Parenteral Products

Parenteral Products Kushal
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Parenteral products
Q. Define sterile products and parenteral products.
Sterile products:
Sterile products are pharmaceutical doses forms that have the common characteristics of
being prepared to be sterile. i.e. free from contaminating micro-organisms . The sterile
doses forms are-
Various small and large volume injectable preparations,
Irrigation fluids intended to both the body wounds or surgical openings,
Dialysis solutions,
Biological preparations as vaccines, toxoids, antitoxin, blood preparations,
Ophthalmic products,
Some products of recombinant DNA technology.
Parenteral products:
Parenteral products or injections are sterile, pyrogen free preparations intended to be
administered parenterally. The term Parenteral has been derived from the Greek wards ‘Para’ &
‘Enteron’ mean outside of the intestine i.e. it denotes the route of administration other than the oral
route. Actually the Parenteral refers to the injectable routes of administration.

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Why and when the parenteral routes of administration are used?
In general parenteral routes of administration are used when rapid drug action is desired as
in emergency situations, such as in emergency situation. Such as when the patient is
uncooperative, unconscious or unable to accept or tolerate medication by the oral route or
when the drug itself is ineffective in other route.
Parenteral routes of administration:
Drugs may be injected into almost any organ or area of the body including
a. The joints (Intra-articular),
b. A joint fluid area (Intra-synovial),
c. The spinal column (Intra-spinal),
d. The spinal fluid (Intra-thecal),
e. Arteries (Intra-arterial),
f. In the cerebellum (Intra-cerebellar),
g. In the heart (Intra-cardiac).
However injections are given:
a. Into the vein (Intravenous),
b. Into the muscle (Intramuscular),
c. Into the skin (Intradermal),
d. Under the skin (subcutaneous).
Intravenous route:
Substances are introduced directly into the blood stream by Intravenous route. The most
common site is the vein situated in front of the elbow. The volume can vary less than 1ml to
in excess of 500ml.
The most advantages of IV route is that IV administered drugs provide rapid action
compares to other routes of administration because here drug administration is not a
factor. Optimum blood level may be achieved with accuracy and immediately.
On the negative side, once a drug is administered intravenously, it cannot be retrieved. In
the case an adverse drug reaction to the drug is occurred. In this case the drug cannot be
easily removed from the circulation. But it is possible for administered drug by vomiting.
IV drugs are mainly in aqueous solution. O/W emulsions may be administered by this route
by controlling the globule size.

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Intramuscular route:
Intramuscular injections are performed deep into the skeletal muscles. The volume is
usually not more than 5ml to be administered in the gluteal region and 2ml in the deltoid of
the arm. This route is used for the aqueous solutions and other suspensions. If they were
administered intravenously blockage of the small vessels may occur. This may leads to
gangrene.
Intradermal route:
Injections are made into the skin between the inner layer (dermis) and outer layer
(epidermis). The volume that can be injected intradermally is not more than 0.1-0.2ml. this
route is used for the agents which are used for diagnostic determinations, desensitization or
immunization. The usual site for intradermal injections is the arteriole surface of the
forearm.
Subcutaneous or hypodermic route:
Injections are made under the skin into the subcutaneous tissue. The volume that can be
injected intradermally is not more than 1ml. this route is not suitable for aqueous
suspensions or oily suspensions, because these may cause pain and irritation in the injection
site.
Mention the importance of route of administration on formulation:
During the formulation of a parenteral product, the route of administration must be taken
under consideration. The important factors are:
a. Volume:
One of the most important factors is incorporating the drug into the appropriate
volume. The IV route is the only route by which larger volumes can be administered.
Volume up to 10ml can be administered by intraspinally, while the IM route is limited to
3ml, subcutaneous to 2ml, intradermal to 0.2ml.
b. Solvent system:
The choice of solvent system is directly related to the intended route of administration
of the product. IV and intraspinal injections are generally restricted to direct aqueous
solutions, while oily solutions, emulsions and suspensions are injected intramuscularly
and subcutaneously.
c. Isotonicity:
Isotonicity is another factor which must be taken into consider. Subcutaneous and IM
injection need not to isotonic and in some cases, a hypertonic solution will facilitate the
absorption of drug. IV needs not to be isotonic because of the low circulation of CSF in
which abrupt change can give rise to many side effects.

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Ideal properties of a parenteral product:
a. They should be chemically table and non-toxic.
b. They should be free from all microorganisms.
c. They should be free from pyrogens.
d. They should be free from foreign particles.
e. They should be free from all type of chemical contamination.
f. They should be isotonic with the body fluid.
g. They should be tissue specific.
h. They should have matching specific gravity with the body fluids.
i. Multidose injections must have preservatives.
j. It must not compete with its packaging material.
Classification of parenteral products:
The classifications of parenteral products are as follows:
1. According to their origin:
According to their origin parenteral products are classified into two groups:
a. Biological parenteral products: Vaccines, antitoxins etc.
b. Non-biological parenteral products: sterile morphine injections.
2. According to USP and national formulary:
a. Solutions:
Solutions of medicaments are suitable for injection, bearing the titles of the form
injection. e.g. morphine injection, insulin injection.
b. Dry solids or concentrated liquids for solutions:
Dry solids or concentrated liquids are used with the addition of suitable solvents.
Which yield solutions conforming in all respects to the requirement for injections.
These are distinguished by the titles of the form, “for injection” or “sterile”. e.g.
sterile ampicillin for injection, sodium thiopental for injection.
c. Suspensions:
Solid are suspended in a solid suitable medium and which are not to be injected
intravenously or into the spinal canal, distinguished by the titles of the form “sterile
suspension”. e.g. sterile Ephedrine suspensions.
d. Dry suspensions:
Dry suspensions are used with the addition of suitable solvents. Which yield
solutions conforming in all respects to the requirement for injections. These are
distinguished by the titles of the form, “sterile for suspension”. e.g. sterile ampicillin
for suspension.

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e. Emulsions:
Emulsions are fluids in fluid media, which is suitable for parenteral administration.
These are not injected unto the spinal cord and distinguished by the titles of the
form, “sterile emulsion”. e.g. sterile phytonadione emulsion.
3. According to the sterilization technique:
According to the sterilization technique, parenteral products are divided into 3 classes:
a. Aseptically prepared product,
b. Bulk sterilized product,
c. Terminally sterilized product.
Advantages of parenteral dosage form:
1. In emergency case when rapid onset of drug action is required from a drug, it may be
given by the intravenous injections of an aqueous solution.
2. Drugs can be administered when they cannot be given orally, because the
unconsciousness and uncooperativeness of the patient.
3. Drugs which are irritant to the stomach or which are unstable to stomach or which are
not well absorbed in small intestine, can be given by the parenteral dosage form.
4. Parenteral routes are performed in case of diarrhoea or vomiting, where patients are
unable to swallow.
5. The therapeutic dose of the drug is controlled more readily by parenteral administration
since the irregularities of intestinal absorption are circumvented.
6. The parenteral routes are preferred to produce local action. Such as, administration of
local anesthetics, Procaine HCl.
7. Since the drug normally administered by a professionally trained person, may be
expected that the dose was actually and accurately administered.
8. Drugs having low therapeutic index are very much suitable for parenteral route.
Disadvantages:
1. It requires asepsis at administration site.
2. Self-medication is difficult.
3. It requires trained person to administer.
4. Risk of local tissue damage, irritation, swelling, inflammation at the site of injection.
5. Without pharmacological antagonist it’s impossible to antagonize the therapy.
6. It is a painful route of administration.
7. Patient may experience psychological pain.
8. Daily and frequently administration is quiet difficult.
9. Administration due to wrong route may prove fetal.
10. It is quite expensive compare to other dosage form.

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Factors to be considered for the formulation of injection:
Injections are sterile products intended for the administration of bodily tissue. There a
formulation involves careful consideration of all the following interrelating factors:
a. The proposed route of administration,
b. The vehicles in which the medicaments to dissolved or suspended,
c. The volume of injection,
d. The osmotic pressure of the solution,
e. The pH of the solution,
f. The use of preservatives,
g. The stability of the medicaments,
h. Method of sterilization,
i. The specific gravity of the injection,
j. The properties of the suspension for injection,
k. The properties of the emulsion for injection,
l. Containers or closures for injection,
m. Particulate contamination,
n. Presence of pyrogens,
o. Bio pharmacy of injection,
p. Local irritation,
q. Incompatibility,
r. Presence of particulate.
Formulation of parenteral products:
The formulation of parenteral product involves the combination of one or more ingredient
with a medicinal agent to enhance the convenience, acceptability or effectiveness of the
product. The formulation differs from various types of parenteral products. Generally the
following things are required for a parenteral product.
1. Vehicle,
2. Solutes (active ingredient and added substance),
3. Containers and closures.
Vehicles:
Since the most parenteral products are dilute, the component present in the highest
proportion is the vehicle. A vehicle has no therapeutic activity and is non-toxic. However, it
is of great importance in formulation since it represent he active ingredient from to body
tissue for absorption. Absorption normally occurs most rapidly and completely when a drug
is presented as aqueous solution. Modification of vehicle with water miscible liquids or
substitution with water immiscible liquid normally decreases the rate of absorption.

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Types of vehicles:
The vehicles used for parenteral product usually are 3 of types:
a. Water,
b. Water miscible vehicle,
c. Water immiscible vehicle,
1. Water:
The vehicle for greatest importance for parenteral product is water, since aqueous
preparations are well tolerated by the body and are the safest and easier to administer.
The high dielectric constant of water makes it possible to dissolve ionizable electrolytes
and its hydrogen bonding potential brings about the solution of such organic substances
as alcohol, aldehyde, ketone and amines. Some aqueous vehicles are officially
recognized. These vehicles include:
a. Water for injection:
It is the most widely used solvent in the large scale manufacture of injections. This
water is purified by distillation or by reverse osmosis. Although it is not required to
be sterile, it must be pyrogens free. The water is used in the manufacture of
parenteral products which are terminally sterilized.
b. Sterile water for injection:
This is water for injection which are being sterilized and packed in single dose
containers of not greater than 4 liter size. As WEI must be pyrogens free it may not
contain an antimicrobial agent or other added substances. This water is intended to
be used as a solvent, vehicle or diluents, for already sterilized and packed injectable
medications. The water is aseptically added to the vial of medication to prepare the
desired injections. For examples, a suitable injection may be prepared from dry
powder, “sterile ampicillin Na” by the aseptic addition of sterile WFI.
c. Bacteriostatic water for injection:
This is the sterile water for injection containing one or more suitable antimicrobial
agents. It is packed in prefilled syringes or vials containing not more than 30ml of
water. The water is used as a sterile vehicle in the preparation of small volumes of
injectable preparations. Generally if volumes of greater then 5ml of solvent are
required, sterile WFI rather than bacteriostatic WFI is preferred. In using the
bacteriostatic agents with the active ingredients being suspended or dissolved.
d. Bacteriostatic NaCl injection:
It is a sterile isotonic solution of NaCl in WFI. it contains one or more suitable
antimicrobial agents. NaCl is present in the concentration of 0.5%to make the

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solution isotonic. It is packed in containers not more than 30ml in size. When this
solution I used as vehicle, care must be taken to assure the compatibility of added
medicinal agents with the preservatives present as well as NaCl.
e. Ringer’s injection USP:
It is the sterile solution of NaCl, KCl and CaCl2 in water for injection. The three agents
are present in concentrations similar to that found in physiological fluids. The
solution is used as a vehicle for other drugs or alone as an electrolyte replenisher
and fluid extender.
2. Water miscible vehicles:
A number of solvent that are miscible with water have been used as a portion of vehicle
in the formulation for parenterals. These solvents are used primarily to effects the
solubility of certain drugs and to reduce hydrolysis. The most important solvent in this
group are:
a. Ethyl alcohol,
b. Liquid propylene glycol,
c. Propylene glycol.
Ethyl alcohol is used particularly in the preparations of solutions of cardiac glycosides
and glycol in the solution of barbiturates, certain alkaloids, and certain antibiotics. Such
preparations are given intramuscularly.
3. Non-aqueous vehicles:
The most important groups of non-aqueous vehicles are the fixed oils. The most
commonly used fixed oils are corn oil. Cotton seed oil, peanut oil, and sesame oil. These
fixed oils are particularly as vehicles for hormone preparations.
The USP specifies restrictions on the use of fixed oils in parenteral product as:
a. They must remain clear when cooled at 10 to ensure the stability and clarity of
injectables upon storage condition,
b. The oils must not contain mineral oil or paraffin as these materials are not absorbed
by body tissue,
c. The oils must meet officially stated requirements of iodine number and
saponification value.
Ideal properties of vehicles:
a. The vehicle should afford adequately solubility of active ingredients and stability of
the product.
b. The releasing capacity of the vehicle should be maximum.

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c. The vehicle should be non-toxic, non-irritant and non-sensitizing.
d. The vehicle should not exert pharmacological activity of its own.
e. The vehicle should not affect the action of active ingredients.
f. The vehicle must not cause hemolysis of RBC.
g. The vehicle should be unaffected by pH change.
h. The vehicle should be pure and free from foreign particles.
Solutes:
The physical and chemical purity of solutes used for sterile preparation must also be
exceptional. Obviously, contaminations entering a product with a solute have the same
effect as if they entered via the vehicle. Even small traces of contaminations may be
detrimental to products, necessitating purification of solute. Therefore the compounder
should use the best grade of chemicals obtainable and use its analytical profile to determine
that each lot of chemical used in the formulation meets the required specifications. In
addition, solute should be free from microbial contamination and pyrogens.
Added substituents:
The USP permits the addition of suitable substances to the official preparations intended for
injection for the purpose of increase their stability and usefulness. The added substance
include—
a. Antimicrobial agent,
b. Antioxidants,
c. Tonicity contributors,
d. Chelating agent,
e. Buffers,
f. Solubilizes,
g. Antifungal agent,
h. Local anesthetics,
i. Suspending agent,
j. Stabilizers.
Factors to be considered for the selection of added compound:
For the selection of added compound, following factors are considered—
a. The added substance must increase the stability of the product,
b. These product must not adversely affect the product,
c. The added substance must not non-toxic, non-irritant, and non-inflammatory,
d. The added substance must not interfere with the active ingredient,
e. The added substance must not interfere with the assay of the API,
f. They must be stable in wide range of temperature and pH,

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g. They should be pharmacologically inert.
Antimicrobial agents:
A preservative is a substance that prevents or inhibits the microbial growth and may be
added to pharmaceutical preparation for this purpose to avoid consequent spoilage of
preparation by microorganism. They should be in sufficient concentration to kill or prevent
the growth of the microorganisms. Such substances must be added in sufficient
concentration within a range of 0.1-0.15%. These are also included in unit or multidose
preparation in ampules or vials.
For selection of a good antimicrobial agent, it should have the following characteristics:
a. It should be effective against wide range of microorganism or fungi at normal
temperature,
b. It should be effective at relatively low concentration,
c. It should be non-toxic and non-irritant,
d. It should not impair the active ingredients color,
e. It should have high water solubility,
f. It should be stable and non-volatile,
g. It should be inert,
h. It should not cause pain at the injection site,
i. It should be compatible with other added substances,
j. It should remain stable during sterilization and storage
Some preservatives with its concentration:
Preservatives Concentration
Methyl paraban 0.1 - 0.2%
Propyl paraban 0.005 - 0.035%
Benzal konium chloride 0.01%
Cetrimide 0.001%
Benzoic acid 0.1 - 0.2%
Salicylic acid 0.1 - 0.2%
Cresol 0.3-0.5%
Chlorcresol 0.1-0.3%
Benzyl alcohol 2.0%
Chloroform 0.02%

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Antioxidants:
Many drugs are sensitive to oxygen and antioxidant is a substance which inhibits oxidation
and thus it prevent the decomposition by oxidative process. The decomposition of many
readily oxidisable therapeutic agents is reduced by adding a small quantity of substance that
will stop auto oxidation process. Even small amount of air entrapped in a vial or ampule can
cause oxidative degradation.
How an antioxidant protect a product from oxidation:
An antioxidant can protect the product from oxidation by different ways.
a. By acting as a reducing agent,
b. By blocking an oxidative chain reaction,
c. Some substance acts as synergists by increasing the effectiveness of the blocking
agents.
d. By using chelating agents that complex with metal ions which can catalyze oxidative
reactions.
Ideal characteristics of an antioxidant are:
a. It should be natural and should not react chemically with other components,
b. If it decomposed, the decomposed product must be non-toxic,
c. It should be effective at low concentration,
d. It should be non-toxic and non-irritant,
e. It must be compatible with the active ingredients,
f. It should not impair the active ingredients color or odor,
g. It should have high water solubility,
h. It should be stable and non-volatile.
Some antioxidant with their concentration:
Antioxidants Concentration
Antioxidants: Reducing agent
Ascorbic acid 0.02 - 0.1%
Sodium bisulfate 0.15%
Phosphoric acid 0.01%
Tocopherols 0.5%
Antioxidants: Blocking agents
Butylated hydroxyl Anisole (BHA) 0.02%
BHT 0.005 – 0.01%

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Synergists
Citric acid 0.01%
Tartaric acid 0.02%
Chelating Agent
EDTA salts 0.01 – 0.075%
Tonicity contributors:
Tonicity contributors are the substances which are often included in parenteral products
particularly in large volume preparation to make it isotonic with blood or other body fluid.
The components which are used as tonicity contributors reduce the pain at the site of the
injection. Adjustment of tonicity to isotonic condition is important to preserve the integrity
of RBC by addition of NaCl, Borax etc.
Components used as Tonicity contributors:
Ingredients Concentration
NaCl 0.9%
Dextrose 5.5%
Mannitol 2.5%
Lactose 5.0%
Glycerin 2.25%
Buffers:
Change in pH of preparations may occur during storage because of degradative reactions in
the product, interaction of the product with the packaging material or container or loss of
gas or vapors. So, buffers are used to maintain a required product, because a change in pH
can accelerate a number of degradative reactions and also affect the biological effectiveness
of the product.
The principle buffer systems employed for parenteral preparations are acetate, citrate and
phosphate.
Buffer systems with concentration;
Name of buffer Systems Concentration
Acetate CH3COOH + CH3COONa 1 – 2%
Citrate Citric acid + Na-citrate 1 – 3%
Phosphate H3PO4 + its salt 0.8 – 2%
Carbonate H2CO3 + NaHCO3 1 – 2%

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Solubilizing agent:
Solubilizing agents are used in parenteral preparation for proper solubility of the drugs.
Otherwise the drug would not be absorbed properly after administration. For example:
Propylene glycol  50%
Polyethylene glycol  30%
Polysorbate  4%
Wetting, suspending and emulsifying agent:
In a parenteral suspension, a wetting agent is used to reduce the interfacial tension
between the solid particle and the liquid, so as to prevent the formation of lump. They also
act as antifoaming agent to subside the foam produced during shaking.
The commonly used wetting agents are:
Tween – 80,
Polysorbate 20 and 40,
Sorbate trioleate,
Lecithin.
For example cortisol acetate and procaine penicillin are poorly water soluble and often form
a lump is aqueous solvent. So a suitable wetting solvent is often included in this formulation.
Commonly used suspending agent:
Suspending agent Concentration
Methyl cellulose 1.0%
Na-CMC 0.75%
Acacia 2.0%
Gelatin 2.0%
Pectin 0.2%
Emulsifying agents are used in the formulation of sterile emulsions. For this purpose,
lecithin is generally used. Gelatin may be added in aqueous vehicle and prolong the effect of
the drug.

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Pyrogens:
Pyrogens are the fever producing organic substances arising from microbial contamination
and responsible for many of the febrile, which occur in patients following injection.
Pyrogens are the product of metabolism of microorganisms. The most potent pyrogenic
substances are constituents of cell wall of gram-negative bacteria. Gram-positive bacteria
and fungi also produce pyrogens but of lower potency and of different chemical nature.
Endotoxins are higher molecular weight lipopolysaccharides. Studies have shown that lipid
portion of the molecule is responsible for the biological activity.
Actions of pyrogens in human body:
Pyrogens when present in parenteral drug products and injected into patients can cause
fever, chills, pain in the back and legs and malaise. When bacterial pyrogens are introduced
into the body, leukocyclic phagocytosis is believed to occur and endogenous pyrogens are
produced. The endogenous pyrogens then produce familiar physiological effects.
Sources of pyrogens:
Water is probably the most potential source of pyrogenic contamination, since water is
essential for growth of micro-organisms. The other potential source of pyrogens may be
medicament, any added buffering or stabilizing substances, the apparatus used in
manufacture, the final containers and the method of storage during preparation and
sterilization. Undoubtedly, the major source is the solvent and especially WFI BP.
How pyrogens can be removed:
As pyrogens are thermo stable, water soluble and unaffected by common bactericides,
therefore none of the methods can be relied upon to remove pyrogens. The following
pathways can be done to remove pyrogens:
a. Pyrogens are non-volatile and they can be removed from water by distillation and by
collecting the distillate in a sterile condition.
b. To be pyrogen free solutes must be prepared from vehicles free from pyrogens and
must be stored in a manner designed to prevent in the solute, then the solute must
be purified by recrystallization.
c. Containers may be made pyrogen free by adequate cleaning and heating, usually at
310o
C for 3-4 hours. A study shows that heating at 600o
C for 60seconds destroys
pyrogen. However autoclaving temperature don not destroy pyrogens during normal
cycle.
d. Rubber closures, plastic containers cannot make pyrogen free by applying heat. So,
they made pyrogen free by effective washing through rinsing with WFI, prompt
sterilization and protective storage.

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e. Pyrogens may also be removed by heating the substance with strong alkali or
oxidizing solutions. Another method which has been used in adsorption on
adsorptive agents. Since the adsorption phenomenon also may cause selective
removal of chemical substances from the solution, this method has limited
application.
Manufacturing of parenteral products:
The following processing steps are involved in the large scale productions of parenterals:
a. Planning,
b. Cleaning containers and equipment,
c. Compounding the product,
d. Filtration of solute,
e. Filling,
f. Sealing,
g. Sterilization,
h. Labeling,
i. Packaging,
A. Planning:
Early planning is essential for every manufacturing process. Stock ingredients, containers
and other components as well as the equipment should be ready for use when needed.
B. Cleaning containers and equipment:
Containers and equipment, coming in contact with the parenteral product must be
cleaned over carefully.it should obvious that unused containers and equipment will be
contaminated with debris such as dust, fiber, chemical films and other material arising
from sources such as atmosphere, cartons and manufacturing process and human
hands. Residues from previous use must be removed from used equipments before it
will be suited for reuse.
A variety of machines are available for cleaning new containers for parenteral products.
The selection of particular type will be determined by the physical type of containers,
the type of contamination and the number to be processed in a given period of time.
C. Compounding the product:
The basic principle of compounding of the product is essentially same as those used
historically by pharmacists. However, large scale production requires appropriate
adjustment in the processes and their control.

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A master formula should be developed and each batch formula sheet should be
prepared from the master formula and confirmed for accuracy. All measurements of
quantities should be made as accurately as possible and checked by a second qualified
person.
D. Filtration of solute:
After a product has been compounded, it must be filtered if it is a solution. The primary
objective of filtration is to clarify a solution. A high degree of clarification is termed as
polishing. The term is used when particular matter down to approximately 2 m in size is
removed. A solution with a high degree of clarity conveys the impression of high quality
and purity.
Membrane filters are used extensively for filtration of parenteral products due to their
particle retention effectiveness, non-shedding property, non-reactivity and disposal
characteristics.
After filtration the solution must be protected from environment contamination until it
is sealed in the final container. Normally it is best accomplished by collecting the filtrate
in a container that is a part of the close system. The filtrate is fed directly from the
collecting vessel to a filling machine through sterile house connection.
E. Filling:
Normally the compounded product is in the form of either a liquid or a solid. So, filling
method is different in two cases.
a. Liquid filling:
Many devices are available for filling containers with liquids. The filling of small number
of containers may be accomplished with a hypodermic syringe and needle. The liquid is
drawn into the syringe and force through the needle into the container. A device for
providing greater speed of filling is the Cornwall pipet. This has two way valve between
the syringe and needle and a means for setting the stroke of the syringe so that some
volume would delivered each time.
b. Solid filling:
Sterile solids such as antibiotics are more difficult to subdivide evenly into container
than are liquids. The rate of flow of solid material is slow and often irregular.
Some sterile solids are subdivided into containers by individual weighing. A scoop is used
to provide an approximate quantity, but the quantity filled into the container finally is
weighed on a balance. This is a slow process.
When the solid is obtainable in a relatively free flowing form, machine methods of filling
may be employed. A type of filling machine which operates on a vacuum principle on
which a vacuum is pulled on a cavity into which the powder flows before being
discharged into container.

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F. Sealing:
a. Ampules:
Filled container should seal as soon as possible to prevent the containers from being
contaminated by the environment. Ampules are sealed by melting a portion of the glass
neck. Two types of seals are employed normally, tip seals and pull seals.
1. Tip seals:
Tip seals are made by melting enough glass at the tip of the neck of an ampule to form a
bead of glass and close the opening. These can be made rapidly in a high temperature
glass-oxygen flame. To produce a uniform bead, the ampule neck must be heated evenly
on all sides. Care must be taken to adjust the flame temperature and interval of heating
properly to completely close the opening with a bead of glass. Insufficient hating will
leave on open capillary through the center of the bead. An incompletely sealed ampoule
is called leaker.
2. Pull seals:
Pull seals are made by heating the neck of the ampoule below the tip leaving enough of
the tip for grasping with forceps or other mechanical devices. The ampoule is rotated in
the flame from the single burner. When the glass has softened the tip is grasped firmly
and pulled quickly away from the body of the ampoule, which continues to rotate. Pull
sealing is lower but sealing is more perfect.
b. Vials and bottles:
Vials and bottles are sealed by closing the opening with a rubber closure (stopper). This
must be accomplished as rapidly as possible after filling with proper care to prevent the
contaminations of the contents. During the critical exposure time, the open containers
should be protected from the contamination by a blanket of HEPA filtered laminar air
flow.
c. Closures:
The closure must fit to the mouth of the container strongly enough to produce a seal but
not so snugly that it is difficult to introduce into the neck of the container. Closures re
inserted mechanically using an automated process, especially with high speed
processing.
Rubber closures are held in place by means of all caps. The caps cover the closure and
are crimped under the tip of the vial or bottle to hold them in place.

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G. Sterilization:
The parenteral products should be sterilized after being sealed in its final container by
terminal sterilization process. Thermo labile products are sterilizes by autoclaving or by
dry heat sterilization at temperature for 115o
C for 90 min or for 121o
C for 20 min. oily
injection are sterilizes by hot air oven at 160o
C for 120 min or for 170o
C for 60 min. Heat
sensitive products are sterilized by non-thermal process, using by filtration of bacteria
proof filters. Subsequently all operations must be carried out in ascetic manner so that
contamination will not be introduced in the filtrate.
H. Labeling:
The labeling of an injection must provide the physician and the user will all of the
information needed to ensure the safe and proper use of the product.
A properly made label should contain:
a. The name of the preparation,
b. The percentage of drug in liquid preparation,
c. The amount of API in dry preparation,
d. The volume of liquid to be added to prepare an injection or suspension from a dry
preparation,
e. The route of administration,
f. The name of the manufacturer and the address,
g. The lot number and the batch number,
h. The manufacturing and expire date
Since all of this information cannot be written in an immediate container, it may be
provided on accompanying printed matter.
The container label is so arranged that a sufficient area of the container remains
uncovered for its full length or circumference to permit inspection of the container.
I. Packaging:
Packaging of pharmaceutical preparation is designed to:
a. Convey the required information for the patients or the containers,
b. Represent the product to the user,
c. Protect the product during shipment and handling provides an attractive
appearance.

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19
According to the USP, the requirement for the parenteral product packaging includes the
following:
a. The labeled container should be packaged in card board or plastic container so that
there is no breakage during transportation and handling.
b. Ampoules should be packed in partitioned boxes.
Quality control of parenteral products:
The three general areas of QC are:
a. Incoming stock,
b. Manufacturing or in process control,
c. QC of finished product.
1. Incoming stock control:
For sterile products incoming stock control encompasses routine test of ingredients as
well as special evaluation. Such as:
a. Pyrogen test on WFI,
b. Glass tests on containers,
c. Identity test of rubber closures.
It may also necessary to perform microbial load tests (bilburden) to determine the number
and type of the microorganism present.
2. In-process control:
In-process control of sterile products involves all of the innumerable tests, regarding and
observation made throughout the manufacturing process of the product including:
a. Conductivity measurement during the distillation of WFI,
b. Confirmation of the volume of fill in the product containers,
c. Recording of cycle time and temperature for thermal sterilization of the product,
d. Confirming the count and identity of labels for the product.
3. QC for finished products:
QC for finished products involves a number of tests including:
a. Leaker test,
b. Clarity test,
c. Pyrogen test,
d. Sterility test,
e. pH test for large volume,
f. Assay test (potency or drug content).

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20
Leaker test:
The leaker test is intended to detect incompletely sealed ampules so that they may
discover. Tip sealed ampoules are more likely to be incompletely sealed than are those that
have been pull sealed. In addition, small cracks may occur around the seal or at the base of
the ampoule due to improper handling.
Leakers are usually detected by producing a negative pressure within an incomplete sealed
ampoule when the ampoule is entirely submerged in a deeply colored dye solution usually
0.5-1% methylene blue. After carefully rinsing the dye solution from the outside, color from
the dye will be visible with in the leaker. Only a tiny drop may penetrate a small opening.
Leakers re then discarded.
Importance:
Ampules are intended to provide a hermetically sealed container for a single dose of a
product; therefore, there is no interchange between the contents of the sealed ampoule
and its environment. If capillary pores are present, micro-organisms or other dangerous
contaminants may enter the ampoule or the contents may leak of the outside and spoil the
appearance of the package.
Clarity test:
The presence of particular matter in parenteral preparation is unaccepted. Since, it may
suggest the user that the product is of inferior quality. It has been recognized that the
presence of particle in solution, particularly in IV solution may be harmful. The particles of
lint, rubber, insoluble chemicals and other foreign matter can produce emboli in the vital
organs in the animals and man.
However it is important to how large particles are evaluated. Since erythrocyte have a
diameter of 4.5µm, particles of more than 5µm should basis for evaluation.
The USP specifies that each final container of an injection should be inspected individually
and that container that contains visible particles can be seen should be discarded. To
perform this, all of the product units from a production line are inspected individually by
human inspectors under a good light and against a black and white background. A moving
particle is easier to see than one of that stationary. To see heavy particles, it may be
necessary to invert the container as the final step in inspection.

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21
Pyrogen test:
The presence of pyrogens in the parenteral preparation is determined by the following
methods:
a. Biological method,
b. Chemical method.
Biological method:
The presence of pyrogens in the parenteral preparation is determined by a qualitative fever
response tests in rabbits. Rabbits are used as the test animal because they show
physiological response to pyrogens similar to that of human beings. The test is done by
introducing a sample of product to be tested to the vein of the rabbit and rectal
temperatures are noted at 1, 2 and 3 hours after administration of the injection. If there is
any rise of the temperature of 0.6o
C or more above the normal temperature which has been
taken before giving the injection then the test is considered positive. But the rabbits do not
show any rise of temperature, the product is considered as free from pyrogens.
Chemical method:
The bacterial endotoxin test is an in-vitro test based on the formation of gel or the
development of the color in the presence of bacterial endotoxins and the lysate of the
amoebocyte of the horseshoe crab. In the presence of bacterial endotoxins from gram
negative bacteria, a firm gel is formed with in 60min, when incubated in 370
C. The LAL test is
performed in a test tube and simpler and more rapid than rabbit test.
The LAL test is a semi quantitative test. The test is designed to provide a means for
estimating the concentration of bacterial endotoxins present in samples. The sensitivity of
lysate is given in terms of endotoxin units (EU).
Advantages of LAL test over rabbit test:
a. The LAL test is economic, quicker and more accurate than rabbit test,
b. The highly potent drugs cannot be tested on rabbits, because they may die,
c. Radioactive pharmaceutical easily tested by LAL test,
d. LAL test gives an quantitative measurements,
e. It is 5-10 times more sensitive than rabbit test.
Disadvantages:
LAL is only effective to determine the endotoxins from gram negative bacteria; however, it
does not determine endotoxins other than from the gram negative bacteria.

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22
Sterility test:
All products labeled sterile must pass the sterility test having been subjected to an effective
sterilization process. The result gives evidence that the sterilization procedure has been
repeated effectively. These tests are performed on a sample selected to represent the
entire lot of the material.
The USP has stated two basic methods for sterility testing:
a. Direct inoculation of test sample on culture media,
b. Filtration technique.
The membrane filter technique now has been accepted by the USP for the large and small
volume parenterals. The liquid is filtered through a sterile membrane filter of microbial
retentive porosity under strict aseptic environmental conditions. The microorganisms are
retained on the filter and liquid under test passes into the filtrate, carrying away potentially
inhibitory substances. In addition, the filter may be rinsed with a sterile liquid to remove
potentially inhibitory substances that may have altered to the m.o.s. The filter then cultured
in to the culture medium and inoculated for growth. If any growth of microorganism
species, it is sufficient to proof that the sterilization process has not been effective.
Bubble point teat:
Bubble point teat (BPT) is the integrity test of the filter membrane based on the amount of
pressure required force the air through a wet porous membrane. Each membrane has a
specific BPT which is dependent on the pore size of the membrane and the liquid wetting
the membrane. A test at pressure 20psi for about one minute is usually sufficient to detect
leaks.
Principle:
Membrane filters which have discard uniform passages that penetrate from one side of the
media to the other, can be regarded as a fine uniform capillaries. The BPT is based on the
fact that when these capillaries are full of liquid, the liquid is held by surface tension. The
minimum pressure required to force the liquid out of the capillary must be sufficient to
overcome surface tension.
The capillary pressure is higher in the small pore than in that of a large pore. The bubble
point pressure is governed by the following equation:

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23
Where,
P = Bubble point pressure,
K = Shape correction factor,
D = Pore diameter,
r = Surface tension of the liquid,
= liquid to membrane contact angel.
How to perform BPT:
BPT is performed by the following steps:
a. The membrane filter is wetted with distilled water,
b. The filter is set to the membrane filter holder,
c. N2 gas is connected to the filter through the pressure gauge,
d. The end of N2 gas delivery pump is sinking into a small container full of water.
e. Since pores of the filter are full of liquid, there is no passage of gas at zero pressure.
There is no passage of gas if the pressure is increased slightly.
f. When the bubble point pressure is reached, a small bubble forms at the largest
opening. As pressure is further increased, rapid bubbling begins to occur.
Isotonic solution:
A solution having the same osmotic pressure as a specific body liquid is said to be isotonic
with that body fluid. Solution which exerts a different OP are called paratonic solutions.
Those exerting a lower OP are hypotonic and those exerting a higher OP are hypertonic.
Aqueous solutions for injection should preferably be made isotonic with plasma in order to
minimize any possible adverse effects such as pain irritation etc. the solutions which are not
isotonic with plasma may be harmful to use. When a hypotonic solution is injected into a
blood stream, it may enter to the RBCs, in an attempt to produce equilibrium. The cells swell
rapidly and burst leading to hemolysis. The damage is irreversible and it may lead to a
serious danger to red cells.
When hyper tonic solutions are injected into the blood stream, the water comes out from
the membrane of RBCs in order to reach equilibrium. The cell shrink become create in
outline. When osmotic pressure returns to normal, the blood cell assumes their normal
shape. Therefore grossly hypertonic solutions may be without damage to the cells. The
injections which are hypertonic are slowly injected intravenously to ensure rapid dilution in
the blood stream and minimal crenulation of RBCs.
The substance used to adjust the osmotic pressure of parenteral solutions to that of plasma
must be inert and non-toxic. NaCl is the most used substance as isotonic solution, although
dextrose may also be used for IV infusion.

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24
Various methods are required to render a particular solution isotonic with blood plasma.
The most important methods are:
a. The freezing point depression method,
b. The NaCl equivalent method,
c. The isotonic solution V-value method.
NaCl equivalent method for calculation of isotonic preparation:
The procedure of calculation of isotonic preparation with NaCl equivalents may be outlined
as follows:
a. Step I:
Calculate the amount of NaCl (in grams) represents by the ingredients in the
preparation. If the number of grams of a substance include in a prescription is multiplied
by its NaCl equivalent (E value), the amount of NaCl represented that substance is
determined.
b. Step II:
Calculate the amount of NaCl (in grams) alone that would be contained is an isotonic
solution of the value specified in the preparation and the amount NaCl in a 0.9% solution
of the specified volume.
c. Step III:
Subtract the amount of NaCl represented by the ingredients in the prescription (Step I)
from the amount of NaCl alone, which would be represented in the specific volume of an
isotonic solution (Step II). The answer represents the amount of NaCl to be added to
make the solution isotonic.
d. Step IV:
If an agent other than NaCl such as boric acid, dextrose, sodium or potassium nitrate is
to be used to make the solution isotonic, divide the amount of NaCl (Step III) by the NaCl
equivalent of other substance.

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