Course Name: Pharmaceutical Technology-I

Course Code: Phrm 3125

 Emulsion

• “An emulsion is a biphasic system consisting of two immiscible (or

partially miscible) liquids, one of which is distributed uniformly in the
form of fine droplets (the dispersed phase) throughout the other phase
(the continuous phase)”.
• Since emulsions are a thermodynamically unstable system, a third
agent, the emulsifier is added to stabilize the system”.

• The particle size of the globules ranges from 0.25 to 25 µm. An

emulsifying agent and mechanical energy are needed to join the phases.
• The dispersed phase is the internal phase or discontinuous phase and
the dispersion medium is the external phase or continuous phase.
 Advantages and disadvantages of emulsion dosage form

Advantage of emulsion dosage form Disadvantage of emulsion dosage form:

• The unpleasant taste or odor can be • Emulsions are thermodynamically
masked by emulsification. unstable and have short shelf-life.
• Improved bioavailability. • Emulsions are difficult to prepare.
• Sustained Release medication. • Choice of suitable emulsifying
• Used for intravenous administration agent is difficult.
of lipid nutrients.
• External application e.g., lotion,
cream.
• Patient acceptance.
 Types of Emulsion

1. Based on dispersed phase

• Oil in Water (O/W): Oil droplets dispersed in water.
• Water in Oil (W/O): Water droplets dispersed in oil.
• Multiple emulsions (e.g. w/o/w emulsions).
2. Based on mode of administration:
• Oral: castor oil, liquid paraffin.
• External: o/w or w/o of emulsion.
• Parenteral: Vitamins
• Rectal: enema.
3. Based on particle size
• Macroemulsions (0.2 – 50 mm)
• Microemulsions (0.01 – 0.2 mm)
• Nano-emulsions (50 – 1000 nm)
 Differences between O/W and W/O Emulsions

Oil in Water Water in oil

Water is the dispersion medium and oil is the Oil is the dispersion medium and water is the
dispersed phase. dispersed phase.
Water soluble drugs are more quickly released Oil soluble drugs are more quickly released
from O/W type emulsions. from W/O type emulsions.
They are preferred for formulations meant for They are preferred for formulations meant for
internal use as bitter taste of oils can be masked. external use like creams.
They are non-greasy and easily removable from They are greasy and not water washable.
the skin surface.
They are used externally to provide cooling They are used externally to prevent evaporation
effect e.g. Vanishing cream of moisture from the surface of skin e.g. Cold
cream.
O/W type emulsions give a positive conductivity W/O type emulsions do not give a positive
test as water is the external phase which is a conductivity test as oil is the external phase
good conductor of electricity. which is a poor conductor of electricity.
 Emulsifying Agents

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.

Emulsion assist in formation of emulsion by three mechanisms.

1. Reduction in interfacial tension – thermodynamic stabilization
2. Formation of a rigid interfacial film–mechanical barrier to
coalescence.
3. Formation of an electrical double layer–electrical barrier to approach
of particles.
 Criteria for an ideal emulsifying agents
An ideal emulsifying agent should possess 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 concentration used.
• It should be organoleptically inert i.e., should not impart any color, odor 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.
 Classification of Emulsifier/emulsifying agents

1. Natural:
a. Vegetable source: Gum acacia, tragacanth, agar, starch, pectin, iris
moss.
b. Animal source: wool fat, egg yolk, gelatin.
2. Semi synthetic: Methyl cellulose, Na CMC
3. Synthetic:
a. Anionic: Sodium Lauryl Sulphate
b. Cationic: Cetrimide, benzalkonium chloride.
c. Non-ionic: e.g., Glyceryl ester- glyceryl monoesters etc.
4. Inorganic: Milk of magnesia, Mg oxide, Mg trioxide etc.
5. Alcohols (polyols): Carbowax, cholesterol and lecithin.
 THE HLB SYSTEM

HLB (Hydrophilic-Lipophilic Balance)

• The ratio between the hydrophilic portion of the molecule to the
lipophilic portion of the molecule.
• Higher the HLB, higher the hydrophilicity and produce an o/w emulsion.
• Low HLB numbers (3-6) indicate a lipophilic molecule and produce a
w/o emulsion.

• Spans are lipophilic have low HLB

• Tweens are hydrophilic have high HLB.
Calculation of HLB: HLB scale:

Griffin Equation: HLB Value Application

HLB = 20 (1-S/A) 0-3 Antifoaming agents
Where, 4-6 W/O emulsifiers
S= Saponification of number of esters 7-9 Wetting agents
A= acid number of fatty acid 8-18 O/W emulsifiers
Davis equation: 13-15 Detergents
10-18 Solubilizers
HLB = Hydrophilic group number–
Lipophilic group number +7
 Theories of Emulsion

Oriented-
Monomolecular
Interfacial wedge or Phase volume
adsorption
Tension theory interfacial film theory
theory
theory
 1. Interfacial Tension Theory

• When two immiscible liquids come in contact, the force causing each liquid
to resist breakage is known as interfacial tension. When a high interfacial
tension existed between two liquids emulsification is difficult, and if the
tension could be reduced emulsification facilitated.

• The explanation that in oil in water dispersion, the

interfacial tension is so great that when two
globules of dispersed phase approach each other it
withdraws the liquid from between them, with the
result they coalesce. When the interfacial tension is
greatly reduced by the addition of emulsifier the
globules remain separate.
 Oriented-Wedge Theory

• Assumes monomolecular layers of emulsifying

agent curved around a droplet of the internal
phase of the emulsion. It is based on the
assumption that certain emulsifying agents orient
themselves about and within a liquid in a manner
reflective of their solubility in that particular
liquid.

• An emulsifying agent having a greater

hydrophilic character than hydrophobic character
will promote an O/w emulsion and a W/O
emulsion results through use of more
hydrophobic than hydrophilic emulsifiers.
 Oriented adsorption theory

As per this theory, the added emulsifying agent forms a mechanical film by
getting adsorption at the interface of the liquid and offers stability to
emulsion.
However, this theory could not explain the formation of type of emulsion.
 Viscosity theory

As per this theory, an increase in viscosity of an emulsion will lead to an

increase in stability. This theory failed to explain about the milk which
shows considerable stability even though its viscosity is less.
 Stability Emulsions

A stable emulsion is one in which the dispersed globules

retain their initial character and remain uniformly
distributed throughout the continuous phase.
A stable emulsion is characterized by the following:
• Absence of flocculation and creaming
• Absence of coalescence of globules and separation of
the layers.
• Absence of deterioration due to microorganisms
• Maintenance of elegance with respect to appearance,
odor, color and consistency.
 Causes of instability of pharmaceutical emulsions

A. Physical instability Flocculation and creaming, coalescence

and breaking, phase inversion
B. Chemical instability Emulsifying agent, presence of
electrolytes, oxidation, pH change,
addition of insoluble substances.
C. Microbial deterioration Gas production, color change, pH
change, odor change, pathogens
D. Adverse storage Temperature
condition
Physical Instability
Flocculation:
Flocculation is the aggregation of dispersed globules into loose
clusters/clumps within emulsion. The individual droplets/globules retain their
identity but cluster behaves physically as a single unit.

Overcome method:
The presence of high charged density on dispersed globules ensures the
presence of high energy barrier and thus reduce the incidence of flocculation
in the primary medium.
Creaming:
• Under the influence of gravity, the dispersed droplets tend to move upward or
downward depending on the density differences between two phases.
• Creaming is a reversible process and gentle shaking can re-distribute the droplet
throughout the continuous phase.
Overcome method:
The factors affecting creaming are described by stoke’s law:
V= 2r2 (d1-d2) g/9ƞ
Where, V= rate of creaming
r = radius of globules
d1 = density of dispersed phase
d2 = density of dispersion medium
g = gravitational constant
ƞ = viscosity of the dispersion medium
According to Stroke's law, creaming of emulsion can be avoided by
following way:
a. Radius of globules: Size of globule Creaming
b. Difference in density of disperse phase and continuous phase
c. Viscosity of dispersion medium: Viscosity Creaming.
d. Storage condition
Coalescence
• Coalescence is the process by which emulsified particles merge with each to
form large particles. This type of closed packing induces greater cohesion
which leads to coalescence.
• In this process, the emulsifier film around the globules is destroyed to a certain
extent. This step can be recognized by increased globule size and reduced
number of globules.
Coalescence is observed due to:
✓ Insufficient amount of the emulsifying agent.
✓ Altered partitioning of the emulsifying agent.
✓ Incompatibilities between emulsifying agents.
✓ The major factor to prevent coalescence is the mechanical strength of the
interfacial film.
Cracking/ breaking

• Separation of the internal phase from the external phase is called breaking of the
emulsion.
• When an emulsion cracks during preparation, i.e. the primary emulsion does not
become white but acquires an oily translucent appearance. In such a case it is
impossible to dilute the emulsion nucleus with water and the oil separates out.

Figure: Cracking/ breaking

Cracking of emulsion can be due to:
1. addition of an incompatible emulsifying agent: e.g., monovalent soap
+ divalent soap.
2. chemical or microbial decomposition of emulsifying agent: e.g.,
alkali soap decompose by acid.
3. exposure to increased or reduced temperature
4. addition of common solvent.
Phase Inversion
• This involves the change of emulsion type from o/w to w/o or vice versa.
• When we intend to prepare one type of emulsion say o/w, and if the final
emulsion turns out to be w/o, it can be termed as a sign of instability.
 Identification test
Test O/W emulsion W/O emulsion
1. Dilution test/ Miscible with water Miscible with oil
Miscibility test
2. Conductivity test Water being the continuous Oil being the continuous
phase will conduct electricity phase, will not conduct
throughout the system. electricity throughout the
system.
3. Dye test
Water soluble dye The external phase appears red. The external phase appears
e. g. amaranth colorless.
Oil soluble dye The external phase appears
The external phase appears
e.g. Scarlet red C or red.
colorless.
Sudan III
4. Fluorescence test Shows spotty fluorescence Continuous fluorescence
5. Cobalt chloride test Color changed from blue to Color is not changed.
pink
Figure: Dilution test
Dye test Cobalt chloride test
 Methods of preparation

• Dry gum method.

• Wet gum method.
• Bottle method: For volatile & non-viscous oils.
• Other method (homogenizer).
Proportion 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
 1. Continental or dry gum method

Emulsifier is triturated with the oil in perfectly dry porcelain mortar.

Water is added at once

Triturate immediately, rapidly and continuously (until get a clicking sound

and thick white cream is formed, this is primary emulsion)

The remaining quantity of water is slowly added to form

the final emulsion
 2. English or Wet Gum Method

Triturate gum with water in a mortar to form a mucilage

Oil is added slowly in portions the mixture is triturated

After adding all of the oil, thoroughly mixed for several minute to form
the primary emulsion

Once the primary emulsion has been formed remaining quantity of water
is added to make the final emulsion
 3. Bottle or Forbes Bottle Method

It is extemporaneous preparation for volatile oils or oil with low viscosity.

Gum + oil (dry bottle)

Shake

Water (volume equal to oil) is added in portions with vigorous shaking to form
primary emulsion

Remaining quantity of water is added to make the final emulsion

 Preservation of emulsions

Number of ingredients in emulsion support the growth of microorganism which

result into change in color, odor and taste of emulsion. Therefore, there is need to
include the preservative.

Sources of contamination: Rules for prevention of contamination:

• During the development or
• Use of uncontaminated raw material.
production.
• Meticulous housekeeping.
• Impure raw material.
• Careful cleaning of equipment.
• Poor sanitation.
• Maintenance of pH.
• Improper ratio of o/w/gum.
• Maintain o/w/gum ratio.
• pH change.
Selection of preservative:
Concentration of preservative required in an emulsion depend on its ability
to interact with microorganism.
The preservative selected on distribution coefficient Ko/w.
It should effective in both phase, soluble in both phase.

Example:
Esters of parahydroxy benzoic acid: benzoic acid (0.1-2%), methyl
paraben & propyl paraben (0.1-2%), Chloroform (0.25%)
Course Name: Pharmaceutical Technology-I
Course Code: Phrm 3125
• Liquid form of a dose of a drug used as a drug or
medication intended for administration or consumption.
• Liquid dosage forms are either monophasic or biphasic.
• A monophasic liquid dosage form is one which contains
only one phase. That is, it is a true solution. A true
solution is a homogenous mixture of solid, liquid or gas in
a liquid.
• A biphasic liquid dosage form contains two phases.
▪ Solutions: Solutions are clear liquid preparations containing one or more
active ingredients dissolved in a suitable vehicle.
▪ Suspensions (Solid in liquid dispersion): liquid preparations containing one
or more active ingredients suspended in a suitable vehicle.
▪ Emulsions (liquid in liquid dispersion): emulsions are two phase system in
which one liquid is dispersed throughout another liquid in the form of small
particles.
▪ Colloids: A system in which finely divided particles, which are
approximately less than 1 μm in size, are dispersed within a continuous
medium in a manner that prevents them from being filtered easily or settled
rapidly.
 Solution

• Pharmaceutical solutions are a homogenous one- phase system.

• Pharmaceutical solutions are liquid dosage forms that prepared by
dissolving the active ingredients in an aqueous or non-aqueous
solvents.
• A solution is a chemically and physically homogenous mixture of
two or more active ingredients which may be solids, liquids, gases
or a combination of these.
 Advantages of solution

• The drug is immediately available for absorption thus therapeutic response is

fast.
• Flexible dosing.
• Designed for any route of administration.
• Easier to swallow therefore easier for children, old age and unconscious
people.
• Homogenous system, the drug will be uniformly distributed throughout the
preparation compared to suspension and emulsion which need shaking.
• Some drugs can irritate the gastric mucosa if localized in one area. Irritation is
reduced by administration of a solution of the drug.
 Disadvantages of solution

• Solutions are bulky and inconvenient to transport and store.

• Drug stability is often reduced in solution by hydrolysis, precipitation,
color change or oxidation.
• Solution provide suitable media for the growth of micro-organisms and
may require the addition of preservative.
• Technical accuracy is needed to measure the dose on administration
(needs an accurate spoon to measure the dose)
• In solution, unpleasant taste or odors are difficult to mask.
• Inconvenient for poorly water soluble drugs.
 Solubility Expression

The solubility of a drug may be expressed in a number of ways such as

molality, molarity, normality and percentage. For substances whose
solubilities are not definitely known, general expressions of relative solubility
may be used.
Descriptive terms for approximate solubility:
 Factors affecting the “ rate of” Solubility

1. Particle size: An increase in surface area to the solvent will increase

the rate of solution. So the particle size should be reduced by
comminution before it is dissolved.
2. Agitation: Agitation increases the rate of the solution by removing it
from the surface of the solute. The more concentrated solution around
it the less concentrated the solvent.
3. Temperature: Heating a liquid also causes the solution to take place
more rapidly by an increasing frequency in which solvent molecules
collide with the surface of the dissolving mixture.
 Factors affecting “Solubility” of solute

1. Temperature
Endothermic reaction: It is the process of solution where absorption
of applied heat takes place in the solutes. So, an increase in temperature
will cause more of the solute to go in the solution.
Exothermic reaction: In this process solutes give off heat during the
process of solution. So, solubility will decrease with an increase in
temperature.
Example: Substances which are more soluble in cold than hot water.
Methylcellulose and calcium salts such as Ca(OH)2.
2. Molecular structure
The general rule “like dissolves like”.
3. Effects of other substance
Example: Iodine is very slightly soluble in water but when added to a
concentrated solution of KI in water, it dissolves immediately.
4. pH: Many organic substances that are used medicinally are either weak
acids or bases. And their aqueous solubility depends upon the pH of the
solvent.
• Saturation solubility is the maximum conc. of a solution which
prepared at a given temp.
• Saturated solution: contain the maximum amount of solute that
solvent accommodate at room temp. & pressure.
• Or A solution in which no more solute can be dissolved at a given
temperature.
• Unsaturated solution: An unsaturated solution contains less than the
maximum amount of solute and that completely dissolved leaving no
remaining substance at normal temperature.
• Supersaturated solution: contain a larger amount of solute than the
solvent can normally accommodate at that temp. & pressure. obtained
by preparing a saturated sol. at a higher temp.
❑ Methods of preparing Solution
(a) Simple Solution
(b) Solution by Chemical Reaction
(c) Solution by Extraction

(a) Simple Solution: Prepared by dissolving the solute in a suitable solvent

(by stirring or heating).
Examples: Calcium hydroxide solution USP (lime water).
(b) Solution by Chemical Reaction: Prepared by reacting two or more
solutes with each other in a suitable solvent.
For example: Calcium lactate mixture is prepared by calcium carbonate
and lactic acid.
Magnesium Citrate is prepared by reacting official magnesium carbonate
with citric acid.

(c) Solution by Extraction: Plant or animal origin are prepared by suitable

extraction process. Preparations of this type may be classified as solutions
but more often, are classified as extractives.
 Classification of solution

(i) According to the route of administration - -

- Oral solutions through oral route
- Otic solutions instilled in the ears
- Ophthalmic solutions instilled in the eyes
- Topical solutions applied over skin surface
ii) According to composition and uses
- Syrups: aqueous solution containing sugar.
- Elixir: sweetened hydro-alcoholic (combination of water and ethanol
solution).
- Spirit : solution of aromatic materials in alcohol.
 Classification of solution Cont..

- Aromatic water: solution of aromatic material in water.

- Tincture/fluid extract: solution prepared by extracting active constituents
from crude drugs.
- Injection: Certain solution prepared to be sterile and pyrogen- free and
intended for parenteral administration.
iii) According to the vehicle
- Aqueous solutions: Solution that contain water as the solvent.
e.g. sugar in water, carbon dioxide in water, etc.
- Non-aqueous solutions: Solution that contain a solvent other than water.
e.g. Ether, benzene
Type of water used as vehicle (solvent) for solution
Type of non-aqueous solvent used as vehicle for solution:
 Aqueous solutions
• Syrups
Syrups are liquid oral preparations in which the vehicle is a concentrated
solution of sucrose or other sugars in water. The concentration of sugar in
syrup is 66.7 % W/W.
Syrups are further classified into 2 classes-----
a) Simple syrups: The simple syrups do not contain any medicament, but
contains some pleasantly flavored substances. These syrups are used as
a medium for other liquid preparations.
b) Medicated syrups: These syrups contain some medicinal substance
along with other ingredients.
❑ Components of syrup:
• Sugar
• Flavoring agent
• Coloring agent
• Antimicrobial preservatives
• Miscellaneous: special solvent,
solubilizing agent, thickening
agent.
❑ Advantages of syrups
• Syrups prevent oxidation and
decomposition of drugs.
• Syrups are sweet in taste and therefore
bitter taste of drugs can be reduced.
❑ Disadvantages of syrups
• Syrups are not preferred for diabetic
patients.
• On continuous take syrup promote dental
decay.
• Douches: Douches are aqueous solutions used to cleanse,
deodorize, soothe or medicate wounds, body orifices or
cavities. It function as a cleansing or antiseptic agent.
Eye douches are used to remove foreign particles from the
Douches
eye.
• Enemas: Enemas are preparations intended for
introducing in the rectum for cleansing therapeutic or
diagnostic purposes. It is used to evacuate faeces in
constipation or before an operation.
Enema
• Mouth washes: Aqueous solutions with a pleasant taste and odor
used to make clean and deodorize the buccal cavity. Generally they
contain antibacterial agents, alcohol, glycerin, sweetening agents,
flavoring agents and coloring agent.

• Gargles: Aqueous solutions containing antiseptics or antibiotics used

to treat throat infections. Available in concentrated form with direction
for dilution with warm water before use. They are brought in to contact
with mucous membrane of the throat and are allowed to remain in
contact with it for a few seconds e.g. Povidone Iodine gargle.
• Linctuses: Viscous liquid and oral preparations that are
generally prescribed for the relief of cough. They contain
medicament which have demulcent, sedative or
expectorant action. Linctuses should be taken in a small
doses sipped and swallowed slowly without diluting it
with water in order to have maximum and prolonged
effect of medications. Simple syrup is used a vehicle for
most of the linctuses. Tolu syrup is preferred in certain Linctuses

cases because of its aromatic odor and flavor.

• Lotions: Liquid preparations meant for external
application without friction. They are applied
direct to the skin with the help of some absorbent
material such as cotton, wool or gauze soaked in
it.
Lotions may be used for local action as cooling,
soothing or protective purpose. They are generally
prescribed for antiseptic action. Example: Lotion
Calamine lotion.
• Nasal drops: solutions of drugs that are instilled in to the nose with a dropper.
They are usually aqueous and not oily drops. Nasal drops should be isotonic
having neutral pH and viscosity similar to nasal secretions by using methyl
alcohol.
• Eye lotions: Aqueous solutions used for washing the eyes. The eye lotions are
supplied in concentrated form and are required to be diluted with warm water
immediately before use. It should be isotonic and free from foreign particles to
avoid irritation to the eye.
• Ear drops: solutions of drugs that are instilled in to the ear with a dropper.
These are generally used for cleaning the ear, softening the wax and for treating
the mild infections.
 Non-aqueous solutions

• Elixirs: Elixirs are clear, flavored, sweetened, hydro-alcoholic

preparations for oral administration. They are more stable than mixtures.
Main ingredients of elixir are ethyl alcohol, water, glycerin, propylene
glycol, flavoring agent, syrup and preservatives. Elixirs are classified into
two classes…..
✓ Non-medicated and medicated elixir
a) Non medicated elixirs: These elixirs do not contain any medicament
but contain some aromatic or pleasantly flavored substances. These are
used as solvents for other liquid preparations e.g. Dexamethasone Elixir
USP.
b) Medicated elixirs: These elixirs contain some medicinal substance
along with other ingredients such as antibiotics, antihistamines, sedatives.
• Spirits: Alcoholic or hydro-alcoholic solutions of volatile substances.
Some spirits are used as favoring agents, others are medicinal.
• Collodions: Collodions are fluid preparations for external use. They are
applied with a brush or rod. After applying on the skin the vehicle
evaporates and leaves a protective film covering the site. They are of two
types-
a) Un-medicated: It contains no medicament and is used for
protecting small cuts and wounds.
b) Medicated: It contains medicament.

Liniments:
• Liniments are viscous liquid preparations for external
application. It is applied to the unbroken skin with friction
and rubbing. Liniments should never be applied to broken
skin because they cause irritation.
• Liniments contain medicaments possessing analgesic,
rubefacient, soothing, counter irritant or stimulating Liniments

properties.
 Formulation of pharmaceutical solution

• Active Pharmaceutical ingredients

Additives/excipients include:

• Vehicle/ Solvent: - Purified Water • Viscosity modifiers- e.g. cellulose

- Oil derivatives.
• Co-solvents- To enhance solubility of the • Antioxidants- e.g. butylated
therapeutic substance in vehicle hydroxytoluene .
• e.g., propylene glycol , glycerol, ethanol. • Coloring & Flavoring agents (oral
• Preservatives – prevention of microbial only) .
contamination.
• Buffering agents- to regulate the
• Sweetening agents, e.g. glucose, pH of the formulation
saccharin, aspartame
 Consideration

❑ Formulation Consideration ❑ Manufacturing Consideration

• Solubility • Raw Materials
• Stability • Equipments
• Preservatives • Manufacturing Procedure
• Pharmaceutical elegance
✓Viscosity modifiers
✓Sweetening agents
✓Flavoring agents
✓Coloring agents
Stability
Preservatives
 PREFORMULATION
PREFORMULATION
Course Name: Pharmaceutical Technology-I
Course Code: Phrm 3125
 Preformulation

Definition:
•“It is the study of the physical and chemical properties of the drug prior to
compounding process”
• Investigation of physico-chemical properties of the new drug compound
that could affect the drug performance and the development of an
efficacious dosage form.
• Characterization of physical, chemical and mechanical properties of new
drug molecule in order to develop the elegant, stable, effective and safe
dosage form.
Objectives:

a) To develop the elegant dosage forms (stable, effective & safe)

b) It is important to have an understanding of the physical description of a
drug substance before dosage form development.
c) It is 1st step in rational development of a dosage form of a drug substance
before dosage form development.
d) It generates useful information to the formulator to design an optimum
drug delivery system.
Goals of Preformulation:

✓ To establish the physico-chemical parameters of new drug substance.

✓To establish the kinetic rate profile.
✓ To establish the compatibility with the common excipient.
✓ To choose the suitable dosage form for the drug substance.
✓ To formulate new dosage form of already existing drug.
 Preliminary evaluation and Molecular Optimization

• Once a pharmacologically active compounds has been identified, a project team

consisting of representatives from the disciplines has responsibility for assuring that
the compound enters the development process in its optimum molecular form.
• When the first quality sample of new drug becomes available, analytical
experiments should be conducted to determine the magnitude of each suspected
problem area.
• If a deficiency is detected the project team should decide on the molecular
modifications that would most likely improves the drug properties. Salts, prodrugs,
solvates, polymorphs or even new analogs may emerge from these modification
efforts.
• Among these modification, the salt and prodrug approaches are the most common.
Most salts of organic compounds are formed by the addition or removal of a
proton to form an ionized drug molecule, which is then neutralized with a counter
ion. For example: Ephedrine Hydrochloride is prepared by addition of a proton.
• Salt formation is limited to molecules with ionizable groups, prodrug may
be formed with any organic molecule having a chemically reactive
functional group.
• Through the formation of a prodrug, a variety of side chains or functional
groups may be added to improve the biologic and pharmaceutical properties
of a compound.
Erythromycin estolate is an example of prodrug with improved
pharmaceutical properties.
Figure: Flow diagram illustrating the multidisciplinary development of a drug candidate
 Major/ Principle Areas of Preformulation Research

Physico-Chemical Properties:

1. Bulk Characterization 2. Solubility Analysis 3. Stability Analysis

• Crystallinity and polymorphism • Ionization constant- pKa • Stability in formulations

• Hygroscopicity • pH solubility profile • Solution Stability

• Particle size • Common Ion Effect-Ksp • pH Rate Profile

• Bulk density • Thermal Effects • Solid State Stability

• Powder flow properties • Solubilization • Bulk Stability

• Partition Coefficient • Compatibility

• Dissolution
 Bulk Characterization

A drug candidate at this stage had not all of its solid forms identified, and there is a
great potential for new polymorphs to emerge. Bulk properties for the solid forms such
as particle size, bulk density and surface morphology are also likely to change during
process development.

i. Crystallinity:
• Generally most of drugs exist in solid state. Very few are in liquid state like
valproic acid and even less in gaseous form like some general anesthetics. A crystal
structure is a unique arrangement of atoms in a crystal.
• Physical properties affected by the solid-state properties can influence both the
choice of the delivery system and the activity of the drug, as determined by the rate
of delivery. Chemical stability, as affected by the physical properties, can be
significant.
• A crystalline particle is characterized by definite external and internal structures.
The crystal habit describes the outer appearance of crystals (platy, equant, needle,
blades, etc) whereas the polymorphic state refers to the definite arrangement of
molecules inside the crystal lattice.
Figure: Different habits of crystal
ii. Polymorphisms:

• Polymorphism is the ability of the compound to crystallize as more than

one distinct crystalline species with different internal structure.
• Formation of different polymorphs depends on solvents, temperature,
pressure, rate of cooling, etc.
• Polymorphic transition can also occur during milling, granulating, drying
and compressing operations.
• Different polymorphs vary in physical properties such as dissolution,
solid-state stability, compatibility, etc.
Polymorphs:
Polymorphs can be classified in two types:
a. Enantiotrophs: If one form stable over certain pressure and temperature
range, while the other polymorph is stable over different pressure and
temperature range. e. g., sulfur.
b. Monotrophs: only one polymorph is stable at all temperature below the
melting point, with all other polymorph being unstable.
For example: glyceryl stearate, chloramphenicol palmitate.
Transition temperature:

At a specified pressure, usually 1 atmosphere, the temperature at which two

polymorphs have identical free energies is the transition temperature, and at
that temperature, both forms can coexist and have identical solubilities in any
solvent as well as identical vapor pressure.
During preformulation, it is important to identify the polymorph that is stable at
room temperature and to determine whether polymorphic transitions are
possible within the temperature range used for stability studies and during
processing (drying, milling, etc.).
iii. Hygroscopicity:

• Hygroscopicity is the tendency of a solid substance to take up moisture

from the surrounding atmosphere.
• Adsorption and equilibrium moisture content can depend upon the
atmospheric humidity, temperature, surface area, exposure and
mechanism for moisture uptake.
Classified based on the amount of rate of water uptake when a solid is
exposed to controlled Relative Humidity value at a specified temperature.

a. Deliquescent : a substance which absorb sufficient moisture from the

atmosphere to dissolve itself at higher extreme. Example: sodium chloride.
b. Efflorescent: a substance which loses water to form a lower hydrate or
become anhydrous at lower level.
c. Hygroscopic : a substance that exist in a dynamic equilibrium with water.
iv. Particle size:

• Various chemical and physical properties of drug substances are affected by

their particle size distribution and shapes. The effect is not only on the
physical properties of solid drugs but also in some instances on their
biopharmaceutical behavior.
• Particle size and surface area of a solid drug are inversely related to each
other.
For example: the bioavailability of griseofulvin and phenacetin is directly
related to the particle size distributions of these drug.
v. Powder Flow
Pharmaceutical powders may be broadly classified as -
a. Free flowing
b. Cohesive (non free- flowing).
Most powder flow properties are significantly affected by-
✓ Changes in particle size,
✓ Density,
✓ Shape,
✓ Electrostatic charge, and
[[
✓ Adsorbed moisture, which may arise from processing or formulation.
As a result a free flowing drug candidate may become cohesive during
development, thus necessitating an entirely new formulation strategy.
Flow properties of powder can be determine by the parameters like angle of
repose, Hausner’s ratio, Carr’s index and compressibility of any powdered
sample. Flow properties based on density measurement.
Angle of Repose:
The maximum angle which is formed between the surface of pile of powder and
horizontal surface is called angle of repose.
Tan Ɵ = h/r
Where,
h = Height of heap of pile
r = radius of base of pile

Angle of Repose
❑ Relationship between angle of repose and flow properties:

Angle of repose Flow properties of powder

vi. Bulk Density
➢ Bulk density is of great importance when considering the size of high dose
capsule product or the homogeneity of a low dose formulation in which there
are large differences in drug and excipient densities.
➢ Bulk density of a compound varies substantially with the method of
crystallization, milling, or formulation. Once a density problem is identified, it
is often easily corrected by milling, or formulation.
Types of Density
1. True density: The true density or absolute density of a sample excludes the
volume of the pores and voids within the powder sample.
2. Bulk density: The bulk density value includes the volume of all of the pores
within the powder sample.
Bulk density:
It is obtained by measuring the volume of known mass of powder that passed
through the screen.
Bulk density = Mass
Volume
Tapped density: It is obtained by mechanically tapping the measuring cylinder
containing powder.
Carr’s index: A volume of powder is filled into a graduated glass cylinder and
repeatedly tapped for a known duration. The volume of powder after tapping is
measure.

Carr’s index = Tapped density ─ Poured(Bulk) density × 100

Tapped density
vii. Thermal Analysis:
Differential Scanning Calorimetry (DSC) and Differential thermal analysis
(DTA) measure the heat loss or gain resulting from physical or chemical
changes within a sample as a function of temperature.
Example of endothermic (heat-absorbing) process are fusion, boiling,
sublimation, vaporization etc.
 Solubility Analysis

An important physical-chemical property of a drug substance is solubility,

especially aqueous solubility. A drug must possess some aqueous solubility for
therapeutic efficacy in the physiological pH range of 1 to 8. For a drug to enter
into systemic circulation, to exert therapeutic effect, it must be first in solution
form. If solubility of drug substance is less than desirable, than consideration
must be given to increase its solubility.
Preformulation solubility studies include-

i. pKa determination,
ii. Temperature dependence,
iii. pH solubility profile,
iv. Solubility products,
v. Solubilization mechanism
vi. Rate of dissolution
i. pKa determination (Dissociation constant):

• Determination of dissociation constant of a drug is important since solubility,

consequently absorption, can be changed by changing in pH.
• Many drugs are either weakly acidic or basic compounds and, in solution,
depending on the pH value, exist as ionized or un-ionized species.
• The un- ionized species is lipid-soluble thus dissolve in lipid material of the
membrane and hence more readily absorbed.
Whereas, The ionized species is lipid-insoluble therefore permeation is slow.
The factors that are important in the absorption of weakly acidic and basic
compounds are the pH at the site of absorption, the ionization constant, and
the lipid solubility of the un- ionized species.
The percentage of ionization can be calculated according to Henderson
Hasselbach equation-
For acidic compounds:
pH = pKa + log [ ionized drug]
[un-ionized drug]
For basic compounds:
pH = pKa + log [un-ionized drug]
[ ionized drug]
For weakly acidic drug with pKa value greater than 3, the unionized form is
present within the acidic contents of the stomach, but the drug is ionized
mainly in the neutral media of the intestine.
For basic drugs such as erythromycin and papaverine (pKa 8 to 9), the
ionized form is predominant in both the stomach and the intestine.
ii. pH Solubility Profile and common ion effect:
• The solubility of an acidic or basic drug depends on the pKa value of the
ionizing functional group and the intrinsic solubilities for both the ionized
and un-ionized form.
• The saturation solubility for such compounds (acidic or basic drug ) at particular
pH is the sum total of solubility of ionized and unionized forms .
• The common ion effect describes the effect on ​equilibrium that occurs when
a common ion (an ion that is already contained in the solution) is added to a
solution. The common ion effect generally decreases ​solubility of a solute.
iii. Effect of Temperature:
• The solubility of solute in a solvent is dependent on temperature, nature of
solute and nature of solvent.
• The heat of solution represents the heat released or absorbed when a mole of
solute is dissolve in a large quantity of solvent.
• Most of the substances are endothermic, absorbing heat in the process of
dissolution. For these substances, an increase in temperature results in
increase in solubility.
 Effect of temperature cont…

• Exothermic substances give off heat in the process of dissolution. The

solubility of such substances would decrease with increase in temperature.
• Care should be taken as heat may destroy a drug or cause other changes in
the solution e.g., on excess of heating the sucrose solution converted into the
invert sugar.
iv. Solubilization
For drug candidates, with either poor water solubility or insufficient solubility for
projected solution dosage form, preformulation study should include limited
experiments to identify possible mechanism for solubilization.

Methods for Increasing Solubility:

a) Change in pH e) Complexation
b) Co-Solvency f) Hydrotropy
c) Dielectric Constant g) Chemical Modification of drug
d) Solubilization by Surfactant
v. Partition Coefficient:

The partition coefficient is defined as the ratio of unionized drug distributed

between the organic and aqueous phase at equilibrium.

Measurement of a drug’s lipophilicity and an indication of its ability to cross cell

membrane is the oil/water partition coefficient in systems such as octanol/water
and chloroform/water.
vi. Dissolution:
In many instances, dissolution rate in the fluids at the absorption site, is the rate
limiting steps in the absorption process.
For example: drugs that are administered orally in the solid dosage forms such as
tablet, capsule, suspension and drug administered I.M. in form of pellets or
suspension.
The dissolution rate of a solid in its own solution is adequately described by the
Noyes-Nernst equation:

AD (Cs – C) Where,
dC / dt = --------------------
dC/dt = rate of dissolution
hv
A = surface area of the dissolving solid
D = diffusion coefficient
C= solute concentration in the bulk medium
h= diffusion layer thickness
V = volume of the dissolution medium
Cs = solute concentration in the diffusion layer
 Stability Analysis

• Preformulation stability studies are usually the first quantitative assessment of

chemical stability of a new drug. Factor effecting chemical stability critical in

rational dosage form design include temperature, pH and dosage form diluents.
• The method of sterilization of potential product will be largely dependent on the
temperature stability of the drug. Drugs having decreased stability at elevated
temperatures cannot be sterilized by autoclaving but must be sterilized by another
means, e.g., filtration.
• The effect of pH on drug stability is important in the development of oral drugs.
Oral dosage forms must be protected from the highly acidic environment of the
stomach.
i. Solid state stability:
• Chemical instability normally results from either of the following reaction
hydrolysis, oxidation, photolysis and pyrolysis. Chemical structure of the drug is
the determination of drug to either of these attacks.
• Esters and lactase and to lesser extent, amides are to prone to solvolysis,
instauration or electron rich center in the structure make the molecule vulnerable
for free radical mediated or photo-catalyzed oxidation, physical properties of
drugs. Amorphous materials are less stable than their crystalline forms. Denser
materials are more stable to ambient stress.
ii. Solution stability:
• As compared with the dry form, the degradation is much rapid in solution
form. It is important ascertain that the drug doesn’t degrade when exposed
to GI fluid.
• The pH based stability study, using different stimulator GI condition can be
designed.
• A poor solution stability of drug may urge the formulator to choose a less
soluble salt form, provided the bioavailability is not compromised.
Course Name: Pharmaceutical Technology-I
Course Code: Phrm 3125
“Suppositories are solid dosage forms intended for insertion in to body
cavities or orifices (Rectum, Vagina & Urethra) where they melt or
dissolved & exert localized or systemic effect.”

All types of suppositories are melt at normal body temperature after

introducing in body cavity and produce their effect.
❑ Advantages of Suppository:

• It is the alternated dosage form for drugs which have less bioavailability
when it is taken orally.
• Drugs having bad odor and taste can be used in suppository form.
• It is suitable for unconscious patients which can not taken drugs orally.
• Drugs which produce irritating effect in GIT can be given by suppository.
• It is suitable for infants and old people who find difficulty in swallowing
of drugs.
• Avoid fast pass metabolism.
❑ Disadvantages of Suppository
• The manufacturing process is more difficult as compare with other
formulation.
• Rectal inflammation may occur with repeated use.
• The most important problem is storage condition because it stored at
low temp. (10-20℃ ). Other than the bases get liquefied.
• Leakage problem is also most critical problem along with suppository
after introducing in body cavity at elevated temperature.
• Patient may be embarrassed.
❑ Therapeutic uses of Rectal suppositories

• Rectal suppositories are primarily intended for the treatment of

constipation and hemorrhoids.
• Suppositories are also administered rectally for systemic action. e.g.
Analgesic, anti-spasmodic, sedatives, tranquilizers.
• They are also used in conditions where oral medication would not
be retained or absorbed properly such as during nausea and vomiting
or in paralytic ileus.
 TYPES OF SUPPOSITORY

(A) Rectal Suppository:

The weight of suppository used in children is about 1g and
in adult about 2g. The shape of suppository used in rectal is
torpedo shape. The length is about 5 cm.

(B) Urethral Suppository:

The weight of this type suppository is about 2g and 60-75
mm long in Females. Those intended for males weigh 4 gm
each and are 100-150 mm long. It is available in pencil
shape.
(C) Vaginal Suppository /Pessaries:
It is about 3-5g in weight. It contains the drugs which are
used in treatment of the infections of female genitourinary
tract and for contraception. It is in oviform shape or
compressed on a tablet press into conical shape. It is
containing the combination of polyethylene glycol of
different molecular weights as suppository bases. Vaginal Suppository

(D) Nasal Suppository:

These suppositories are meant for introduction into nasal cavity. It is about
1g in weight. The glycero- gelatin is used as suppository bases.
(E) Ear Cone
It is also known as AURINARIES. These are meant for introduction into the
ear. It is cylindrical in shape. It is about 1g in weight.

Fig: Typical suppository shapes.

(A) Bullet or torpedo; (B) round oval;
(C) elongated oval; (D) tampon;
(E) teardrop or cone.
Anatomy and physiology of the rectum
• The rectum is about 15 to 20 cm long and 1.5 to 2 cm width. It hooks
up with the sigmoid colon and with the anal canal.
• It is a hollow organ with a relatively flat wall surface, without villi
and the rectal valves.
• The rectal wall is formed by an epithelium which one cell layer thick.
• The rectal tissues are drained by the inferior, middle and superior
hemorrhoidal veins, but only the superior vein connects with the
hepatic-portal system.
• The transverse folds in rectum keep stool in place until the person is
ready to go to the toilet.
• Rectum contains about 2 to 3 ml of mucous, which has a pH of 7.4.
• The entire surface area of rectum is 200-400 cm2 .
 Absorption of drugs from the rectum

There are three separate veins in rectum…

• The upper rectal (superior haemorrhoidal) vein drains into the portal
vein and therefore this blood passes through the liver before reaching
the heart.
• The lower and middle rectal (inferior and middle haemorrhoidal) veins
drain into the interior vena cava, hence this blood goes directly to the
heart and into the general circulation.
• This means that drug molecules from the rectum can enter the general
circulation either directly or by passing through the highly
metabolizing liver.
Fig: Blood Circulation in the Rectum Fig: Position of suppository in the Rectum
• Drug absorbed in the middle and lower part of the rectum will pass
directly to the general circulation and avoid first-pass metabolism in
the liver.
• Bioavailability from the upper part of the rectum will be low or
certain drugs, as much will be metabolized by the liver during its ‘first
pass’ and only a proportion of the drug molecules will enter the
general circulation intact.
• Thus, avoiding the first-passage through the liver is possible by
keeping the dosage form, and thus the released drug, in the lower part
of the rectum.
• A suppository will first dissolve in the fluid or melt on the mucous
layer depending on whether it is hydrophilic or lipophilic.
• Due to osmotic effects of the dissolving vehicle, water is drawn to the
rectum or vagina, and as the suppository dissolves or melts and spreads,
drugs dissolved in the suppository will diffuse out toward the mucosal
epithelial surfaces.
• Suspended drugs will first need to leave the vehicle (it is water
immiscible) under the influence of either gravity or motility movements
and then begin to dissolve in the rectal fluid.
• Dissolved drug molecules will have to diffuse through the mucous layer
and then into and through the epithelium forming the rectal wall. The
process of absorption will be by passive diffusion.

• The quantity of fluid available or drug dissolution is very small

(approximately 3ml) spread in a layer of approximately 100μm thick
over the organ.
• For lipophilic melting suppositories, there is no need for fluid to be
present to soften and spread the suppository. As the suppository liquifies
under heat, the same drug transport observed in dissolving suppositories
will occur in melting suppositories.
Figure: Illustration of
suppository delivery.
 Physiological Factors affecting rectal absorption

• Quantity of fluid: The quantity of fluid available or drug dissolution

is very small (approximately 3ml). Thus, the dissolution of slightly
soluble substances is the slowest step in absorptive process.
• Properties of rectal fluid: The rectal fluid is neutral (pH 7-8).

• Contents of the rectum: When systemic effects are desired, greater

absorption may be expected from an empty rectum as the drug will be
in good contact with the absorbing surface of the rectum.
• Circulation route: The lower hemorrhoidal veins surrounding the
colon receive the absorbed drug and initiate its circulation throughout
the body, bypass the liver.
 Suppository Bases

Suppository bases plays important role in maintaining their shape, solidity &
also play important role when inserted into the body cavity.
Ideal Properties of Suppository bases:
The following properties should be required for bases---
• Bases should be existing in solid form at room temperature.
• It should not irritate and produced inflamed sensation in body cavity.
• It should be stable during storage condition, no change in color, shape, odor.
• It should retain hardness and it should not react with drugs and additives.
• It should have good emulsifying and wetting property.
• Can be easily manufactured by compression or molding.
If the base is fatty it has the following additional requirements...
• It should have acid value less than 0.2 or zero.
• Saponification value ranges from 200 to 245.
• Iodine value less than 7.
 Classification of Suppository Bases

They are classified into 2 types:

Fatty bases

Water soluble and

miscible bases
 Fatty Bases

Fatty bases: Designed to melt at body temperature.

1. Theobroma oil (Cocoa butter):
Cocoa butter is a mixture of glyceryl ester of different unsaturated fatty
acid. It is yellowish-white solid, brittle fat, which smells and tastes like
chocolate.
Advantages
• A melting range of 30-35ºC (86-95ºF) (solid at room
• temperature but melts in the body).
• Readily liquefy on heating and solidify on cooling.
• It is innocuous, bland, and non-reactive.

Fig: Cocoa butter

Disadvantages
i. Polymorphism: Cocoa butter exhibits marked polymorphism.
• Each form of cocoa butter has different melting point and drug release rates.
• If melted at not more than 360 C and slowly cooled, it forms stable beta
crystals with normal melting point.
• If overheated then cooled, it produces unstable gamma crystals which melt
at about 150 C or alpha crystals melting at 200 C.
• Cocoa butter must be slowly melted over a warm bath to avoid the form of
unstable crystalline form.
ii. Adherence to the mould: Cocoa butter tends to stick to the mould and
sticking may be prevent by adequate lubrication.
iii. Rancidity on storage.
iv. Leakage from body cavity.
v. Costly.
2. Synthetic Fat:

To overcome the disadvantages of Theobroma oil synthetic substitutes were

searched.

Advantages:
• Their solidifying points are unaffected by overheating.
• They have good resistance to oxidation because their unsaturated fatty
acids have been reduced.
• The difference between melting and setting points is small. Hence, they
set quickly, the risk of sedimentation is low and they are easier to
administer.
• They usually contain a proportion of w/o emulsifying agents and
therefore their emulsifying and water absorbing capacities are good.
• No mould lubricant is needed because they contract significantly on
cooling.

Disadvantages:
• They become brittle if cooled quickly, avoid refrigeration during
preparation.
• They are less viscous than Theobroma oil when melted and at this stage
sedimentation is greater. Thickeners such as magnesium stearate,
bentonite reduce this problem.
 Water soluble and water miscible Bases

1. Glycero-gelatin:
• This is a mixture of glycerol and water into a stiff jelly by adding gelatin.
• The commonest Glycerol suppositories Base BP, which has 14% w/w
gelatin, 70% w/w glycerol and water Q.S to 100%.
• It is used for making jellies, suppositories and pessaries and its proportion
is changed according to its intended purpose.
Disadvantages:
• Physiological action: osmosis occurs during dissolving in the mucous
secretions of the rectum, producing a laxative effect.
• They are more difficult to prepare and handle.
• Unpredictable solution time.
• Hygroscopic.
2. Macrogols (Polyethylene Glycols):
• Polyethylene Glycols are long chain polymers of ethylene oxide and
water.
• Lower molecular weight PEGs (PEG 400 and 600) are liquid, those
around 1000 are semi-solid and those above 4000 are waxy solids.
• The PEG suppositories can be prepared by both moulding and cold
compression methods.

Advantages of Macrogols:

• The mixtures have melting point above 420 C. Hence, cool storage is not
required, they are satisfactory for use in hot climates, and administration
is easy because they are not slippery to handle.
• Because of this high melting point they do not melt in the body but
gradually dissolve and disperse, freeing their medication slowly and
providing longer action than fatty bases.
• They do not stick to the mould.
• High viscosity is produced when they disperse in the body.
• They absorb water well and have excellent solvent properties.
• Products have clean smooth appearance.
Disadvantages of Macrogols
• They are hygroscopic and therefore attract water after administration,
resulting in an uncomfortable sensation for the patient.
Remedy: Incorporation of at least 20% water in the base and moistening
before insertion can help to reduce this problem.
• The good solvent properties may result in retention of the drug in the
liquefied base with consequent reduction in therapeutic activity.
• PEG bases can develop peroxides on storage, therefore airtight
packaging is recommended.
• Incompatible with several drugs and materials e.g. benzocaine, penicillin
and plastic
 Method of Preparation of Suppositories

There are 3 methods to prepare suppository dosage forms.

2.
3.
1. Moulding Hand
Compression
rolling
 Hand Molding

Hand molding is useful when we are preparing a small number of suppositories

 Compression molding

The cold mass of the base containing drug is compressed into suppositories
using a hand operated machine.

Advantages:
1. It is a simple method
2. It gives suppositories that are more
elegant than hand moulded suppositories
3. In this method sedimentation of solids
in the base is prevented.
4. Suitable for heat labile medicaments.
Disadvantages:
1. Air entrapment may take place.
2.This air may cause weight
variation.
3. The drug and/or the base may be
oxidized by this air.
 Pour Molding

Use a suppository mould which is made of metal or plastic. Traditional

metal moulds are in two halves which are clamped together with a screw.

Suppository mould
Steps:

The base is melted and precautions are taken not to overheat it.

The drug is incorporated in it.

The molten liquid mass is pored into chilled (lubricated if cocoa

butter or glycerogelatin is the base) molds.

After solidification the cone shaped suppositories are produced.

Lubricants for use with suppository bases:
• Lubricating the cavities of the mould is helpful in producing elegant
suppositories and free from surface depression.
• The lubricants must be different in nature from suppository base;
otherwise, it will become absorbed and will fail to provide a buffer film
between the mass and the metal.
• The water-soluble lubricant is useful for fatty bases while the oily
lubricant is useful for water soluble base.
• The lubricant should be applied with fairly stiff brush.
Course Name: Pharmaceutical Technology-I
Course Code: Phrm 3125
“Disperse System”
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).

Suspension:

A Pharmaceutical suspension is a biphasic coarse dispersion in which

internal phase (therapeutically active ingredient) is dispersed uniformly
throughout the external phase.
The internal phase consisting of insoluble solid particles having a range
of size (0.5 to 5 microns) which is maintained uniformly through out the
suspending vehicle with aid of single or combination of suspending agent.

The external phase (suspending medium) is generally aqueous in some

instance, may be an organic or oily liquid for non oral use.
The suspension have dispersed particles above the colloidal size that is
mean particle diameter above 1 micro-meter.
 Classification of Suspension

1. Based on General Classes: 3. Based On Electrokinetic Nature of

✓ Oral suspension
✓ Externally applied suspension
✓ Parenteral suspension
2. Based On Proportion Of Solid Particles
✓Dilute suspension (2 to10% w/v solid)
✓Concentrated suspension (50% w/v
solid)
Solid Particles
✓Flocculated suspension
✓Deflocculated suspension
4. Based On Size Of Solid Particles:
✓Colloidal suspension (< 1 micron)
✓Coarse suspension (>1 micron)
✓Nano suspension (10 ng)
 Advantages of suspension

• Used for insoluble drug or poorly soluble drugs, which required to be given
orally in liquid dosage forms (children, elderly patient).
• Suspension can improve chemical stability of certain drug.
e.g., Procaine penicillin G.
• Drug in suspension exhibits higher rate of bioavailability than other dosage
forms.
Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
• Duration and onset of action can be controlled.
e.g., Protamine Zinc-Insulin suspension.
• Suspension can mask the unpleasant/bitter taste of drug.
e.g., Chloramphenicol.

Disadvantages of suspension
• Physical stability, sedimentation and compaction can causes problems.
• It is bulky, sufficient care must be taken during handling and transport.
• It is difficult to formulate.
• Uniform and accurate dose may not be achieved.
 Ideal/ desired features of Pharmaceutical Suspension

• It should settle slowly, readily re-dispersed on gentle shaking of the

container.
• It should pour readily and evenly from its container.
• The suspended particles should not form a cake.
• Suspended particles should be small and uniformly sized.
• Viscosity must not so high.
• It should be physically, chemically and microbiologically stable.
 Theory of Suspension

Sedimentation Behavior:
Sedimentation means settling of particle (or) floccules occur under gravitational
force in liquid dosage form.
Theory of Sedimentation:
Or
The equation of stokes' law reflects that larger particles exhibit greater velocity
of sedimentation. The velocity of sedimentation is inversely proportional to
the viscosity of dispersion medium.

According to the stokes’ equation, the velocity of sedimentation of particles

in a suspension can be reduced by---
✓ decreasing the particle size
✓ minimizing the difference between the densities of the particles and the
vehicle.
The velocity of sedimentation decreases as the viscosity of the vehicle
increases. The viscosity and density of any vehicle are related to each other.
 Sedimentation Parameters

1. Sedimentation volume (F) or height for flocculated suspensions:

Sedimentation volume is a ratio of the ultimate volume of sediment (Vu ) to
the original volume of sediment (V0) before settling.

F= Vu/ V0

Where,
Vu = Final or ultimate volume of sediment
V0 = Original volume of suspension before settling

Normally, F is less than 1 (F < 1).

Sedimentation Volume
❑ Degree of flocculation (β)
It is the ratio of the sedimentation volume of the flocculated suspension, F, to
the sedimentation volume of the deflocculated suspension, F ∞
ß=F/F∞

(Vu/Vo) flocculated
ß = --------------------
(Vu/Vo) deflocculated
The minimum value of ß is 1,when flocculated suspension sedimentation
volume is equal to the sedimentation volume of deflocculated suspension.
 Factors to be considered for Suspension formulation

i. Particle Size control:

Too large or too small particles should be avoided.
Larger particles will---
✓ Settle faster at the bottom of the container.
✓ Particles > 5μm impart a gritty texture to the product which may
cause irritation if injection or instilled to the eye.
✓ Particles > 25 μm may block the needle.
Too fine particles will easily form hard cake at the bottom of the container.
ii. Wetting of the particles:
It is difficult to disperse solid particles in a liquid vehicle due to the layer of
adsorbed air on the surface. Thus, the particles, even high density, float on
the surface of the liquid until the layer of air is displaced completely. The use
of wetting agent allows removing this air from the surface and easy
penetration of the vehicle into the pores.

Alcohol, glycerin, and propylene glycol are frequently used to remove

adsorbed air from the surface of particles when aqueous vehicle is used to
disperse the solids. When the particles are dispersed in a non-aqueous
vehicle, mineral oil is used as wetting agent.
Solid particles that are not easily wetted by aqueous vehicle after the
removable of the adsorbed air are referred to as hydrophobic particles. The
interfacial tension must be reduced so that air is displaced from the solid
surface by liquid. So it is necessary to reduce the interfacial tension between
the particles and the vehicle by using surface-active agents to improve the
wettability.

Sodium lauryl sulfate is one of the most commonly used surface-active

agents. Hydrophilic particles are easy to disperse in the aqueous vehicle once
the adsorbed air is removed. Hydrophilic particles do not require the use of
surface-active agents.
The main function of wetting agent:
1. To reduce the contact angle between surface of solid particles and
wetting liquid via displace the air in the voids.
2. Surfactant
Example: tragacanth mucilage, glycerin, glycols, bentonite and
polysorbates.
 INTERFACIAL PHENOMENA

• Interface: When phases exist together, the boundary between two of them is
known as an interface.
• Surface: The term surface is the boundary between either a gas–solid or a gas–
liquid interface.
• Surface tension: The tension is the tendency of liquid
surfaces at rest to shrink into minimum surface area
possible.

• Interfacial tension- It is the force per unit length

existing at the interface between two immiscible
liquid phases. Fig: Surface and interface
iii. Brownian movement:
When a colloidal solution is viewed through a powerful microscope, the
colloidal particles can be seen moving in a random zig-zag path. This zig-zag
motion of colloidal particles is called Brownian movement. This random
motion is due to the collisions between the colloidal particles.

Brownian movement of particle prevents

sedimentation by keeping dispersed material in
random motion. Fig: Brownian movement
iv. Electrokinetic properties:

Zeta Potential:
• The zeta potential is defined as the “difference in potential between the surface
of the tightly bound layer (shear plane) and electro-neutral region of the
solution”.
• The development of a net charge at the particle surface affects the distribution
of ions in the surrounding interfacial region, resulting an increased concentration
of counter ions (ions of opposite charge to that of the particle) close to the
surface. Thus, an electrical double layer exists around each particle. The liquid
layer surrounding the particle exists as two parts; an inner region, called the
stern layer, where the ions are strongly bound and outer, diffuse region, where
they are less firmly attached.
Fig: Diagram showing the distribution of ions around a charged particles.
• Within the diffuse layer there is a notional boundary inside which the ions
and particles form a stable entity. When a particle moves (e.g., due to
gravity), ions within the boundary move with it, but any ions beyond the
boundary do not travel with the particle. This boundary is called surface
of hydrodynamic shear or slipping plane.
• The potential exist at the boundary is known as the zeta potential.
• The magnitude of zeta potential gives an indication of potential stability
of the colloidal system.

• If all the particles in suspension have a large negative or positive zeta

potential then they will tend to repel each other and there is no tendency
to flocculate.
• However, if the particles have low zeta potential values then there is no
force to prevent the particles coming together and flocculating. The
general dividing line between stable and unstable suspension is generally
taken at either +30mV or -30mV. Particles with zeta potentials more
positive than + 30mV or more negative than -30mV are normally
considered stable.
 Flocculation and deflocculation

Flocculated Suspension:
In flocculated suspension, formed flocs (loose aggregates) will cause increase
in sedimentation rate due to increase in size of sedimenting particles.
✓Hence, flocculated suspensions sediment more rapidly.
✓Here, the sedimentation depends not only on the size of the flocs but
also on the porosity of flocs.
✓In flocculated suspension the loose structure of the rapidly sedimenting
flocs tends to preserve in the sediment, which contains an appreciable
amount of entrapped liquid.
✓The volume of final sediment is thus relatively large and is easily re-
dispersed by agitation.

Deflocculated suspensions
✓ In deflocculated suspension, individual particles are settling, so rate of
sedimentation is slow which prevents entrapping of liquid medium which
makes it difficult to re-disperse by agitation. This phenomenon also called
‘caking’ or ‘claying’.
✓ In deflocculated suspension larger particles settle fast and smaller
remain in supernatant liquid so supernatant appears cloudy.
 Difference between Flocculated and Deflocculated suspension
SI Flocculated suspension
1 Particles forms loose aggregates and
form a network like structure.
2 Rate of sedimentation is high.
3 Sediment is rapidly formed
4 Sediment is loosely packed and does
not form a hard cake.
5 Sediment is easy to re-disperse.
6 Not elegant in appearance.
7 Clear supernatant.
8 High sedimentation volume.
9 Floccules stick to the sides of the
bottle.
Deflocculated suspension
Particles exist as separate entities.
Rate of sedimentation is slow.
Sediment is slowly formed
Sediment is very closely packed and a hard
cake is formed.
Sediment is difficult to re-disperse.
Comparatively elegant in appearance.
Cloudy supernatant.
Low sedimentation volume.
They don’t stick to the sides of the bottle.
 Viscosity of suspension

• Viscosity of suspensions is great importance for stability and pourability

of suspensions.
• Suspensions have least physical stability amongst all dosage forms due
to sedimentation and cake formation.

As the sedimentation is governed by Stokes's law,

or

• So as the viscosity of the dispersion medium increases, the terminal

settling velocity decreases yielding higher stability to the suspension.
• On the other hand, as the viscosity of the suspension increases, its
pourability decreases and inconvenience to the patients for dosing
increases.
• Thus the viscosity of suspension should be maintained within optimum
range to yield stable and easily pourable suspension.
❑ Different approaches to increase viscosity of suspensions:

1. Viscosity Enhancers:
- Some natural gums ( acacia, tragacanth)
- Polymers, cellulose derivatives ( sodium CMC, methyl cellulose)
- Clays ( bentonite)
- Sugars ( glucose, fructose).

2. Co-solvents:
Some solvents which themselves have high viscosity are used as co-solvents to
enhance the viscosity of the dispersion medium.
3. Structured vehicles
 Method of preparation of suspension

The formulation of a suspension depends on whether the suspension is

flocculated or deflocculated.

Three approaches are commonly involved----

• Use of structured vehicle
• Use of controlled flocculation
• Combination of both of the methods
Flow chart of formulation of Suspension
A. Structured vehicles:
Structured vehicles called also thickening or suspending agents.
• They are aqueous solutions of natural and synthetic gums.
• These are used to increase the viscosity of the suspension.
• It is applicable only to deflocculated suspensions.
e.g. methyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and
tragacanth.
• These structured vehicles entrapped the particle and reduces the
sedimentation of particles. Thus, the use of deflocculated particles in a
structure vehicle may form solid hard cake upon long storage.
Too high viscosity is not desirable as:
a) It causes difficulty in pouring and administration.
b) It may affect drug absorption since they adsorb on the surface of
particle and suppress the dissolution rate.

Structured vehicle is not useful for Parenteral suspension because they

may create problem in syringeability due to high viscosity.
B. Controlled flocculation of particles is obtained by adding flocculating
agents, which are----
i. Electrolytes
ii. Surfactants
iii. Polymer

i. Electrolytes
Electrolytes decrease electrical barrier between the particles and bring them
together to form floccules. They reduce zeta potential near to zero value that
results in formation of bridge between adjacent particles, which lines them
together in a loosely arranged structure.
The use of an electrolyte may be illustrated by the addition of monobasic
potassium phosphate, a negative flocculating agent, to a suspension of
bismuth subnitrate, positively charged particle.

1. In first caking Zone: The addition of monobasic potassium phosphate

(KH2PO4) to the suspended bismuth subnitrate particles causes the positive
zeta potential to decrease due to the adsorption of the negatively charged
phosphate anion, which accompanied by increase in Vu/Vo curve.
Caking Diagram: Showing the Flocculation of a Bismuth Subnitrate Suspension by means of the flocculating Agent
2. In non caking Zone: With the continued addition of the negatively charged
electrolyte KH2PO4, the zeta potential eventually falls to zero and then
increases in the negative direction, while Vu/Vo remains unchanged.

3. In 2nd caking Zone: At a certain point, continuous addition of negatively

charged electrolyte (KH2PO4) resulted in changing the overall zeta potential of
particles to negative and the repulsive force again dominate. The suspension
becomes deflocculated and the sedimentation volume starts to fall. Finally
caking is observed which is a clear indication of deflocculated texture of the
suspension.
ii. Surfactants
• Both ionic and non-ionic surfactants can be used to bring about flocculation
of suspended particles.
• At a particular concentration, the surfactants trim down the surface free
energy by reducing the interfacial tension between the liquid medium and
solid drug particles. This may lead to form closely packed agglomerates.
However, at a particular surfactant concentration, when the particles possess
less surface free energy, they are attracted towards each other by Van der
Waal’s force and form a loose agglomerate.

✓ Ionic surface-active agents may cause neutralization of the charge on each

other by Van der Waals forces and form loose agglomerates.
✓ Non-ionic surfactants: When the surfactants reduce the interfacial
tension, they are adsorbed on to more than one particle thus forming a
loose flocculating structure.

iii. Polymers:
For example: Starch, alginates, cellulose derivatives.
Polymers possess long chain in their structures. Part of the long chain is
adsorbed on the surface of the particles and remaining part projecting out
into the dispersed medium. Bridging between these later portions, also
leads to the formation of flocs.
 Quality Control of suspension

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 sedimentation volume
• Zeta potential measurement
• Re-dispersibility and centrifugation tests.
• Rheological measurement
• PH
• Stress-test
PHARMACEUTICAL
EXCIPIENTS
 Excipients

• An excipient is a pharmacologically inactive substances formulated

together with the active pharmaceutical ingredient (API) of a
medication.

• Formulation of API with excipients is primarily to ensure an

efficacious drug product with desired properties and a robust
manufacturing process.
Purpose of Excipients
Excipients are used for a number of reasons, such as-

✓ Provide bulk to the formulation.

✓ Facilitate drug absorption or solubility & other pharmacokinetic
considerations.
✓ Aid in handling of “API” during manufacturing.
✓ Provide stability and prevent from denaturation.
 Ideal Characteristics of An Excipients
An excipient must be:-

• Chemically stable • Economical

• Non reactive • Having efficiency in regards with

• Non toxic the intended use.

• Low equipment and process sensitive • Compatible with all the other

• Inert to human body components of the formulation.

• Acceptable with regards to organoleptic

characteristics.
 List of Pharmaceutical Excipients

• Fillers • Chelating Agents • Flavoring Agents

• Viscosity imparting Agents • Sweeting Agents
• Binders
• Coating Agents • Sorbents
• Disintegrants
• Antioxidants
• Antiadherent
• Buffering Agents
• Glidants
• Surface Active Agents
• Lubricants
• Preservatives
• Solvent & Co-solvent
• Coloring Agents
Some Common Tablet Excipients
 Diluents/ Fillers

Diluents are fillers designed to make up the required bulk of the tablet, when the
drug dosage itself is inadequate to produce this bulk.
The dose of some drugs is sufficiently high that no filler is required e.g. aspirin.

Function of fillers:
✓ To provide required bulk of the tablet,
✓ Facilitating precise metering & handling in preparation of dosage forms.
Diluents also used in tablet for secondary reason:
✓ Improved cohesion
✓ To permit use of direct compression manufacturing
✓ To promote flow.
 Diluents/ Fillers

Typical features of fillers:

A good filler should be inert, compatible with the other components, Non-
hygroscopic, relatively cheap, compactable, and preferably tasteless or
pleasant tasting.
Example:
Lactose, Starch, Dextrose, Mannitol, Sorbitol, Calcium carbonate, and
Magnesium stearate.
Microcrystalline cellulose (Avicel) used for direct compression.
 Binders and adhesives

Binders hold the ingredient in a tablet together. Binders promote adhesion of

the particles of the formulation, allowing a granulation to be prepared and
maintaining the integrity of the final tablet.

Function:
✓ Binders are added in a wet or dry state during wet granulation to form
granules.
✓To provide cohesiveness to powder in tableting operation.
✓To increase hardness of the tablet.
 Binders and adhesives

Typical features of Binders:

A binder should be compatible with other constituents of formulation & add

sufficient cohesion to the powders .

Classification & examples: according to their application:

1. Solution binders dissolved in a suitable solvent (water or alcohol) can be
used in wet granulation. Example includes: gelatin, cellulose, cellulose
derivatives.
2. Dry binders added to powder e.g.; Cellulose, methyl cellulose, Polyvinyl
pyrrolidone (PVP), and Polyethylene glycol.
 Disintegrants

Disintegrants are substance or mixture of substances added to the drug

formulations, which facilitate dispersion or breakup of tablets
(disintegration) & contents of capsules into smaller particles for quick
dissolution when it comes in contact with water in the GIT.
Ideal properties of disintigrants:
✓Good hydration capacity,
✓ Poor solubility and poor gel formation capacity.
Examples: Starch, Sodium starch glycolate, Polyvinylpyrrolidone (PVP),
Microcrystalline cellulose, Na-carboxymethyl cellulose (CMC), and alginate.
 Lubricants

Lubricants are intended to reduce the friction during tablet ejection between
the walls of the tablet and the walls of the die cavity in which the tablet was
formed.

Types of lubricants:
1. Hydrophilic lubricants: poor lubricants, no glidant or anti-adherent
properties. For example: Boric acid, Na- benzoate.
2. Hydrophobic lubricants: Most widely used today.
They are generally good lubricants & effective at low concentration. Also have
both anti- adherent & glidant properties. Example: Stearic acid, Talc, calcium
and magnesium stearate, starch.
 Lubricants

For these reasons, hydrophobic lubricants used much more frequently than
hydrophilic. Example: Magnesium stearate.

Roles of lubricants:
1.True Lubricant Role: To decrease friction at the interface between a tablet’s
surface & die wall during ejection and reduce wear on punches.
2. Anti-adherent Role: Prevent sticking to punch faces or in case of
encapsulation lubricants. Prevent sticking to machine dosators, tamping pins,.
3. Glidant Role: Enhance product flow by reducing inter-particulate friction.
 Antiadherents

Antiadherents or anti-sticking agents prevent sticking or adhesion of tablet

surface to the die walls and the punches.

Example:
Magnesium stearate, talc & starch used as anti-adherents.
 Glidants

Glidants are substances that promote flow of tablet granules or powder

material by reducing the friction between particles.

Functions:
✓Glidants used to promote powder flow by reducing inter-particle friction &
cohesion.
✓ Glidants used in combination with lubricants as they have no ability to
reduce die wall friction.
Example: Fumed silica, talc, & cornstarch.
 Sorbents

Sorbents are materials that soak up oil from the water.

Types & examples of sorbents:

1. Natural sorbents: peat moss, sawdust, feathers & anything else natural that
contains carbon.
2. Synthetic sorbents: polyethylene and nylon.

Functions of sorbents:
Used for tablet/capsule moisture-proofing by limited fluid soring (taking up of
a liquid or a gas by adsorption) in a dry state.
 Coating agents

Coating is a process by which an essentially dry, outer layer of coating material

is applied to the surface of a dosage form and agents used in this process are
called coating agents.
Types of coating agent: 3 types of coating agents are used pharmaceutically---
1. Film coating.
2. Sugar coating.
3. Enteric coating.
Function of coating agents: Protection from gastric acid, taste masking,
elegance, ease of swallowing, and identification.
Example: Hydroxypropyl Methyl Cellulose (HPMC), Methyl Cellulose (MC).
 Solvents

A solvent is a substance that can dissolve a solute (chemically different liquid,

solid or gas) resulting in a solution. A solvent is usually a liquid but it can also
be solid or gas.
Solvent classification:
Solvents classified into two groups---
✓ Polar
✓ Non-polar
 Solvents

Normally solvation of solvent depends upon its classification.

Generally polar solvents dissolve polar compound best & non-polar solvents
dissolve non- polar compound best.

Examples & uses of solvent:

✓ Polar solvent as water in which a drug is freely soluble.
✓ Oils used as emulsion, IM. injection. & liquid fill oral preparation.
✓ Aqueous methanol is the standard solvent in sample extraction.
✓ Other acceptable non-aqueous solvents are glycerol, propylene glycol,
ethanol used generally for a lipophilic drug.
 Co-solvents
Co-solvents are defined as water-miscible organic solvents that are used in liquid
drug formulations to increase the solubility of poorly water soluble substances or
to enhance the chemical stability of a drug .
Properties of co-solvent:
✓ Increase the solubility of a drug.
✓ An ideal co-solvent should possess values of dielectric constant between 25 and
80.
✓ The most widely used system that will cover this range is a water/ethanol blend.
✓ Should not cause toxicity or irritancy when administrated for oral or parental
use.
Examples: sorbitol, glycerol, propylene glycol & syrup.
 Anti-microbial Preservatives

Preservatives are used in pharmaceutical products-

✓ To prevents an increased risk of contamination and proliferation by
opportunistic microbes.
✓ Added to various pharmaceutical products in order to prolong their shelf
life.
 Anti-microbial Preservatives

Ideal properties of preservatives:

✓ Preservative must exert a wide spectrum of antimicrobial activity at low
inclusion levels.
✓ Preservative maintain activity throughout product manufacture, shelf life and
usage.
✓ Not compromise the quality or performance of product, pack or delivery system.
✓ Not adversely affect patient safety or tolerance of product.

Examples: Methyl & Ethyl parabens, Propyl paraben, Benzoic acid & its salts,
Sorbic acid and its salts.
 Methyl Paraben

Chemistry: It is the methyl ester of parahydroxy-benzoic acid.

Physical properties:
Description: Colorless crystals or white powders.
Solubility: soluble in water and ethanol, slightly soluble in
benzene and acetone.
Use: it is used in Pharmaceutical formulation to prevent
microbial growth
 Antioxidants

An antioxidant is a molecule that inhibits the oxidation of other molecules.

Oxidation is a chemical reaction that transfer electrons or hydrogen from a
substance to an oxidizing agent.

Ideal Properties of Antioxidants:

✓ Effective at a low, non-toxic concentration.
✓ Stable & effective under normal conditions of use, over a wide pH and
temperature range.
✓ Soluble at the required concentration.
✓ Compatible with a variety of drugs & pharmaceutical excipients.
 Antioxidants

✓ Free from objectionable odor and taste.

✓ Colorless in both the original and oxidized form.
✓ Non-toxic both internally & externally at the required conc.
✓ Unreactive (does not adsorb, penetrate, or interact) with containers or
closures.
✓ Reasonable cost.
Example: BHT (Butylated Hydroxy Toluene), BHA (Butylated Hydroxy
Anisol), Sodium sulfite.
 Butylated Hydroxy Anisol (BHA)

Chemistry: 1,1-dimethylethyl-4-methoxy phenol.

Physical Properties:
Description: White or slightly yellow, waxy solid having a faint,
characteristic odor.
Solubility: Insoluble in water, soluble in alcohol, Chloroform or ether.
Uses: It is used as an antioxidant in Pharmaceutical Products containing fats
and oils.
 Butylated Hydroxy Toluene (BHT)

Chemistry: 1,1-dimethylethyl-4-methyl phenol.

Physical Properties:
Description: White, tasteless crystals with a mild odor, stable in light or air,
melting point 70C.
Uses: It is used as antioxidant to retard oxidative degradation of oils and
fats in various Pharmaceuticals.
 Chelating Agents

Molecules that are capable of forming complexes with the drug involving
more than one bond; it’s a complex compound contains one or more ring
in its structure .

For example: Ethylene Diamine is bidentate and Ethylene Diamine Tetra-

Acetic Acid (EDTA) is hexadentate.
 Chelating Agents

Example and uses of chelating agents :

• EDTA: ethylene diamine tetra-acetate used for estimation of metals ions.
• EDTAH4: ethylene diamine tetra-acetic acid used for softening water.
• Calcium Disodium Edetate: used in treatment of heavy metal poisoning
mostly caused by lead.
• Disodium Edetate: used in hypercalcemic states. Also useful in the treatment
of cardiac arrhythmias.
 Buffering Agents

These are materials which, when dissolved in solvent will enable the solution to
resist any change in pH when an acid or an alkali be added. The choice of suitable
buffer depends on the pH and buffering capacity required.
Properties of buffering agents:
✓ Should have a low toxicity.
✓ Should be buffered at the range of 7.4 as pH of body is 7.4.
✓ Should be non-irritant.
Examples: Most of buffering system based on carbonate, citrates, gluconates,
lactates, phosphates, or tartrates.
 Viscosity Imparting Agents

Agents used to increase or decrease the viscosity of a liquid either to serve as adjacent
for palatability or to improve pour ability. They are also called thickening agents.
Viscosity imparting agents are of two types:
1. Viscosity modifier: decrease the viscosity of a liquid to improve pour ability and
make it more palatable.
2. Viscosity enhancer: increase the viscosity of a liquid to improve pour ability and
make it more palatable.
Most commonly used viscosity imparting agents are:
Hydroxy ethyl cellulose, Hydroxy propyl methylcellulose (HPMC), Methyl cellulose
(MC), Polyvinyl alcohol (PVA)
 Humectants

• A humectant attracts & retains the moisture in the nearby air via absorption,
drawing the water vapor into and/or beneath the organism/object's surface.
• Humectants absorb water vapors from atmosphere till a certain degree of
dilution is attained. Aqueous solution of humectants reduce the rate of loss
moisture.
Ideal properties of humectants:
✓ Must absorb moisture from atmosphere & retain the same under normal
conditions of atmospheric humidity.
✓ Should be colorless or not of too intense color.
 Humectants

✓ Should have good odor and taste.

✓ Should not be too costly.
✓ Should be nontoxic and nonirritant.
✓ Should be noncorrosive to packaging materials
✓ Should not solidify under normal conditions.

Classification of humectants with examples :

3 types of humectants as- inorganic humectants, metal organic humectants and
organic humectants.
1. Inorganic humectants: Calcium chloride is example. It has compatibility
problems and corrosive in nature, so not frequently used in cosmetics.
 Humectants

2. Metal organic humectants: Sodium lactate is limited used in cosmetics

because of compatibility problems, corrosive nature and pronounced taste.

3. Organic humectants:
✓ These are widely used in cosmetics.
✓ They include polyhydric alcohols, their esters and ethers.
✓ The most commonly used organic humectants are glycerol, ethylene
glycol, polyethylene glycol (PEG), diethylene glycol, tri-ethylene glycol,
propylene glycol, propylene glycol, glycerin, sorbitol, mannitol, glucose.
 Surfactants
Compounds that lower surface tension (or interfacial tension) between two
liquids or between a liquid & a solid and increase the solubility. Also known as
surface active agents.
Properties of surfactants:
A surfactant must fulfill 2 structural requirements:
i. A surfactant must contain a lipophilic region.
ii. A surfactant must contain a hydrophilic region.
Both hydrophilic & lipophilic region must be balanced, then will be
concentrated at an interface and therefore surface tension will be lowered.
 Surfactants

Types of surfactants:
Four types of surfactants based on charge of the hydrophilic region:
i. Anionic surfactant (the hydrophilic region is negatively charged i.e. an
anion) example: Sodium lauryl sulphate: used as excipient on dissolved
aspirins.
ii. Cationic surfactant (hydrophilic region is positively charged i.e. a
cation): Cetyl trimethyl ammonium bromide (cetrimide) - is an
effective antiseptic agent against bacteria and fungi.
 Surfactants

iii. Non-ionic surfactants:

Tween 80 (polyoxyethylene sorbitol monooleate)- Polysorbate 80 is an
excipient that is used to stabilize aqueous formulations of medications
for parenteral administration.
iv. Amphoteric surfactant:
Lecithin: act as a wetting, stabilizing agent and a choline enrichment
carrier, helps in emulsifications and encapsulation, and is a good
dispersing agent. N-dodecyl alanine.
 Anti-foaming Agents

Anti-foaming agents are effective at discouraging the formation of stable

foams by lowering surface tension and cohesive binding of liquid phase.

Example: Simethicone, Organic phosphates, Alcohols, Paraffin oils,

Stearates and glycols.
 Wetting Agents

Wetting agents are used to improve the flow of the liquid vehicle across the
particle surface, which in turn improves the homogeneity of distribution of
the drug particles throughout the formulation.

Function:
Aid wetting and dispersion of hydrophobic active pharmaceutical
ingredients.
Example: Sodium Lauryl Sulphate (SLS), Tween 80, Spans, Lecithin etc.
Wetting Agents
 Emulsifying Agents

The function of an emulsifying agent (emulsifier) is to maintain the

dispersion state of the emulsion for an extended period of time after the
cessation of agitation, i.e. to impart kinetic stability to the emulsion.

Or, Prevent coalescence of the dispersed globules.

Classification of emulsifying agents:

Emulsifying agents may be classified into two groups
i. Synthetic or semi-synthetic surface active agents and polymers and
ii. Naturally occurring materials and their derivatives.
 Acidifying and Alkalizing Agents

❑ Acidifying Agents:
Substance that are used in liquid preparations to provide acidic media for
product stability.
Example: Citric acid, Acetic acid, Fumaric acid, Hydrochloric acid, Nitric acid.

❑ Alkalizing agents:
Alkalizing agents are substances that are used in liquid preparations to provide
alkaline media for product stability.
Example: Ammonia solution, Ammonia carbonate, Diethanolamine, Potassium
hydroxide, Sodium Borate, Sodium carbonate.
 Flavoring Agents

✓ Flavoring agents are added to improve the smell and thus to increase
patient acceptance.
✓ Water soluble flavors have limited acceptance due to poor stability.
✓ Flavor oils are added to tablet granulation in solvents, are dispersed are
clays or other adsorbents.
✓ Various dry flavors are also available.
✓ The four basic taste sensations are salty, sweet, bitter, sour.
✓ Certain flavors used to mask these specific taste sensations e.g. clove oil,
citric and syrup, glycerin, rose oil, orange oil, menthol.
 Coloring Agents

The pharmaceutical ingredients that impart the preferred color to the formulation
are called coloring agents.

Two types of coloring agents:

1. Natural Coloring agents:
2. Synthetic coloring agents.
Example:
White: Titanium dioxide.
Blue: Brilliant blue, Indigo carmine.
Red: Amaranth Carmine
Yellow: saffron.
Brown: caramel
 Sweetening Agents
Sweetening agents employed in liquid formulations designed for oral
administration specifically to increase the palatability of the therapeutic agent.
Example: Sucrouse, Saccarine, Aspertame, Sorbitol.
Uses of sweetening agent:
• The main agents employed in oral preparations are sucrose, liquid glucose,
glycerol, sorbitol, saccharin sodium & aspartame.
• Aspartame is an artificial sweetening agent. The use of artificial sweetening
agents in formulations is increasing.
• Thus use of sugars in oral formulations for children and patients with diabetes
mellitus must be avoided.