Unit 3 Parenteral and External Preparations: Structure
Unit 3 Parenteral and External 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
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
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
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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
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.
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.
These conditions of pressure and temperature indicate that higher the pressure
applied, higher the temperature obtained and less time is required for
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.
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.
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.
i) Microporous plastics – Also known as membrane filter and are made from
cellulose acetate, cellulose nitrate, polycarbonate and polyvinyl chloride.
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.
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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.
SAQ 1
What are the advantages of filtration sterilization?
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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.
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.
SAQ 2
SAQ 3
List the various methods of sterilization?
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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:
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
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.
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.
vi) They should have matching specific gravity to body fluids as in case of
intra spinal injections.
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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
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.
3.3.4 Packaging
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
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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
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.
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.
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.
SAQ 4
SAQ 5
List the tests that are carried out for the evaluation of the parentral product.
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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.
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
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.
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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
viii) Packaging
i) Eye lotions
ii) Ophthalmic ointments
iii) Contact lens solutions
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
SAQ 7
What are ophthalmic ointments?
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External
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3.5.1 Ointments
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.
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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.
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.
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.
i) Dermatological factors
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.
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.
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.
SAQ 8
What are the emulsion bases?
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SAQ 9
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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
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.
i) Hydrocarbon bases
ii) Water miscible bases
iii) Water soluble bases
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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?
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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.
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3.10 TERMINAL QUESTIONS Parenteral and
External
Preparations
1. Why saturated steam is an efficient sterilizing agent?
3.11 ANSWERS
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
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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
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.
a) Hydrocarbon bases
b) Water miscible bases
c) Water soluble bases
Terminal Questions
• 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
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