Containers are in intimate contact with the product. No container presently available is totally non reactive, particularly with aqueous solutions . Both the chemical and physical characteristics are given primary consideration in the selection of a protective container . Glass containers traditionally have been used for sterile products , many of which are closed with rubber stoppers. Interest in plastic containers for parenterals is increasing and such containers are being used for commercial ophthalmic preparations and IV solutions.

1. PRESENTATION ON:
CONTAINERS AND CLOSURES FOR
PARENTERALS
DEPARTMENT OF PHARMACEUTICAL SCIENCES
DR. HARISINGH GOUR VISHWAVIDYALA,
SAGAR, (M.P.)
SUBMITTED BY: SAPNA SINGH RAJPUT
M.PHARMACY, 1ST SEMESTER

2. CONTENTS
 Containers
 Plastic containers
 Glass containers
 Chemical Resistance
 Physical Characteristics
 Container use considerations
 Rubber Closure
 Composition and reactivity
 Physical Characteristics
 Testing
 References

3. CONTAINERS
Containers are in intimate contact with the
product. No container presently available is
totally non reactive, particularly with aqueous
solutions . Both the chemical and physical
characteristics are given primary consideration
in the selection of a protective container . Glass
containers traditionally have been used for
sterile products , many of which are closed
with rubber stoppers. Interest in plastic
containers for parenterals is increasing and such
containers are being used for commercial
ophthalmic preparations and IV solutions.

4. Plastic Containers
 The principal ingredient of the various plastic
materials used for Containers is the thermoplastic
polymer. The basic structural unit for each type
commonly encountered in the medical field is given in
table.
 Although most of the plastic materials used in the
medical field have a relatively low amount of added
ingredients some contain a substantial amount of
plasticizer, fillers, antistatic agents, antioxidants and
other ingredients added for special purposes. These
ingredients are not usually chemically bound in the
formulation and therefore may migrate out of the
plastic and into the product under the conditions of
production and storage .

6. CONTD…
 As the name indicate thermoplastic
polymers melt at elevated temperatures.
All of the polymeric material listed in
table except low density polyethylene
and polystyrene can be autoclaved if they
have been formulated with low amount of
plasticizers, although most of them soften
at autoclaving temperatures and care
must be exercised to avoid fusing
adjacent surfaces or otherwise deforming
them.

7. CONTD…
 Plastic containers are mainly used
because they are light in weight, are non
breakable, and when low in additives,
have low toxicity and low reactivity with
the products. Tissue toxicity can occur
with certain polymers, but additives are a
more common cause. Reactivity due to
sorption has been found to occur most
frequently with the polyamide polymers
but additives leached from any of the
plastic materials may interact with the
ingredients of the product.
 Most polymers are adversely affected by
the elevated temperatures required for
thermal sterilization and have a relatively
high permeability for water vapour.

8. CONTD…
 A relatively new group of plastics, the
polyolefins, deserve special mention. The
two of interest today in the parenteral field
are polypropylene and the copolymer
polyethylene-polypropylene. Polypropylene
is the most widely used. It is a liner polymer
that can be produced to be highly
crystalline. Because of its crystallinity, it has
a high tensile strength, a high melting point
of 165 degree celcious and a relatively low
permeability to gases and water vapours.It is
translucent, abrasion resistant and has a
high surface gloss.

9. CONTD…
 It withstand normal autoclaving temperatures. It
must be stabilized with an antioxidant, however the
type and concentration of which must be carefully
controlled to avoid leaching on one hand and
degradation of the plastic on the other.
 Flexible polyethylene containers are used for
ophthalmic solutions to be administered in drops and
flexible polyvinyl chloride bags for IV solutions. The
latter have particular advantage over glass bottles in
that no air from the patient's bedside need enter the
container as the liquid flows out, the bag simply
collapses.

10. CONTD…
 The new group of polymers, the polyolefins, have
made possible the development of bottles that are
rigid enough to hold their shape during processing
but can collapse under atmospheric pressure as
outflow of the solution occurs during IV
administration to a patient. Thus the characteristics
of a rigid container are utilized during processing and
handling, but the advantages of collapsibility of a
flexible container is achieved for aseptic
administration.
 The USP has provided test procedures for evaluating
the toxicity of plastic materials.

11. CONTD…
 Essentially, the test consist of three
phases (1) implanting small pieces of
plastic material intramuscularly in
rabbits, (2) injecting eluates using sodium
chloride injection, with and without
alcohol, intravenously in mice and
injecting eluates using polyethylene
glycol 400 and seasame oil
intraperitoneally in mice and (3) injecting
all four eluates sucutaneously in rabbits.
The reaction from the test samples must
not be significantly greater than non
reactive control samples.

12. Glass Containers
Glass is still the preferred material for
containers for injectable products. Glass is
composed principally of the silicone dioxide
tetrahedron, modified physiochemically by
such oxides as those of sodium, pottasium,
magnesium, calcium, boron and iron. The
two general type of glass are sodalime and
borosilicate. The glass that is most resistant
chemically is composed almost entirely of
silicon dioxide, but it is relatively brittle
and can only be melted and molded at high
temperatures.

13. CONTD…
 Boric oxide somewhat modified the above
characteristics as it enters the structural
configuration, but most of the other oxides
apparently enter the spaces within the structure
and reduce the strength of intraatomic forces
between the silicon and oxygen. Therefore the
latter oxides lower the melting point of the glass
and are comparatively free to migrate.
Consequently, they also lower the chemical
resistance of the glass, i.e. they May migrate into
a product over a prolonged period of contact,
particularly with aqueous solutions.

14. CONTD…
 In solutions the oxides may hydrolyzed to
raise the pH, catalyze reactions. Glass flakes
are also sometimes produced as a result of
the solution. These interactions are markedly
accelerated during elevated temperature
required for autoclaving.

15. Chemical Resistance
 The USP provided the powdered glass and
water attack test for evaluating chemical
resistance of glass. The test results are
measures of amount of alkaline constituents
leached from the glass by purified water under
controlled elevated temperature conditions ,
the powder glass test are performed on
ground, seized glass particles and the water
attack test is performed on whole containers.

16. CONTD…
 The conditions of the test must be rigidly
controlled to obtain reproducible results
since the quantity of alkaline constituents
leached is small. The water attack test is
used only with containers that have been
exposed to sulfur dioxide fumes under
controlled humidity conditions. Such
treatment neutralize the surface alkaline
oxides thereby rendering the glass more
resistant chemically.

17. CONTD…
 On the basis of results from the official
tests, glass compounds are classified into
four types.

18. Physical Characteristics
 The protection of light sensitive products
from the degradative effect of ultraviolet
rays may be one of the important physical
characteristics of a glass container.
Ultraviolet rays can be completely
filtered out by the use of amber glass
however the colour of amber glass is
produced largely by the presence of iron
oxide, trace of which may subsequently
be leached into the product.

19. CONTD…
 If the product contains ingredients
subject to iron catalyzed chemical
reaction, amber glass cannot be used.
The product must then be protected from
ultraviolet rays by means of an opaque
carton surrounding a Flint (colourless)
glass container. In addition to other
physical characteristics, glass Containers
should have sufficient physical strength to
withstand the high pressure differential
that develop during autoclaving, shipping,
and storage , a low coefficient of thermal
expansion to withstand thermal shock
during washing and sterilization.

20. CONTD…
 Glass Containers may be manufactured by
drawing from glass tubing or by blow
molding. Ampoules, cartridges and vials
drawn from tubing have a thinner, more
uniform wall thickness with less distortion
than containers made by blow molding.
The greater strength of blown vials and
bottles, however, may be essential for
handling by mechanical processing
equipment.

21. CONTD…
 Glass Containers are sometimes coated
internally with silicon fluid to produce a
hydrophobic surface. To achieve
permanency, the silicon must be baked at
a temperature of approximately 150
degree. This additional operation is
justified for such applications as to
reduce the adherence of heavy, costly
suspension or emulsions, or to increase
the slippage of a plunger in syringe
barrel.

22. Container use Considerations
 The size of single dose Containers is
limited to 1000 ml by the USP and
multiple dose Containers to 30 ml, unless
permitted otherwise in a particular
monograph. The size limitation for
multiple dose vials is intended to limit
the number of entries for withdrawing a
portion of the contents of the vial with
the accompanying risk of microbial
contamination of the remaining contents.

23. CONTD…
 The particular advantage of these
containers is flexibility of dosage offered
to the physician. Single dose Containers
are intended to provide sufficient drug for
just one dose, the integrity of the
container being destroyed when opened
so that it cannot be reclosed and used
again. Single dose Containers may range
from liter bottles of IV solutions to 1 ml
or smaller cartridges.

24. Rubber Closures
 Rubber closures are used to seal the
opening of cartridges, vials, and bottles,
providing a material soft and elastic
enough to permit entry and withdrawal of
a hypodermic needle without loss of the
integrity of the sealed container.

25. Composition and Reactivity
Rubber Closures are compounded of several
ingredients, principally, natural rubber
(latex) or synthetic polymers, an vulcanizing
agent usually sulfur, an accelerator such as
2- mercaptobenzothiazole, an activator
usually zinc oxide, fillers such as carbon
black or limestone and other ingredients
such as antioxidants and lubricants. These
ingredients are combined by kneading them
into homogeneous plastic mass on a roller
mill and then vulcanized in the desired
shape by means of mold under high
pressure and temperature.

26. CONTD…
 Ideally, closures should be completely non
reactive with the product with which they
are in contact. No such ideal compound
exist so each rubber compound should be
tested for compatibility with each
preparation with which it is to be used.
Two general compatibility problems exist,
namely the leaching of ingredients from
the rubber compound with subsequent
reaction with ingredients of the product
and the removal of ingredients from the
product by sorption by rubber compound
or by vapour transfer through the closure.

27. Physical Characteristics
 Several properties of rubber closures are
significant, particularly elasticity, hardness and
porosity. Rubber closures must be sufficient elastic
to provide a snug fit between the closure and the
neck and lip of the glass container. They must also
spring back to close the hole made by the needles
immediately after withdrawal. Rubber closures
must not be so hard that they require an excessive
pressure to insert the hypodermic needle and in
doing so, must not produce large number of
fragments as the hollow Needle cut through the
closure (coring).

28. CONTD…
 Although porous, they should not permit
the easy transfer of water vapour and
gases in either direction. Minimal water
vapour transfer is important, for example
to prevent the absorption of water by
freeze dried products. Plastic or lacquer
coatings are sometimes applied to the
surface that will be in a contact with the
product. These coatings sometimes
reduce vapour transfer, sorption and
leaching but they do not usually provide
the complete barrier desired. Teflon
liners provide an effective barrier against
sorption and leaching.

29. Testing
Methods of testing for a lot to lot uniformity
of rubber closures have been studied for
many years, but because of the nature of
rubber compound, consistent test results
have been difficult to obtain. Progress has
been made, however and the LISP now
describe physicochemical and biologic tests
but without test limits.

30. CONTD…
 The physicochemical tests on aqueous
extracts include pH, turbidity (nephelos),
residue on drying, iodine number, and
heavy metals content. The biologic tests
on saline, polyethylene glycol 400 , and
cottonseed oil extracts include acute and
chronic toxicity in mice and rabbits.

31. REFERENCE
 Lachman/ Liberman’s, “ The Theory and Practice
of Industrial Pharmacy”, 4th edition, 2013, (reprint
2015), CBS Publishers and Distributers Pvt Ltd,
New Delhi, India, 839-845.

32. THANK YOU