Ajit Kumar Jha
1st Sem. M. Pharma.
School of Pharmacy
Apeejay stya university
Parenteral refers injectable route of
It derived from Greek words Para (Outside) and
So it is a route of administration other than the
alimentary canal. This route of administration
bypasses the alimentary canal.
PRIMARY PARENTERAL ROUTES
Routes Usual volume
Types of medication
Sub cutaneous 0.5-2 5/8 in. ,
Need to be isotonic Insulin, vaccines
Intra muscular 0.5-2 1.5 in. ,
Can be solutions,
emulsions, oils or
Nearly all drug
Intra venous 1-100 Vein puncture
1.5 in. ,
Nearly all drug
LVP 101 and larger
1.5 in. ,
Solutions and some
Nearly all drug
S. No. ADVANTAGES DISVANTAGES
1. Quick onset Wrong dose or over dose can be
2. Vomiting and unconscious
patients can take
Pain at site
3. Prolonged action by
Trained person required
4. Nutritive fluids (glucose,
electrolytes) can be given
5. Drugs with poor absorption
or instability from GIT
NECESSITY OF ASEPTIC
CONDITIONS IN PRODUCTION,
Small Volume Parenteral
• According to USP : “ an injection that is
packaged in containers labelled as containing
100 ml or less”
• All the sterile products packaged in vials, ampoules,
cartridges, syringes, bottles or any other container
that is 100ml or less fall under the class of SVP.
• Ophthalmic products packaged in squeezable
plastic containers, although topically applied to the
eye rather than administered by injection, also fall
under the classification of Small Volume Injections
(SVI) as long as the container size is 100ml or less.
• SVP aqueous solutions can be administered by
intravenous route because of local irritation. Small
volume parenteral products can be formulated and
packaged in several ways and include a wide
variety of products like :
• Pharmaceutical products, Biological products,
Allergenic extracts, Radiopharmaceutical products,
Genetically engineered or biotechnology products,
Liposome and lipid products.
• An injection is a preparation intended for
parenteral administration and/or for constituting
or diluting a parenteral article prior to
• Types of preparations :-
Drug for injection
Drug injectable emulsion
Drug injectable suspension
Drug for injectable suspension
• Definition:- According to the USP 24/ NF 19 “As those
preparations intended for injection through the skin or
other external boundary tissue, rather than through the
• so that the active substance they contain are
administered using gravity or force directly into a blood
vessel,organ,tissue or lesion.
• Highly Resistant Borosilicate Glass
• Treated Soda lime Glass
• Regular Soda Lime Glass
• N.P (Non-parenteral) Glass
Type 4 is not used for parenteral packaging,
others all are used for parenteral packaging.
Plastic containers are used but they face following problems
To provide closure for multiple dose vials, IV fluid bottles, plugs for disposable syringes and bulbs for
ophthalmic pipettes, rubber is the material of choice.
Problems associated with rubber closures are
• Chemical instability
• Physical instability
• Characteristics of Good Pharmaceutical rubbers
• Good ageing qualities
• Satisfactory hardness and elasticity
• Resistance to sterilization conditions
• Impermeable to moisture and air
• Butyl Rubbers
• Natural Rubbers
• Neoprene Rubbers
• Polyisoprene rubbers
• Silicone Rubbers
1. Cleaning of containers, closures and equipments
2. Collection of materials
3. Preparation of parenteral products
5. Filling the preparation in final containers
6. Sealing the containers
8. Evaluation of parenteral preparation
9. Labeling and packaging
Formulation of parenteral
• In the preparation of parenteral products, the following substances
are added to make a stable preparation:
The active drug
Aqueous vehicle (e.g. water for injection, water for injection free from CO2
Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)
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)
Formulation of SVP :
• Aqueous vehicle :
• Types :- purified water, WFI, sterile WFI,
bacteriostatic WFI, sterile WF Irrigation.
• Preparation :- Distillation, ion exchange or
• Except purified water all are pyrogen free
• Non aqueous vehicle :
• Because of safety
Several SVPs are marketed as oily solutions
The oil must be vegetable in origin (sesame, olive, or
Product USP Oil
Diethyl stilbestrol Sesame, cotton
Penicillin G procaine Vegetable
Co solvents :-
Are used to increase the stability of poorly soluble drug
in water and prevent drug chemical degradation by
Eg. propylene glycol or in combination with ethanol and
Ingredients or added substances
• Antimicrobial preservatives :
• Maintain the stability of the product during
• Phenylmercuric nitrate and Thimerosal
0.001% , Benzethonium chloride 0.01%,
Benzyl alcohol 0.5- 10.0%, Phenol or cresol
0.5%, chlorobutanol 0.5%.
• Buffers :
• Added to maintain pH Results in stability of
drug against hydrolytic degradation or
enhance the solubility of drug in solution.
• Common buffers used in SVPs
pH Buffer system Conc. %
3.5-5.7 Acetic acid-acetate 0.22
2.5-6.0 Citric acid-citrate 0.5
6.0-8.2 Phosphoric acid- 0.8-2
8.2-10.2 Glutamic acid- 1-2
Antioxidants function by preferentially with molecular oxygen and
minimizing or terminating the free radical auto-oxidation
eg. Reducing agents: Ascorbic acid 0.02-0.1%, Sodium
Bisulfite 0.1-0.15%, Thiourea 0.005%
Blocking agents: Ascorbic acid esters 0.01-0.015%,
• Tonicity adjusters :
• Electrolytes: Nacl
• Non electrolytes: Glucose, Mannitol, Glycerine
• Eg. Of isotonic: Dextrose injection 5% & Nacl
• Some solutions are iso-osmotic but not isotonic
this is because the physiology of the cell
membranes must be considered.
• For eg. the cell membrane of the RBC is not semi-
permeable to all drugs it allows ammonium
chloride, alcohol, boric acid, glycerin, propylene
glycol, and urea to diffuse freely.
• In the eye the cell membrane is semi permeable to
boric acid and a 2% solution is an isotonic
• But even though a 2% solution of boric acid is an
isotonic with the eye and is iso-osmotic, it is not
isotonic with blood since boric acid can freely diffuse
through the RBC– and it may cause HEMOLYSIS.
• Tonicity can be measurement by: osmometer
• Other ingredients :
• Bulking agents – for freeze dried preparations(solids) eg
mannitol, lactose sucrose, dextrose.
• Suspending agents – Carboxy methyl cellulose, sorbitol.
• Emulsifying agents – lecithin, polysorbate 80
• Ophthalmic ointments bases – petrolatum.
Production facilities of parenterals
• The production area where the parenteral
preparation are manufactured can be divided
into five sections:
Finishing & packaging area
It is not aseptic area.
All the parenteral products must be free from foreign particles &
Clean-up area should be withstand moisture, dust & detergent.
This area should be kept clean so that contaminants may not be carried
out into aseptic area.
In this area the ingredients of the parenteral preparation are mixed &
preparation is made for filling operation.
It is not essentially aseptic area but strict precautions are required to
prevent any contamination from outside.
The parenteral preparations are filtered, filled into final
container & sealed should be in aseptic area.
The entry of personnel into aseptic area should be limited &
through an air lock.
Ceiling, wall & floor of that area should be sealed & painted.
The air in the aseptic area should be free from fibers, dust and
The High efficiency particulate air filters (HEPA) is used for air.
UV lamps are fitted in order to maintain sterility.
After filling, sealing & sterilization the parenteral
product are held up in quarantine area.
Randomly samples were kept foe evaluation.
The batch or product pass the evaluation tests are
transfer in to finishing or packaging area.
Finishing & packaging area:
Parenteral products are properly labelled and packed.
Properly packing is essential to provide protection
against physical damage.
The labelled container should be packed in cardboard
or plastic container.
Ampoules should be packed in partitioned boxes
EVALUATION OF PARENTERAL
• The finished parenteral products are subjected to
the following tests, in order to maintain quality
• A) sterility test
• B)clarity test
• C)leakage test
• D)pyrogen test
A) sterility test
• It is a procedure carried out to detect and
conform absence of any viable form of microbes
in or on pharmacopeia preparation or product.
1) Method of sterility testing
i ) METHOD 1 Membrane filtration method
ii) METHOD 2 Direct inoculation method
Membrane filtration method
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
Composition of culture medium for
L- cystine 0.5gm -
Sodium chloride 2.5gm 5.0gm
Dextrose 5.0/5.5gm 2.3/2.5gm
Pancreatic digest of casein 15.0gm 17.0gm
Papaic digest of soya bean - 3.0gm
Dibasic potassium phosphate - 2.5gm
Granular agar (moisture<15%) 0.75gm -
Yeast extract (water soluble) 5.0gm -
Sodium thioglycollate or
Resazurin (0.10%w/v fresh
Purified water 1000ml 1000ml
Components Culture medium
Membrane filter 0.45μ 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 media
(Fluid Thioglycollate medium)
Incubate at 30-350 C for not less then 7 days
Transfer in 100 ml culture media
(Soyabeans-Casein Digest medium)
Incubate at 20-250 C for not less then 14 days
Observe the growth in the media Observe the growth in the media
Direct inoculation method (METHOD
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 and 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.
• 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
• The sealed ampoules are subjected to small cracks which
occur due to rapid temperature changes or due to
Filled & sealed ampoules
Dipped in 1% Methylene blue solution
Under negative pressure in vacuum chamber
Vacuum released colored solution enter into the ampoule
Vials & bottles are not suitable for this test because the
sealing material used is not rigid
Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek
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
Dissolve the subs being examined in, or dilute it with a pyrogen free saline
Warm the liquid being examined to approx. 38.5o 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
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
Limulus amebocyte lysate [LAL]
• Limulus amebocyte lysate [LAL] test another method
for the determination of pyrogenic endotoxins
• In this method the test solution is combined with a
cell lysate from the ameabocyte [blood cells] of horse
• Any endo toxin that might be present will be
coagulated with protien fraction of the ameabocytes
and results in the formation of a gel
• This consider to be simple,rapid and of greater
sensitivity that the rabbit test
• Assay is performed according to method given In
the monograph of that parental preperation in
• Assay is done to check the quantity of
medicament present in the parenteral
• Lachman/Lieberman’s “The Theory and Practice Of Industrial
Pharmacy” Fourth Edition 2013, Edited by: Roop K Khar, SP
Vyas, Farhan J Ahmad, Gaurav K Jain, CBS Publishers and
Distributors Pvt Ltd, New Delhi.
• Doornbos C and Hann P. Optimization Techniques in Formulation
and Processing. In Encyclopedia of Pharmaceutical Technology.
Swarbrick J and Boylan JC, Eds., Vol. II, Marcel Dekker, New
• Modern Pharmaceutics Fourth Edition, Revised and Expanded,
Edited By G.S.Banker & C.T.Rhodes, Marcel Dekker pg387-389.
• The Science & practice of Pharmacy, By Remington, Vol-01,
21st Edition, Lippincott Publication, pg-838-840.