Parenteral and

UNIT 3 PARENTERAL AND EXTERNAL External

Preparations
PREPARATIONS
Structure

3.1 Introduction
Objectives
3.2 Sterilization
Steam Sterilization
Dry Heat Sterilization
Filtration Sterilization
Gas Sterilization
Radiation Sterilization
3.3 Sterile Dosage Forms
Parenterals
Formulation of Parenteral Products
Preparation of Parenteral Products
Packaging
Evaluation of Parenteral Products
Large Volume Parenterals
Irrigation Solutions
Dialysis Solutions
3.4 Ophthalmic Products
Eye Drops
Other Ophthalmic Products
3.5 Semisolid Dosage Forms
Ointments
Factors affecting Selection of Ointment Base
Preparation of Ointment Base
3.6 Creams
3.7 Jellies
3.8 Pastes
Method of Preparation of Pastes
3.9 Summary
3.10 Terminal Questions
3.11 Answers

3.1 INTRODUCTION

In the previous units you have studied about the dosage form and their
classification mainly based on their physical form. All the dosage form must
be prepared in the hygienic condition as they are to be used by human beings.
You have already studied tablets and capsules, their formulation i.e. the
ingredient required to prepare a table or capsule or any liquid dosage forms.
Different types of additives are added in different dosage form. 45
Pharmaceutics In this unit, you will study about the sterilization, a method by which all living
organisms are eliminated or killed in a preparation. Since a single sterilization
method is not suitable for all types of products so different methods of
sterilization are described. Sterilization is most important in injections,
biological preparations like vaccine and ophthalmic products and these
preparations are known as sterile dosage form. These preparations are
manufactured under strictly aseptic condition to minimise the contamination.
These preparations must be free from microbes and their products.

In this unit, one section is devoted to semisolid dosage forms, their formulation
and preparations. These are all generally external use preparation for protective
or emollient action or for the topical action of drug contained in them

Objectives

After studying this unit, you should be able to:

• understand the method and importance of sterilization;

• explain the ophthalmic products; and
• understand the semisolid dosage forms and its uses.

3.2 STERILIZATION

The term sterilization means the complete destruction of all living organisms
and their spores or complete removal of organisms from the preparation.
Various methods used for sterilization of pharmaceutical products are:

i) Steam sterilization
ii) Dry heat sterilization
iii) Filtration sterilization
iv) Gas sterilization
v) Radiation sterilization

The method used for sterilization of a pharmaceutical product is determined by

the nature of its ingredients.

3.2.1 Steam Sterilization

Steam sterilization is a method of choice of sterilization in cases where the

product can withstand the conditions of sterilization.

Steam sterilization is carried out in an autoclave and uses steam under pressure
and is also known as autoclaving.

Water boils at 100°C under atmospheric conditions. Steam above 100°C can
not be obtained under atmospheric conditions. If steam at higher temperature is
required, the pressure must be increased. If the pressure is increased then water
will boil at higher temperature corresponding to the pressure and steam at high
temperature can be obtained. Pressure itself has no sterilizing power; steam is
46
used under pressure only to obtain high temperature to destroy the micro- Parenteral and
organisms quickly. Steam is known as saturated when it is at a temperature External
corresponding to the liquid boiling point appropriate to its pressure. Preparations

The mechanism of microbial destruction in moist heat is by denaturation and

coagulation of the essential proteins of the organism when moisture is present.
Coagulation and destruction occur at lower temperature compared to the dry
conditions.

Steam under pressure or saturated steam is an efficient sterilizing agent

because –

i) Saturated steam is a better heating agent than hot air, so it rapidly heats the
load to sterilizing temperature by liberation of latent heat.

ii) When saturated steam condenses it contracts to a small volume so more

steam flows quickly into every article in the load.

iii) Saturated steam provides higher temperature and moisture (by

condensation) which is essential for killing micro organisms.

The usual steam pressures, the temperature obtained under these pressures and
the appropriate time required for sterilization i.e. the conditions for steam
sterilization are.

115°C at 10 pounds pressure for 30 minute, 121°C at 15 pounds pressure for 20

minute and 126°C at 20 pounds for 15 minutes.

These conditions of pressure and temperature indicate that higher the pressure
applied, higher the temperature obtained and less time is required for
sterilization.

The most commonly used temperature in autoclaving is 121°C. This

temperature attained in the autoclave must also be reached by the interior of the
load to be sterilized and must be maintained for specified time. The time
required to attain this temperature by the load is known as latent period. Latent
period vary with the nature of the load. For example smaller container will be
heated and attained this temperature in a short time and the larger container
will take a long time. This latent period must be added to the total time to
ensure adequate exposure time of sterilization.

Before starting sterilization by steam, air must be removed from the chamber
because a combination of air and steam gives a lower temperature than pure
steam under the same pressure.

Steam sterilization is used for pharmaceutical preparation which –

i) can withstand the required temperature

ii) can be penetrated by steam
iii) are not adversely affected by moisture
47
Pharmaceutics Steam sterilization is used for packaged sealed containers containing aqueous
solutions, bulk solution, surgical dressing, instruments and glass ware.
Other methods of moist heat sterilization are

i) Sterilization of vaccine at 56° ± 1°C in a water bath for one hour.

ii) Pasteurisation: At 71.6°C for 15 second and the quickly cooled. This
method is used for pasteurisation of milk.

iii) Tyndallisation: Heating at 80°C for one hour, on each of three successive
days.

iv) Heating with bactericide: The product is sterilized by heating at 100°C

for 30 minutes with an added bactericide.

3.2.2 Dry Heat Sterilization

Dry heat sterilization is carried out in hot air oven. These ovens are
thermostatically controlled and heated by electricity or gas.
The mechanism of microbial destruction in dry heat sterilization is by the
dehydration of the microbial cell followed by slow burning or oxidation. In dry
heat sterilization higher temperature and long exposure time are required
because dry heat is less effective than moist heat in killing microorganisms.
Dry heat sterilization is usually done at temperatures of 160° to 170°C for two
hours. The exposure time depends on the size and type of the product. The load
in the sterilizer should be arranged in such a manner so as to permit free
circulation of hot air inside the chamber.
Dry heat sterilization is used for sterilization of fixed oils, glycerine, paraffin
and various heat stable powders like zinc oxide and talc. This method is also
used for glass ware and surgical instrument.

3.2.3 Filtration Sterilization

Filtration sterilization involves physical removal of the microorganisms from

the product by passing through a filter medium. Filter medium removes the
microorganisms by absorption or a sieving mechanism. Filtration sterilization
is used for sterilization of the medicinal preparation containing thermolabile
medicaments. But these medicaments must be stable in the solution form.

There are four classes of bacterial proof filter media.

i) Microporous plastics – Also known as membrane filter and are made from
cellulose acetate, cellulose nitrate, polycarbonate and polyvinyl chloride.

ii) Sintered glass filters are made from borosilicate glass.

iii) Fibrous pads are made from asbestos and wood cellulose.

iv) Sintered ceramics filters are available in the form of filter candles and are
made from porcelain or diatomaceous earth.
48
Microporous plastic or membrane filters are the most commonly used filters Parenteral and
for sterilization now-a-days. These filters are available in a variety of pore External
sizes. The pores are uniform in size and occupy approximately 80% of the Preparations
filter. The flow rate or rate of filtration is high due to high degree or porosity.
The pore size of the filter medium is most important in removal of
microorganisms, the other factors such as charge on the filter, pH, temperature
and pressure or vacuum applied should also be considered.

Advantages and Disadvantages of Filtration Sterilization

The advantages of filtration sterilization are

i) Complete removal of living as well as killed microorganisms from the

product
ii) Thermolabile liquids can be sterilized by this method
iii) Less time is required for filtration of small quantities of solution
iv) This method of sterilization requires relatively inexpensive equipment.

Disadvantages of filtration sterilization are that

i) Aseptic processing is required.

ii) Sterility tests are obligatory for the solutions sterilized by this method.
iii) Faults in the filter media are not immediately detected.
iv) Absorption of medicament may occur.

Filtration sterilization is used for sterilization of small volumes of liquids and

for thermolabile liquids.

SAQ 1
What are the advantages of filtration sterilization?

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

3.2.4 Gas Sterilization

The sterilization methods described above are not suitable for heat sensitive
and moisture sensitive material. These materials can be sterilised by gas
sterilization. Various gases like ethylene oxide, propylene oxide, formaldehyde
ozone etc. are used. But ethylene oxide is most commonly used. This gas when
mixed with air in more than 3% concentration is highly inflammable so for safe
use ethylene oxide is diluted by mixing with an inert gas such as carbon
dioxide or fluorinated hydrocarbons. 49
Pharmaceutics The sterilising activity of ethylene oxide is by its interference with the
metabolism of the bacteria. It is an alkylating agent and cause alkylation of
proteins and other important cell constituents.

Gas sterilization by ethylene oxide is carried out in special sterilizers. Efficacy

of ethylene oxide sterilization is affected by concentration, time, relative
humidity and temperature. Efficacy of sterilization is enhanced and also the
exposure time can be reduced by increasing the humidity (about 60%) or by
increasing the temperature (50-60°C). If the humidity or temperature cannot be
increased for sensitive materials than exposure time have to be increased. The
exposure time required for sterilization by ethylene oxide is 4 to 16 hours.

The most important advantage of ethylene oxide is its high penetrating power
so it can be used for pre-packed articles such as medical and surgical supplies,
and plastic disposable syringes and appliances.

The disadvantage of ethylene oxide, sterilization is that it is a slow process and

long exposure as well as desorption (removal of gas from the material after
sterilization) time.
This method of sterilization is used for thermolabile, moisture sensitive
material and final plastic packaged materials. This method can also be used for
sterilization of some heat labile enzyme preparation, antibiotics and other drugs
provided the chemical reaction does not occur with the gas.

3.2.5 Radiation Sterilization

Radiation sterilization is done by exposing the material to radiations like ultra

violet light, gamma rays, alpha and beta rays etc.

The mechanism of sterilization by radiation involves an alteration of the

chemicals within the microorganism to form new chemicals which can destroy
the microorganisms or by destroying the chromosomal nucleoproteins of the
microorganism.

In case of sterilization by radiation, there is small rise in temperature. The

exposure time is short, the materials can be sterilised in their final containers.
This method of sterilization requires specialized equipment. This method is
expensive and precautions must be taken to protect the operators from harmful
effect of radiation so the use of this technique of sterilization is limited.

SAQ 2

Fill in the blanks:

a) Sterilization is complete destruction or removal of …………………. from

the preparation.
b) Steam sterilization is done by ……………….. under pressure at 121°C for
……………. minutes.
c) The mechanism of microbial destruction in moist heat sterilization is by
………………….. and ………………………. of the essential proteins e.g.
50 the organism.
d) Oils can be sterilised by ………………………… Parenteral and
e) Membrane filters are used for sterilization of ………………………… External
liquids. Preparations

SAQ 3
List the various methods of sterilization?

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

3.3 STERILE DOSAGE FORMS

The most important characteristic of sterile dosage forms is that they are
prepared to be sterile, i.e. they are free from any living microorganisms. Sterile
dosage forms include:

i) parenterals, i.e. injections, irrigation fluids and dialysis solutions,

ii) biological preparations such as vaccines, toxoids and anti-toxins, and
iii) ophthalmic preparations.

3.3.1 Parenterals

The term parenteral originated from Greek words para and enteron meaning
outside the intestines and it includes routes of administration except oral route.
But now-a-days parenteral is generally used for injections.

Injections are sterile, pyrogen free preparation. (Pyrogens are the metabolic
products of microorganisms and they increase the body temperature i.e. they
cause fever. So the injection must be pyrogen free).

Routes

Various routes of parenteral administration are

i) Intracutaneous or intradermal – injected into the skin

ii) Subcutaneous or hypodermic – under the skin
iii) Intramuscular – into a muscle
iv) Intravenous – into a vein

Some less commonly used routes are:

i) Intraarterial – into a artery

ii) Intracardiac – into the heart 51
Pharmaceutics iii) Intraarticular – in the joint
iv) Intrasynovial – in a joint fluid area
v) Intrathecal – into spinal fluid
vi) Intraspinal – in the spinal column

Parenteral route of administration is used for the following purposes:

a) When rapid action of drug is required e.g. in the emergency cases.

b) This route is used when the drug is ineffective by other routes like it may
be inactivated in the gastrointestinal tube (GIT) or it may not be absorbed.
c) When the patient is unable to take the drug by oral route or is
unconconscious or uncooperative.

Parenteral route of administration have some disadvantages also. These are:

i) The injections are to be administered by a trained person like physician or

nurse. This may sometime pose difficulties for the patient.

ii) If the injection is administered by wrong route it may prove fatal.

iii) Sometime in case of adverse reactions to the drug, the drug cannot be easily
removed from the circulation especially when the drug is injected
intravenously.

Parenteral preparations may be given in the form of aqueous or non-aqueous

solutions, suspensions and emulsions or in the form of freeze dried powders
which is reconstituted immediately prior to injection.

Intravenously administered medicines must be in aqueous solution and they

must mix with the blood. Volume of the solution may vary from a few
millilitres to litres that can be given by parenteral route. But only the
intravenous route is suitable for very large volumes.

Essential qualities of a parenteral product:

i) Parenteral products must always be sterile and free from pyrogens and
other microbial products.

ii) Parenteral solutions must be free from particulate matter (dust, fibres) and
meet the standard for particulate matter.

iii) They are packaged in such container that will maintain the quality and
sterility of the preparation.

iv) They must contain a minimum quantity of added substance like buffering
agent, stabilizers and antimicrobial preservatives.

v) They should be isotonic with body fluids.

vi) They should have matching specific gravity to body fluids as in case of
intra spinal injections.
52
3.3.2 Formulation of Parenteral Products Parenteral and
External
Formulation of parenteral products requires a vehicle and other added Preparations
substance. But in case of parenteral products a minimum number of absolutely
necessary additives in smallest quantity must be added.

A. Vehicle

All parenteral products formulated in the liquid form require a suitable

vehicle for dissolving or suspending the medicament. Water is the vehicle
of choice for most injections because aqueous preparations are easily
tolerated and can be administered safely and easily. The water used for
parenteral product must be pyrogen free; it is known as water for injection
and is purified by distillation or by reverse osmosis.

Bacteriostatic water for injection is sterile water which contains a

antimicrobial agent. Sometime injection water is free from dissolved gases
and carbon dioxide is required. It is freshly prepared by boiling water for
injection.

Although water is generally preferred for an injection but sometime non-

aqueous vehicles may be necessary (a) when the medicament is insoluble in
water (b) when the medicament is susceptible to hydrolysis (c) when a
prolonged action or a depot effect is required.

The non-aqueous solvents used in parenteral products are fixed vegetable

oils, polyethylene glycols, propylene glycols, alcohol and glycerine.
Sometimes ethyl oleate, isopropyl myristicate and dimethyl acetamide are
also used. Only injections must not be administered intravenously, they are
administered intramuscularly.

The non-aqueous vehicle used must be non-irritating and non-toxic. It must

not exert its own pharmacological activity and must not react with
medicament.

B. Added substances in parenteral products

i) Solubilising agents: Solubilising agents are used for solubilising the

insoluble or poorly soluble drugs in the vehicle. Solubility can be
increased by adding solubilizers like carbowaxes, tween and
polysorbates, by using co-solvent or by complex formation e.g. the
solubility of glycosides and barbiturate can be increased by replacing
part of water with alcohol or glycerine (co-solvent) sometimes the
solubility can be increased by forming soluble complex e.g. caffeine is
dissolved by sodium benzoate.

ii) Stabilizers: Drugs present in the injection may undergo hydrolysis or

oxidation during preparation and storage. Stabilisers are the substances
to prevent these changes in the drugs. Since most decomposition is
catalysed by hydrogen or hydroxyl ions so adjustment of pH is the most
53
Pharmaceutics important method of stabilisation of injection. Sometimes water may be
replaced by another suitable vehicle to minimize hydrolysis.

The methods used to prevent oxidation of medicament are use of water

for injection free from dissolved air, addition of a reducing agent or
antioxidant and replacement of air in the container with an inert gas.
Sodium metabisulphite is most commonly used reducing agent for
injections. The antioxidant used must be non-toxic and must not have
any side effect, stable and efficient.

iii) Buffering agents: pH in some solutions is adjusted to within a definite

pH range to increase the stability and solubility of medicament, to
minimise pain and irritation on injection, to minimize growth of
microorganisms and to enhance the physiological activity. The pH of a
injection may be changed due to leaching of alkali from glass container,
extraction of impurities from closures or by degradation of
medicaments.

There are some medicaments that lose activity outside a optimum pH

range. For such products the pH range is maintained within the desired
limits by adding buffering agents. Acetates, citrates and phosphate
buffers are used to maintain the pH of injections.

iv) Tonicity factors: The parenteral preparation should be isotonic with

blood serum or other body fluids where they are injected. In case of
intravenous injection, isotonicity is always desirable because a
hypotonic solution may cause haemolysis and hypertonic solution may
cause crenulations (shrinkage) of the cells. The isotonicity of a solution
is adjusted by adding substance like sodium chloride and borax.

v) Antimicrobial preservatives: Antimicrobial preservatives are added in

injection to prevent multiplication of microorganisms, which may be
accidentally introduced into the preparation during use. These
preservatives are used in multidose containers and in injections
sterilized by filtration. Preservatives are not added in single dose
containers because they are sterilized after packaging and remain sterile
until opened and the solution is injected. Frequently used antimicrobial
preservatives are: phenol (0.5%), cresol (0.3%), chlorocresol (0.1%),
phenyl mercuric acetate and nitrate (0.001%).

vi) Wetting, suspending and emulsifying agents: These agents are

sometimes used in suspension and emulsion to stabilise the product or
to maintain the particle size and prevent lump formation. Sodium
carboxy methyl cellulose, methyl cellulose and polyvinyl pyrrolidone
are used as suspending agent. Parenteral emulsions are formulated by
using lecithin as emulsifying agent.

3.3.3 Preparation of Parenteral Products

Once the formulation ingredients i.e. vehicles and other additives are decided,
54 the production is carried out under rigid aseptic conditions. The contamination
of the product can occur from the atmosphere, the equipments and apparatus Parenteral and
used in preparation and the personnel in the area. For this, the area in which the External
parenteral products are made is maintained bacteria free. The air in this area Preparations
must be filtered to make it free from fibres, dust and microorganisms. For the
air filtration, high efficiency particulate air (HEPA) filters are used. These
filters are very efficient and remove particles upto 0-3μ with an efficiency of
99.97%. The entire area and all working surfaces must easily cleansable and
disinfectable. A specified procedure i.e. washing hands, treating hands with
antiseptics, wearing gloves, changing dress and shoes is always followed for
entering the aseptic area. The clothing worn by the personnel in the area must
be sterilized. All the equipment which is to be used in the aseptic area must be
sterilized.

The usual method of preparation of parenteral products involves dissolution of

required ingredients in the selected aqueous, non-aqueous or combination of
solvents. The solution is then clarified by passing through a membrane filter.
The filtered solution is then transferred into the final container with least
possible exposure. These containers are then sealed and sterilized by a suitable
method of sterilization. Autoclaving is method of choice of sterilization. Other
techniques of sterilization are used if autoclaving cannot be used due to the
nature of the ingredients (described in previous section).

3.3.4 Packaging

Injections are packaged in single dose container or multiple dose containers.

Single dose containers are hermetically sealed container containing a single
dose and cannot be resealed or reused. Multiple dose containers are also
hermetically sealed container but they contain several doses of the
medicaments. The contents can be withdrawn in successive portion without
changing the purity and quality of the remaining product. Single dose container
may be ampoule or vials made of high quality glass.

3.3.5 Evaluation of Parenteral Products

The following tests are carried out for the evaluation of the parenteral products.

i) Sterility test
ii) Pyrogen test
iii) Clarity test
iv) Leakage test

i) Sterility test

All parenteral products are tested for sterility i.e. for absence of any living
microorganism. For the sterility testing suitable nutrient media which must
be sterile itself and capable of allowing the growth of microorganisms is
selected. The sterility testing is done under aseptic conditions so that no
microorganism gets accidental access to the material under test or the
nutrient media. All the factors which may interfere with the sterility test
55
Pharmaceutics must be excluded. An aliquot portion of the material under test is
transferred to the sterile media and it is incubated under appropriate
conditions of humidity, temperature and time. If bacterial growth is
observed in the media, the material may be non-sterile. But for
confirmation tests one or two tests are run successively. If for the third
time, the test fails than is material is declared to be non-sterile.
ii) Pyrogen test

Pyrogen testing for parenteral product is done by injecting suitable amount

of the injection into the ear vein of the rabbits and the rises in body
temperature of rabbits are observed. If, no fever is recorded in the rabbits,
the product is said to be pyrogen free.

iii) Clarity tests

Test for clarity is done to check the presence of particles or fibres etc. in the
product. Many devices are now-a-day available which detect the particles
and are based on light absorption, light scattering or change in electrical
resistance by the particles. Clarity test can also be done manually by
holding the container against strongly illuminated black and white screen.

iv) Leakage test

Leakage test is carried out to check the leakage of containers due to faulty
sealing or any cracks. For this test the sealed containers are dipped in
coloured solutions and vacuum is created. The coloured solution will enter
inside the ampoule on release of vacuum. The presence of dye indicates
leakage in the container.

3.3.6 Large Volume Parenterals

Large volume parenterals (LVPs) solutions are administered in large volume

from 100 ml to litres. They are administered by slow intravenous infusion to
provide nutrition or to replenish electrolytes of body fluids. They are supplied
in large single dose container. Since they are administered in large volumes,
antibacterial preservatives or other additives must not be added to these
solutions.

3.3.7 Irrigation Solutions

Irrigation solutions are used to bath or wash wounds, surgical incisions or body
tissues. They are also subjected to same stringent standards as the parenteral
solution. These solutions are not injected into the vein. Some examples of
irrigation solutions are sodium chloride irrigation, Ringer’s irrigation etc.

3.3.8 Dialysis Solutions

Dialysis is the process of separating substance due to their difference in

diffusibility through membrane. The solutions used for dialysis are known as
dialysis solutions. Two types of solutions are used for dialysis:
56
i) Peritoneal dialysis is used to remove toxic substance in case of poisoning or Parenteral and
kidney failure. External
Preparations
ii) Haemodialysis is used to remove toxins from the blood.

SAQ 4

Fill in the blanks:

a) Pyrogens are the metabolic products of microorganisms, they increase

the ……………………….
b) Intravenous injection is administered into a …………………………
c) Parenteral products should be ………………………. with the body fluids.
d) The preservatives are used in multidose containers and in injections are
sterilized by …………………………

SAQ 5
List the tests that are carried out for the evaluation of the parentral product.

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………
……………………………………………………………………………………

3.4 OPHTHALMIC PRODUCTS

Ophthalmic products are meant for instillation into the eye in the space
between the eye lids and the eye balls. The ophthalmic products which are
applied topically to the eye are solutions, suspension, gels, ointments and drug
impregnated inserts. These products are used topically to treat infections of eye
or eye lids, allergic or infectious conjunctivitis or inflammation, glaucoma and
dry-eye. To treat all these conditions the ophthalmic products contain
anaesthetic, antimicrobial, anti-inflammatory, astringent, miotics and other
glaucoma agents, mydriatics, nasoconstrictors or artificial tears.

Ophthalmic products are also sterile preparation like parenteral products. They
are also prepared under same aseptic conditions and methods.

3.4.1 Eye Drops

Eye drops are oily or aqueous solutions or suspension for use in the eye. The
preparation of eye drops require some special properties with regard to

i) sterility and preservation

ii) isotonicity 57
Pharmaceutics iii) buffering
iv) viscosity
v) surface activity
vi) clarity
vii) bioavailability, and
viii) packaging
i) Sterility and preservation

Sterility is the most important requirement for eye drops. Contaminated

eye drops can cause serious damage to the eye. The eye is protected by the
epithelium of cornea and the tears. But damage to cornea may cause
serious damage to eye. The eye drops are sterilized in their final container
in an autoclave. In case of thermolabile medicament filtration sterilization
can be used this has the advantage of removing particulate matter.

Since the eye drops are packaged in multi application containers so to

maintain sterility during use, it is necessary to include antimicrobial
preservatives in the formulation. Preservatives are not added in products
which are used during surgery because preservatives can cause irritation in
the already traumatized eyes. These preparations are packaged in single
use containers due to absence of preservatives. The preservative used must
be stable, chemically and physically compatible with contents of
formulation and container, non-irritant, non-toxic and non-allergic. The
preservatives used in eye drops are benzalkonium chloride (0.004 –
0.01%), phenyl mercuric acetate and phenyl mercuric nitrate 0.004% and
thiomersal 0.005 – 0.01%.

ii) Isotonicity

Eye drops which are isotonic to lacrimal secretions are best tolerated and
cause minimum irritation. Boric acid in 1.9% concentration is isotonic
with lacrimal secretions. Addition of the drug and other additives to this
boric acid solution may change its tonicity, so to prepare the eye drops the
drug and other additives are first dissolved in sterile water and then the
isotonicity is adjusted by adding a isotonic vehicle. Phosphate buffer
solutions are also suitable for use in eye drops.

iii) Buffering

The pH of normal tears is about 7.4. Tears have some buffering capacity
and as such eye can tolerate a deviation from pH towards alkalinity than
towards acidic range. The pH of eye drops is adjusted and maintain for
stability of formulation, to solublise the drug, to increase the
bioavailability of drug, to increase the preservative action and for comfort
to the patient eye. Many drugs have a lower activity and least stability at
pH (6-8) which is comfortable to eye hence a compromise pH is selected
and maintained by buffering to greatest activity and maintained stability.
Isotonic phosphate buffers are used for buffering of eye drops.
58
iv) Viscosity Parenteral and
External
The capacity of eye to retain liquid is limited. Excessive liquids are Preparations
rapidly drained from eye. Eye drops are administered in small amount
drop wise, so the contact with tissues is very less. But if the viscosity of
preparation is increased, the drug will remain in contact with tissues for
longer periods to enhance therapeutic effectiveness. Viscosity as eye drops
can be increased by adding thickening agents like suitable grades of
methylcellulose, hydroxyl propyl methyl cellulose and poly vinyl alcohol.

v) Surface activity

Eye drops are more effective if it is able to wet the tissues intimately as
wetting of the tissues enhances penetration of drug into the cornea and
other tissues. Surfactants may be used in eye drops to increase the wetting
property. When Benzalkonium chloride is used as preservative in eye
drops it serves the dual purpose of preservative and surfactants. Other
surfactants used are polysorbates, dioctyl sodium sulphosuccinate,
polyoxypropylene etc.

vi) Clarity

Ophthalmic solutions must be free of all particulate matter and absolutely

clear for patient comfort and safety. Various types of filter media can be
used for clarification but membrane filters are the best option.

For the preparation of ophthalmic suspensions, micronized or finely sub-

divided drug particles must be used. These particles must be easily and
uniformly distributed by shaking and must not aggregate during storage.

vii) Ocular bioavailability

Ocular bioavailability and activity of medicament may be affected by

some physiological factors like protein binding to the proteins present in
tears, metabolism of some drugs by lysozyme present in tears and lacrimal
drainage. All these factors must be considered during the formulation of
eye drops.

viii) Packaging

Ophthalmic solutions of suspensions are packaged in small containers

holding. 2, 2.5, 5, 10 and 30 ml of product. The containers used for eye
drops must preserve the sterility of content, protect the contents from
environmental factors and must not react with the contents. The container
must be convenient to handle. Some eye drops are packaged in small glass
bottles with a separate glass or plastic dropper but now-a-days soft plastic
containers having a fixed built-in dropper are preferred. These plastic
containers are easy to use and also prevent external contamination of the
product.
59
Pharmaceutics Preparation of eye drops involves the following stops:

a) Preparation of a preservative vehicle

b) Dissolution of medicaments and additives
c) Clarification
d) Sterilization

3.4.2 Other Ophthalmic Products

Some other ophthalmic products are:

i) Eye lotions
ii) Ophthalmic ointments
iii) Contact lens solutions

i) Eye Lotions: Eye lotions are sterile aqueous solutions containing no

bactericide used for irrigating the eye and are applied with an eye bath.

ii) Ophthalmic ointments: These are sterile preparation meant for application
to the eye. The ointment base for ophthalmic use must be sterile, non-
irritant, and free from particulate matter and allow diffusion of medicament
into the secretions of eye. The ophthalmic ointments base generally
contains yellow soft paraffin and mineral oil.

iii) Contact lens solutions: These are aqueous solutions used for cleaning,
disinfecting, rinsing, hydrating, lubricating and storage of contact lenses.

These solutions are used for proper care of the lenses so that they retain
their shape, optical characteristic and also for their safe use.
SAQ 6

Fill in the blanks:

a) The pH of normal tears is ……………………………

b) Ophthalmic solutions are clarified by using …………………………
c) Eye drops isotonic to lacrimal secretions are best tolerated and cause
…………………………..
d) Benzalkonium chloride serves the dual purpose of preservative and
…………………………….. in eye drops.

SAQ 7
What are ophthalmic ointments?

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………
60
…………………………………………………………………………………… Parenteral and
External
…………………………………………………………………………………… Preparations

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

3.5 SEMISOLID DOSAGE FORMS

Semisolid preparations are mainly meant for topical application. Semisolid

preparations are applied to the skin or mucosa. These preparations are
formulated in the form of ointments, creams, pastes and gels. Medicated
preparations are used for the therapeutic effect of the drug contained in them.
Non-medicated preparations are used as emollient and protective.

3.5.1 Ointments

All ointment contains an ointment base and the medicament is dissolved or

suspended in the base. Ointment base is a semisolid vehicle in which
medicament may be incorporated. In preparing ointment, selection of an
ointment base is very important as nature of the base who affects the activity of
the ointment. An ideal ointment base should be non-toxic, non-irritant, inert,
stable, smooth, and compatible with the skin and medicament. It should release
the medicament readily and help in penetration of the medicaments. Various
type of ointment bases are available which may be used in combination or
alone as per the requirement.

Ointment bases are classified in four groups:

i) Hydrocarbon or oleaginous bases

ii) Absorption bases
iii) Water miscible or emulsion bases
iv) Water soluble bases

i) Hydrocarbon or oleaginous bases

Hydrocarbon bases are water insoluble bases and are used for their
emollient and protective effect. They restrict loss of water and keep the
skin soft. They are inert and sticky. They do not help in the absorption of
medicament, since they are immiscible with water so difficult to wash off.
Only a small amount of water or aqueous preparation may be incorporated
in these bases.

Some examples of hydrocarbon bases are soft paraffin, hard paraffin, liquid
paraffin and paraffin ointment BP etc.
61
Pharmaceutics ii) Absorption bases

Absorption bases are hydrophilic in nature and they can absorb water or
aqueous solution resulting in formation of water in oil emulsions. These
bases are good emollient, easy to spread on the skin and assist penetration
of oil-soluble medicament. These bases are not easily washed off with
water due to external oil phase of the emulsion. Example of absorption
bases are wool fat, lanolin (hydrous wool feet), wool alcohol, bees wax and
simple ointment B.P. etc.

iii) Water miscible or emulsion bases

These bases are oil in water emulsions and have cream like appearance.
They can be easily washed from skin because of aqueous external phase.
They are miscible with exudates from lesions, have high cosmetic
acceptance because of cream appearance. They give good contact with the
skin and do not interfere with skin functions.

iv) Water soluble bases

Water soluble bases are also known as greaseless because they are
completed water washable. Large amount of aqueous solutions cannot be
incorporated in these bases because they soften with the addition of water.
Water soluble bases are developed from polyethylene glycol (PEG), which
is a polymer of ethylene oxide and water. CH2OH (CH2 O CH2)n − CH2OH
in which n represents the average number of oxyethyl groups. These bases
are described by numbers e.g. polyethylene glycol 3350, PEG 1500, PEG
400 etc. The number indicates the average molecular weight higher
molecular weight PEG are solids and lower molecular weight PEG are
liquids and molecular weight in between are semisolids. These bases are
water soluble, help in penetration of drug due to good absorption, good
solvent and compatibility with many medicaments. These bases can take up
only small quantity of water. They can affect the activity of some
antibacterial agent and polythene and bakelite are dissolved by PEG’s so
containers made of these plastic cannot be used for polyethylene glycol
ointments.

3.5.2 Factors Affecting Selection of Ointment Base

i) Dermatological factors

a) Absorption and penetration

b) Release rate of drug from base.
c) Affect on skin function
d) Miscibility with skin secretions
e) Compatibility with skin secretions
f) Freedom from irritant effect
g) Emollient properties
62 h) Ease of application and removal
ii) Pharmaceutical factors Parenteral and
External
a) Solvent properties Preparations
b) Stability
c) Consistency
d) Emulsifying properties

3.5.3 Preparation of Ointments

The method of preparation of ointments depends on the nature of the

ingredients. Ointments are prepared by any one of the following method:

i) Trituration or incorporation method

ii) Fusion method
iii) Chemical reaction method
iv) Emulsification method

i) Trituration or incorporation method

This method is used for the extemporaneous preparation of the medicated

ointment. The insoluble medicament must be finely subdivided for uniform
distribution of the drug in the ointment. The medicament is evenly
distributed by triturating with a small amount of base or one of the
ingredients of base and it is diluted with gradually increasing amount of
base. Solids which are soluble are first dissolved and then added to the
ointment base by trituration.

Liquid substance may also be added in the same manner but due
consideration must be given to the quantity of liquids that can be taken up
by the ointment base. The ointment is finally passed through an ointment
mill to get a uniform product free from grittiness.

ii) Fusion method

Fusion method is used for preparation of ointment bases and for medicated
ointments. In fusion method all or some of the ingredients are combined by
melting together and then cooled with continuous stirring until congealed.
The heat-labile or volatile substance are added when the mixture is cooled
to a temperature that will not cause decomposition or volatilization. The
materials with the highest melting point are heated first and then the other
ingredients in descending order of melting point are added. This method
requires less heat and avoid over heating of low-melting point substance.
Alternative method involves melting of all the constituents together under
slowly increasing temperature. By this alternative method melting can be
done at lower temperature and less time due to the solvent action exerted
by the first melted components on the others.

For the preparation of medicated ointments by fusion method, the soluble

solids medicaments are dissolved in the melted base and stirred until cold.
Insoluble solids are finely sub-divided and added in small amounts at a 63
Pharmaceutics time with stirring to the base when the base starts thickening. Stirring is
done to uniformly disperse the medicament and is continued until the
preparation is thick enough to prevent sedimentation.

iii) Chemical reaction method

Sometimes the preparation of ointment involves chemical reaction. For

examples ointments containing combined iodine. It is also known as non-
staining iodine ointment. If iodine is present in the free form in the
ointment it will stain the skin or clothes but the non-staining iodine
ointment does not stain the skin because iodine is present in the combined
form.

This ointment contains arachis oil, which is a fixed oil. Fixed oils absorb
iodine which combines with the double bonds of the unsaturated
components of the oil and it is not free to give stain. This combined iodine
is then incorporated in a suitable base.

iv) Emulsification method

This method is used in the preparation of ointments by using emulsion
bases. Emulsification method involves both melting and emulsification
process. The water immiscible constituents are melted together to about 70-
75°C and heat stable water soluble components are separately dissolved in
water and heated to the same temperature. The aqueous solution is then
added slowly with stirring to the melted oily phase at maintained
temperature and then the mixture is cooled slowly with continuous stirring.

SAQ 8
What are the emulsion bases?

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

SAQ 9

How ointment bases are classified?

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………
64
3.6 CREAMS Parenteral and
External
Preparations
Creams are semisolid ointment like preparations containing one or more
medicaments dissolved or suspended in either oil-in-water or water-in-oil
emulsions. Pharmaceutical cream bases are either oil-in-water emulsion or any
water washable base. Creams are preferred because they are easy to apply and
to remove. They are used for topical application on skin or for rectal or vaginal
use.

Bacterial and mould growth can occur in aqueous creams hence suitable
preservatives must be added and all hygienic precautions must be taken
throughout the preparation of creams.

3.7 JELLIES

Jellies are transparent or translucent, non-greasy, semisolid preparations

generally applied externally. They are used for medication, lubrication and
some miscellaneous applications like in patch testing and in
electrocardiography.

Jellies are prepared by adding a gelling agent to an aqueous solution of the

medicament. The various gelling agents used are acacia, alginic acid, bentonite
carbomer, sodium carboxy methyl cellulose, cetostearyl alcohol, colloidal
silicon dioxide, sodium alginate etc.

3.8 PASTES

Pastes are semisolid preparations for application to the skin. Pastes are stiffer
than ointment because they contain a larger portion (50%) of finely powdered
solids. Pastes are emollient and they are porous because of their powder
contents. Due to porosity perspiration can escape and the powders can absorb
serous secretion, so they are less macerating than ointments. Pastes are less
greasy than ointments even when prepared in an oleaginous base because less
amount of base is used. The pastes adhere well to the skin and form a thick
coat that gives a protective action. They remain in place after application and
do not spread as is the case with ointments. Pastes are not suitable for
application to the hairy parts of the body because of their stiffness. Pastes are
applied generously over the area or spread on dressing and applied.

The bases used for pastes are:

i) Hydrocarbon bases
ii) Water miscible bases
iii) Water soluble bases
65
Pharmaceutics 3.8.1 Methods of Preparation of Pastes

Pastes are prepared by trituration and fusion method like ointments. Fusion
and/or trituration method is used when the base is semisolid. If the base is
liquid, than trituration method is used.

SAQ 10
What are the bases used for the paste?

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

……………………………………………………………………………………

3.9 SUMMARY

Sterilization is the process of removing all living organisms and their spores
from any product. Sterilization can be done by steam, by using dry heat, by
filtration, radiation or by using various gases. Sterilization is most important in
the preparation of sterile dosage forms like parenterals and ophthalmic
preparation. All the parenteral preparations must be sterile, pyrogen free and
free from particulate matter. They are to be maintained at a specific pH for
stability, solubility and therapeutic action. These preparations must be isotonic
with body fluid to prevent any type of reactions. All the multidose containers
must contain a suitable preservative to cover any accidental contamination
during use. Formulation of parenteral product requires careful consideration of
selection of vehicle and other additives to be used. The additives which are
used in parenteral products are used in minimum amount when absolutely
necessary. These products are prepared under aseptic condition to prevent
contamination of the product. Various tests are carried out for the evaluation of
parenteral products which are sterility test, pyrogen test, clarity test and
leakage test.

Ophthalmic products are meant for instillation into the eye. The preparation of
ophthalmic products requires some special properties with regard to sterility,
preservation, isotonicity, buffering, viscosity, clarity, bioavailability and
packaging.

Semisolid dosage forms are mainly meant for topical application. They are
formulated in the form of ointments, creams, pastes and jellies. The
formulation of theses semisolid preparations require a base or the semisolid
vehicle to carry the medicament. Various bases are used as per the requirement
of the product. Semisolid dosage forms can be prepared by trituration, fusion,
chemical reaction and emulsification methods.
66
3.10 TERMINAL QUESTIONS Parenteral and
External
Preparations
1. Why saturated steam is an efficient sterilizing agent?

2. What are the advantages of parenteral route of administration?

3. What are the special properties of ophthalmic preparations with regard to

its formulation?

4. Name various tests carried out in the evaluation of parenteral products.

5. Name various methods of preparation of ointments.

3.11 ANSWERS

Self Assessment Questions

1. The advantages of filtration sterilization are

a) Complete removal of living as well as killed microorganisms from the

product
b) Thermolabile liquids can be sterilized by this method
c) Less time is required for filtration of small quantities of solution
d) This method of sterilization requires relatively inexpensive equipment.

2. a) All living organisms and their spores.

b) Steam, 20 minutes.
c) Denaturation and Coagulation.
d) Dry heat sterilization
e) Thermolabile

3. Various methods used for sterilization of pharmaceutical products are:

a) Steam sterilization
b) Dry heat sterilization
c) Filtration sterilization
d) Gas sterilization
e) Radiation sterilization

4. a) Body temperature
b) Vein
c) Isotonic
d) Filtration
67
Pharmaceutics 5. The following tests are carried out for the evaluation of the parenteral
products.

a) Sterility test
b) Pyrogen test
c) Clarity test
d) Leakage test
6. a) 7.4
b) Membrane filters
c) Minimum irritation
d) Surfactant

7. Ophthalmic ointments: These are sterile preparation meant for application

to the eye. The ointment base for ophthalmic use must be sterile, non-
irritant, and free from particulate matter and allow diffusion of medicament
into the secretions of eye. The ophthalmic ointments base generally
contains yellow soft paraffin and mineral oil.

8. These bases are oil in water emulsions and have cream like appearance.
They can be easily washed from skin because of aqueous external phase.
They are miscible with exudates from lesions, have high cosmetic
acceptance because of cream appearance. They give good contact with the
skin and do not interfere with skin functions.

9. Ointment bases are classified in four groups:

a) Hydrocarbon or oleaginous bases
b) Absorption bases
c) Water miscible or emulsion bases
d) Water soluble bases

10. The bases used for pastes are:

a) Hydrocarbon bases
b) Water miscible bases
c) Water soluble bases

Terminal Questions

1. Steam under pressure or saturated steam is an efficient sterilizing agent

because –

• Saturated steam is a better heating agent than hot air, so it rapidly heats
the load to sterilizing temperature by liberation of latent heat.
• When saturated steam condenses it contracts to a small volume so more
steam flows quickly into every article in the load.
• Saturated steam provides higher temperature and moisture (by
68 condensation) which is essential for killing micro organisms.
2. Advantages of parenteral route of administration are: Parenteral and
External
• Rapid action of drug e.g. in the emergency cases. Preparations
• This route is used when the drug is ineffective by other routes like it
may be inactivated in the G.I.T. or it may not be absorbed.
• When the patient is unable to take the drug by oral route or is
unconconscious or uncooperative.

3. The preparation of eye drops requires some special properties with regard
to sterility, preservation, isotonicity, buffering, viscosity, clarity, surface
activity, bioavailability and packaging.

4. The following tests are carried out for the evaluation of the parenteral
products:

• Sterility test
• Pyrogen test
• Clarity test
• Leakage test

5 • Trituration method
• Fusion method
• Chemical reaction method
• Emulsification method

69