DISPERSED SYSTEMS

INTRODUCTION

 Pharmaceutical dispersed systems are formulations that contain two or more immiscible
components, such as oil and water. These systems, which might include emulsions, suspensions,
and liposomes, are used to increase the solubility, bioavailability, and stability of medications.
 Dispersed systems consist at least two phases, the
substance that is dispersed known as the dispersed (or) internal phase and a continuous (or)
external phase. Each phase can exist in solid, liquid, or gaseous state.

CLASSIFICATION OF COLLOIDS

i. Based on physical state of dispersed phase and dispersion medium

ii. Based on nature of interaction between dispersed phase and dispersion medium

LYOPHILIC LYOPHOBIC ASSOCIATION

(AMPHIPHILIC)
Disperse phase contains large Dispersed phase Dispersed phase consists of
organic molecule lying contains inorganic aggregates of small organic
within colloidal range. particles Ex: Gold molecules or ions whose size is
below the colloidal range.
Molecules of the dispersed Small interaction Hydrophilic or liphilophilc
phase is solvated i.e. they are (solvation) between portion of the molecule is
associated with the molecules particles and dispersion solvated depends on solvent
adjust with dispersion medium. system.
medium.
Dispersion are generally These dispersions are CMC can be reduced by addition
stable in presence unstable even in small of electrolyte
electrolytes concentration of
 electrolytes
iii. Based on molecular size in the dispersed phase

Class Size range Example

Molecular dispersion < 1 nm Glucose solution
Colloidal dispersion 1 nm – 0.5 μm Gold sol, acacia mucilage
Coarse dispersion > 0.5 μm Pharmaceutical suspension

Class Characteristic Example

Multimolecular Individual particles of dispersed phase consist Gold sol
of aggregates of atoms or small molecules.
Macromolecular The particles of dispersed phase are sufficiently Starch
large to be colloidal solution. These are called
natural polymers.

iv. Based on appearance of colloids

Class Characteristic Example

Sols Fluid. Glucose
When dispersion medium is water, called hydrosol or aquosol. solution
When alcohol, alcosol.
When benzene, benzosol.
Gels Solid. Jelly
Viscosity varies.

v. Based on electric charge on dispersion phase

Class Characteristic Example

(+) When dispersed phase in a colloidal solution has (+) ve Metal
charge. hydroxides
(-) When dispersed phase in a colloidal solution Ag sol
has (-)ve charge.

TYPES OF DISPERSE SYSTEM

i. Molecular
• Dispersed particles lower than 1.0 nm in size.
• In this particles invisible in electron microscope
• Pass through semipermeable membranes and filter paper
• Particles do not settle down on standing
• Undergo rapid diffusion
• E.g. ordinary ions and glucose
ii. Colloidal
• Dispersed particles lower than 1.0 nm to 0.5 μm in size.
• In this particles not resolved by ordinary microscope.
• Passes through filter paper but not pass through semipermeable membrane.
• Particles made to settle by centrifugation.
• Diffuse very slowly.
• E.g. magmas and gels

iii. Coarse
• Dispersed particles greater than 0.5 μm in size.
• In this particles are visible under ordinary microscope.
• Do not pass through filter paper or semipermeable membrane.
• Particles settle down under gravity.
• Do not diffuse.
• E.g. suspensions and emulsions

ADVANTAGES & DISADVANTAGES

Advantages Disadvantages
Smaller infused volume Expensive
Prolonged plasma volume concentration Coagulopathy
Minimal peripheral oedema Pulmonary oedema
Anaphylactoid reactions

SIZE AND SHAPE OF COLLOIDS

• The physical stability of disperse systems is determined by forces of interaction between the
particles including:
i. Electrical double layer interaction
ii. Van der Waals attraction
iii. Solvation forces
iv. Steric repulsion arising from adsorbed polymeric material

• Particles lying in the colloidal size have large surface area when compared with the surface area
of an equal volume of larger particles.

• Specific surface: The surface area per unit weight or volume of material.

• The possession of large specific surface results in:

a) Platinium is effective as catalyst only when found in colloidal form due to large surface area
which adsorb reactant on their surface.
b) The color of colloidal dispersion is related to the size of the particles.

• The shape of colloidal particles in dispersion is important.

• The more extended the particle the greater its specific surface the greater the attractive force
between the particles of the dispersed phase and the dispersion medium.
• Flow, sedimentation and osmotic pressure of the colloidal system is affected by the shape of
colloidal particles.
• Even particle shape may also influence the pharmacologic action.

• Some common colloidal systems:

a) Aerosol (Liquid or Solid in Gas)
b) Foam (Gas in Liquid)
c) Emulsion (Liquid in Liquid)
d) Sol (Solid in Liquid)
e) Smoke (Solid in Gas)
f) Fog (Liquid in Gas)

Types of Colloids

i. Lyophilic colloids

• Lyophilic colloids are solvent loving.

• The particles in a lyophilic system have a great affinity for the solvent.
• If water is the dispersing medium, it is often known as a hydrosol or hydrophilic.
• These are readily solvated (combined chemically or physically, with the solvent) and dispersed,
even at high concentrations.
• The dispersed phase does not precipitate easily.
• If the dispersion medium is separated from the dispersed phase, the sol can be reconstituted by
simply remixing with the dispersion medium.
• Hence these sols are called reversible sols.
• Prepared simply by dissolving the material in the solvent being used.
• E.g. Sols of gum, gelatin, starch, proteins and certain polymers (rubber) in organic solvents and
Dissolution of acacia in water
ii. Lyophobic Colloids

• The particles resist solvation and dispersion in the solvent.

• The concentration of particles is usually relatively low.
• Less viscid (sticky).
• These colloids are easily precipitated on addition of small amounts of electrolytes, by heating
or by shaking.
• Once precipitated, it is not easy to reconstitute the sol by simple mixing with the dispersion
medium.
• Hence these sols are called irreversible sols.
• E.g. Sols of metals and their insoluble compounds like sulphides and oxides

iii. Association Colloids

• Molecules or ions which have affinity for both polar and non-polar solvents.
• Via formation of micelles.
• Below CMC, amphiphiles are adsorbed at the air/water interface.
• As amphiphiles concentration increases, both the interphase and bulk phase become saturated
with monomers.
• Any further addition leads to CMC.
• Amphiphiles then aggregate to form micelles.
 LYOPHILIC LYOPHOBIC ASSOCIATION
(AMPHIPHILIC)
Disperse phase contains large Dispersed phase Dispersed phase consists of
organic molecule lying contains inorganic aggregates of small organic
within colloidal range. particles Ex: Gold molecules or ions whose size is
below the colloidal range.
Molecules of the dispersed Small interaction Hydrophilic or liphilophilc portion
phase is solvated i.e. they are (solvation) between of the molecule is solvated depends
associated with the molecules particles and dispersion on solvent system.
adjust with dispersion medium.
medium.
Dispersion are generally These dispersions are CMC can be reduced by addition of
stable in presence unstable even in small electrolyte
electrolytes concentration of
electrolytes

Applications

i. Therapeutic Use: Copper colloid for cancer and mercury colloid for syphilis
ii. Stability: Prevention of flocculation
iii. Absorption enhancement: Sulphur colloid is used for absorption enhancement.
iv. Targeted drug delivery: Colloids are also used for liver and colon targeting

v. Blood clotting: Blood is a colloidal solution and is negatively charged. Due to high content of
proteins, on applying a solution of FeCl 3, bleeding stops as Fe3 +¿¿ ions neutralize the ion charges
on the colloidal content of blood.

PROPERTIES OF COLLOIDAL DISPERSION

 Size
• Within the size range of colloidal dimensions is often a wide distribution of sizes of the
dispersed colloidal particles.
• The molecular weight or particle size is therefore an average value, the magnitude of which is
dependent on the experimental technique used in its measurement.
• When determined by the measurement of colligative properties such as osmotic pressure, a
number average value, M n, is obtained which, in a mixture containing n1 , n2 , n3 , … moles of
particle of mass M 1, M 2, M 3, … respectively, is defined by:

n1 M 1 +n2 M 2+n M3 +… … … Σ ni M i
Mn = n1 +n 2+¿n … … ¿
3
= Σn i
3
• In the light-scattering method for the measurement of particle size, larger particles produce
greater scattering and the weight rather than the number of particles is important, giving a
weight-average value, Mw, defined by:

m1 M 1+ m2 M 2+m M 3+ …… …
2
Σ ni M i
Mw = m1 +m2+¿ m …… ¿
3
= Σ ni M i
3

 Shape
• Many colloidal systems, including emulsions, liquid aerosols and most dilute micellar
solutions, contain spherical particles.
• Small deviations from sphericity are often treated using ellipsoidal models.
• Ellipsoids of revolution are characterized by their axial ratio, which is the ratio of the half-axis
a to the radius of revolution b as shown in given figure.
• Where this ratio is greater than unity, the ellipsoid is said to be a prolate ellipsoid (rugby ball
shaped), and when less than unity an oblate ellipsoid (discus-shaped).
• High molecular weight polymers and naturally occurring macromolecules often form random
coils in aqueous solution. Clay suspensions are examples of systems containing plate-like
particles.

Kinetic Properties

a) Brownian Motion
• The zig-zag movement of colloidal particles continuously and randomly.
• This Brownian motion arises due to the uneven distribution of the collisions between colloid
particle and the solvent molecules.
• Brownian movement was more rapid for smaller particles.
• It decreases with increase the viscosity of medium.

b) Diffusion
• As a result of Brownian motion, colloidal particles spontaneously diffuse from a region of
higher concentration to one of lower concentration. The rate of diffusion is expressed by Fick’s
First Law.

dm dC
dt
= - DA dx
c) Sedimentation
• Consider a spherical particle of radius a and density σ falling in a liquid of density ρ and
viscosity η. The velocity v of sedimentation is given by Stokes’ Law:

v= 2a 2g (σ- ρ )/9η

• If the particles are only subjected to the force of gravity, then, due to Brownian motion, the
lower size limit of particles obeying the equation is about 0.5 µm.

• A stronger force than gravity is therefore needed for colloidal particles to sediment and use is
made of a high-speed centrifuge, usually termed an ultracentrifuge, which can produce a force of
about 106 g.

• In a centrifuge, g is replaced by ω2x, where ω is the angular velocity and x the distance of the
particle from the center of rotation.

d) Osmotic pressure
• Limited to a molecular weight range of about 104−106 Da.
• Below 104 Da the membrane may be permeable to the molecules under consideration.
• Above 106 Da the osmotic pressure will be too small to permit accurate measurement.
• If a solution and solvent are separated by a semi-permeable membrane, the tendency to equalize
chemical potentials (and hence concentrations) on either side of the membrane results in a net
diffusion of solvent across the membrane.

• The pressure necessary to balance this osmotic flow is termed the osmotic pressure.

• For a colloidal solution the osmotic pressure, Π, can be described by:

Π /¿C=RT/M+BC

• Where C is the concentration of the solution, M the molecular weight of the solute and B a
constant depending on the degree of interaction between the solvent and solute molecules.

e) Viscosity
• Viscosity is an expression of the resistance to flow of a system under an applied stress.
• Constants are obtained initially by determining [η] for a polymer fraction whose molecular
weight has been determined by another method such as sedimentation, osmotic pressure or light
scattering.
• The molecular weight of the unknown polymer fraction may then be calculated.
• This method is suitable for use with polymers, such as dextran used as blood plasma
substitutes.

Optical Properties

a) Light scattering
• The same effect when a beam of sunlight enters a dark room through a slit.
• This happens due to the scattering of light by particles of dust in the air.
Faraday-Tyndall effect

• When a strong beam of light is passed through a colloidal sol, the path of light is illuminated (a
visible cone formed).
• This phenomenon results from the scattering of light by the colloidal particles.
• Unlike solutions, colloidal suspensions exhibit light scattering.

b) Ultramicroscopy
• Colloidal particles are too small to be seen with an optical microscope.
• Light scattering is employed in the ultramicroscope first developed by Zsigmondy, in which a
cell containing the colloid is viewed against a dark background at right angles to an intense beam
of incident light.
• The particles, which exhibit Brownian motion, appear as spots of light against the
dark background.
• The ultramicroscope is used in the technique of microelectrophoresis for measuring particle
charge.

c) Electron microscopy`
• Capable of giving actual pictures of particles.
• Used to observe the size, shape and structure of colloidal particles.
• The high resolution is defined in terms of d, the smallest distance by which two objects are
separated yet remain distinguishable.
• The smaller the wavelength of the radiation used, the smaller is d and the greater the resolving
power.
• An optical microscope uses visible light as its radiation source and has as a diameter of about
0.2 µm.
• Radiation source is a beam of high-energy electrons with an wavelengths of 0.01 nm and has a
diameter of about 0.5 nm.
• Beams are focused using electromagnets.
• The whole system is under a high vacuum.
• Only dried samples can be examined.
• A recent development which overcomes these problems is environmental scanning electron
microscopy (ESEM).

Electric Properties

• The particles of a colloidal solution are electrically charged and carry the same type of charge,
either negative or positive.
• The colloidal particles therefore repel each other and do not cluster together to settle down.
• The charge on colloidal particles arises because of the dissociation of the molecular
electrolyte on the surface.
• Zeta potential is the indicator of the net electric charge on the colloidal system & their stability.

a) Ion dissolution
• Ionic substances can acquire a surface charge by virtue of unequal dissolution of their
oppositely charged ions.
• H +¿¿ and OH −¿¿ are potential-determining ions for metal oxides and hydroxides.
• They determine the electric potential at the particle surface.

b) Ionization
• The charge is controlled by the ionization of surface groupings.
• E.g. polystyrene latex having carboxylic acid at the surface which ionizes to give negatively
charged particles.
• The ionization of these groups and so the net molecular charge depends on the pH of the
system.
• At a certain definite pH, specific for each individual protein, the total number of positive
charges will equal the total number of negative charges and the net charge will be zero. This pH
is termed the isoelectric point of the protein, and the protein exists as its zwitter ion.
• A colloidal preparation of protein is least soluble at its isoelectric point and is readily
desolvated by very water-soluble salts such as ammonium sulfate.
• Thus, insulin may be precipitated from aqueous alcohol at pH 5.2.

c) Ion adsorption
• A net surface charge can be acquired by the unequal adsorption of oppositely charged ions.
• Surfaces in water are often negatively charged than positively charged, because cations are
generally more hydrated than anions.
• Consequently, the former have the greater tendency to reside in the bulk aqueous medium
whereas the smaller, less hydrated and more polarizing anions have the greater tendency to
reside at the particle surface.
• Surface-active agents are strongly adsorbed and have a pronounced influence on the surface
charge, imparting either a positive or negative charge depending on their ionic character.

d) Electric double layer

• The surface charge on solid influences the distribution of ions in the aqueous medium.
• Ions of opposite charge to that of the surface, termed counter-ions, are attracted towards the
surface.
• Ions of like charge, termed co-ions, are repelled away from the surface.
• However, the distribution of the ions will also be affected by thermal agitation which will tend
to redisperse the ions in solution.
• Hence, electric double layer is formed.

• The double layer is divided into two parts:

i. The inner, which may include adsorbed ions
ii. The diffuse part where ions are distributed as influenced by electrical forces and random
thermal motion

• The two parts of the double layer are separated by a plane, the stern plane, at about a hydrated
ion radius from the surface.
• Thus, counter-ions may be held at the surface by electrostatic attraction.
• The center of these hydrated ions forms the stern plane.

**************** Heterogeneous Colloidal Dispersion True

Dispersion Solution
Pass Through - Semipermeabil does +
Membrane not pass
Visibility of Particles Eye, Optical microscope Electron Microscope -
Sedimentation + Ultracentrifugation -
Thermal motion Small Middle High
Colligative Properties - Small High
Difuse - Slow Fast
Optical Properties Frequently opaque Opalescent (Tyndall Transparent
Effect)
Separability Paper Filters Membrane Filters None
GEL

 The gel is a semi-solid preparation.

 Dispersion of small and large molecules in aqueous liquid carriers.
 Physical or covalent interactions occur between colloidal particles within a
liquid carrier.  Gelling agent is used to give them a gelatinous consistency.
 The gels are formed using synthetic polymers such as Carbomer
934 and celluloses such as hydroxypropyl cellulose and hydroxypropyl methylcellulose,
tragacanth gum, pectin and natural agar gum are used in the gel formula.
 Gel is also defined as semi-rigid systems in which the movement of the
dispersing medium is restricted by an interlacing 3D network of particles or solvated
macromolecules of the dispersed phase.
 A high degree of physical or chemical cross-linking can be involved.
 Chemical cross-links are usually covalent bonds.
 Physical cross-links are weak interactions.
 Sodium alginate gels when exposed to calcium ion, due to the formation of ionic bonds that
bridge alginate chains.
 Gelatin, collagen, agarose, and agar agar form physical cross-links.

 Some gel systems are as clear as water while certain gels are turbid because the ingredients
may not be completely molecularly dispersed (soluble or insoluble), or they may form
aggregates, which disperse light.
 Concentration of gelling agents is usually < 10% i.e. usually, 0.5 to 2% range.
 Gels in which the macromolecules are distributed so that no apparent boundaries exist
between them are called single-phase gels.
 When the gel mass consists of floccules of small, distinct particles, the gel is classified as a
two-phase system and frequently called a magma or a milk.
 Gels and magmas are considered colloidal dispersions because they contain particles of
colloidal dimension.
CHARACTERISTICS OF GEL

 Have large proportion of water and water is the vehicle for drug solubility.
 Used topically or in body cavities.
 Either clear or turbid preparations depending on ingredient solubility.
 Can thicken on prolonged storage.

IMPORTANT TERMINOLOGIES

Imbibition: The taking up of a certain amount of liquid without a measurable increase in

volume.

Swelling: The taking up of a liquid by a gel with an increase in volume. Only liquids that solvate
a gel can cause swelling. The swelling of protein gels is influenced by pH and the presence of
electrolytes.

Syneresis: Syneresis occurs when the interaction between particles of the dispersed phase
becomes so great that on standing, the dispersing medium is squeezed out in droplets and the gel
shrinks. Syneresis a form of instability in aqueous and non-aqueous gels. Separation of a solvent
phase is thought to occur because of the elastic contraction of the polymeric molecules.
Macromolecules swell during gel formation which increases the elastic forces.

Thixotropy: A reversible gel–sol formation with no change in volume or temperature, a type of

non-Newtonian flow.

Xerogel: Xerogel is formed when the liquid is removed from a gel and only the framework
remains. E.g. Gelatin sheets and tragacanth ribbons.

ADVANTAGES

1. Gels are used to achieve optimal cutaneous and percutaneous drug delivery.
2. They can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH.
3. Gels are having property to avoid enzymatic activity and drug interaction
with food and drinks. 4. They can substitute for oral administration of medication when the route
is unsuitable. 5. They can avoid the first pass effect, that is, the initial pass of drug
substance through the human body.
6. They avoid systemic and portal circulation following gastrointestinal absorption.
7. Gels are not deactivated by liver enzymes because the liver is bypassed.
8. They are non-invasive and have patient compliance.
9. They are applied over skin for slow and prolonged absorption.
10. Gels have also been applied in pharmacy to some viscous suspension for oral use for
example Aluminium hydroxide gel.
11. They have localized effect with minimum side effects.

DISADVANTAGES

1. Gels have possibility of allergenic reactions.

2. Enzyme in epidermis may denature the drugs of gels.
3. Drugs of larger particle size do not absorb through the skin.
4. They have poor permeability of some drugs through the skin.
5. Selection of area to be examined carefully during application of gels.
6. Gels which are used for the introduction into body cavity, or the eyes should be sterilized.
7. They may cause application side reactions.
8. They may cause skin allergy during application.

CLASSIFICATION

i. Single-phase: Hydrogels, Xerogels, Organogels

ii. Double-phase

SINGLE-PHASE GEL SYSTEM

 Called as single-phase or one-phase system as there is no definite boundary between dispersed

macromolecules and the liquid.
 Gelling agent is soluble in dispersion liquid.
 E.g. hydrophilic polymers.
 It has a clear appearance.
 It has pseudoplastic flow.
 High molecular weight polymer is used as gelling agents.

DOUBLE-PHASE GEL SYSTEM

 Called as double-phase or two-phase system as there is definite boundary between dispersed

macromolecules and the liquid.
 Gelling agent is insoluble in dispersion liquid.
 E.g. Aluminum hydroxide gel.
 It has a turbid appearance.
 It exhibits thixotropic flow.
 Contain gelatinous cross-linked precipitate of one substance in the aqueous phase.

SINGLE-PHASE SUB-CLASSIFICATION

1. Hydrogels
 A network of polymer chains that are hydrophilic.
 Sometimes found as a colloidal gel in which water is the dispersion medium.
 These are highly absorbent natural or synthetic polymeric networks.
 They possess a degree of flexibility to a natural tissue.
 Due to high water content it can be as high as 90%.
 Commonly includes polyvinyl alcohol, sodium polyacrylate, acrylate polymers and co-
polymers.

Uses of Hydrogels
 They can be used as scaffolds in tissue engineering and as environment sensitivity detector
 They can be used on sustained release DDS, contact lenses, ECG medical electrode and Glue

2. Xerogels
 They can be described as dried gels.
 These are open networks formed by the removal of all swelling agents from gel.
 Retain high porosity of 15-50%.
 Large surface area.
 Very small pore size range of 1-10 nm.

3. Organogels
 Non-crystalline, non-glassy thermo-reversible (thermoplastic) solid material.
 They are composed of a liquid organic phase.
 Phase is entrapped in a 3D cross-linked network.
 Liquid could be an organic solvent, mineral oil, or vegetable oil.
 Based on self-assembly of structuring molecules.

PROPERTIES OF GELS

 Gelling agent must be inert, safe, and unreactive with other ingredients.
 Gelling agent must produce a solid-like nature on storage which is easily broken when
exposed to shear forces produced by squeezing, shaking, or application.
 Should allow for incorporation of suitable antimicrobial agents.
 Topical gel must not be sticky.
 Ophthalmic gel must be sterile.
 The viscosity or gel strength increases with increase in the effective cross-link density of the
gel. The gel remains uniform on prolonged storage and does not freely settle.

JELLIES
 A class of gels.
 Structurally coherent matrix contains a high proportion of liquid i.e usually water.
 Transparent, translucent, or non-greasy.
 Intended for internal or external application.
MEDICATED JELLIES
 Mainly used on mucous membrane and skin.
 Solvent evaporates leaving behind a residual film.
 E.g. Ephedrine sulphate jelly is used as a vasoconstrictor.

LUBRICATING JELLIES
 For lubrication of diagnostic equipment.
 Eg. Surgical gloves, cystoscopes, catheters

MISCELLANEOUS JELLIES
 These are meant for various applications.
 Eg. Patch testing, electrocardiography

ADVANTAGES
 They are easy administration.
 They are easier for patients who have problems swallowing solid formulations.
 They are convenient for disabled and bedridden patients.
 They allows high drug loading.
 They have rapid onset of action.

EXCIPIENTS USED ON JELLIES PREPERATION

i. Gelling agent: Pectin, Tragacanth, Gelatine, Gums (Xanthan, gellan), Carrageenans, Sodium
alginate, Cellulose derivatives

ii. Stabilizers: Propylene glycol, Sorbitol

iii. Preservatives: Parabens (Methyl, Propyl), Benzalkonium chloride, Sodium benzoate

PREPARATION OF GELS

 The process of gel formation involves finding a balance between the concentrations of the
gelator and the solvent.
 Initially when gelator is added to the solvent, the mixture remains liquid.
 As the concentration of the gelator increases to a certain critical concentration (gelling point),
gelation occurs through swelling to form the semi-solid gel.
 Further increasing the concentration of the gelator beyond the gelling point will increase gel
viscosity.
 The exact gelling point varies depending on the properties of the gelator and the solvent such
as molecular weight of the polymer and flexibility of the polymer chain.

GENERAL PREPARATION STEPS

 Dissolve solid excipients in the solvent.

 Mix the solution using a mechanical stirrer.
 The gelator is added slowly to the stirred mixture to avoid aggregation.
 Stirred continuously until the polymer dissolves and a gel forms.
 Gel is allowed to settle for 1-2 days to reach final consistency.
FORMULATION COMPONENTS

1. Gelling agents
Usually organic hydrocolloid polymers.
Sometimes hydrophilic inorganic substances are also used.

Natural: Tragacanth, Starch, Pectin, Gelatin, Carrageenan

Semi-synthetic: Micro-crystalline HPMC, CMC, Sodium CMC
Synthetic/Acryclic: Polyacrylic acids

2. Preservatives
 Since gels are susceptible to microbial growth.
 E.g. Parabens, benzoic acid, chlorocresol

3. Hygroscopic agents
 After application of gel on skin, solvent evaporates.
 Leads to formation of flakes on skin.
 Hygroscopic agents are added to prevent this.
 E.g. Glycerin, sorbitol, propylene glycol

4. Chelating agents
 Form complexes with heavy metals.
 They deactivate the heavy metals and prevent degradation of dosage form.
 E.g. Ethylene diamine tetra acetic acid (EDTA)

CLASSIFICATION OF PREPARATION OF GEL

1. Thermal
 Lipophilic colloids form gelatin when subjected to thermal changes.
 Many are more soluble in hot water than cold.
 When temperature is reduced, the degree of hydration is reduced, and gelatin occurs.
 E.g. Gelatin, agar sodium oleate, cellulose derivatives

2. Flocculation
 Gelation is produced by adding enough salt to precipitate, but not enough to induce complete
precipitation.
 Rapid mixing is essential to avoid pockets of high concentrations of precipitant.
 E.g. Solution of ethyl cellulose, polystyrene in benzene can be gelled by rapid mixing with
suitable amounts of a non-solvent such as petroleum jelly.
 Addition of salts to hydrophobic solution causes coagulation and gelation is rare.

3. Chemical reaction
 Gelling is induced by chemical reactions between solute and solvent.
 E.g. Aluminum hydroxide gel is prepared by interaction in aqueous solution of aluminum salt
and sodium carbonate.
PREPARATION METHODS

1. Fusion method
 Various waxy materials are used as gelling agents.
 These are melted.
 The drug is added after the waxy materials are fluid enough.
 Stirred slowly until gel is formed.

2. Cold method
 Water is cooled to 4-10 0C.
 Gelling agent is slowly added and agitated until solution is formed.
 Temperature is maintained below 100 0C for the entire process.
 Drug is slowly added to the solution with gentle stirring.
 Left to stand at room temperature and become gel.

3. Dispersion method
 Gelling agent is dispersed in water.
 Stirred at 1200 rpm for 30 minutes.
 Drug is dissolved in a non-aqueous solvent with preservatives.
 The drug solution is added to the gelling agent solution with continuous stirring.

EVALUTION PARAMETERS

1. Physical Evaluation
 Examined physically for appearance.
 Should be clear with the right texture.
 May contain colour and if coloured, should have uniform colouring.
 Transparent.
 Should have the right consistency.

2. Stickiness & Grittiness

 Can be determined by mildly rubbing jelly between fingers.
 Checked for stickiness and grittiness.
 Excessive stickiness

3. PH
 PH should be maintained to ensure proper gel consistency.
 Checked using digital pH meter.
 0.5 g of jelly is dispersed in 50 ml of water.

4. Viscosity
 Jellies should have the right viscosity.
 Excessive viscosity can retard drug release.
 It can also make the dosage form unpalatable.
 Suboptimal viscosity can render the dosage form moot.
 Determined by using Brookfield viscometer.
5. Spreadability
 Topical preparation must have good spreadibility.
 25 gm placed between two slides.
 Compressed by keeping 1000 g weight for 5 minutes.
 Time taken to separate is recorded.
 Less time means better spreadibility

6. Drug Content
 The amount of API in a stated amount of jelly must be as stated.
 Jellies are crushed in a mortar and the mixture equivalent to the drug is dissolved in 100 ml
volumetric flask.
 6.8 pH buffer is used, and volume is made up to the mark.
 The solution is then filtered and analysed spectrophotometrically.

7. Extrudability Study
 Formulations are filled in a collapsible tube.
 Based on the quantity of gel in percentage and the gel extruded from the collapsible tube on
application of weight in grams required to extrude at least a 0.5 cm ribbon of gel in 10 seconds.

8. Skin Irritation Study

 Albino mice are used.
 Hair is removed from the backs 3 days prior.
 2 batches of animals.
 Gel containing API is applied on the backs.
 A piece of cotton wool soaked in the saturated drugs solution is placed on the back as control.
 Treated daily for 7 days.
 Skin is visually examined for erythema and oedema.

9. In-vitro Dissolution Study

 Involves the use of a diffusion cell.
 Animal or human skin is fastened using a holder.
 Passage of compounds from the epidermal surface to a fluid bath is measured.

10. Stability Study

 Freeze-thaw cycling is performed.
 Product is exposed to 4 0C temperature for a month.
 Followed by 250 C for a month.
 Finally, at40 0C for a month and observed for syneresis.
 Then exposed to room temperature.
Suspension

 A heterogenous system.
 A coarse dispersion of drug.
 Contain two phases i.e. Continuous/ external phase &
Dispersed/internal phase.
The two phases are insoluble for each other.
Size range 0.5 to 5 μ.
 Size range maintained throughout the vehicle.

Continuous/External Dispersed/Internal
Liquid/semi-solid Solid particulate
Vehicle/solvent Intended for physiologic action

INTERNAL PHASE EXTERNAL PHASE

 Consists of particulate matter.  Aka suspending medium.
 Essentially insoluble. Generally aqueous.
Dispersed uniformly throughout continuous phase.  May be organic or oily liquid
Using single or combination of suspending agents. for external use.

REASON FOR SUSPENSION

i. When the drug is insoluble in vehicle.
ii. To mask unpleasant taste of drug.
iii. To increase drug stability.
iv. To achieve controlled or sustained release.

TYPES
Suspensions can be classified based on various parameters.
i. Physical state

 Liquid- Alumina
 Aerosol- Salbutamol inhalation
 Foam- Hydrocortisone acetate

ii. Proportion of solid particles

 Dilute- Cortisone acetate, Prednisolone acetate
 Concentrated- Zinc oxide

iii. Size of dispersed particles

 Molecular- Particle size < 1 nm.
 Colloidal- Particle size between 0.1-0.2 μ.
 Coarse- Particle size > 0.2 μ.

iv. Route of administration

 Oral- Paracetamol suspension
 Topical- Calamine lotion (Dispersed phase is usually in high conc. of > 20% w/v)
 Parenteral- Procaine penicillin G suspension (Conc. between 0.5-5 % w/v)

v. State of dispersed phase

 Flocculated- Suspended particles form agglomerates.
 Deflocculated- Discrete suspended particles.

FLOCCULATED DEFLOCCULATED
Form light fluffy agglomerates. Remain as individual particles.
Rate of sedimentation is faster. Rate of sedimentation is slower.
Sediment does not form hard cake. Sediment forms dense hard cake.
Redistribution on shaking is easy. Redistribution on shaking is hard.
Sediment volume is high. Sediment volume is low.
Supernatant liquid becomes clear. Supernatant liquid remains cloudy.

Pharmaceutical suspension classification based on indication:

i. Antacid oral suspension
ii. Antibacterial oral suspension
iii. Dry powders for oral suspension
iv. Analgesic oral suspension
v. Anthelmintic oral suspension
vi. Anticonvulsant oral suspension
vii. Antifungal oral suspension

APPLICATIONS
 Usually applicable for drugs which are insoluble or poorly soluble.
E.g., Prednisolone suspension.

 To prevent degradation or improve stability of drugs.

E.g., Oxytetracycline suspension.
 To mask bitter taste.
E.g., Chloramphenicol palmitate suspension.
 Can be formulated for topical application.
E.g., Calamine lotion.
 Can be formulated for parenteral application and control absorption rate.
 Vaccines can be formulated as suspensions.
E.g., Cholera vaccine.
 X-ray contrast agents as suspensions.
 Clear visualisation during x-ray examinations.
 Suspensions are administered orally.
E.g., Barium sulphate.
 Pleasing odour, colour, and flavour.
E.g., Levocetirizine syrup for children.

IDEAL PROPERTIES OF SUSPENSION

 No dense hard cake formation from sediments.
 Chemical stability.
 Smooth texture.
 Free from gritty particles.
 Easy and rapid redispersion of sediment cake on vigorous shaking.
 Homogenous dispersion of solute for dose uniformity.

PROPERTIES OF SUSPENSION
1. Sedimentation
 Settling of particles or floccules.
 Under the influence of gravitational force.
 Stokes equation is used for studies.
Limitations:
a. Applies to only spherical particles in a very dilute suspension i.e. 0.5 to 2 gm per 100 ml.
b. Applies to only particles which settle freely without collision.
c. Applies to only particles with no physical or chemical attraction.

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

 Ratio of the ultimate volume of sediment (Vu) to the original volume (Vo) before settling.
 F= Vu/Vo
Vu: Final or ultimate volume of sediment
Vo: Original volume of suspension before settling
 Value of F ranges from -1, 0, and +1.
 F<1 means Vu<Vo.
 F=1 means Vu=Vo.
 F<1 or F=1, system is in flocculated equilibrium.
 Shows no clear supernatant on standing.

 F>1 means Vu>Vo.

Sediment volume is greater than the original volume.
Due to the network of floccules formed.
These floccules form loose and fluffy sediment.

 Sedimentation volume is a qualitative parameter.

2. Degree of flocculation
 Ratio of sedimentation volume of the flocculated suspension (F) to the sedimentation volume
of the deflocculated suspension (Fꚙ).
 β= F/Fꚙ
Or
 β= {(Vu/Vo)flocculated}/{(Vu/Vo)deflocculated}
 Minimum value is 1.
1 when F is equal to Fꚙ.

3. Brownian motion
 Prevents sedimentation.
 Keeps dispersed particles in random motion.
 Brownian motion depends on:
a. Density of the dispersed phase
b. Density of dispersion medium
c. Viscosity of dispersion medium
 Inter-molecular contact keeps the solute particles suspending.
Solute particle size should not be below critical radius

 Criteria for Brownian motion:

a. Particle size range is 2 to 5 mm.
b. Density of particle is favourable.
c. Viscosity of medium is favourable.

Equation : Di²= RTt/N3πηr

R- gas constant, r- radius of the particle
T- Temp. in degree Kelvin, t- time
N- Avogadro’s number
η- viscosity of medium

4. Zeta potential
 Difference in potential between the surface of tightly bound layer and electro-neutral solution.
 Tightly bound layer is called shear plane.
 Potential drops off rapidly at first.
Followed by gradual decrease as distance increases.
 Ions close to surface act as screen and reduce electrostatic attraction.
 Governs the degree of repulsion between adjacent similarly charged particles.
 Particle is surrounded by oppositely charged particles- fixed/stern layer.
 The ions in this layer move with the surface.

 The surface charge is not completely balanced by the stern layer.

A second layer is required.
This layer is called the diffuse layer.
Contains both (+) and (-) ions.
But opposite charge to the surface predominates.
A net charge opposite to surface exists.

 Study of electrical double layer is required due to the use of ionic surfactants.
These contain charged surfaces to form a stable suspension.

 Zeta potential affects stability of dispersed

systems.
 If reduced below a certain level, attractive
forces exceed repulsive forces.
 Particles come together to form floccules.
 Flocculated suspension occurs in zeta potential
between -20 to +20 mV.
 Diffuse layer lies between stern later and
slipping plane.
 Electro-neutral layer lies beyond slipping
plane.
5. Particle size
 Critical for any suspension.
 Must be reduced within range.
 Neither too large nor too small.
 Large particles:
a. Sediment faster.
b. Size > 5 μ impart gritty texture and cause irritation.
c. Size > 25 μ can prohibit syringe uptake.
 Too small a particles can form hard cakes.

6. Wetting of particles
 Hydrophilic materials- talc, ZnO
 Hydrophobic materials- sulphur, charcoal

 Layer of adsorbed air on the surface.

Particles float on the surface until layer of air is displaced.
Wetting agent removes the air layer.
Allows the vehicle to penetrate the solute particles.

 Hydrophobic materials are easily wetted by non-polar liquids.

 Wetting agents- surfactant, hydrophilic colloids, solvents.
 Reduction in particle size increases surface area. This makes the system thermodynamically
unstable.
 They system tends to approach a stable state by reducing the surface free energy to zero.
 This can be achieved by:
a. Decreasing the interfacial area either by flocculation or aggregation.
b. Decreasing the interfacial tension.

Surfactant
 HLB value between 7 and 9.
 Hydrocarbon chain is adsorbed by hydrophobic part.
Polar group projects out into aqueous medium.
 Wetting occurs due to reduction in interfacial tension.
 Usual surfactant conc.- ~ 0.1%.

Oral use- Polysorbates (Tween) and sorbitan (Span)

External- Sodium lauryl sulphate (SLS)
Parenteral- Polysorbates, poloxamers (polyoxyethylene),
and lecithin

Hydrophilic colloids
 Materials such as acacia, bentonite, tragacanth, alginates, xanthan gum, etc.
 Behave as protective colloids.
Coat the solid hydrophobic particles.
 Multi-molecular layer.
 Imparts hydrophilic character and promotes wetting.
 May act like surfactants.
May cause deflocculation.
At low concentrations.

Solvents
 Materials such as alcohol, glycerol, and glycol.
 Water miscible.
 Reduces liquid-air interfacial tension.
 Solvent penetrates loose agglomerates of powder.
 Displaces air from pores.
 Enables wetting to occur by dispersion medium.
 Alcohol, glycerine, propylene glycol are used as wetting agents.
When aqueous vehicles are used.

ADVANTAGES
 Can mask unpleasant/bitter taste of drug.
 Higher rate of F than other dosage forms.
Solution > suspension > capsule > Compressed tablet > Coated tablet
 Can improve chemical stability of certain drugs.
 Duration and onset of action can be controlled.
E.g., protamine zinc-insulin suspension.
 Easier route of administration.

DISADVANTAGES
 Physical instability
Sedimentation
Compaction
 Bulky packaging requires special care while handling and transport.
Difficult to carry around.
 Relatively more difficult to formulate.
Dose uniformity cannot be ensured.
 Accurate dose cannot be ensured.