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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5724_Библиотеки_им_академика_М_И_Перельмана.pdf
245
Dosage Forms
discourage addition of medicaments to bottles of infusion
fluids and suggest some suitable means of administering
additional intravenous drugs.
Irrigation and Dialysis Solutions
Irrigation and dialysis solutions are quite similar to parenteral
solutions as they are subjected to same standards. The
difference is in their use. These solutions are not injected into
the vein but are used outside the circulatory system. Since
these types of solutions are generally used in large volumes so
they are packed in large volume plastic containers.
Irrigation solutions are used tor bathing or washing the
wounds. surgical incisions or body tissues. A large number
of official and patent irrigation solutions are available in the
market. Some of them include Ringer’s irrigation USP, sodium
chloride irrigation USP, sterile water for irrigation USP.
Dialysis Solutions
Dialysis may be defined as the process by which the substances
are separated from one another due to their difference in
diffusibility through membranes. The solutions used in dia-
lysis are known as dialysis solutions. In cases of poisoning
or kidney failure or in cases where kidney transplantation is
to be done, dialysis is an emergency life-saving procedure.
In the case of renal failure, the removal of waste products
and the maintenance of electrolyte balance is done either by
haemodialysis or intraperitoneal dialysis.
Haemodialysis
Haemodialysis is used to remove toxins from the blood.
In this method blood from a convenient artery is shunted
through a polyethylene catheter through an artificial dialyzing
membrane bathed in dialyzing fluid. The dialyzing membrane
is permeable to urea, electrolytes and dextrose but not to
plasma proteins and lipids. Substances such as urea which are
in excess in the blood pass out in the fluid. After the dialysis
Introduction to Pharmaceutics
246
the blood is freed from air bubbles and clots and is returned
back to the body circulation through a suitable vein.
The fluids used in the artificial kidney are called haemo-
dialysis solutions. Large quantities of such solutions are used
daily in kidney units of the hospitals and it is not possible
to handle such a large volumes. This problem is solved by
preparing 35 × or 40 × strong solutions which are diluted
afterwards.
Labelling: The concentrated haemodialysis solutions must be
labelled with:
The name of the solution, e.g., concentrated haemodialysis
solution (35 × or 40 × as the case may be).
The strength of each ingredient.
The batch number.
Instructions regarding its dilution.
Storage conditions.
Intraperitoneal Dialysis
In this technique the peritoneal cavity is irrigated with the
dialysis solution and the peritonium acts as the semipermeable
membrane thereby the toxic substances normally excreted by
the kidney are removed. A number of dialysis solutions are
commercially available which contain dextrose, vitamins,
minerals, electrolytes and amino acids. The solutions are
made hypertonic to plasma to avoid absorption of water from
the dialysis solution into the circulation. The intraperitoneal
dialysis solutions must be sterile and should be free from
pyrogens. These solutions are similar in composition to
haemodialysis solutions except in the following respects:
Because these solutions are ready for use so they are in very
dilute form.
They always contain calcium and magnesium ions.
They do not contain any potassium ions if the need arises
then potassium chloride is administered separately.
In these solutions anhydrous dextrose is used whereas in
haemodialysis solutions dextrose (monohydrate) is used
because such solutions are not injected.
In these solutions the solvent used is water for injection.
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Dosage Forms
Labelling
The name of the solution, e.g., peritoneal dialysis solution.
The strength of each ingredient.
The batch number.
The volume in the container.
The instructions that the solution is not for intravenous use.
An instruction to discard the unused part of the solution.
Evaluation of Parenteral Preparations
In the preparation of parenteral products strict quality control
tests must be carried out throughout the entire process of
preparation of a parenteral product to give assurance that the
final product meets the required standards. Raw materials
must be subjected to quality and pyrogen tests. Various tests,
readings and observations must be made during the process
to assure that the specifications are being met. Various tests
and assays should be performed on the finished preparation
to ensure that it meets the required specifications. In addition
to the usual chemical and biological tests the following tests
should be carried out on the parenteral preparations for their
standardization.
Sterility test
Pyrogen test
Clarity test
Leaker test
Sterility Test
Since all parenteral preparations are required to be sterile, they
should be tested for sterility and must comply with the official
test for sterility described in USP. These tests are performed
on all lots of injections in their final containers. The samples
may be taken at random to represent the entire lot of the
preparation. Hence the word ‘Lot’ for sterility testing means
that group of product containers which has been subjected to
same sterilization procedures.
According to USP there are two basic methods for sterility
testing: (a) Direct inoculation of test samples on culture media;
(b) Filtration technique.
Introduction to Pharmaceutics
248
In the direct inoculation method an aliquot quantity of the
material under test is transferred to culture tubes containing
a measured volume of a suitable culture medium like fluid
Thioglycolate Medium or Thioglycolate Broth Medium. This
whole operation, i.e., opening the containers, taking aliquot
quantity of the material under test and transferring it to the
culture medium contained in the tubes must be carried out
under aseptic conditions and every precaution must be taken
to prevent the accidental entry of micro-organisms into the
test. These tubes are plugged with sterilized cotton wool
and incubated for seven days at a temperature of 30 to 35°C.
Positive and negative control tubes containing the culture
media must be incubated under same conditions to confirm
sterility and growth promoting properties of the medium. The
material under test is considered sterile if there is no growth
of micro-organisms in the tubes but if there is any turbidity
or growth then the test must be repeated 2nd time with fresh
sample of material and culture medium because in the first
test the bacterial growth may be due to accidental entry of
micro-organisms. If the 2nd test also shows the growth it may
be repeated 3rd time very carefully and if this time also growth
appears then the material fails to pass the sterility test.
If the product has antimicrobial properties they must
be neutralized or eliminated by dilution. For solids or oily
materials which make the culture medium turbid and make it
difficult to conclude whether the turbidity is due to microbial
growth or due to material itself, the normal test may have
to be modified by subculturing the medium. If turbidity
in subculture does not appear the material is sterile but if
turbidity appears it is due to microbial growth which shows
that the material is not sterile.
Pyrogen Testing
Pyrogens: Pyrogens are the metabolic products of micro-
organisms and are produced by all micro-organisms, i.e., gram-
negative, gram-positive and fungi, but gram-negative bacteria
generally produce most potent pyrogenic substances. They are
soluble, filterable, thermostable and non-volatile substances.
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Chemically they are lipid in nature, sometimes containing
phosphorus and are usually attached to polysaccharide or an
amino acid carrier.
When introduced in human beings they cause febrile
reactions which include chills and fever with headache and
pain in the back and legs. Pyrogens are rarely fatal but they
produce significant discomfort to the patient.
The major source of pyrogens in parenteral preparations is
the water used for the preparation of injections which can be
rendered free from pyrogens by proper distillation of water
and storing the water under suitable conditions which does
not allow the bacterial contamination to take place. Other
solvents and chemicals used in the preparation are another
source of pyrogens. Antibiotics produced by fermentation
process generally contain pyrogens which must be effectively
removed from pharmaceutical preparations containing these
antibiotics. Containers and equipment used in the process
may be another source of pyrogens which can be washed
thoroughly with apyrogenic water to reduce the pyrogenic
contents. They can be sterilized by keeping in hot air oven
at a temperature of 175°C for 3 to 4 hours. Pyrogens can be
destroyed by heating in an autoclave in the presence of an acid,
alkali or oxidising agent. They can be removed by adsorbing
on some adsorbing agent like activated charcoal, asbestos pads
or aluminium hydroxide gel but this method is not suitable for
pharmaceutical preparations because some of the drugs may
also be adsorbed with the pyrogens. It is better to prevent the
introduction of pyrogens than an attempt to remove them.
Pyrogen Test
Pyrogen tests are performed on all aqueous parenteral pre-
parations. In this test rabbits are used as test animals because
they show similar physiological response to pyrogenic sub-
stances like that of man but the rabbits are very sensitive to
external stimuli, therefore, they must be handled very carefully.
Only the healthy and mature rabbits should be used (Fig. 5.22).
The test is made by introducing a suitable quantity of
the sample to be tested into the ear vein of the rabbit. Rectal
Introduction to Pharmaceutics
250
temperature is noted at 1, 2 and 3 hours after the introduction
of the injection. If there is any rise in temperature of 0.6°°or
more above the normal temperature which has been taken
before giving the injection. then the test is considered positive
and the preparation contains pyrogens but if the rabbits do not
show any rise in temperature then the product is considered
free from pyrogens. Generally 5–8 rabbits are used for this test
and average is calculated. Nowadays number of specialized
equipments are available for performing the pyrogen test.
LAL Test
The Limulus amebocyte lysate (LAL) test is a method used
to detect bacterial endotoxins, primarily lipopolysaccharides
(LPS), which are potent pyrogens. Pyrogens are substances
that can induce fever when introduced into the body.
In short, the LAL test involves collecting a sample, often from
pharmaceutical products like injectable drugs, and exposing
it to a reagent derived from the blood cells of the horseshoe
Fig. 5.22: Pyrogen testing.
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crab Limulus polyphemus. If endotoxins are present, they will
trigger a reaction in the LAL reagent, typically resulting in
clot formation or a color change. By measuring this reaction,
scientists can determine the presence and concentration of
endotoxins in the sample.
The LAL test is highly sensitive and widely used in the
pharmaceutical and medical device industries to ensure
the safety of products intended for human use, as even
small amounts of endotoxins can cause severe reactions in
patients.
Clarity Test
The presence of particulate matter in parenteral preparations
particularly those which are given intravenously are of serious
concern. The particles larger than the size of red blood cells
are dangerous, they may block the blood vessels with serious
results. Therefore, it is very necessary to check the final
packages for clarity.
During the preparation of injections the particulate matter
may enter from the environment including shedding from the
body and clothes of persons, ceilings, walls and furniture of
the room from glass and rubber apparatus, the vehicles and the
materials used. The particulate matter may also be introduced
during administration if the infusion sets or syringes and
needles are not properly cleaned and stored.
For checking the clarity of single dose or multidose packag-
ings the unlabelled containers are held by the neck against
strongly illuminated screen of which white surface is used
for dark coloured particles and black surface for the detection
of light coloured particles. The contents of the containers are
slowly inverted and rotated and the solution examined for the
presence of turbidity, dust or any other foreign particles. If any
particulate matter is visible, the package is rejected. Certain
instrumental methods have been developed and are widely
used in the industries.
As per I.P. 96 permitted limit of maximum no. of particulate
matter particles for the product is as follows:
a. Particle size of 10 μ or larger: 50 particle/ml
Introduction to Pharmaceutics
252
b. Particle size of 25 μ or larger: 5 particles/ml
c. Particle size of 50 μ or larger: Nil
Leaker Test
All the ampoules which have been sealed by fusion must be
subjected to leaker test to check that there should not be any
passage for leaking of the contents from the containers. This
test is performed by dipping the ampoules in a deeply coloured
dye solution for which 1% solution of methylene blue is used.
The whole process is carried out in a vacuum chamber under
negative pressure. When the vacuum is released the coloured
solution will enter the ampoules with defective scaling. After
careful washing of ampoules from outside, the dye can be seen
in the leaker ampoules.
This test is not performed on vials and bottles because of
flexibility of rubber, moreover the dye will badly stain the
rubber stoppers.
Packaging of Parenteral Product
The packaging of parenteral preparations is an extremely
important part of the product. The package must be neat
and attractive in appearance so as to convey to the user the
quality, purity and reliability of the product. The label on
the package should be neat and clean and must provide the
necessary information regarding identity, strength and for its
use. Furthermore, the package should protect the product from
physical damage during transport, handling and storage. The
light-sensitive products should be protected from ultraviolet rays.
Containers including closures for injectables must not
interact physically or chemically with the preparation so
as to alter its strength or effectiveness. The glass used for
the preparation of containers must be of very high quality,
clear, colourless or of a light amber colour so as to permit
the inspection of its contents. Products sensitive to alkalies
should be packed in neutral glass or in such glass containers
which have passed the limit tests for alkalinity. Injections are
generally packed either in single dose containers or in multi-
dose containers.
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Dosage Forms
Single-dose Container
A single dose container is a hermetically sealed container
which contains only one dose of the sterile drug. When such
container is once opened it cannot be re-sealed with assurance
that sterility has been maintained. Commonly single dose
injections are known as ampoules which are sealed by fusion
of glass of the container under aseptic conditions.
Multi-dose Container
A multi-dose container contains a number of doses and are
scaled in such a way that the rubber closures allow the
withdrawal of doses by puncture with hypodermic needles,
thus successive portions of the contents can be withdrawn
without changing the strength, quality or purity of the
remaining portion.
The closures used in multi-dose containers create many
problems which must be taken care of before selecting the
closure. The main problems are absorption of materials from
the products and shedding of undesirable soluble or insoluble
components to the preparation. Sometimes the closures react
with the products.
Plastic containers are not very commonly used for
packaging the injections. However, the use of plastic containers
is increasing day by day for packaging infusion and dialysing
fluids and for blood. These types of containers have advantages
over glass containers that they are unbreakable, light and
disposable, occupy less storage space and easy to handle.
EYE DROPS AND EYE OINTMENTS
These are the products which are to be instilled into the eye in
the space between the eyelids and the eyeballs. They may also
be injected into various regions of the eye. Though they are
not parenterals by definition but have many similar and often
identical characteristics.
Ophthalmic preparations must be sterile and are prepared
under the same conditions and by the same methods as other
Introduction to Pharmaceutics
254
parenteral preparations. Solutions used during surgery must
be sterile and should not contain any preservative. They
should be supplied in single-use containers and any solution
remaining at the end of the operation must be discarded.
Since the capacity of the eye to retain liquid and ointment
preparations is limited so they are generally administered in
small volumes.
Types of Ophthalmic Products
Various ophthalmic products include:
Eye drops
Eye ointments
Eye Drops
Eye drops are sterile aqueous or oily solutions or suspensions
for instillation into the eye. They are usually applied into the
space between the eyeball and eyelids or onto the corneal
surface. The main requirement of eye drops is that they should
be sterile, usually isotonic, buffered and free from foreign
particles to avoid irritation to the eye. They usually contain
substances having antiseptic, anaesthetic, anti-inflammatory,
mydriatic or miotic properties of substances used for diagnostic
purposes.
Most of the eye drops contain aqueous vehicles rather than
oily vehicles. Aqueous eye drops may support bactenal and
fungal growth therefore these must be preserved by adding
a suitable preservative for which purpose phenylmercuric
nitrate or acetate 0.002%, benzalkonium chloride 0.01% and
chlorhexidine acetate 0.01% may be used. Phenylmercuric
nitrate should not be used in eye drops which are intended
for prolonged treatment and benzalkonium chloride is
not suitable as preservative for eye drops containing local
anaesthetics.
The eye drops must be protected from contamination
during use and must be used within two weeks after first
opening of the container. Due to this reason eye drops should
be prescribed in small amount, i.e., 5 to 10 ml for a limited