrium, and show no
clear supernatant on standing

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 Fig.1: Suspensions quantified by sedimentation volume (f)
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 Degree of flocculation (β)

 Merupakan parameter yang sangat berguna untuk flokulasi

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 The Sedimentation Behavior of Flocculated and
Deflocculated Suspensions:

Flocculated Suspensions
Dalam suspensi terflokulasi, terbentuk “flock” (agregat longgar) yang
akan menyebabkan peningkatan laju sedimentasi akibat peningkatan
ukuran partikel. Oleh karena itu, flokulasi suspensi menjadi lebih
cepat.
.
 Di sini, sedimentasi tidak hanya tergantung pada ukuran gumpalan
tetapi juga pada porositas flocks. Dalam suspensi flokulasi struktur
gumpalan longgar berisi sejumlah cairan. Volume sedimen relatif besar
dan mudah didispersikan kembali dengan agitasi.

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 Fig 2: Sedimentation behaviour of flocculated and deflocculated suspensions
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 Deflocculated suspensions

 Dalam suspensi deflocculated, setiap partikel dalam suspensi akan

menetap, sehingga laju sedimentasi lambat yang mencegah penjebakan
medium cair yang membuatnya sulit untuk kembali terdispersi oleh
goncangan.
 Fenomena ini disebut ‘cracking’ atau ‘claying’. Dalam suspensi
deflocculated partikel yang lebih besar turun cepat dan yang lebih kecil
tetap dalam supernatan cair sehingga supernatan nampak berawan,
sedangkan pada suspensi flokulasi, partikel terkecil terlibat juga dalam
flocs, sehingga supernatan tidak nampak berawan.

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 Flocculating Agents
Flocculating agen mengurangi potensi zeta dari partikel
bermuatan yang tersuspensi dan dengan demikian
menyebabkan agregasi (flock formation) partikel-partikel.

Examples of flocculating agents are:

 Neutral electrolytes such as KCl, NaCl.
 Surfactants
 Polymeric flocculating agents
 Sulfate, citrates, phosphates salts

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  Elektrolit Netral misalnya NaCl, KCl selain bertindak
sebagai agen flokulasi, juga menurunkan tegangan antar
muka larutan surfaktan. Jika partikel mempunyai muatan
permukaan yang rendah maka ion monovalen cukup untuk
menyebabkan flokulasi misalnya steroid.

 Untuk partikel yang mempunyai muatan permukaan tinggi

seperti “insoluble polimers dan poly-electrolit sprcies”,
trivalent flocculating agent.

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 Method of Floccules Formation

Methods used to form floccules are :

1 . Electrolytes

 Elektrolit mengurangi barrier listrik antar partikel dan

membawa mereka bersama-sama untuk membentuk
floccules. Elektrolit mengurangi zeta potensi mendekati nilai
nol sehingga menghasilkan jembatan antar partikel yang
berdekatan, akhirnya terbentuk flock yang berstruktur
longgar.

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  Jika kita mendispersikan partikel bismut subnitrate dalam air
kita menemukan bahwa berdasarkan potensi mobilitas
elektroforesis, karena adanya kekuatan tolakan yang kuat
antara partikel yang berdekatan, sistem ini “peptized” atau
“deflocculated”. Dalam pembuatan serangkaian suspensi
subnitrate bismut yang mengandung berbagai konsentrasi
kalium fosfat monobasa “hubungan antara potensi zeta dan
volume sedimentasi, caking, dan flokulasi dapat ditunjukkan
pada gambar berikut.

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 Fig 3: Caking diagram, showing the flocculation of a bismuth subnitrate
suspension by means of the flocculating agent.

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  The addition of monobasic potassium phosphate to the suspended
bismuth subnitrate particles causes the positive zeta potential to
decrease owing to the adsorption of negatively charged phosphate
anion.
 With continued addition of the electrolyte, the zeta potential
eventually falls to zero and then increases in negative directions.
 Only when zeta potential becomes sufficiently negative to affect
potential does the sedimentation volume start to fall.
 Finally, the absence of caking in the suspensions correlates with the
maximum sedimentation volume, which, as stated previously, reflects
the amount of flocculation.

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 2. Surfactants
Surfaktan ionik dan non-ionik dapat digunakan untuk
membuat partikel tersuspensi terflokulasi
 Konsentrasi optimum diperlukan karena senyawa ini juga bertindak
sebagai agen pembasahan untuk mencapai dispersi.
 Konsentrasi optimum surfaktan menurunkan energi bebas permukaan
dengan mengurangi tegangan permukaan antara media cair dan
partikel padat. Hal ini cenderung untuk membentuk “closely packed
agglomerates”.
 Partikel-partikel yang memiliki sedikit energi bebas permukaan
tertarik satu sama lain dengan gaya van der-waals dan membentuk
aglomerat longgar.

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 3. Polymers
Polimer memiliki rantai panjang dalam strukturnya.
EXAMPLE: Starch, alginates, cellulose derivatives, carbomers,
tragacanth
Bagian dari rantai panjang teradsorpsi pada permukaan
partikel dan bagian yang tersisa memproyeksikan keluar ke
media, kemudian menjembatani antara bagian, juga
mengarah pada pembentukan flocs.

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 Viscosity of Suspensions
 Viskositas suspensi sangat penting untuk stabilitas dan pourability suspensi. Seperti

kita ketahui suspensi memiliki stabilitas fisik paling rendah di antara semua bentuk
sediaan karena sedimentasi dan pembentukan cake.

 Sehingga viskositas medium pendispersi meningkat, kecepatan pengendapan

menurun sehingga fasa terdispersi lebih lama dan mereka tetap tersebar untuk waktu
yang lebih lama yang akan menghasilkan stabilitas yang lebih tinggi untuk suspensi.

 Di sisi lain bila viskositas suspensi meningkat, akan menurun pourability dan

meningkat ketidaknyamanan kepada pasien untuk dosis.

 Dengan demikian, viskositas suspensi harus dipertahankan dalam kisaran optimum

untuk menghasilkan suspensi yang stabil dan mudah dituang.

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Different Approaches To Increase The Viscosity
of Suspensions
Various approaches have been suggested to enhance the viscosity
of suspensions. Few of them are as follows:
1. Viscosity Enhancers

 Some natural gums (acacia, tragacanth), cellulose

derivatives (sodium CMC, methyl cellulose),
clays(bentonite, veegum), carbomers, colloidal silicon
dioxide (Aerosil), and sugars (glucose, fructose)
digunakan untuk meningkatkan viscosity medium
pendispersi, yang kemudian dikenal dengan
“suspending agents”.
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 • List of Suspending Agents

• Alginates
• Methylcellulose
• Hydroxyethylcellulose
• Carboxymethylcellulose
• Sodium Carboxymethylcellulose
• Microcrystalline cellulose
• Acacia, Tragacanth, Xanthan gum
• Bentonite
• Carbomer
• Powdered cellulose
• Gelatin

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 2. Co-solvents

 Beberapa pelarut yang memiliki viskositas tinggi

digunakan sebagai co-pelarut untuk meningkatkan
viskositas medium dispersi:Glycerol, propylene
glycol, sorbitol.

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  Sebagian suspending agents memiliki dua fungsi
yaitu: bertugas sebagai suspending agent dan
memelihara viscositas dari solution. Suspending
agents membentuk film disekitar particle sehingga
menurunkan interparticle attraction.
 Suspensi yang baik harus mempunyai sifat thixotropy.
 Pada kondisi didiamkan, suspensi cukup kental untuk
mencegah sedimentasi dan terbentuk flock tetapi,
ketika agitasi diterapkan viskositas berkurang dan
memberikan karakteristik aliran baik dari mulut
botol.
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  Thixotropy

 Thixotropy is defined as the isothermal

slow reversible conversion of gel to sol. Thixotropic
substances on applying shear stress convert to sol
(fluid) and on standing they slowly turn to gel
(semisolid).

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 Other Formulation Aspects
Introduciton

• Suspensi yang sempurna adalah, yang menyediakan keseragaman

konten. Formulator sering menghadapi masalah penting mengenai
distribusi ukuran partikel, luas permukaan spesifik, penghambatan
pertumbuhan kristal dan perubahan bentuk polimorfik. Formulator
harus memastikan bahwa suspensi seharusnya tidak berubah setelah
penyimpanan jangka panjang dan tidak mempengaruhi kinerja
suspensi.
• Pilihan pH, ukuran partikel, viskositas, flokulasi, rasa, warna dan bau
adalah beberapa faktor yang paling penting yang harus dikendalikan
pada saat formulasi.
• Formulation Components: The various components, which are
used in suspension formulation, are as follows.

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  Components Function

API Active drug substances

Wetting agents They are added to disperse solids in continuous

liquid phase.
Flocculating agents They are added to floc the drug particles

Thickeners They are added to increase the viscosity of

suspension.
Buffers They are added to stabilize the suspension to a
and pH adjusting agents desired pH range.
Osmotic agents They are added to adjust osmotic pressure
comparable to biological fluid.
Coloring agents They are added to impart desired color to
suspension and improve elegance.
Preservatives They are added to prevent microbial growth.

External liquid vehicle They are added to construct structure of the final
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suspension.
 Wetting Agents
Bahan hidrofilik mudah dibasahi oleh air sedangkan bahan hidrofobik
tidak. Namun bahan hidrofobik mudah dibasahi oleh cairan non-
polar. Luasnya pembasahan oleh air tergantung pada hydrophillicity
bahan. Ketidakmampuan pembasahan mencerminkan ketegangan
antar muka yang lebih tinggi antara materi dan cair. Ketegangan
antar muka harus dikurangi sehingga udara dipindahkan dari
permukaan padat oleh cairan.

 Non-ionic surfactants are most commonly used as wetting agents in

pharmaceutical suspension. Non-ionic surfactants having HLB value between 7-10
are best as wetting agents. High HLB surfactants act as foaming agents. The
concentration used is less than 0.5 %. A high amount of surfactant causes
solubilization of drug particles and causes stability problem.
• Ionic surfactants are not generally used because they are not compatible with
many adjuvant and causes change in pH.

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 Surfactants
 Surfaktan menurunkan tegangan permukaan antara partikel
obat dan cairan sehingga cairan meresap dalam pori-pori
partikel obat menggusur udara dari partikel obat dan
dengan demikian memastikan pembasahan.
 Surfaktran pada optimum konsentrasi memfasilitasi dispersi
particl. Generally we use non-ionic surfactants but ionic
surfactants can also be used depending upon certain
conditions.
 Disadvantages of surfactants adalah menyebabkan berbusa.
 Selain itu rasanya pahit. Some surfactants such as polysorbate
80 interact with preservatives such as methyl paraben and
reduce antimicrobial activity.
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  All surfactants are bitter except Pluronics and
Poloxamers.
 Polysorbate 80 is most widely used surfactant both
for parenteral and oral suspension formulation.
 Polysorbate 80 is also adsorbed on drug particle and
decreases its zeta potential. This effect of
polysorbate80 stabilizes the suspension.
 Polysorbate 80 stabilized suspensions through steric
mechanism. At low concentration of polysorbate
80,only partial stabilization of suspension was
observed.
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 • Dalam ketiadaan polisorbat 80, diamati adanya kesulitan dalam re-
dispersi partikel mengendap.

Polysorbate 80 is most widely used due to its following

advantages
 Merupakan non-ionik sehingga tidak ada perubahan pH medium
 Tidak ada toksisitas.
 Aman untuk penggunaan internal.
 Kurang berbusa kecenderungan namun harus digunakan pada
konsentrasi kurang dari 0,5%.
 Kompatibel dengan sebagian besar ajuvan.

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Polysorbate 80
 Hydrophilic Colloids

 Koloid hidrofilik mantel partikel obat hidrofobik (satu atau lebih dari
satu lapisan). Ini akan memberikan hydrophillicity partikel obat dan
memfasilitasi pembasahan.
 Mereka menyebabkan deflocculation suspensi karena gaya tarik-
menarik ditolak. Contohnya: acacia, tragacanth, alginates,
guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum,
Methylcellulose etc.

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  Solvents

 Pelarut yang paling umum digunakan digunakan

adalah alkohol, Gliserin, polietilen glikol dan
polipropilena glikol. Mekanisme yang mereka
berikan dalam pembasahan adalah bahwa mereka
larut dengan air dan mengurangi tegangan antar
muka udara-cairan. Cairan Menembus pada partikel
dan memfasilitasi pembasahan.

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 Quality Control of Suspensions
The following tests are carried out in the final quality control of
suspension:
 Appearance Color, odor and taste
 Physical characteristics such as particle size determination and
microscopic photography for crystal growth
 Sedimentation rate and
 Zeta Potential measurement
 Sedimentation volume
 Redispersibility and Centrifugation tests
 Rheological measurement
 Stress test pH
 Freeze-Thaw temperature cycling
 Compatibility with container and cap liner
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 Ideal Requirements of Packaging Material
 It should be inert.
 It should effectively preserve the product from light,
air, and other contamination through shelf life.
 It should be cheap.
 It should effectively deliver the product without any
difficulty.

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 Pharmaceutical
emulsion

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 Emulsion
Emulsi terdiri dari dua cairan yang tidak bercampur dan
terdisprsi secara seragam sebagai tetesan diameter lebih
besar dari 0,10 m.
The system is stabilized by the presence of emulsifying
agent. The particle diameter of the disperse phase
extends from 0.1 to 100 m.

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 A. Two immiscible liquids, not yet emulsified.

B. An emulsion of Phase II dispersed in Phase I.

C. The unstable emulsion progressively separates.

D. The surfactant positions itself on the interfaces between Phase II and

Phase I, stabilizing the emulsion

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 Pharmaceutical application of emulsions:
• Oral, rectal and topical administration of oils and oil-soluble
drugs.
• The unpleasant taste or odor can be masked by emulsification
• The absorption and penetration of medicament are enhanced
by emulsification
• Intramuscular injections of water-soluble drugs or vaccine to
provide slow release.
• The use of sterile stable i.v emulsion containing fats,
carbohydrates and vitamins as a potential nutrition

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 Examples:
 Oral use:
Cod-liver, Liquid paraffin, castor oil emulsions

 External use
Turpentine Liniment BP, Oily calamine lotion BP.

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 DIFFERENCE BETWEEN O/W AND W/O EMULSIONS
Oil in water emulsion (o/w)
Water is the dispersion medium and oil is the
dispersed phase
They are non greasy and easily removable from
the skin surface
They are used externally to provide cooling
effect e.g. vanishing cream
Water soluble drugs are more quickly released
from o/w emulsions
They are preferred for formulations meant for
internal use as bitter taste of oils can be masked. external use like creams.
O/W emulsions give a positive conductivity
test as water is the external phase which is a
good conductor
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of electricity.
50
Water in oil emulsion (w/o)
Oil is the dispersion medium and water is the
dispersed phase
They are greasy and not water washable
They are used externally to prevent evaporation of
moisture from the surface of skin e.g. Cold cream
Oil soluble drugs are more quickly released from
w/o emulsions
They are preferred for formulations meant for
W/O emulsions go not give a positive
conductivity test as oil is the external phase which
is a poor conductor of electricity.
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 Test for identification of emulsion type:
 Dilution test (miscibility test)
 Staining test (dye solubility test)
 Conductivity measurement

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Conductivity Test
This test is based on the basic principle that water is a good conductor of electricity. Therefore
in case of o/w emulsion , this test will be positive as water is the external phase. In this test.
An assembly consisting of a pair of electrodes connected to a lamp is dipped into an emulsion.
If the emulsion is o/w type, the lamp glows.

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 Dye Solubility Test
In this test, when an emulsion is mixed with a water soluble dye such as amaranth and
observed under the microscope, if the continuous phase appears red, then it means that the
emulsion is o/w type as water is the external phase and the dye will dissolve in it to give
color but if the scattered globules appear red and continuous phase colorless, then it is w/o
type. Similarly if an oil soluble dye such as Scarlet red C or Sudan III is added to an
emulsion and the continuous phase appears red, then it w/o emulsion.

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 Theories of emulsification:

 Δ F =  ΔA

 Semakin kecil Δ F sistem lebih stabil secara termodinamika.

Δ F =  6V / d

 Sistem ini mencoba untuk kehilangan kelebihan energi bebas

permukaan. Penambahan emulsifier yang berkonsentrasi pada

antarmuka dengan peleburan dari tetesan, akan mengubah energi bebas
permukaan.

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 Instabilities In Emulsions

 Pembuatan Emulsi adalah thermodynamically unstable sehingga

penanganan harus baik sehingga stabilitas kimia serta stabilitas fisik

sediaan tetap utuh sepanjang shelf life.

 Seharusnya tidak ada perubahan berarti dalam ukuran partikel rata-

rata atau distribusi ukuran tetesan fasa terdispersi dan kedua tetesan
fasa terdispersi harus tetap merata di seluruh sistem.

 Instabilities seen in emulsion can be grouped as:

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 Creaming
Emulsi dikatakan Cream ketika minyak atau lemak naik ke permukaan,
tetapi tetap dalam bentuk gelembung-gelembung, yang dapat
didistribusikan di seluruh media dispersi dengan getaran. Sebuah
minyak viskositas rendah cenderung lebih mudah terbentuk
creaming dari yang viskositas tinggi.

Peningkatan viskositas medium mengurangi kecenderungan untuk

Creaming. Creaming adalah fenomena reversibel yang dapat
diperbaiki dengan goncangan ringan.

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 The factors affecting creaming are best described by
Stoke’s Law:

V= 2r2 (d1-d2) g/9

 Where V= rate of creaming
 r=radius of globules
 d1= density of dispersed phase
 d2= density of dispersion medium
 g= gravitational constant
  = viscosity of the dispersion medium

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 The following approaches can be used for decreasing
Creaming
• Reduction of globule size: According to stoke’s law, rate of
creaming is directly proportional to the size of globules. Bigger is the
size of the globules, more will be the creaming. Therefore in order to
minimize creaming, globule size should be reduced by
homogenization.

• Increasing the viscosity of the continuous phase: Rate of

creaming is inversely proportional to the viscosity of the continuous
phase i.e. more the viscosity of the continuous phase, less will the
problem of creaming. Therefore to avoid creaming in emulsions, the
viscosity of the continuous phase should be increased by adding
suitable viscosity enhancers like gum acacia, tragacanth etc.
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 Cracking
 Kadang-kadang, hal itu terjadi bahwa emulsi pecah selama
pembuatan, yaitu, emulsi primer tidak menjadi putih tapi
memperoleh penampilan tembus berminyak.
 Dalam kasus seperti itu, tidak mungkin untuk mencairkan inti
emulsi dengan air dan minyak memisahkan keluar (proses
ireversibel)
Cracking pada emulsi bisa terjadi berkaitan dengan:
 penambahan agen pengemulsi kompatibel,
 dekomposisi secara kimia atau mikroba pada agen pengemulsi,
 penambahan electrolytes,
 Perubahan suhu atau perubahan pH.

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 Phase Inversion
 In phase inversion o/w type emulsion changes into w/o type
and vice versa.
 It is a physical instability.
 It may be brought about by the addition of an electrolyte or
by changing the phase volume ratio or
 by temperature changes.
 Phase inversion can be minimized by using the proper
emulsifying agent in adequate concentration,
 keeping the concentration of dispersed phase between 30 to 60
percent
 and by storing the emulsion in a cool place.

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 Points to be considered during formulations of emulsions
 Stability of the active ingredient
 Stability of the excipients
 Visual appearance
 Color
 Odor (development of pungent odor/loss of fragrance)
 Viscosity, extrudability
 Loss of water and other volatile vehicle components
 Concentration of emulsifier
 Order of addition of ingredients
 Particle size distribution of dispersed phases

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  pH
 Temperature of emulsification
 Type of equipment
 Method and rate of cooling
 Texture, feel upon application (stiffness, grittiness, greasiness,
tackiness, spreadibility)
 Microbial contamination/sterility (in the unopened container and
under conditions of use)
 Release/bioavailability (percutaneous absorption)
 Phase distribution, Phase Inversion (homogeneity/phase separation,
bleeding

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 Packaging, Labeling and Storage of Emulsions

 Depending on the use, emulsions should be packed in suitable

containers. Emulsions meant for oral use are usually packed in well
filled bottles having an air tight closure.
 Light sensitive products are packed in amber coloured bottles.
 For viscous emulsions, wide mouth bottles should be used. The label
on the emulsion should mention that these products have to be
shaken thoroughly before use (kocok sebelum digunakan).
 External use products should clearly mention on their label that they
are meant for external use only.
 Emulsions should be stored in a cool place but refrigeration should
be avoided as this low temperature can adversely effect the stability of
preparation.
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 Preservation of Emulsions
 Preservation from microorganisms:
 It is necessary to preserve the emulsions from microorganisms as these can
proliferate easily in emulsified systems with high water content,
particularly if carbohydrates, proteins or steroidal materials are also
present.
 Contamination due to microorganisms can result in problems such as color
and odor change, gas production, hydrolysis, pH change and eventually
breaking of emulsion.
 Therefore is necessary that emulsified systems be adequately preserved. An
ideal preservative should be nonirritant, nonsensitizing and nontoxic in the
concentration used.
 It should be physically as well as chemically compatible with other
ingredients of the emulsions and with the proposed container of the product.
 It should not impart any taste, color or odor to the product.

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  It should be stable and effective over a wide range of pH and
temperature.
 It should have a wide spectrum of activity against a range of bacteria,
yeasts and moulds. The selective preservative should have high water
solubility and a low oil/water partition coefficient.
 It should have bactericidal rather than bacteriostatic activity.

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 Examples of antimicrobial preservatives used to
preserve emulsified systems include
 parahydroxybenzoate esters such as methyl, propyl and butyl
parabens,
 organic acids such as ascorbic acid and benzoic acid,
 organic mercurials such as phenylmercuric acetate and
phenylmercuric nitrate,
 quarternary ammonium compounds such as cetrimide,
 cresol derivatives such as chlorocresol
 and miscellaneous agents such as sodium benzoate,
chloroform and phenoxyethano

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 Preservation from oxidation:
 Oxidative changes such as rancidity and spoilage due to atmospheric
oxygen and effects of enzymes produced by micro-organisms is seen in
many emulsions containing vegetables and mineral oils and animal
fats.
 Antioxidants can be used to prevent the changes occurring due to
atmospheric oxygen.
 Antioxidants are agents having a high affinity for oxygen and
compete for it with labile substances in the formulation.

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 The ideal antioxidant should be:
 nontoxic, nonirritant,
 effective at low concentration under the expected conditions of
storage and use,
 soluble in the medium and stable.
 Antioxidants for use in oral preparation should also be odorless and
tasteless.

 Some of the commonly used antixidants for emulsified systems

include alkyl gallate such as ethyl, propyl or dodecyl gallate, butylated
hydroxyanisole (BHT), butylated hydroxytoluene (BHT)

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 Preparation of Emulsions
 Preparation of emulsions depends on the scale at
which it is produced.
 On small scale mortar and pestle can be used but
its efficiency is limited. To overcome these
drawback small electric mixers can be used
although care must be exercised to avoid excessive
entrapment of air.
 For large scale production mechanical stirrers
are used to provide controlled agitation and
shearing stress to produce stable emulsions.

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 The methods commonly used to prepare emulsions can be
divided into two categories:
A-Trituration Method
This method consists of dry gum method and wet gum method.
1- Dry Gum Method
In this method the oil is first triturated with gum with a little
amount of water to form the primary emulsion. The trituration
is continued till a characteristic ‘clicking’ sound is heard and a
thick white cream is formed. Once the primary emulsion is
formed, the remaining quantity of water is slowly added to
form the final emulsion.

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 2- Wet Gum Method
As the name implies, in this method first gum and water
are triturated together to form a mucilage. The required
quantity of oil is then added gradually in small proportions
with thorough trituration to form the primary emulsion.
Once the primary emulsion has been formed remaining
quantity of water is added to make the final emulsion.

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 B- Bottle Method
This method is employed for preparing emulsions containing
volatile and other non-viscous oils. Both dry gum and wet gum
methods can be employed for the preparation.
As volatile oils have a low viscosity as compared to fixed oils,
they require comparatively large quantity of gum for
emulsification.
In this method, oil or water is first shaken thoroughly and
vigorously with the calculated amount of gum. Once this has
emulsified completely, the second liquid (either oil or water) is
then added all at once and the bottle is again shaken vigorously
to form the primary emulsion. More of water is added in
small portions with constant agitation after each addition to
produce the final volume.

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  Methods for preparing Emulsions for External use:
 Emulsions meant for external application such as creams,
lotions and liniments contain in their formula waxy solids
which require melting before mixing.
 Such emulsions may be prepared by melting the oily
components separately at 60 0C.
 Similarly in another vessel, the aqueous components are mixed
and are warmed gently to 60 0C.
 The aqueous phase is then added to the oily phase at the same
temperature and stirred until cold.


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 Table: 1 Proportions of Oil, Water and Gum required for formation of
primary emulsion'

Type of Oil Oil Water Gum

Fixed Oil 4 2 1
Mineral Oil 3 2 1
Volatile Oil 2 2 1

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 Emulsifying Agents are the substances added to an emulsion to
prevent the coalescence of the globules of the dispersed phase.
 They are also known as emulgents or emulsifiers.
 They act by reducing the interfacial tension between the two phases
and forming a stable interfacial film.
 The choice of selection of emulsifying agent plays a very important
role in the formulation of a stable emulsion.
 No single emulsifying agent possesses all the properties required for
the formulation of a stable emulsion therefore sometimes blends of
emulsifying agents have to be taken.

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 Criteria For The Selection of Emulsifying Agents
An ideal emulsifying agent should posses the following characteristics:
• It should be able to reduce the interfacial tension between the
two immiscible liquids.
• It should be physically and chemically stable , inert and
compatible with the other ingredients of the formulation.
• It should be non irritant and non toxic in the conc., used.
• It should be organoleptically inert i.e. should not impart any color
, odour or taste to the preparation.
• It should be able to produce and maintain the required viscosity of
the preparation.
• It should be able to form a coherent film around the globules of
the dispersed phase and should prevent the coalescence of the droplet
of the dispersed phase.
•

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 1-Natural emulsifying agents from vegetable sources
 These consist of agents which are carbohydrates and include gums
and mucilaginous substances. Since these substances are of variable
chemical composition,
 these exhibit considerable variation in emulsifying properties. They are
anionic in nature and produce o/w emulsions. They act as primary
emulsifying agents as well as secondary emulsifying agents (emulsion
stabilizers).
 Since carbohydrates acts a good medium for the growth of
microorganism, therefore emulsions prepared using these emulsifying
agents have to be suitable preserved in order to prevent microbial
contamination.
 E.g. tragacanth, acacia, agar, pectin and starch.

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 2-Natural emulsifying agents from animal source
The examples include gelatin, egg yolk and wool fat (anhydrous lanolin).
Type A gelatin (Cationic) is generally used for preparing o/w
emulsion while type B gelatin is used for o/w emulsions of pH 8 and
above.
Lecithin and cholesterol present in egg yolk also act as emulsifying
agent. They show surface activity and are used for formulating o/w
emulsions.
However they are used only for extemporaneous preparation and
not for commercial preparation as it darken and degrade rapidly in
unpreserved systems.
Wool fat is mainly used in w/o emulsions meant for external use.
They absorb large quantities of water and form stable w/o emulsions
with other oils and fats.

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 3- Semi-synthetic polysaccharides
 Includes mainly cellulose derivatives like sodium carboxy methyl
cellulose, hydroxyl propyl cellulose and methyl cellulose.
 They are used for formulating o/w type of emulsions.
 They primarily act by increasing the viscosity of the system. e.g.,
methyl cellulose, hydroxypropyl cellulose and sodium carboxy methyl
cellulose.

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 4- Synthetic emulsifying agents
• This group contains surface active agents which act by getting
adsorbed at the oil water interface in such a way that the hydrophilic
polar groups are oriented towards water and lipophillic non polar
groups are oriented towards oil, thus forming a stable film.
• This film acts as a mechanical barrier and prevents coalescence of the
globules of the dispersed phase.
• They are classified according to the ionic charge possessed by the
molecules of the surfactant e.g., anionic, cationic, non-ionic and
ampholytic.

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 4.1. Anionic Surfactants
 The long anion chain on dissociation imparts surface activity, while the
cation is inactive.
 These agents are primarily used for external preparations and not
for internal use as they have an unpleasant bitter taste and irritant
action on the intestinal mucosa.
 e.g., alkali soaps, amine soaps, metallic soaps, alkyl sulphates and
phosphates and alkyl sulphonates.


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 4.2. Cationic surfactants
• The positive charge cations produced on dissociation are responsible
for emulsifying properties.
• They are mainly used in external preparations such as lotions and
creams.
• Quaternary ammonium compounds such as cetrimide, benzalkonium
chloride and benzethonium chloride are examples of important
cationic surfactants.
• These compounds besides having good antibacterial activity are also
used in combination with secondary emulsifying agents to produce
o/w emulsions for external application.

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 4.3. Non-ionic surfactants
• They are the class of surfactants widely used as emulsifying agents.
• They are extensively used to produce both o/w and w/o emulsions
for internal as well as external use. The emulsions prepared using these
surfactants remain stable over a wide range of pH changes and are not
affected by the addition of acids and electrolytes.
• They also show low irritancy as compared to other surfactants.
• E.g. glyceryl esters such as glyceryl monostearate, propylene glycol
monostearate, macrogol esters such as polyoxyl stearates and
polyoxyl-castor oil derivatives, sorbitan fatty acid esters such as spans
and their polyoxyethylene derivatives such as tweens (polysorbates).

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 5- Finely Divided Solids
 This group consist of finely divided solids having balanced hydrophilic
lipophillic properties.
 They accumulate at the oil/water interface and form a coherent
interfacial film around the droplets of dispersed phase globules and
prevent coalescence.
 If the solid particles are preferentially wetted by oil, a w/o emulsion is
formed while if wetting is done by water then o/w emulsion is seen.
 e.g., bentonite, aluminium magnesium stearate, attapulgite, colloidal
anhydrous silica and hectorite. The emulsions formed using finely
divided solids are stable and less prone to microbial contamination.

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 Quality control tests for Emulsions
The following are the quality control tests done for
emulsions:
 Determination of particle size and particle count:
Determination of changes in the average particle size or the size
distribution of droplets is an important parameter used for the
evaluation of emulsions. It is performed by optical microscopy,
sedimentation by using Andreasen apparatus and Coulter counter
apparatus.
 Determination of viscosity: Determination of viscosity is done to
assess the changes that might take place during aging. Emulsions
exhibit non-newtonian type of flow characterstics.
 The viscometers which should be used include cone and plate viscometers.

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  Determination of phase separation: This is another parameter
used for assessing the stability of the formulation.
Phase separation may be observed visually or by measuring the volume
of the separated phases.
 Determination of electrophoretic properties: Determination
of electrophoretic properties like zeta potential is useful for assessing
flocculation since electrical charges on particles influence the rate of
flocculation.
O/W emulsion having a fine particle size will exhibit low resistance
but if the particle size increase, then it indicates a sign of oil droplet
aggregation and instability.

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 Stability testing
Stability of emulsions is an important parameter for the formulator.
Stability testing of emulsions involves determining stability at long term
storage conditions, accelerated storage conditions, freezing and thawing
conditions. Stress conditions are applied in order to speed up the stability
testing.
The stress conditions used for speeding up instability of emulsions include:
 Centrifugal force, Agitational force, Aging and temperature

 The following physical parameters are evaluated to assess the effect of any
of the above stress conditions:
Phase separation
Viscosity
Electrophoretic properties
Particle size and particle count

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