PARENTERALS

The term of parenteral is derived from Greek word

para meaning outside and enteron meaning the
intestine. • Thus Parenterals administration should
include the administration of drug by any route other
than intestine. • Parenteral products are considered to
be those sterile drugs, solutions, emulsions,
suspensions.

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1. Definition:

Parenteral preparations are sterile preparations

containing one or more active ingredients intended
for administration by injection, infusion or
implantation into the body. They are packaged in
either single-dose or multidose containers.

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 Advantages:
 Quick onset of action.
 Suitable for the drugs which are not administered by oral route.
 Useful for unconscious or vomiting patients.
 Duration of action can be prolonged by modifying formulation.
 Suitable for nutritive like glucose & electrolyte.
 Suitable for the drugs which are inactivated in GIT or HCl (GI fluid).
 Bypass hepatic first pass effect.

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Dis-Advantages:
 Injections may cause pain at the site of injection
 Only trained person is required
 If given by wrong route, difficult to control adverse effect
 Sensitivity or allergic reaction at the site of injection

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Necessities of Parenteral preparations: –

 Sterility (must)
 Free from Pyrogen (must)
 Free from particulate matter (must)
 Clarity (must)
 Stability (must)
 Isotonicity (should)

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 Parental Routes of Administration
1. Subcutaneous
2. Intramuscular (IM)
3. Intravenous (IV)
4. Intra-arterial (IA)
5. Intrathecal
6. Intraarticular
7. Intrapleural
8. Intracardial
9. Intradermal
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 Formulation of parenterals
1. Therapeutic agents

2. Vehicles
 Water

 Water miscible vehicles

 Non-aqueous vehicles
1. Added substances (Additives)
 Preservatives
 Solubilizing agents
 Tonicity-adjusting agents
 pH adjusting agent
 Antimicrobials
 Antioxidants
 Chelating agents
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 THERAPEUTIC INGREDIENTS:

a) Insulin, b) Antibiotics, c)Anticancer, d) Steroids, e) Vaccines, f) Antipyretic, g) Analgesics,

h) Anti-inflammatory, i) LVP’s like Dextrose, NaCl or combination etc.….

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.

Water for injection (WFI):

 It is the water intended to be used in the manufacture of injectable products, which are to

be sterilized after their preparation.

 It is the most frequently used solvent.

 It contains no added substances.

 It is prepared by distillation or reverse osmosis

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NONAQUEOUS SOLVENTS: -
 The main reasons for using non- aqueous vehicles are-
 Drug shows poor aqueous solubility.
 If prolonged/ sustained release of drug desired (Steroids).
 Drug susceptible to hydrolysis (Barbiturates).
 The solvents should be non-toxic, non-irritant, and inert

 The solvents should not exhibit any pharmacological activity of its own.

 The solvents should not influence the activity of medical agent.

 Examples: Fixed oils like Corn oil, Cotton seed oil, Peanut oil, Castor oils etc.

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WATER MISCIBLE VEHICLES:-
(i) Alcohol-

 It is used as solvent and co-solvent.

 It is miscible with water and dissolves several water insoluble drugs (eg- Digoxin,
Ergotamine).

 It also has preservative action.

 Disadvantages: (a) It causes pain and tissue damage, (b) Exhibit pharmacological activity
and interfere with activity of main drug.

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Propylene Glycol-

 It is used for some particular drugs like Digoxin, Phenobarbitone.

 It is non toxic and water miscible.

 Disadvantages: Those injections by using this solvent should not be given through
intramuscular and subcutaneous route, as it causes severe irritation.

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Preservatives:
 It is used to inhibit the growth of microorganisms.
 Used in Multidose containers and Single dose products that is not terminally sterilized.
 Preservative efficacy testing is done on proposed formulation to assure on effective
preservative concentration.
 Examples: Benzalkonium chloride, Sodium benzoate

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Antioxidants:

 by blocking an oxidative chain reaction.

 Certain antioxidants act as synergistic which increase the effectiveness of other
antioxidants particularly those blocking reaction.
 Examples: Salts of Sulphur dioxide, including bisulphate, metabisulphite, are commonly
used.
Chelating agent:

They form complexes and inactivate metals such as iron and zinc that catalyze oxidative
degradation of drug molecules.

 Examples: Edetate disodium, Citric acid and Tartaric acid.

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BUFFERS:
PH of the formulation is maintained at the desired
level by incorporating a suitable buffer.
Eg: sodium citrate and sodium bicarbonate.

Surfactants:
These are used to disperse a water-insoluble drug
to form a colloidal dispersion i.e, they enhance the
solubility of the drug. Surfactants are mainly used in
parenteral suspension and emulsions.
Eg: polysorbate 80, propylene glycol.
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 Tonicity contributors:
Injections need to be isotonic with blood serum or
any other body fluids.
Tonicity adjustment is done using 0.9% NaCl, 2%
boric acid.

Preservative:
These are the substances which prevent growth of
microbes.
Eg: benzalkonium chloride, metacresol,phenol etc
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 Evaluation tests for
parenterals

1.Leakage test:
 The leaker test is performed by immersing the ampoules in a dye solution, such as
1% Methylene blue, and applying a Vacuum (Negetive pressure) at least 27 inch
Hg or more of vaccum is created for about15- 30 mins.

 This negetive pressure causes the methylene blue solution to enter the ampoules
with defective sealing.

 The vacuum is released; ampoules are washed externally and observed the
presence of dye in the ampoules. The presence of dye confirms the leakage.

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 2. PYROGEN TEST:

Preliminary test:

 If animals are used for the first time in a Pyrogen test or have not been used
during the 2 previous weeks, condition them 1 to 3 days before testing the
substance by injecting IV 10ml per kg pyrogen free saline solution warmed to
about 38.5°

 Record the temperature of the animals, beginning at least 90 mins before injection
and continuing for 3 hours after injection.

 Any animal showing a temperature variation of 0.6° or more must not be used in
main test.

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Main Test:
Insert a clinical thermometer into the rectum of each rabbit and normal reading of body
temp. are taken prior to the injection of test solution. Two readings are taken at an interval
of 30 mins and mean is calculated. This reading is the initial temp. of the rabbits.

The test solution is injected into the ear vein of each rabbit. The volume of injection is 10
ml/kg and not less than 0.5ml/kg of body weight.

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 Record the temperature of each animal at half-hourly intervals for 3 hours after
injection.

The difference between the initial temperature and the maximum temperature which
is the highest temperature recorded for a rabbit is taken to be its response.

Interpretation
of Result

Individual Temperature Temperature rise in

No. of Rabbits Test
rise (°c) groups (°c)

3 Rabbits 0.6 1.4 Passes

If above not passes 3+5 =8

0.6 3.7 Passes
rabbits

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 LAL (Limulus Amoebocyte Lysate)TEST /BACTERIAL ENDOTOXIN
TEST

 This is a sensitive test used to detect endotoxins from gram-negetive bacteria.

 The endotoxins upon reaction with lysate from an insoluble gel clot. The lysate is
obtained by the lysis of amoebocytes (blood cells) of the horseshoe crab, Limulus
polyphemus.

 The addition of a solution containing endotoxins to a solution of a lysate produces

turbidity, precipitation or gelatin of the mixture.

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PRINCIPLE
The test is based on the formation of gel (or developmenyt of colour) in the
presence of bacterial endotoxins and lysate solution. The lysate consists of
proclotting enzyme and coagulogen (clottable protein) which are required for the
reaction to occur.
There are 3 types of LAL test:

(i) The Gel Clot test: The lysate solution is mixed with an equal volume of test solution
in a pyrogen free test tube. The test tube is allowed to stand for 60 minutes. Now the
tube is inverted and observed for the formation of gel clot. The formation of solid gel
confirms the presence of endotoxin.

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The Turbidimetric test: The test is based on the measurement of opacity change in the LAL
test due to formation of gel clot. Opacity is directly proportional to the endotoxin
concentration.

The Kinetic Cromogenic test: It is based on the measurement of colour change which is
caused by the release of chemical para-nitroanilide, which is a biproduct of clotting reaction
during LAL test. The quantity of para-nitroanilide produced is directly proportional to the
endotoxin concentration.

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. STERILITY TEST

 Sterility test is used to identify the presence or absence of viable microorganism in

sterile preparations that are required to be sterile.

 The test is carried out under aseptic conditions to avoid contamination of the product
during the test.

 The test is based on the principle that when micro-organisms are supplied with nutrient
medium and water and incubated at favorable temperature, then the micro-organisms
will multiply. The presence of micro-organisms can be identified by the turbidity in the
clear medium.

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 i) MEMBRANE FILTRATION METHOD:

 A membrane has a nominal pore size not greater than 0.45μ and diameter of
approximately 50mm.

 This method basically involves filtration of Sample through membrane filters.

 The filtration is assisted under Vacuum, after filtration completion the membrane is cut
into 2 halves aseptically and one halve each is placed in two test tubes containing 100 ml
of FTM and 100 ml of SCDM medium.

 Incubate the media- FTM (Fluid Thioglycollate Medium) at 20ºc- 25ºc and SCDM
(Soyabean-casein Digest Medium) at 30ºc- 35ºc for not less than 14 days.

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 (ii) DIRECT INOCULATION METHOD:

 It involves a direct inoculation of required volume of a sample in two tests tube

containing a culture medium that is FTM, SCDM.

 If the test substance contains antimicrobial properties then it is neutralized by adding

suitable inactivating substances to the medium.

 Volume of the preparation under examination is not more than 10% of the volume of the
medium.

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 Interpretation of results

 If the material being tested renders the medium turbid so that the presence or absence
of microbial growth cannot be easily determined by visual inspection,14 days after the
beginning of incubation, transfer portion (< 1 ml) of the medium to fresh vessels of
the same medium and then incubate original and transfer vessel for not less than 4
days.

 If No evidence of microbial growth is found- complies with test for sterility.

 If evidence of microbial growth is found- does not comply with test for sterility.

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PARTICULATE TEST/ CLARITY TEST

 Particulate matter refers to the extraneous, mobile, undissolved particles, other than gas
bubbles, unintentionally present in the solutions.

 Method A-Visual method:

The filled containers are examined by holding the neck of the containers against strong
illuminated screen. The containers are slowly inverted and rotated and the contents are
examined for the presence of any foreign particles. Black surface is used for the detection of
light colored particles and white surface for dark colored particles. If any foreign particle is
visible, then that container is discarded.

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 Method B-Microscopic particle count test:

A measured sample solution is filtered through a membrane filter. The collected particles on
the surface of the filter are then counted with the help of microscope at 100 X
magnification. The whole method is carried out under aseptic condition.

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STERILIZATION:

Sterilization is a physical method of microbial

control by which an article, surface or medium is
made free from all forms of viable
microorganisms.

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 Classification:

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 AUTOCLAVE

Strong metallic chamber made of stainless steel A

cover fitted with steam vent , pressure gauze and
safety valve Rubber gasket is fitted on inner side
of the lid, in order to make autoclave airtight Cover
is closed with wing nuts and bolts . The electrically
heated element is fitted at the bottom to heat the
water to convert into steam. The perforated inner
chamber is placed on the stand .

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The material to be sterilised is loosely packed into
it. A sufficient quantity of water is poured into the
chamber after removing the perforated chamber.
The level of the water is adjusted in such a way
that it does not touch the bottom of the perforated
chamber . The material is packed in the perforated
chamber . The lid is then closed with wing nuts and
bolts.

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The autoclave is switched on to heat the water.
The vent is open and safety valve is set at the
required pressure . When steam start coming out
from the vent and it continues for 5 minutes, it is
then closed. It indicates that air has been removed.
The steam pressure start raising and it comes to
the desired pressure i.e. 10 lbs/square inch with
corresponding temperature 115°C or 15 lbs/
Sq.inch with corresponding temperature 121°C.
Autoclave…
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 Tindalization:
In this method, the solution to be sterilized is
packed and sealed in its final container and
heated at 80°C for one hour on each of three
successive days . The first heating destroys the
vegetative cells but not the bacterial spores.
These bacterial spores germinate into the
vegetative forms in the interval between the first
and the second heating and are killed in the
second heating . The third heating provides a
safeguard against any spores which may not
germinate until the second interval.
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 Pasteurisation:

Pasteurisation It is a partial sterilisation method

which is used to make milk safe and also to
improve its keeping properties. The process kills
only 97 to 99 per cent microorganism, but it does
not kill bacterial spores .

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 HEATING WITH A BACTERICIDAL
AGENT

this sterilization method is suitable for injectables

and is an official method in bp which has now
been replaced by tyndalisation.

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 HEATING WITH A
BACTERICIDAL AGENT

the procedure involves heating the parenteral

solutions in their final containers at 90-100 for 30
minutes in boiling water or in steamer by adding a
bactericidal agent .

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 HEATING WITH A
BACTERICIDAL AGENT

however ,this method is not suitable for

Parenterals used for intracisternal ,intrathecal
or peridural administration ,as toxicity can be
exhibited by the bactericidal agent .

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 Sterilization by filtration

Filtration is the process of separation of

particulate matter from liquids and gases by
allowing them to pass through a porous screen
like material.
It is a unique sterilization technique which unlike
other sterilization processes is not destructive.

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 Sterilization by filtration

It actually removes the microbes by retaining them

on the filter medium rather than destroying them.
The principle application of this method is for the
clarification and sterilization of thermolabile
preparations such as injections, antibiotics,
enzymatic preparations.

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 Sterilization by filtration

A wide variety of filters such as membrane filters,

sintered glass filters, porcelain filters etc, each
varying in their efficiencies pore size, mechanism
and applications are used for the purpose of
sterilization.

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 GASEOUS STERILIZATION

it is brought about with chemically reactive gases like ethylene

oxide, formaldehyde, ozone etc.

this method of sterilization is of particular importance in case of

heat-sensitive materials.

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 GASEOUS STERILIZATION

ETHYLENE OXIDE:

it is acyclic ether which is highest reactive and

inflammable . it is availablele as a colourless liquid
at temperatures below 10.8 degree centigrade.

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 GASEOUS STERILIZATION

it has remarkable property of penetrating

through many packaging materials like
plastic ,rubber ,paper board ,fabric thus
achieving suitable concentrations in each article
and resulting in efficient sterilization

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 GASEOUS STERILIZATION

MECHANISM OF ACTION:

being an alkylating agent ,ethylene oxide causes

alkylation of the sulfhydryl, amino ,hydroxy and
carboxyl groups present on proteins and amino
groups of microbial and ultimately microbial
death.

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 GASEOUS STERLIZATION

FORMALDEHYDE:

it is marketed as formalin which is 37% w/v

aqueous solution of formaldehyde. formalin
when heated to temp.. of 70-75 produces
formaldehyde gas. which is used for sterilization.

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 Radiation sterilization

Depending on its intensity, wavelength and duration

of exposure, radiation exerts various effects on
microbial cells. Sterilizing radiations are of two types

1. Ionizing ( gamma rays and high energy photons)

2. non-ionizing (UV rays)

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 Radiation sterilization

1. non-ionizing radiations:

Mode of action: UV radiations causes excitation of

atoms or molecules of nucleic acids to higher
energy levels . This results in the generation of
reactive chemical species which causes bonding
b/w the adjacent pyrimidine bases.

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 Radiation sterilization

The thymine dimer so formed induces mutations in

the DNA and inhibits correct DNA replication during
cell reproductions.

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 Radiation sterilization

Ionizing radiations:

X-rays and gamma rays and high energy

electron beam are important sources of ionizing
radiations.

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 Radiation sterilization

Mode of action:
These are highly lethal to DNA and other vital cell
components. They bring about these effects by
ionization of water and generation of active free
radicals.

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 Radiation sterilization

The reactive chemical species so generated

causes disintegration of essential cellular
components like proteins and enzymes resulting
in lethal mutations and subsequent cell death.

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 HOT AIR OVEN

Dry heat sterilization is usually carried out in hot

air oven. It comprises of an insulated polished
stainless steel or aluminum double walled
chamber. The outer wall contains electric
heaters to prevent the development of cool
spots inside the chamber.

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 HOT AIR OVEN

Heat is transferred to the articles by conduction,

convention and radiation. A fan is fitted in the
chamber to facilitates air circulation. The shelves in
the chamber are perforated to allow good air flow.
Door is insulated with asbestos jacket to provide
the tight seal.

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 HOT AIR OVEN

Temperature monitoring is achieved through

thermocouples. Articles to be sterilized should
be wrapped in paper or enclosed in cardboard
tubes or aluminum containers to provide post-
sterilization protection against contamination.

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 h

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 Incineration:

Incineration is a process of sterilization which

involves complete burring of contaminated
materials.

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 CONTAINERS AND CLOSURES FOR
PARENTERALS

Any container for parenteral product should maintain

the integrity of the product as a sterile, pyrogen-free,
high purity preparation till it is used. It should also be
attractive, allow the withdrawal of the contents and be
strong enough to withstand processing and shipping;
and finally it should not interact with the product.

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GLASS CONTAINERS:
on the basis of the tests performed glass is classified into 4
types.

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 TYPES OF GLASS USES
TYPE-I OR BOROSILICATE GLASS USED IN MAKING AMPOULES AND VIALS
(NEUTRAL GLASS) FOR BUFFERED AND UNBUFFERED
SOLUTIONS

TYPE-II OR SODA LIME GLASS USED FOR BUFFERED AQ, PREPARATIONS

(SURAFCE TREATED) ( WITH PH BELOW 7) DRY POWDERS AND
NON AQ. SOLUTIONS.

TYPE-III OR SODA-LIME GLASS USED FOR NON-AQUEOUS SOLUTIONS

AND DRY POWDERS.

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small volume Parenterals such as injections and infusion
solutions are packed in single dose containers made of
type-i glass. large volume Parenterals such as infusion
fluids, parenteral nutrition solutions etc. are packed in
glass bottles of 500ml capacity but they have been
replaced by plastic bags.

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PLASTIC CONTAINERS:
plastic containers are preferred over glass
containers due to following characteristics,
they are light in weight
they are unbreakable

POLYVINYL CHLORIDE (PVC):

pvc collapsible bags are used for packing LVP.

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POLYETHYLENE:

semi-rigid polyethylene containers are used for

packing electrolyte solutions, nutrition solutions,
dialysis solutions upto range of 100ml, 3 lts and 5
litres.

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 CLOSURES

the properties which are to be considered in the

selection of closure material includes”:

ELASTICITY
HARDNESS
FRAGMENTATION
PERMEABILITY
THEY SHOULD BE RESISTANT TO STERILIZATION
CONDITIONS

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natural and synthetic rubber is considered as an
ideal material for closure as it conforms to most of
the aforesaid requirements. Rubber closures are
composed of a multitude of ingredients which are
homogeneously mixed, plasticized and vulcanized
at high temp and finally moulded into desired
shapes.

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Rubber closures are available in various shapes
based on their intended use. These include
flanged closures for freeze –dried products,
punctured closures with a provision for the
attachment of adapting for infusion sets, plunger
type closures for disposable syrings and rubber
seals for cartridges.

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 Quality Control Test for Glass
Containers

a) Powdered Glass Test

b) Water Attack Test

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 Powdered Glass Test:

It is done to estimate the amount of alkali from

powdered glass with happen at elevated
temperature. When glass is powdered, leaching of
alkali is enhanced, which can be titrated with
0.02N sulphuric acid using methyl red as an
indicator.

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10g of specimen/sample + 50ml of highly purified
water. Autoclave it at 121C.
Cool it and decant solution in another flask
again add 15ml water and decant solution.
Titrate the decant solution with 0.02N
sulphuric acid using indicator and record the
volume

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 Water Attack Test:

Water Attack Test: This test is for Type II glass.

The principle involve in this is whether the alkali
leaches from surface of container.

Rinse thoroughly container with high purity

water. Fill it by 90% of it’s capacity with water

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Autoclave it at 121C̊ for 30 minutes. Then it
is cooled and liquid is decanted.

Decanted liquid is titrated with 0.01M HCl using

methyl red as an indicator.

The volume of HCl consumed is recorded and

compare with limits

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 Volume of Number of Volume of test
containers containers to be solution (ml)
tested
Less than or equal 10 50
to 5ml
6-30 ml 5 50
Above 30 ml 3 100

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Capacity of container
(ml) Volume of acid consumed by each 100ml of
test solution (ml)
Type-I / type-II Glass Type-III glass

1 2 20
1-2 1.8 17.6
2-5 1.3 13.2
5-10 1 10.2
10-20 0.8 8.1
20-50 0.6 6.1
50-100 0.5 4.8
100-200 0.4 3.8
200-500 0.3 2.9

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 12 July 2018
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