4[1]._Dispersi_Kasarklasiber

References

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

Pharmaceutical Dosage Forms and Drug Delivery Systems, Howard C. Ansel, Nicholas G. Popovich, and Loyd V. Allen, 7th Ed., Lippincott Williams & Wilkins 1999.

Chapter 8, Coarse Dispersions, in: Physical pharmacy by Alfred Martin, Pilar Bustamante, and A.H.C. Chun, 4th Ed., Lea & Febiger, 1993

Ch.28 (Suspensions) and Ch.29 (Liquid Emulsions), in: A practical guide to contemporary pharmacy practice, Judith E. Thompson, Williams & Wilkins,1998

The term "Disperse System" refers to a system in which one substance (The Dispersed Phase) is distributed, in discrete units, throughout a second substance (the continuous Phase or vehicle).

Each phase can exist in solid, liquid, or gaseous state

DISPERSE SYSTEMS

Dispersed Systems

Two phase systems Emulsions -> Liquid in a liquid Suspension -> Solid in a liquid Foam -> air in a liquid

Dispersed Systems

Physical stability

Settling & Creaming

Stokes’ Law

η ⇑ v ⇓ Stability

Particles need to come into contact (collide) to coalesce

Therefore, higher concentrations (via creaming/settling) promote coalescence or caking

DISPERSE SYSTEMSDISPERSE SYSTEMS

Another important factor is DENSITY. It is possible to manipulate the density of the

dispersion medium by adding nonionic substances.

e.g. SORBITOL

PVP (polyvinyl pyrolidone)

GLYCERIN

SUGAR

PEG (polyethylene glycol)

Calculations

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

Determine the velocity of settling of sulfur in water. The average particle radius is 5.5 µm. The density of sulfur and water at 250 C. is 1.96 and 0.997 g/c.c., respectively. The viscosity of water at 250 C. is 0.00895 poise.

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

take to completely settle?

Particle size determination: From the previous example, calculate the average

particle size of sulfur.

What is the necessary viscosity to reduce the sedimentation rate from 0.0071 cm/sec to 0.00071 cm/sec?

Physical Stability -> Phase Separation

Phases separation starts with growth in particle size Physical contact -> first step in coalescence Flocculation and aggregation

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

Dosing uniformity

Importance Aerosols (emulsion or suspension) Multiple dose Multiple use - if don't deliver uniform dose get an

enrichment or reduction in concentration with each dose Single dose -> same process but less important Results in over- or under- dosing Example

Steroids like Betamethasone can lead to side effects or ineffective therapy

Dispersion

What is a dispersion at molecular level? What makes them physically stable? Interfacial Phenomena

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

What happens at interface is critical!!

Suspensions

Pharmaceutical suspensions are uniform dispersions of solid drug particles in a vehicle in which the drug has minimum solubility. Colloidal suspension 1 nm to 0.5 µm Coarse suspension 1 to 100 µm

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

SUSPENSIONSSUSPENSIONS

Examples of Pharmaceutical Suspensions: 1. Antacid oral suspensions 2. Antibacterial oral suspension 3. Dry powders for oral suspension (antibiotic) 4. Analgesic oral suspension 5. Anthelmentic oral suspension 6. Anticonvulsant oral suspension 7. Antifungal oral suspension

Suspensions: Advantages

Many patients prefer a liquid form over a solid form

Suspensions provide greater flexibility in the administration of doses

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

Some drugs are chemically unstable when in solution but stable when suspended

Desired features in a pharmaceutical suspension

1. Therapeutic efficacy - if the drug does not exert pharmacological activity after administration, it has failed in its purpose.

2. Chemical stability - no degradation or decomposition of vital components within the formulation during processing, storage, handling or administration.

3. Physical stability - the suspension should not settle too quickly and should be readily redispersed on gentle shaking.

4. The particle size should remain fairly constant throughout the shelf-life of the product. You don't want dissolution or aggregation of the particles within the suspension.

5. The suspension should pour easily and evenly from the container.

6. The formulation should be aesthetically pleasing to the eye, nose and mouth. The appearance, viscosity, texture and any other properties detected by the senses must be considered.

Desirable Features

particles should settle slowly formulation should allow the easy redispersion of

sedimented particles a flocculated suspension is desirable than a

deflloculated suspension a suspension should not be too viscous to reduce

the sedimentation rate

Settling and Aggregation

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

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

flock

cake

Pemisahan Zat-zat Terdispersi

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

berlaku Bila konsentrasi zat terdispersi 5 – 10 % Hk. Stokes tak

berlaku (partiekel saling mempengaruhi sehingga cepat terjadi pengendapan

Flokulasi Susunan yang terbentuk merupakan ikatan yang lemah

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

Pemisahan Zat-zat Terdispersi (lanjutan)

Deflokulasi Susunan yang terbentuk merupakan ikatan yang kuat Tidak mudah memisah dari endapannya apabila dikocok Sulit tersuspensi kembali Dapat membentuk caking

Agglomerasi gumpalan dengan ikatan yang kuat

Caking Gumpalan yang mengendap dengan masa yang keras

Sedimentation (Settling) rates The well known Stokes’ relation describes the sedimentation

velocity of a particle in suspension:

where v = velocity of the sedimentation or rate of settling in cm/sec;

r = particle radius; D = particle diameter in cm; d1 and d2 = density of the particle and the liquid, respectively, in

(g/cm3); g = acceleration due to gravity (gravitational constant) = 980.7

cm/sec2; = the viscosity of the medium in poises.

18)(

9)(2

21

2

21

2 gddDgddrv

Sedimentation (Settling) rates The various parameters influencing the rate of settling are

contained in the Stokes’ equation. These parameters lead to several manufacturing considerations as well as to the inclusion of certain additives to oral suspension formulations: Reduction of particle size (Recall, however, that reducing the

particle size may also promote caking.)

Solid content - recall that Stokes’ equation is based on a dilute suspension because the presence of other particles hinders settling

Increasing the density of the vehicle (additive)

Increasing the viscosity of the vehicle (within limits since the increase in viscosity also affects flow from the bottle) (additive: suspending agent or viscosity modifier)

Prevention of aggregation/caking (additives: surfactants and flocculating agents)

Sedimentation (Settling) rates

This is usually accomplished by dry milling prior to incorporating the dispersed phase into the vehicle:

1. Micropulverizers are the high-speed equipment that can rapidly,

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

2. To achieve particles less than 10 µm in diameter requires a process called jet-milling or micronizing. The particles are carried into compressed air streams where they collide with one another due to the violent turbulence and high velocities present in these systems. These collisions result in fragmentation and the resultant decrease in particle size.

3. Particles of extremely small dimensions can be produced by spray drying.

(A) -Particle size reduction:

Sedimentation (Settling) rates

Carboxymethylcellulose (CMC), methylcellulose, xanthan gum, and bentonite have been used to thicken the continuous phase and help to support the physical stability of the suspension. These agents are poorly absorbed from the GI tract and essentially pass through unchanged.

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

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

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

(A) -Viscosity Modifiers:

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 Stoke’s law

Stokes equation applies to uniform, perfectly spherical particles settling in a very dilute suspension with no hindrance or turbulance

FACTORS TO BE CONSIDERED FACTORS TO BE CONSIDERED Particle sizeParticle size Density of the vehicle-Density of the vehicle-

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

State Rate of settling Sedimentation volume

Nature

Flocculated Fast High Porous, easy to redisperse

Deflocculated Slow Low Compact, difficult to redisperse

Sedimentation Volume

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

Thixotropic suspensionThixotropic 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.

Formulation of suspension

 component of suspending system wetting agent dispersants flocculating agent thickeners

component of the suspending agent pH control agent osmotic agent coloring agents preservatives to control microbial growth liquid vehicles

METHODS OF PREPARATION

(1) use of controlled flocculation

(2) use of structured vehicle

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

Hydrophilic and hydrophobic particles-

Wetting agent

Controlled flocculation- Most frequently used flocculating agents are electrolytes.

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

Other substances which initiate flocculation are combination of ionic and nonionic surface active agents and lyophilic polymers. These polymers form a bridge between particles and initiate flocculation.

Structured vehicle- Structured vehicles are the aqueous solutions of

natural and synthetic gums.

Methyl cellulose, carboxymethyl cellulose,

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

Preparation & Storage of Suspensions Small scale – mortar & pestle Industrial scale – colloid mill Particle size 1-50 µm Package in wide mouth containers with adequate air

space – shake before use

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

Fig. The four basic types of size reductionequipment used to produce fine solid particles.

(a) crushers and shredders

(b) hammer mills(c) colloid mills(d) fluid energy mills

A typical suspension formula..

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

Suspending Agent

Akasia/Gom Arab (2,5 %) Tragacanth (1 – 2 %)

Tragacanth + air 20 x dicampur homogen Na Alginat (1 – 2 %) Metilselulosa (0,5 – 2 %)

Metilselulossa + air panas 10 x aduk selama 2 jam, + sisa air Na CMC (0,25 – 2 %)

Na CMC + air panas 20 X biarkan 15 menit Bentonit (2 – 5 %), untuk eksternal Veegum (0,5 – 2,5 %)

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

CMC (0,5 – 2 %)

Wetting Agent

Tween 80 Span untuk sediaan Alkohol oral Propilenglikol

Dioktil Na Sulfosuksinat untuk obat Na Lauril Sulfat luar

Preservative

Metil paraben (Nipagin) : 0,12 – 0,18 % (antibakteri)

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

Asam benzoat : 0,1 %

Na benzoat : 0,1 %

Compounding of Suspensions

Solid dosage forms can be used Check literature & reference books Selected vehicles are commercially available A smooth, nongritty product should be prepared Neonatal formulations should not contain

preservatives, colorings, flavorings, and alcohol

Use manufactured liquid product, if available

Desain Pengembangan Formula

Karakter zat aktif : tidak larut dalam sejumlah air yang dibutuhkan

Tujuan formulasi : mendapatkan suspensi yang stabil, yaitu : mudah terdispersi saat pengocokan dan saat

terbentuk endapan Pengendapan terkendali Mudah dituang

Desain Pengembangan Formula (lanjutan)

Memperkecil ukuran partikel- suspending agent- penggerusan- wetting agent

Menaikkan viscosita medium dispersi, yaitu :- suspending agent- pengental

Menurunkan tegangan permukaan- suspending agent- wetting agent

Pengendalian sedimentasi- pengental

Teknik untuk mendapatkan suspensi yang stabil :

EVALUATION OF SUSPENSIONS EVALUATION OF SUSPENSIONS

Sedimentation volume-

F = Vsed/Vtot

The value of F normally lies between 0 to 1 for any pharmaceutical suspension.

The value of F provides a qualitive knowledge about the physical stability of the suspension.

Degree of flocculation-

ß = Ffloc/Fdefloc

(Vsed/Vtot)floc

=-------------------

(Vsed/Vtot)defloc

When the total volume of both the flocculated and the deflocculated suspensions are same, as for example, 100 ml in the Figure; the degree of flocculation,

ß = (Vsed)floc/(Vsed)defloc

Evaluasi sediaan

Parameter Hal yg hrs diperhatikan

Viskositas Disesuaikan sehingga tidak mudah memisah tapi masih cukup mudah untuk dituang

pH dlm range pH stabilita

Stabilita fisik T40 selama 3 bulan penampilan masih baik

Stabilita kadar T40 selama 3 bulan, masih memenuhi

syarat

Evaluasi sediaan

Penampilan : bentuk, bau, rasa Penentuan rekonstitusi

Suspensi kering dalam botol, tambahkan air sampai batas kocok dengan normal, amati apakah sediaan mudah direkonstitusi

Penentuan pH sediaan Penentuan volume sedimentasi

Sediaan dimasukkan kedalam gelas ukur, diamkan Volume sedimentasi merupakan volume endapan setelah

pendiaman dibagi volume sediaan awal Pemeriksaan ukuran partikel Penentuan viscositas dan sifat aliran

Evaluasi sediaan

Parameter yang diperhatikan formulasi dry sirup

Parameter Hal yg hrs diperhatikan

Flow granul/serbuk baik

Homogenitas Perbedaan ukuran partikel antara zat aktif & zat tambahan tidak terlalu besar sehingga kemungkinan terjadi pemisahan/segresi kecil

Stabilita fisik/kadarT40 slm 3 bulan msh memenuhi (diterima)

Setelah rekonstitusi sampai pemakaian yang tertera pada label, penampilan & kadar masih baiksaat rekonstitusi jml pelarut yang ditmbhkan harus = label

Packaging and Storage of Suspensions: 1) Should be packaged in wide mouth containers

having adequate air space above the liquid.

2) Should be stored in tight containers protected from: freezing and excessive heat & light

3) Label: "Shake Before Use" to ensure uniform distribution of solid particles and thereby uniform and proper dosage.

Administration and Counseling for Oral Suspensions

Most oral suspensions are administered by teaspoon or tablespoon. Make certain that you counsel the patient regarding which to use.

Reconstituted products are usually suspensions and an oversized bottle is necessary to allow a headspace to shake the suspension into for adequate redispersion.

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

Administration and Counseling for Oral Suspensions

Some patients don't understand that the medication is for oral administration. For example, make clear to the patient that

the oral antibiotic suspension to treat a middle ear infection is to be taken by mouth and not placed in the ear canal.

If the medication states that the product should be refrigerated, counsel the patient to store it in the refrigerator. Some suspension and emulsion products do not require refrigeration during storage. It probably is dependent on the level of preservative present in the formulation.

Administration and Counseling for Oral Suspensions

Some suspensions can interfere with the bioavailability of other oral drugs.

Examples are: Cholestyramine suspension has been shown to decrease the bioavailability of warfarin,

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

Advise the patient to stagger the administration of their oral drugs by several hours when interferences have been reported.

Acetaminophen Oral Suspension

MANUFACTURING DIRECTIONS

1. Acetaminophen dispersion should be uniformly mixed or levigated. If acetaminophen dispersion is either added to hot syrup base or homogenized for a long time, flocculation may appear. While handling the syrup, mucilage, or drug dispersion, the handling loss should not be more than 1%. If the loss exceeds 1%, it may give poor suspension.

2. Add 180 g of item 13 to the mixer and heat to 90.C.3. Dissolve items 3 and item 4 while mixing. Add and dissolve item 2

while mixing. Cool down to about 50. to 55.C.4. Add and dissolve item 5 while mixing. Filter the syrup through T

1500 filters washed with item 13. Collect the syrup in clean stainless steel tank.

5. Disperse item 9 in item 6 in a separate stainless steel container. Add 40 g of hot item 13 (90.C) at once while mixing. Mix for 20 minutes to make a homogeneous smooth mucilage.

6. Mix item 7 in 10 g of item 13 (25.C) in a separate stainless steel container. Add item 1 while mixing with stirrer. Mix for 25 minutes to make uniform suspension.

Cont

7. Add sugar syrup and mucilage to the mixer. Rinse the container of mucilage with 15 g of item 13 and add the rinsings to the mixer. Cool to 25.C while mixing.

8. Add item 1 dispersion to the mixer. Rinse the container of dispersion with 15 g of item 13 and add rinsings to the mixer. Check the suspension for uniformity of dispersion.

9. Mix for additional 5 minutes at 18 rpm, vacuum 0.5 bar if required.10. Add item 8 to the mixer and mix for 10 minutes. Dissolve item 10 in 7 g of

item 13 and add to the mixer.11. Disperse item 11 in 7 g of item 13 and add to the mixer. Add item 12 to the

mixer.12. Add cold item 13 (25.C) to make up the volume up to 1.0 L.13. Homogenize for 5 minutes at low speed under vacuum 0.5 bar, 18 rpm,

temperature 25.C.14. Check the dispersion for uniformity.15. Check the pH. Limit 5.7 ± 0.5 at 25.C. If required adjust the pH with 20%

solution of Citric Acid or Sodium Citrate.16. Transfer the suspension through 630 micron sieve after mixing for 5

minutes at 18-20 rpm, temperature NMT 25.C, to the stainless steel storage tank.

Acetaminophen Suspension

1. Prepare the solution of dextrose in water and add the other solid ingredients with stirring in the following sequence: citric acid, sodium citrate, orange flavor, Kollidon CL-M, and acetaminophen.

2. A white, homogeneous suspension is obtained.

Acetaminophen Syrup for Children

1. Dissolve Kollidon in water, add acetaminophen and cyclamate, heat to 50.C, and stir to obtain a clear solution.

2. Dissolve the flavors and mix with glycerol. The obtained syrup is a viscous, clear, sweet, and only slightly bitter liquid.

Amoxacillin Powder for Suspension

1. Charge items 3 and 2 in a mixer and mix for 2 minutes.2. Add item 4 and items 6 to 11 and mix for 5 minutes.3. Pass through Fitz Mill, impact forward at high speed using sieve

24228.4. In a separate mixer, charge items 5 and 1 and mix well, passing

through a sifter.5. Add to step 3 and mix for 20 minutes.6. Fill 65.00 g for 100 mL and 39 g for 60-mL pack size.

References

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

Pharmaceutical Dosage Forms and Drug Delivery Systems, Howard C. Ansel, Nicholas G. Popovich, and Loyd V. Allen, 7th Ed., Lippincott Williams & Wilkins 1999.

Chapter 8, Coarse Dispersions, in: Physical pharmacy by Alfred Martin, Pilar Bustamante, and A.H.C. Chun, 4th Ed., Lea & Febiger, 1993

Ch.28 (Suspensions) and Ch.29 (Liquid Emulsions), in: A practical guide to contemporary pharmacy practice, Judith E. Thompson, Williams & Wilkins,1998

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 µm Macroemulsion: Droplets size range approximately

5 µm.

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 emulsionsTypes 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

Emulsion Size

< 0.5 m 0.5-1.5 m 1.5-3 m >3 m

Fig.1 Mineral oil in water emulsion

How can the emulsion be stabilized?

Reduction of the surface tension is the key to avoid the coagulation of the emulsion.

Substances which reduce the surface tension are called surfactants.

The number of surfactants (emulsifiers) is enormous and they are divided up into several groups according to their properties.

Beside O/W or W/O emulsifier surfactants are also used as anti foaming agent, wetting agent, dispersing agent and solubilisator.

Surfactants and Micelles

Surface active agents have a certain affinity for both polar & nonpolar solvents

Amphiphilic nature – adsorb at interfaces At a concentration that is characteristic of each amphiphile, these

molecules will aggregate to produce micelles

Working principle of emulsifier

oil

wateroil

W/O O/WHydrophil head

Lipophil chain

water

•The basic requirements for emulsifier

•Types of emulsifier

•Emulsifying mechanism

emulsifieremulsifier

Properties supplied by the emulsifier

• Reduction of the surface energy

• Generation of steric and electrostatic inhibitions(inhibition of coalescence of the drops)

•Inner phase is dispersed under high shear force to achieve a homogeny monodispers mixture of the drops.

•The drop size of emulsions is typical in a range between 1 and 10 µm (up to 25 µm).

Type of emusifierType of emusifier

1. high molecular compound

2. surfactants

3. solid powder

1. high molecular compound

acacia tragacanthgelatin lecithin almond cholesterol others

2. surfactants

⑴anionic surfactants⑴anionic surfactants

polarityhydrophili

c

Nonpolarity

hydrophobic

Na+

-

Active part （ -）

General topical used emulsions！

Sorbitan—— （ W/O type ） span20 ， 40 ， 60 ， 80 ；

Polyoxyethylene sorbitan monolaurate—— （ O/W type ）

tween20 ， 40 ， 60 ， 80 ，Polyxyethylene fatty acid esterMyrij —— （ O/W type ）

Myrij 45 ， 49 ， 52，

⑵nonionic surfactants⑵nonionic surfactants

Finely divided solids ， can be aggregated atsurface between oil and water to form solid particle membrane

Finely divided solids ， can be aggregated atsurface between oil and water to form solid particle membrane

3. Solid power surfactants

contact angle of solid powder with water phase determine the types of emulsionscontact angle of solid powder with water phase determine the types of emulsions

θ<90° O/W；θ>90°W/O

θ<90° O/W；θ>90°W/O

Emulsification

Emulsifier

EMULSIONSEMULSIONS

Theories of Emulsification: 1) Surface Tension Theory:

- lowering of interfacial tension. 2) Oriented-Wedge Theory:

- mono molecular layers of emulsifying agents are curved around a droplet of the internal phase of the emulsion.

3) Interfacial film theory:

- A film of emulsifying agent prevents the contact and coslescing of the dispersed phase.

Emulsifying Agents: 1) Carbohydrate Materials:

- Acacia, Tragacanth, Agar, Pectin. o/w emulsion. 2) Protein Substances:

-Gelatin, Egg yolk, Caesin o/w emulsion. 3) High Molecular Weight Alcohols:

- Stearyl Alcohol, Cetyl Alcohol, Glyceryl Mono stearate o/w emulsion, cholesterol w/o emulsion.

4) Wetting Agents:

Anionic, Cationic, Nonionic

o/w emulsion

w/o emulsion 5) Finely divided solids:

Bentonite, Magnesium Hydroxide, Aluminum Hydroxide o/w emulsion

1. coemulsifier2 ． preservatives3 ． antioxidants4. sweeting agent

Additives of emulsions

Formula Umum Emulsi

zat aktif (fase minyak), dan atau larut air Emulgator Antioksidan (bila perlu) Pemanis, pengawet, aroma Pewarna (bila perlu)

Tujuan formulasi Pemilihan dan modifikasi emulgator

HLB ?

Cara Menentukan HLB

R/ Parafin cair 25 Setilalkohol 20 Emulgator 2 Pengawet 0,2 Air ad 100

Metoda AligasiFase minyak % HLB HLB butuh

Parafin cair 25 8 25/45 x 8 = 4,5

Setilalkohol 20 15 20/45 x 15 = 6,7

Jumlah 45 11,2

Mis. Emulgator yang digunakan :Span 60 (HLB 4,7)Tween 60 (HLB 14,9)

Jumlah emulgator yang digunakan :Tween 60 14,9 6,5

11,2Span 60 4,7 3,7

Span 60 yg dipakai : 3,7/10,2 x 2 g = 0,72g

Tween 60 yg dipakai : 6,5/10,2 x 2 g = 1,28 g

Methods of emulsion preparationMethods of emulsion preparation

• Prescription laying for emulsions• Drug addition • Preparation method• emulsification facilities • The influcing factors on emulsification• examples

Preparation of Emulsions

High speed impellers in mixing tanks Small scale extemporaneous preparation (See

Ansel) Continental or dry gum method

4 (oil): 2 (water): 1 (gum) English or wet gum method Bottle or Forbes bottle method In-situ soap method

Preparation method 1 ． hand-made method　　　　（ 1 ） dry gum metho

d ：　　 oil ＋ emulsifer（ 2 ） wet gum metho

d ：　

　 water ＋ emusifier

（ 3 ） direct mixture method

water

emulsion

oil

emulsion

oil ＋ water ＋ emulsifer emulsion

Methods of Manufacture

Recall goal Increase surface area Requires energy to create surface

Overcome surface tension Add energy by creating shear gradient within

the liquid Shear gradient

Emulsions: Different ways of production

Hot/Hot ProcessBoth, fat- and water-phase are heat up separately to a certain temp. (70 – 85 °C). The hot oil phase and the hot water phase were combined under vacuum at the high temperature and emulsified. Emulsification is done by the rotor stator system. Subsequently the product is cooled down.

Hot/Cold ProcessThe fat phase is heat up to a temp. (app. 10 °C above the highest melting point of the ingredients). The hot fat phase and the cold water phase were combined under vacuum and emulsified at the mixing temperature. Subsequently the product is cooled down. Advantage: shorter cooling times, saving of energy

Basic Methods

Mechanical stirrers Homogenizers Colloid mills or Rotor-stator Ultrasonifiers

Mechanical Stirrers

Not very efficient -> limits particle size Especially viscous liquids

Advantages Large scale - 1000 gal

Fusion manufacturing of emulsion Keep mixed upon cooling

Homogenization

Compress liquids to high pressure -> spring loaded orifice lets escape creating high shear Develop pressures 500-5000 psi Very high energy -> small particle size

2nd pass -> fine particle size Hand homogenizer & glass syringe used for small scale

Use in Compounding Rx Second most common method besides elbow grease Hard to scale up -> orifice critical in particle size

Ultrasonic Homogenizer

Vacuum Homogenizer

Colloid Mills

1000-20000 rpm High sheer rates Heat build up a problem

Colloid Mill is suitable for Homogenising, Emulsifying, Dispersing mixing.

Ultrasonification

Sound energy produces holes in solution then collapses very high shear

Hard to scale up Film Formation

The emulsifier must be adsorbed quickly around the dispersed drops and condensed film that prevents coalescence

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

Heating of fat phase onto 75 °C,then feed in Main vessel, run homogenizer

600rpm and keep on temperaturePreparation of water phase

Feed water phase slightly in Main vesselVacuum 700mbar

Homogenizer 3000 rpm

Homogenization 3000 rpm; Vacuum 700mbar

Cooling downto 40 °CHomogenizer interval: Run 1500rpm 30s

Pause 150s

Feed additives + parfume,Temperature 40°C; Vacuum 700mbar

Homogenizer 3000 rpm

Preparation of additives, parfume

Homogenization 3000 rpm; 60sTemperature 40 °C; Vacuum 700mbar

Process Diagram Of W/O - Cream Production On Dinex

Deaeration;Temperature 40 °C; Vacuum 50 mbar

Discharge;Temperature 40 °C

Homogenizer 1000 rpm

CreamingCreaming

Aggregates of globules of the internal phase have a greater tendency than do individual particles to rise to the top of the emulsion or fall to the bottom 　　

The difference in the density between the phasesThe difference in the density between the phases

Flocculation

The association of particles within an emulsion to form large aggregates, which can be easily be

redispersed upon shaking.

Physical stability of emulsionsPhysical stability of emulsions

phase inversion

O/W type 　　　 W/O typeO/W type 　　　 W/O type

W/OO /W

The reason for phase inversion ：The reason for phase inversion ：property of emulsifier ：phase volume ratio ：

W/O type——ф50%~60%

O/W type——ф90%

Coalescence and breaking

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

irreversibleirreversible

EMULSIONSEMULSIONS

Stability of Emulsion: An emulsion is considered to be physically unstable if :

a) The internal phase tends to form aggregates of globules.

b) Large globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to form a concentrated layer of the internal phase.

c) If all or part of the liquid of the internal phase becomes "unemulsified on the top or bottom of the emulsion.

Emulsion stability

Stoke’s law – use to optimize Shake well label Preservatives

desired partition coefficient incompatibilities/ionization status acacia based emulsions – parabens

Special Emulsion Systems

Multiple emulsions w/o/w stability issues

Microemulsions surfactant & cosurfactant – spontaneous

formation homogeneous, transparent & stable < 0.2 microns – dispersed phase

Multiple Emulsions

Emulsions of emulsions and consist of more than one dispersed phase, usually oil or water droplets not identical with the continuous phase.

The term “multiple emulsion” has been used to describe emulsion system in which drops of the dispersed phases contain smaller droplets that have the same composition as the external phase

Preperation

The primary emulsion can then be emulsified with a hydrophilic,high HLB surfactant, using lower shear to produce a W/O/W emulsion of reasonable stability

The reverse procedure could be followed to prepare an O/W/O emulsion.

The most promising use of multiple emulsions is in the area of sustained-release drug formulations, since the oil layer between two aqueous phases can behave like a membrane controlling solute release

MICROEMULSIONS Microemulsions are thermodynamically stable,

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

The surfactant may be pure, a mixture, or combined with a cosurfactant such as a medium-chain alcohol (e.g., butanol, pentanol).

These homogeneous systems, which can be prepared over a wide range of surfactant concentrations and oil to water ratios (20–80%), are all fluids of low viscosity.

• Microemulsions are readily distinguished from normal emulsions by their transparency, their low viscosity, and more fundamentally their thermodynamic stability and ability to form spontaneously.

• Emulsions and microemulsions may be differentiated on the basis of particle size.– Microemulsions contain particles at least an order of magnitude

smaller (i.e 10 – 100 nm) than those in conventional emulsions that contain particle at the upper end of the colloidal size range (100 – 100.000 nm)

– Conventional emulsions are termed coarse emulsions or macroemulsions when contrasted with micromulsions

• Ternary phase diagram for oil, water, and surfactant mixtures showing micellar, microemulsion, and multiphase macroemulsion regions with schematic representations of various structures.

Pharmaceutical Applicationsof Microemulsions

• the ability to concentrate and localize significant amounts of both oil and water-soluble materials – the rate of absorption of cyclosporin is more rapid and

less variable than it is with the conventional oily dispersion.

– Microemulsions have also been used for topical delivery where they increase drug absorption.

• For example, cetyl alcohol, which is commonly used as an emulsifier in lotions and creams, is absorbed faster and deeper into the skin when formulated as a component of a microemulsion.

Formulation and Preparation ofMicroemulsions

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

Evaluasi Sediaan Emulsi

1. Pemerian• Warna, bau, rasa

2. Pemeriksaan pH sediaan

3. Pemeriksaan tipe emulsi• Pengenceran• Pewarnaan• Fluoresensi• Daya hantar listrik

4. Pemeriksaan BJ sediaan

5. Pemeriksaan ukuran partikel

6. Penentuan viskositas dan sifat alir

7. Volume sedimentasi

EMULSIONSEMULSIONS

Separation of the internal phase from the external phase is called BREAKING of the emulsion. This is irreversible.

Protect emulsions against the extremes of cold and heat.

Emulsions may be adversely affected by microbial contamination.

Eucalyptus and Mint Emulsion

1. Heat item 1 to 71.C.

2. Combine rest of the ingredients in another container and heat to 71.C as well.

3. Slowly add water at 71.C and mix for 1 hour. Cool the mixture to 35. to 45.C and fill.

A solution is a homogeneous mixture that is prepared by dissolving a solid, liquid or gas in another liquid.

Molecular solutions include:

water solutions aromatic waters syrups tincture spirits Glycerins

Preparation of Solutions

Weigh the sample

Dissolve the sample

filtrate

quality test

package

Water Solutions

A solution is formed in water as a solvent

Aromatic Waters are saturated solutions (unless otherwise specified) of volatile oils or other aromatic or volatile substances in distilled water.

Aromatic Waters

Preparation method of Aromatic Waters

1. Distillation

2. Solution

3.Dilution

Syrups

Concentrated aqueous solution of sugar Alcohol free Flavoring – mask bad taste

Simple syrup – just sugar Cherry, cocoa, orange, raspberry Ora-Sweet & Ora-Sweet SF (sugar free)

Paddock Laboratories Components

Sugar, antimicrobial preservative, flavorant & Colorant

Syrup Components Cont.

Sugar Sucrose most popular

Dextrose Non-sucrose

Sorbitol, glycerin, propylene glycol Glycogenetic – all above

i.e. - Converted into glucose in body Non-glycogenetic

Methylcellulose & hydroxyethylcellulose Ora-Sweet plus

Not absorbed Has syrup like η and feel Good for diabetic patients

Simple Syrup, Syrup NF

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

Syrup NF not saturated – may store in fridge See text for methods of preparation

Rx dilute, not all syrups concentrated Diluted syrup could be used to grow stuff in micro lab – be

careful!! Is why

Don’t give honey to infants Put nitrates in caned hams with honey

Syrup Preservation

Three Methods Maintain high sucrose Conc.

Not less than 85 g sucrose in 100 mL water Store at low temp Antimicrobial preservative

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

Components Cont.

Flavorant Synthetic and naturally Volatile oils

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

Colorant To make more appealing E.g.

Green with mint Brown with chocolate