PARENTERAL

LIDYA AMELIANA
Parenteral -- injectable route of administration.

(Greek) Para (Outside) and enteron (Intestine).

Parenteral is a route of administration other than

the oral route.
Advantages of the Parenteral Route
Rute iv rute tercepat sistemik
emergency
utk cairan, electrolytes, nutrition
Utk px yg tdk dpt makan atau bermasalah GITnya
Menghasilkan konsentrasi obat yg tinggi dlm pembuluh darah
atau jaringan
advantageous in serious bacterial infection
Infus IV provides a continuous amount of needed
medication
without fluctuation in blood levels of other routes
infusion rate can be adjusted
to provide more or less medication as the situation dictates
Drug action can be prolonged by modifying the formulation.
 Disadvantages of the Parenteral Route
Traumatic injury from the insertion of needle
Potential for introducing:
Toxic agents
Microbes
Pyrogens
Impossible to retrieve if adverse reaction occurs
injected directly into the body
Correct syringe, needle, and technique must be used
Rotation of injection sites with long-term use
prevents scarring and other skin changes
can influence drug absorption
Routes of Administration of parenteral
products
Various types of route of administration of parenteral products
are:
Intradermal injection
Subcutaneous (Hypodermis) injection
Intramuscular injection
Intravenous injection
Intra-arterial injection
Intracardiac injection
Intrathecal injection
Intracisternal injection
Peridural injection
Intra- articular injection
Intracerebral injection
 Subcutaneous Injections
Administer medications below the skin into the subcutaneous
fat
outside of the upper arm
top of the thigh
lower portion of each side of the abdomen

Often have a longer onset of action and a longer duration of

action
compared with IM or IV injection

Given at a 45-degree angle

25- or 26-gauge needle, 3/8 to 5/8 inch length
No more then 1.5 ml should be injected into the site
to avoid pressure on sensory nerves causing pain and
discomfort
 Subcutaneous injection
Given:
Vaccines Scopolamine
Epinephrine Insulin
 Intramuscular Injections
Care must be taken with deep IM injections to avoid hitting a
vein, artery, or nerve
In adults, IM injections are given into upper, outer portion of the
gluteus maximus
large muscle on either side of the buttocks
For children and some adults, IM injections are given into the
deltoid muscles of the shoulders
Typical needle is 22- 25 gauge - to 1-inch
needle
IM injections are administered at a 900 angle
volume limited to less than 3 ml
intramuscular
Used to administer
antibiotics
vitamins
iron
vaccines
 Intravenous Injections or Infusions
Fast-acting route because the drug goes directly into the
bloodstream
often used in the emergency department and in critical care
areas
Commonly used
for fluid and electrolyte replacement
to provide necessary nutrition to the patient who is critically
ill

Intravenous (IV) injections are

administered at a 15- to 20-
degree angle
 Intra-arterial injection
The inaction are given directly in to the
artery

Intracardiac injection
These are given into the heart muscle or
ventricle at the time of emergency only.

Intrathecal injection
These are given into the subachonoid space the
surround the spinal cord. This route is used
for spinal anesthesia.
Intracisternal injection
These are given in b/w first & second cervical
nerve.
Used for CSF for diagnostic purpose.
Peridural injection
These are given in b/w the dura matter & inner
aspect of vertebra.
Used for given spinal anesthesia.

Intra- articular injection

These are given in into the articulating ends of
bones in a joint.
Used for lubricating the joints.
Intracerebral injection
These are given into the cerebrum.
 Official types of injections
Injection: Liquid preparation there are drug substance or
drug solution thereof e.g. insulin injection USP.
For injection: Dry solid that upon addition of suitable vehicles
yield solutions confirming in all respect to the requirements to the
injection. e.g. Cefuroxime injection USP.
Injectable emulsions: Liquid preparation of drug substance
dispersed in a suitable emulsion medium. e.g. Propofol USP.
Injectable suspension: Liquid preparation of solid suspended
in a suitable medium. e.g. Methyl Prednisolone Acetate
Suspension USP.
For injectable suspension: Dry solid that upon addition of
suitable vehicle yields preparation confirming in all respect
to the requirements for Injectable suspension.
e.g. Imipenem and Cilastatin injectable suspension USP.
General requirements of parenteral
preparations
Stability
Sterility
Free from Pyrogens
Free from foreign particles
Isotonicity
Specific gravity
Chemical purity
 Formulation of parenteral products
In the preparation of parenteral products, the following
substances are added to make a stable preparation:
The active drug
Vehicles
Aqueous vehicle (e.g. water for injection, water for injection free from
CO2 )
Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)
Adjuvants
Solubilizing agents (e.g. Tweens & polysorbates)
Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)
Buffering agents (e.g. citric acid, sodium citrate)
Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)
Chelating agents (e.g. EDTA)
Suspending, emulsifying & wetting agents (e.g. MC, CMC)
Tonicity factor (e.g. sodium chloride, dextrose)
Therapeutic ingredients:
Insulin
Antibiotics
Anticancer
Steroids
Vaccines
Antipyretic
Analgesics
Anti- inflammatory
LVPs like Dextrose, NaCl or combination etc.
 PREFORMULATION FACTORS
It is study about physical & chemical properties of drug
substance prior formulation is called as preformulation.
pH /pka

Solubility

Thermal/heat effect

Dissociation constant

Compatabilty studies- FTIR / DSC

Oxidation & reduction

particle size
Vehicles

Water
o Should meet compendial requirements
Water miscible vehicles
o Ethyl alcohol
o PEG
o PG
Non aqueous vehicles
o Fixed oils
Adjuvants
Antimicrobials:
Added for fungistatic or bacteriostat action or
concentration
Used to prevent the multiplication of micro-
organisms
Multidose containers must have preservatives unless
prohibited by monograph.
Large volume parenteral must not contain preservative
because it may be dangerous to human body if it contain in
high doses
Ex..
Benzyl alcohol --- 0.5 10 %
Benzethonium chloride --- 0.01 %
Methyl paraben --- 0.01 0.18 %
Propyl paraben --- 0.005 0.035 %
Phenol --- 0.065 0.5 %
Buffers:
Added to maintain pH,
Change in pH may causes degradation of the products
Acetates, citrates, phosphates are generally used.
Factors affecting selection of buffers:
Effective range,
Concentration
Chemical effect on the total product
EXAMPLES:
Acetic acid ,adipic acid, benzoic acid, citric acid,
lactic acid
Used in the conc. of 0.1 to 5.0 %
Chelating agents:
Used to form the complex with the metallic
ions present in the formulation so that the ions
will not interfere during mfg. of formulation.
They form a complex which gets dissolved in
the solvents.
Examples:
Disodium edetate 0.00368 - .05 %
Disodium calcium edetate - 0.04 %
Tetrasodium edetate 0.01 %
 Stabilizers:
As parenterals are available in solution form
they are most prone to unstabilize
Used to stabilize the formulation
Maintain stable
Examples:
Creatinine 0.5- 0.8 %
Glycerin 1.5 2.25 %
Niacinamide 1.25 -2.5 %
Sodium saccharin 0.03 %
Sodium caprylate 0.4 %
Solubilizing agents:
Used to increase solubility of slightly soluble
drugs
they acts by any one of the following:
solubilizers,
emulsifiers or
wetting agents.
Examples:
Dimethylacetamide,
Ethyl alcohol
Glycerin
Lecithin
PEG 40 castor oil
PEG 300
Polysorbate 20, 40, 80
Tonicity- adjusting agents:
Used to reduce the pain of injection.
Buffers may acts as tonicity contributor as
well as stabilizers for the pH.
Isotonicity depends on permeability of a living
semipermaeable membrane
Hypotonic : swelling of cells

(enlargement)
Hypertonic: shrinking of cells (reduction)
Example:
Glycerin
Lactose
Mannitol
Dextrose
Sodium chloride
Sorbitol
 Processing of parenteral preparation
Following steps are involved in the processing of parenteral
preparation:
1) Cleaning of containers, closures & equipments

2) Collection of materials

3) Preparation of parenteral products

4) Filtration

5) Filling the preparation in final container

6) Sealing the container

7) Sterilization

8) Evaluation of the parenteral preparation

9) Labeling & packaging

Evaluation of Parenteral products
Sterility testing
Particulate matter monitoring
Faculty seal packaging or leakage test
Pyrogen testing
LAL test
Assay or drug content uniformity
 Sterility testing
DEFINITION: Sterility Testing: It is a procedure carried out to detect
and conform absence of any viable form of microbes in or on
pharmacopeia preparation or product.
PRINCIPLE : Sterility testing only shows that organisms capable of
growing in selected conditions are absent from the fraction of batch
that has been tested. If the microorganism are present in the product
can be indicated by a turbidity in the clear medium.
OBJECTIVE OF STERILITY TESTING:
For validation of sterilization process.

To check presence of microorganisms in preparation which are

sterile.
To prevent issue of contaminated product in market.
 STEPS INVOLVED IN STERILITY TE TESTING

1) Sampling

2) Selection of the quantity of the product to be used

3) Method of sterility testing

i ) METHOD 1 Membrane filtration method
ii) METHOD 2 Direct inoculation method

4) Observation and interpretation Must be carried out under

aseptic condition.
 Sampling
The sample must be representative of the whole of the bulk
material & a lot of final containers.
MAINLY FOLLOWED BY TWO RULES:
A fixed percentage of the final container are selected.

A fixed number of container are taken independent of the

lot or batch size.

According to Indian Pharmacopoeia following guidelines for
determining the minimum number of items are:

K.I.P.M. GIDA, GORAKHPUR, U.P.

Selection of the quantity of the product to be used
Selection of the quantity of the product to be used for sterility
testing depends mainly on the volume or weight in the
container.
 Method of sterility testing
Membrane filtration method (METHOD 1):
Membrane filtration Appropriate for : (advantage)
Filterable aqueous preparations

Alcoholic preparations

Oily preparations

Preparations miscible with or soluble in aqueous or oily

(solvents with no antimicrobial effect)

All steps of this procedure are performed aseptically in a Class
100 Laminar Flow Hood
 Membrane filter 0.45 porosity

Filter the test solution

After filtration remove the filter

Cut the filter in to two halves

First halves (For Bacteria) Second halves (For Fungi)

Transfer in 100 ml culture Transfer in 100 ml culture media

media (Soyabeans-Casein Digest
(Fluid Thioglycollate medium) medium)

Incubate at 30-350 C for not less then 7 Incubate at 20-250 C for not less then 7
days days

Observe the growth in the Observe the growth in the

Direct inoculation method (METHOD 2):
Suitable for samples with small
volumes
volume of the product is not
more than 10% of the volume of
the medium
suitable method for aqueous
solutions, oily liquids, ointments
an creams
Direct inoculation of the culture
medium suitable quantity of the
preparation to be examined is
transferred directly into the
appropriate culture medium &
incubate for not less than 14
days.
 Observation and results

Culture media is examined during and after at the end of incubation.

The following observations are possible:
1) No evidence of growth Pass the test for sterility.
2) There is evidence of growth Re-testing is performed
same no. of sample, volume & media as in original test
No evidence of growth Pass the test for sterility.

3) There is evidence of growth isolate & identify the

organism.

Re-testing is performed with twice no. of sample if:

No evidence of growth Pass the test for sterility.
There is evidence of growth Fail the test for sterility
 Particulate matter monitoring
Particulate matter is defined as unwanted mobile insoluble matter
other than gas bubble present in the product.
If the particle size of foreign matter is larger than the size of R.B.C..
It can block the blood vessel.
The permit limits of particulate matter as per I.P. are follows:

Source of particulate matter:

1. Intrinsic contamination: The material which are originally
present in the parenteral solution e.g. Barium ions leach in
parenteral & react with sulphur ions in the product to form
barium sulphate crystals.
2. Extrinsic contamination: The material which comes from the
environment e.g. Shedding of material from cloth, body, &
cotton, paper, rubber, tissue etc.
 Methods for monitoring particulate matter
contamination:
1) Visual method
2) Coulter counter method
3) Filtration method
4) Light blockage method
Identification of particulate matter:
1) Microscopy
2) X-ray powder diffraction
3) Mass spectroscopy
4) Polarized light spectroscopy
5) Scanning electron microscopy (SEM)
Faculty seal packaging / leaking testing
The sealed ampoules are subjected to small cracks which
occur due to rapid temperature changes or due to mechanical
shocks.
Filled & sealed ampoules

Dipped in 1% Methylene blue solution

Under negative pressure in vacuum chamber

Vacuum released colored solution enter into the ampoule

Defective sealing

Vials & bottles are not suitable for this test because the sealing
material used is not rigid.
 Pyrogen Testing
Pyrogen = Pyro (Greek = Fire) + gen (Greek = beginning).
Fever producing, metabolic by-products of microbial growth
and death.
Bacterial pyrogens are called Endotoxins. Gram negative
bacteria produce more potent endotoxins than gram + bacteria
and fungi.
Endotoxins are heat stable lipopolysaccharides (LPS) present
in bacterial cell walls, not present in cell-free bacterial filtrates
Stable to at least 175oC; steam sterilization ineffective
Water soluble; monomer unit of LPS can be 10,000 Daltons
(1.8 nm) so endotoxins can easily pass through 0.22m filters
Sources: Water (main), raw materials, equipment, process
environment, people, and protein expression systems if using
gram negative bacteria.
 Biological properties of endotoxin
Pyrogen elevate the circulatory levels of inflammatory cytokines

which may be followed by fever, blood coagulation, hypotension

Low doses of Pyrogen: asymptomatic inflammation reaction

Moderate doses: fever & changes in plasma composition

High doses: cardiovascular dysfunction, vasodilation,
vasoconstriction, endothelium dysfunction, multiple organ failure
& finally death.

Sources of pyrogen
1) Equipment
2) Containers (Glass , plastic , metal)
3) Solvent
4) Solute K.I.P.M. GIDA, GORAKHPUR, U.P.
 Elimination of pyrogens
Dry heat sterilization : For glass wares, metal equipments,

powders, waxes, oils, heat stable drugs

650 o C temp - 1 min
250 o C temp - 30 min
180 o C temp - 240 min
Ultra filtration

Reverse osmosis : RO membrane is composed of cellulose

acetate phthalate/ polyamide

Distillation

Adsorption method
 Principal:
Rabbits are used to perform this test because their body temp
increases when pyrogen are introduced into their bodies by
parenteral route
3 healthy adult rabbits of either sex, each weighing NLT 1.5 kg
are selected
Do not use any rabbit
having a temp higher than 39.8 o C
Showing temp variation >0.2 o C between two successive
reading in the determination of initial temp
Sham test is performed within 7 days of actual test
Animal showing temp increase over 0.6 o C should be removed
from pyrogen testing
 Method :
Dissolve the subs being examined in, or dilute it with a pyrogen
free saline solution
Warm the liquid being examined to approx. 38.5 o C temp before
injection
The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body
weight
Withhold water during test
Clinical thermometer is inserted into the rectum of rabbit to record
body temp
2 normal reading of rectal temp are should be taken prior to the
test injection at an interval of half an hr & its mean is calculated-
initial temp
The solution under test is injected through an ear vein
Record the temp of each rabbit in an interval of 30 min for 3 hrs
The difference between initial temp & maximum temp is recorded-
taken as response
 Interpretation of results
 Bacterial endotoxin (LAL) test )
To detect or quantify endotoxins of gram-ve bacterial origin

Reagent: amoebocyte lysate from horseshoe crab (Limulus

polyphemus or Tachypleus tridentatus).

The name of the test is also Limulus amebocyte lysate (LAL) test

Mechanism of LAL Test:

The test is based on the primitive blood-clotting
mechanism of the horseshoe crab
enzymes located with the crab's amebocyte blood cells
endotoxin

Initiation of an enzymatic coagulation cascade

proteinaceous gel
 Test performance (short)
Avoid endotoxin contamination
Before the test:

interfering factors should not be present

equipment should be depyrogenated the sensitivity of the

lysate should be known

Test:
equal Volume of LAL reagent and test solution (usually 0.1 ml

of each) are mixed in a depyrogenated test-tube

Incubation at 37C, 1 hour

remove the tube - invert at (180) observe the result

pass-fail test
 LAL test
Three different techniques:
1. The gel-clot technique - gel formation
2. The turbidimetric technique - the development of Turbidity
after cleavage of an endogenous substrate
3. The chromogenic technique - the development of color
after cleavage of a synthetic peptide- chromogen complex

Advantages of LAL test

Fast - 60 minutes vs. 180 minutes
Greater Sensitivity ,Less Variability
Much Less False, Positives ,Much Less Expensive
Alternative to Animal Model, cheaper,
particularly useful for:
Radiopharmaceuticals and cytotoxic agents
Blood products
Water for injection