Small Volume

Parenteral
Presented by:
Ajit Kumar Jha
ASU2014010100024
1st Sem. M. Pharma.
(Pharmaceutics)
School of Pharmacy
Apeejay stya university
Parenteral
Parenteral refers injectable route of
administration.

It derived from Greek words Para (Outside) and

enteron (Intestine).

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 Needle Formulation Types of medication
(mL) commonly used constraints administered

SVP
Sub cutaneous 0.5-2 5/8 in. , Need to be isotonic Insulin, vaccines
23 gauge
Intra muscular 0.5-2 1.5 in. , Can be solutions, Nearly all drug
23 gauge emulsions, oils or classes
suspensions
Isotonic preferably

Intra venous 1-100 Vein puncture Solutions, emulsions Nearly all drug
1.5 in. , and liposomes classes
20-22 gauge

LVP 101 and larger Venoclysis Solutions and some Nearly all drug
(infusion unit) 1.5 in. , emulsions classes
18-19 gauge
S. No. ADVANTAGES DISVANTAGES

1. Quick onset Wrong dose or over dose can be

fatal

2. Vomiting and unconscious Pain at site

patients can take

3. Prolonged action by Trained person required

modified formulation
( Depot)
4. Nutritive fluids (glucose, Expensive
electrolytes) can be given

5. Drugs with poor absorption NECESSITY OF ASEPTIC

or instability from GIT CONDITIONS IN PRODUCTION,
COMPOUNDING AND
ADMINISTRATION
 Small Volume Parenteral
• According to USP : “ an injection that is
packaged in containers labelled as containing
100 ml or less”
INTRODUCTION :
• 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
administration
• Types of preparations :-
 Drug injection
 Drug for injection
 Drug injectable emulsion
 Drug injectable suspension
 Drug for injectable suspension
Contd…….
• 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
alimentary canal”
• so that the active substance they contain are
administered using gravity or force directly into a blood
vessel,organ,tissue or lesion.
Containers:
1. Glass:
• 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.
Contd…….
2. Plastic:
Plastic containers are used but they face following problems

• Permeation

• Sorption

• Leaching

• Softening

3. Rubber:
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

• Incompatibility

• Chemical instability

• Physical instability
 Closure:
• Characteristics of Good Pharmaceutical rubbers

• Good ageing qualities

• Satisfactory hardness and elasticity

• Resistance to sterilization conditions

• Impermeable to moisture and air

• Examples:

• Butyl Rubbers

• Natural Rubbers

• Neoprene Rubbers

• Polyisoprene rubbers

• Silicone Rubbers
 Preparatio
n

Area

Admixture Storage
system Area
SYSTEM

COMPONE
NT

Policies
and Personnel
Procedures
 PROCESSING OF
PARENTERALS
S.No. STEPS

1. Cleaning of containers, closures and equipments

2. Collection of materials

3. Preparation of parenteral products

4. Filtration

5. Filling the preparation in final containers

6. Sealing the containers

7. Sterilization

8. Evaluation of parenteral preparation

9. Labeling and packaging

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)
 Formulation of SVP :
• Aqueous vehicle :
• Types :- purified water, WFI, sterile WFI,
bacteriostatic WFI, sterile WF Irrigation.
• Preparation :- Distillation, ion exchange or
reverse osmosis.
• Except purified water all are pyrogen free

• Non aqueous vehicle :

• Because of safety
purity
biocompatibility
 Several SVPs are marketed as oily solutions
The oil must be vegetable in origin (sesame, olive, or
cottonseed oil).
Product USP Oil
Ampicillin(suspension) Vegetable
Diethyl stilbestrol Sesame, cotton
Epinephrine(suspension) Sesame
Penicillin G procaine Vegetable
(suspension)

 Co solvents :-
Are used to increase the stability of poorly soluble drug
in water and prevent drug chemical degradation by
hydrolysis.
Eg. propylene glycol or in combination with ethanol and
polyethylene glycol.
Ingredients or added substances
• Antimicrobial preservatives :
• Maintain the stability of the product during
storage.
• 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

phosphate

8.2-10.2 Glutamic acid- 1-2

glutamate

 Antioxidants :

Antioxidants function by preferentially with molecular oxygen and

minimizing or terminating the free radical auto-oxidation
reaction.

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%,
Tocopherols 0.05-0.075%
• Tonicity adjusters :
• Electrolytes: Nacl
• Non electrolytes: Glucose, Mannitol, Glycerine
• Eg. Of isotonic: Dextrose injection 5% & Nacl
injection 0.9%
• 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
ophthalmic solution.
• 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:
 Clean-up area

 Preparation area

 Aseptic area

 Quarantine area

 Finishing & packaging area

Contd…….
 Clean-up area:
 It is not aseptic area.
 All the parenteral products must be free from foreign particles &
microorganism.
 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.
 Preparation 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.
Contd…….
Aseptic area:
 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
microorganism.
 The High efficiency particulate air filters (HEPA) is used for air.
 UV lamps are fitted in order to maintain sterility.
Contd…….
Quarantine area:
 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
PREPARATIONS
• The finished parenteral products are subjected to
the following tests, in order to maintain quality
control:
• A) sterility test
• B)clarity test
• C)leakage test
• D)pyrogen test
• E)assay
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
(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
Composition of culture medium for
sterility testing
Components Culture medium
Fluid Soybean- casein
Thioglycollate digest
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 0.5gm or -
thioglycolic acid 0.3ml
Resazurin (0.10%w/v fresh 1.0ml -
solution)
Purified water 1000ml 1000ml
 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 Transfer in 100 ml culture media

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

Incubate at 30-350 C for not less then 7 days 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
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 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.
B)clarity test

• 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:
Methods for monitoring particulate
matter contamination:

1) Visual method
2) Coulter counter method
3) Filtration method
4) Light blockage method
C)leakage test
• 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
D)pyrogen test

 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
Method
 Dissolve the subs being examined in, or dilute it with a pyrogen free saline
solution

 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

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
Limulus amebocyte lysate [LAL]
test
• 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
shoe crab

• 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
E)assay

• Assay is performed according to method given In

the monograph of that parental preperation in
the pharmacopoeia
• Assay is done to check the quantity of
medicament present in the parenteral
preperation
 References

• 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
York. 199
• 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.
Thank You……..