Parenteral

preparations
 :Parenteral products must be

Sterile.
Free from pyrogenic (endotoxin)
contamination.
Free from visible particulate matter.
Isotonic although strictness of isotonicity
depends on the route of administration.
Stable (chemically, physically, and
microbiologically).
Compatible with I.V diluents, delivery systems,
and other drug products co-administered.

 :Advantages of Parenterals
Immediate physiological action (emergency ).
Controlled therapeutic response of drug.
Accurate dose administration.
Useful in case of unconscious or uncooperative state.
To achieve a biological effect that is not possible from
oral administration: e.g. Insulin, certain penicillins
To achieve local effect: e.g. local anaesthetics (dentist), local anti-
inflammatory (joints)

Slow onset and prolonged drug action can be

obtained by:
Modifying the formulation.
Using a route of injection other than I.V.
 Disadvantages of Parenterals

Difficult to administer (restriction to use in

hospitals or with specialized personnel)
Painful.
Require asepsis (absence of
microorganisms) at administration.
Impossible to correct an error unless a
direct pharamacological antagonist is
immediately available.
Risk of tissue toxicity from local irritation.
 Classification of
Parenterals

II) Ready to be
I) Ready for III) Ready for
combined with a
injections dilution
vehicle

Solutions-1 Liquid- 1
concentrate
-2 Dry soluble- 1
Suspensions products Dry- 2
insoluble
Emulsions-3 products
 1. Solutions:

Are the most common of all parenteral

products.

Are usually aqueous but may be also found

as mixtures of ether with glycols, alcohol, or
other non-aqueous solvents.

Most solutions have a viscosity and surface

tension similar to water.
 Take IM control release
:Suspensions. 2
there are three grade
sInsulin suspension
according to crystal size

Are dispersed, multi-phased, heterogeneous

system of insoluble solid particles intended
principally for I.M and S.C injections.

Must not cake during shipping and storage and

should be easy to suspend and inject throughout
its shelf life.

Must not be administered directly to the

bloodstream because of the danger of insoluble
particles blocking the capillaries.
The flow properties of parenteral suspensions
are characterized on the basis of:

Syringeability
Itrefers to the handling characteristics of suspension
while drawing it into a syringe.
It also refers to the ease of withdrawal from container into
the syringe, clogging and foaming tendencies, and
accuracy of dose measurement.

Injectability
It refers to the properties of the suspension during
injection.
It includes factors such as pressure or force required for
injection, aspiration qualities and freedom from clogging.

4-Dry Powders:
Parenteral drug products are usually
prepared as dry powder because it is
unstable in solution.
A disadvantage of this parenteral form
is the need to reconstitute the product
with the correct diluent prior to use.
Dry powders may be intended to be
reconstituted as a solution or as a
suspension.
Dry powder is produced by several
:methods

1. Sterile crystallization.

2. Lyophilization (freeze-drying).

3. Spray drying.

 Vehicles

Definition: A vehicle should have no

therapeutic activity and it should be
nontoxic.

Importance in formulation:
Drug carrier.
Rapid and complete absorption
especially when the drug is presented
in aqueous solution.
 Types of
Vehicles

Water-2 Non--3
Aqueous-1
miscible aqueous
vehicles
Vehicles Vehicles
 Only aqueous give
IV
1-Aqueous Haven't any
vehicles particle coz may
block small blood
They are used as isotonic vehicles to which a drug may be
vessels
added at the time of administration.

Examples: Sodium chloride injection, Ringer's injection and

Dextrose injection.

2-Water miscible vehicles

They consist of a number of solvents that are miscible with
water. These solvents are used to: a- enhance solubility of
drugs. b- Reduce hydrolysis.

Examples: Ethyl alcohol (used in the preparation of solution of

cardiac glycosides and certain I.M. antibiotics) and propylene
glycol.
3-Non-aqueous vehicles
The most important are fixed oils.
The USP specifications of fixed oils are:
Must be of vegetable origin (WHY?)
Liquid at room temperature.
Do not rancid readily.
Unsaturation should be within specific limits.
Fatty acid content should be within specific
limits.
Examples: corn oil, cotton seed oil and sesame
oil (usually used in hormone preparation).
N.B. Non aqueous vehicles cannot be used I.V.
 Solutes

-I -II -IV
-III
Added Antimicrobial Antioxidan
Buffers
Substances Agents ts
II- Antimicrobial Agents:
They must be present in adequate concentration at the time of use to
prevent the multiplication of microorganisms.
E.g. Phenylmercuric Nitrate 0.01%, Phenol or Cresol 0.5%,
Chlorobutanol 0.5%.

E.g The binding and inactivation of esters of p-hydroxybenzoic acid by

macromolecules such as Polysorbate 80 or the reduction of
Phenylmercuric nitrate by sulfide residues in rubber closures.

Single dose containers and pharmacy bulk packs that do not contain
antimicrobial agents are expected to be used promptly after opening
or to be discarded.

Refrigeration slows the growth of most microorganisms, but does not

prevent their growth.

III-Buffers:
They are used primarily to stabilize a solution against pH changes.

Buffers used should have low buffering capacity so as not to

disturb the bodies buffering system.
E.g. Acid salts of citrates, acetates, and phosphates.

IV- Antioxidants:
They are required frequently to preserve products from oxidation.
E.g. Sodium bisulfite 0.1%.
Displacing the air (oxygen) in and above the solution by purging
with an inert gas, such as nitrogen, also can be used to control
oxidation of sensitive drugs.
They are used in many parenteral and ophthalmic products to
adjust the tonicity.
E.g. Electrolytes and mono- or disaccharides.

What mean of pyrogen, its sources &how treat it

&control?
Pyrogens(endotoxins)
Pyrogens are products of metabolism of
microorganisms.
The most potent pyrogenic substances are
constituents of the cell wall of gram- negative
bacteria.
Pyrogens, when present in parenteral drug products
and injected into patients can cause fever, chills,
pain in the back and legs, and malaise.
They can rarely cause serious discomfort and shock
like symptoms that can be fatal.

Pyrogens(endotoxins)

The intensity of the pyrogenic

response and its degree of hazard
will be affected by:
1- medical condition of the patient.
2- Potency of the pyrogen.
3- Amount of the pyrogen.
4- Route of administration (intrathecal
is most hazardous followed by
intravenous, intramuscular, and
subcutaneous).
Sources of Pyrogens

Water is the greatest potential source of

pyrogenic contamination; since water is
essential for the growth of microorganisms
(microorganisms metabolize producing
pyrogen).
Pyrogenic materials adhere strongly to glass
and other surfaces.
Residues of solutions in used equipment
often become bacterial cultures, with
subsequent pyrogenic contamination.
Sources of Pyrogens

Pyrogens may remain in equipment for long

periods (since drying does not destroy
pyrogens).
Solutes may be a source of pyrogen.
Bulk drug substances derived from fermentation
will almost be heavily pyrogenic; therefore, all
lots of solutes used to prepare parenteral
products should be tested to ensure that they
will not contribute unacceptable quantities of
endotoxins to the finished product.
Control of Pyrogens

It is impractical to remove pyrogens without

adversely affecting the drug product.
Prevention of the introduction or
development of pyrogens in all aspects of the
compounding and processing of the product.
Time for microbial growth to occur increases
the risk for elevated levels of pyrogens,
therefore compounding and manufacturing
processes should be carried out within one
work day.
Control of Pyrogens
Pyrogens can be destroyed by heating at high
temperatures.
Depyrogenation of glassware and equipment is
done by maintaining a dry heat temperature of
250C for 45 minutes.
Heating with strong alkali or oxidizing solutions
will destroy pyrogens.
Adsorptive agents are used for the removal of
pyrogens from solutions; however this method has
limited application since it may cause selective
removal of chemical substances from the solution.
 Containers and Closures
Containers are an integral part of the formulation
of an injection.
No container is totally insoluble or does not in
some way affect the liquid it contains, particularly

:V I
if the liquid is aqueous.

The selection of a container for a particular

injection must be based on:
1) The composition of the container.
2) The composition of the solution.
3) The treatment to which it will be subjected.
 1-Plastic

Thermoplastic polymers have been

established as packaging materials for
sterile preparations such as:

a) Large volume parenterals. :V I

b) Ophthalmic solution.
c) Small volume parenterals.

 Principle problems exist in using these

material

a- -b
-c
Permeat Leachin
ion Sorption
g
a) Permeation: It is the movement of vapors and other molecules
in either direction through the wall of the plastic container.

b) Leaching: Migration of constituents from the plastic into the

product. Leaching may be a problem when certain constituents
in the plastic formulation such as plasticizers or antioxidants
migrate into the product.

c) Sorption: (absorption and/or adsorption) of drug molecules or

ions on the plastic material. Sorption is a problem when
adsorption of a few drug molecules occurs on specific polymers.
E.g.: Sorption of insulin, vitamin A acetate, and Warfarin sodium
has been shown to occur on PVC bags and tubing when these
drugs were present as additives in IV admixtures.
 Advantage of plastic
Not breakable as glass (1
2) low weight
3) Flexible, e.g. the use of low density polyethylene
polymer for ophthalmic preparations makes it possible
to squeeze the side wall of the container and discharge
one or more drops without introducing contamination
into the remainder of the product.
N.B. The flexible bags of polyvinyl chloride,
currently in use for large volume intravenous
fluid, have the advantage that no air
interchange is required (the flexible wall simply
collapses as the solution flows out of the bag).
 Disadvantage of Plastic

1. They are not as clear as glass and

therefore inspection of the contents
is impeded.

2. Many of the materials used will

soften or melt under the conditions
of thermal sterilization.
Type I glass is suitable for all products,
although sulfur dioxide treatment
sometimes is used for a further
increase in resistance.
Type II glass is suitable for e.g. for a
solution that is buffered has a pH
below 7 or is not reactive with glass.
Type III glass is suitable principally for
anhydrous liquids or dry substances.

Other examples are:

-Wide mouth ampoules with flat or rounded
bottoms to facilitate filling with dry materials or
suspensions and various modifications of the
cartridge for use with disposable dosage units.
Preparations that are light-sensitive must
be protected by:
1) Placing them in amber glass containers.
2) Enclosing flint glass containers in opaque
cartons and labeled to remain on the
container during the period of use.

 Physical properties to be considered in

selection of particular formulation include

C- D-
B- Permeabi
A-Elasticity Hardenes Tendency
to lity to
s vapor
fragment
.transfer
 A-Elasticity

It is critical in establishing a seal with the lip and

neck of a vial or other opening and in resealing after
withdrawal of a hypodermic needle from a vial
closure.

B-Hardness

It should provide firmness but not excessive

resistance to the insertion of a needle through the
closure.

 C-Tendency to fragment

It should be minimal.

D-Permeability to vapor
transfer

It is controlled by appropriate
selection of ingredients.
 -1
Dust

Contaminan -2
:ts include Lint
-3
Microorgani
sm
 The design and control of an aseptic area is
directed toward reducing the presence of
these contaminants so that they are no
longer a hazard to aseptic
filling.

Although the aseptic area must be adjacent

to support areas so that an efficient flow of
components may be achieved, barriers
must be provided to minimize ingress of
contaminants to the critical aseptic area.
 A- Sealed
.walls

B- Manual or
Automatic
.doors

Such barriers may C- Airlock

pass-
:consist of .throughs

D- Ports of
various
.types

E- Plastic
.curtains
 PROPYLANE GLUCOL IMPROVE
SOLUBILITY
2. Drug solubility:
If the drug is insufficiently soluble in water,
then a co-solvent or a solute that sufficiently
maintains the drug in solution must be added.
3. Drug stability:
If the drug has significant degradation
VI
problems in solution, then a freeze-dried or
other sterile solid dosage form must be
developed. Stability might affect the size and
type of packaging system used. Stability also
dictates the expiration date of the product that
in turn will determine the storage conditions.
 Production
Procedures

-A -F
-B C- -D -E
Cleaning Sterilizati
containe Product Filtration Filling Sealing
preparatio on
rsand
equipme n
nt
C- Filtration:

If the product is a solution so it must

be filtered after it has been
compounded.

The filtration clarifies the solution. A

further step is to remove the
particulate down to 0.2 m in size;
this will eliminate microorganisms
and will accomplish cold sterilization.
C-Filtration

Filtration functions by one or more of the

following:
Sieving or screening.
Entrapment or impaction (when a particle
smaller than the dimensions of the passage
way pore becomes lodged in a turn or
impacted on the surface of the passage way).
Electrostatic attraction (causes particles
opposite in charge to that of the surface of
the filter pore to be held on the surface).
 Membrane filters
These filters are used exclusively for
parenteral products because they are;
Non-shedding

Non-reactive

Disposable

Particle-retention effectiveness
Membrane filters

N.B. Non reactivity does not apply in all cases where

polypeptide products may be adsorbed through
some membrane filters. So we use polysulfone and
polyvinyl difluoride (PVDF) which are non-adsorptive
for these products.
The most common membrane filters are composed
of cellulose esters, nylon, polysulfone,
polycarbonate, PVDF or Teflon.
There are reusable membrane filters made of
sintered glass or sintered stainless steel or sintered
metal.
Each filter should be tested for integrity before and
after use.
 V- Sealing

Filled containers should be sealed as

soon as possible to prevent the
contents from being contaminated by
the environment.
 Ampoules

Types of
COMPARE
ampoule
seals

Tip-seals
Pull-seals
(bead-seals)
 Tip-seals (bead-seals)

Made by melting enough glass at the tip

of the neck of an ampoule to form a
bead and close the opening.
It can be done rapidly in a high-
temperature gas-oxygen flame
To produce a uniform bead, the ampoule
neck must be heated evenly on all sides,
such as by burners on opposite sides of
stationary ampoules or by rotating the
ampoule in a single flame.
 Tip-seals (bead-seals)

Excessive heating will cause

expansion of the gases within the
ampoule against the soft bead and
cause a bubble to form.

Insufficient heating will leave an open

capillary through the center of the
bead. An incompletely sealed
ampoule is called a leaker.
 Pull-seals
Made by heating the neck of the
ampoule below the tip, leaving enough
of the tip for grasping with forceps or
other mechanical device after the
glass has been softened.
The ampoule is rotated in the flame
from a single burner.
Pull-sealing is slower but the seals are
more accurate than tip-sealing.
Powder ampoules or other types
 COMPARE
VI- Sterilization

Whenever possible, the parenteral product

should be sterilized after being sealed in its
final container (terminal sterilization).
Since this usually involves a thermal
process (although there is a trend in
applying radiation sterilization to finished
products), due consideration must be given
to the effect of the elevated temperature
on the stability of the product.
 Radiation
Sterilization
This is gaining some momentum as an
alternative terminal sterilization method.
There has been limited understanding of
the molecular changes that may occur in
drug and excipients molecules under
exposure to the high-energy gamma
radiations.
Lower energy beta particles (electron
beam) radiation has seen some success.
The use of radiation for the sterilization of
materials such as plastic medical devices
is well established.
 Dry -heat
Sterilization
May be used for a few dry solids that
are not affected adversely by the high
temperatures and by the relatively long
heating period required.
This is mostly applied to the sterilization
of glassware and metalware.
After sterilization, the equipment will be
sterile, dry, and pyrogens-free (if the
sterilization period is long enough).
 Saturated steam under
pressure(Autoclaving)

It is the most commonly used and the most

effective method for the sterilization of aqueous
liquids or substances that can be penetrated by
steam.
A survival probability of at least is readily
achievable with terminal autoclaving of a thermally
stable product.
Since the temperature employed in an autoclave is
lower than that for dry-heat sterilization, equipment
made of rubber or polypropylene may be sterilized
if the time and temperature are controlled carefully.
 Saturated steam under
pressure(Autoclaving)

For some products, such as dextrose

injection, a shortened cycle using an
autoclave designed to permit a rapid
temperature rise and rapid cooling with
water spray or other cooling methods will
make it possible to use this method.

It is ineffective in anhydrous conditions, such

as within a sealed ampoule containing a dry
solid or an anhydrous oil.
 Saturated steam under
pressure(Autoclaving)

Other products that will not withstand autoclaving

temperatures may withstand marginal thermal methods
such as tyndallization or pasteurization, e.g. 10 to 12
hours at 60C.

These methods maybe rendered more effective for some

injections by the inclusion of a bacteriostatic agent in
the product.

Articles to be sterilized must be probably wrapped or

placed in suitable containers as bags or sheets made of
steam-penetrating paper or polymeric materials.
 Freeze-drying (Lyophilization)
Many parenteral drugs, particularly
biopharmaceuticals, are too unstable in
solution, so such drugs should be subjected
to freeze drying.

Mechanism of freeze-drying
The unstable drugs in solution are placed in
a chamber where the combined effects of
freezing and drying under low pressure will
remove the solvent and residual moisture
from the solute components, resulting in a
dry powder that has sufficient long-term
stability.
 Stages of freeze-drying:
Freezing stage

Primary drying stage

Secondary drying stage

Advantages of freeze-drying:
Product is stored in dry state (few stability
problems)

Product is dried without elevated temperature

Good for oxygen and/or air-sensitive drugs

Rapid reconstitution time.

Constituents of the dried material remain

homogenously dispersed.
 Advantages of freeze-drying:

Sterility of the product can be achieved and

maintained.

Used now for the research in the

preservation of human tissues.

Used in food industry.

Used in recombinant DNA technology.

Proteins and peptides must be freeze dried.
 Disadvantages of freeze-drying:

Volatile compounds may be removed by high

vacuum.

Single most expensive unit operation.

Stability problems associated with individual

drugs.

Some issues associated with sterilization and

sterility assurance of the dryer chamber and
aseptic loading of vials into the chamber.
 Desired characteristics of freeze-
dried products:
Intact cake
Sufficient strength
Uniform color
Sufficiently dry
Sufficiently porous
Sterile
Free of pyrogens
Free of particulates
Chemically stable
Pyrogen testing

a)Rabbit method
In vivo test where three healthy rabbits with
temperature not more than 39.8C are injected
by the test solution in the ear vein, if the
temperature of the three rabbits is raised so
pyrogens present.

b)Limulus Amebocyte Lysate LAL or

Bacterial Endotoxins Test BET test

It is more sophisticated and rapid method

 Particulate Evaluation

/Container
Light
Microscopi closure Safety
obscuratio
c test integrity test
n test
test