Containers and closure system of parenterals

UNIVERSITY INSTITUE OF PHARMACEUTICAL
SCIENCES, PANJAB UNIVERSITY,CHANDIGARH

 Containers
 Glass containers
 Plastic containers
 Closures
 Natural rubber
 Synthetic rubber
 Types of injection containers
 Single dose small volume
 Single dose large volume
 Multiple dose
 Single dose v. multi dose
 Quality control
 References

1. No interaction between the contents and container.
2. Should withstand high temperatures especially during sterilisation.
3. Should protect the contents from harmful light radiations.
4. Must be suitable for repeated use and easy to clean.
5. Should be transparent and colourless.

Lime Soda
Glass
Borosilicate
Glass
Neutral
Glass
Neutral
Tubing for
Ampoules
Lead
Free
Glass
Sulphured
Containers
Silicon
Treated
Containers
Thermoplastic Thermosetting
 Polyethylene
 HDP
 PVC
 PMMA
 Polystyrene
 PTFE
 Polypropylene
 Polyamide
 Polycarbonate
 Phenol-
formaldehyde
 Urea-
formaldehyde
 Melamine-
formaldehyde

General classification for glass containers

Type I glass
containers
Are made of borosilicate glass.
High hydrolytic resistance.
Suitable for most preparation whether or not for
parenteral use.
Type II glass
containers
Made of soda lime silica glass.
High hydrolytic resistance resulting from
suitable treatment of the surface.
Suitable for most acidic and neutral aqueous
preparations whether or not for parenteral use.
Type III glass
containers
Usually made of soda lime silica glass.
Moderate hydrolytic resistance.
Generally suitable for non-aqueous preparations
for parenteral use.

LIME SODA GLASS: “Ordinary Glass”
Contains 75% SiO2, 15% Na2O and 10% CaO with less than 1% of K2O, MgO and Al2O3.
Aluminium oxide improves mechanical strength and chemical durability while
magnesium oxide reduces temperature required in manufacturing.
ADVANTAGES DISADVANTAGES
1. Yields an appreciable quantity
of alkali to water.
2. Flakes separates easily.
3. Surface loses brilliance on
repeated use.
4. High expansion coefficient
makes it liable to fracture with
sudden temperature change.
1. Can be manufactured at a
convenient temperature.
2. Easy to process.
3. Inexpensive.
4. Sufficiently resistant to water
action.

BOROSILICATE GLASS
 The defects of lime soda glass can be largely overcome by decreasing the
proportion of alkali and including boric oxide.
 This improves heat resistance and confers great chemical durability.
 It is used for chemical glassware and containers for alkali sensitive preparations.
 They are now largely replaced by neutral glasses in manufacture of parenteral
containers as they are expensive and difficult to melt and mould.
NEUTRAL GLASS
 It is composed of 72-75% SiO2, 7-10% B2O3, 4-6% Al2O3, 6-8% Na2O, 0.5-2% K2O
and 2-4% BaO.
 This grade of glass lies between lime soda and borosilicate glass.
 They are softer and more easily manipulated than borosilicate but have more
resistance to autoclaving and solutions of pH up to about 8.
 Large transfusion bottles are more convenient to be produced from neutral glass to
make them cost effective.

NEUTRAL TUBING FOR AMPOULES
 Its composition differs because after filling, ampoules are sealed by fusion and
therefore the glass must be easy to melt.
 Consequently, the amounts of alkaline and aluminium oxides are slightly increased
and the content of boric oxide and silica slightly reduced.
 It is satisfactory for the storage of alkali sensitive injections despite these
modifications.
 They have good thermal resistance because of their small capacities and thin walls.
LEAD-FREE GLASS
 Since lead is a cumulative poison, these are desirable for pharmaceutical preparations,
particularly for liquids.
 Classical example is of the sequestering agents like sodium calciumedetate (for lead
poisoning) and trisodium edetate (for hypercalcemia) injections which would have
taken up lead ions from the glass (if not lead free) that is unacceptable in the
parenterals’ formulation. Hence lead free glass is must in these cases.

SULPHURED CONTAINERS
 Surface treatment is the approach for obtaining cheaper containers, particularly for
large volume injections.
 By a process known as “sulphuring”, lime soda glass can be given a neutral surface
through which extraction of alkali ions is very small. The containers are exposed to
moist SO2 at above 500oC when it neutralises the surface alkali to produce sodium
sulphate layer which can be removed by washing to expose a tough silica rich
surface.
 These are used for storing of blood, plasma and infusion fluids.
 It has been used for dry salt penicillin vials because very little alkali will be extracted
during its short storage life.

SILICONE TREATED CONTAINERS
 They are polymers composed of long chains of alternating oxygen and silicon atoms
with organic groups attached to the latter.
 They have good heat and oxidation resistance, chemical inertness and freedom from
colour, odour and toxicity. In addition, organic groups provide water repellent
property.
 The degree of polymerisation and cross- linking between the chains depends upon
the organic groups.
ADAVANTAGES DISADVANTAGES
 Not wetted by aqueous
solution or suspensions, so
not cling to sides.
 With suspensions, the quick
drainage following shaking
makes it easy to see the
position of the needle in the
vial, and the remaining
volume.
 Foaming is reduced.
 Extraction is not entirely
prevented.
 Film gradually comes away
after frequent autoclaving.
 Very little protection
against flaking.
 Unpleasant greasy
appearance.
 Difficult for normal labels
to adhere.

THERMOPLASTIC THERMOSETTING
 On heating, these soften to a
viscous fluid which hardens
again on cooling.
 Hardness depends on degree
of cross linkage or
intermolecular attraction.
 They include:
 Polyethylene
 HDP
 PVC
 PMMA
 Polystyrene
 PTFE
 Polypropylene
 Polyamide
 Polycarbonate
 When heated, these may
become flexible but they do
not become fluid.
 They are usually hard and
brittle at room temperature
because of high degree of
cross-linking.
 They include:
 Phenol- formaldehyde
 Urea- formaldehyde
 Melamine- formaldehyde

POLYETHYLENE
 Flexible, very light but tough plastic.
 Impermeable to water vapour but relatively high permeability to gases.
 Lack of transparency and non- adherence of labels.
 Sterilisation is difficult because of melting point range of 110- 115oC.(soften up at
90oC)
HIGH DENSITY POLYTHENE
 More rigid, handling and filling of containers is easier.
 Permeability to gases is low and resistance to oil is high.
 Can be sterilised by autoclaving because of higher melting point.
 Used for disposable syringes, packaging of infusion fluids, etc.
POLYTETRAFLUOROETHYLENE (PTFE)
 Translucent or opaque material.
 Possess excellent heat resistance.

POLYVINYL CHLORIDE (PVC)
 Less flexible, heavier and more permeable to water vapour.
 Has high clarity, practically unaffected by sunlight and unplasticised material is
non- toxic.
 Less permeable to gases than polythene.
 Surface can be painted readily and plasticised grades with good oil resistance are
obtained.
 Generally used for manufacturing eye ointment tubes.
POLYMETHYL METHACRYLATE (PMMA)
 Hard, strong but light, glass clear material that retains its clarity on exposure.
 Used for aseptic screens, etc.
POLYPROPYLENE
 Similar to HDP but is lighter, much less opaque and has greater heat resistance.
 Better gloss and superior barrier properties.
 Used for disposable syringes, tubings, etc.

POLYSTYRENE
 Hard, rigid, light material that is cheap and easy to mould.
 Odourless and tasteless.
 Excellent dimensional stability that permits manufacture of components to fine
limits of accuracy.
 It is least suitable for sterile products because of its moisture vapour permeability.
POLYAMIDES
 Produces a stronger container that is very resilient.
 It is not transparent and water vapour permeability is relatively high but has good
resistance to vegetable oils and many solvents.
 Used for manufacturing syringes, tubing, clot filters, etc.
POLYCARBONATES
 Excellent dimensional stability and is transparent.
 High impact strength and very good heat resistance; low water absorption.

PHENOL-FORMALDEHYDE
 They are dark and discolour easily.
 Good heat and moisture resistance allows sterilisation by autoclaving.
 Chosen for outer cap of injection bottle.
UREA-FORMALDEHYDE
 Generally used for closures.
 Less heat and moisture resistant.
MELAMINE-FORMALDEHYDE
 This has the advantage of both of the previous types.
 It is popular as bench surface in sterile product units rather than as a material for
production of parenteral container.

Rubber consists of long chain polymers of isoprene units linked together in the cis
position. The chief disadvantages of raw rubber are:
Poor elasticity.
Poor strength.
Hardens when cold and becomes soft and sticky when warm.
Dissolves in many solvents.
To give better physical and chemical properties, we add:
Vulcanising agent- sulphur which forms cross links between the long rubber
molecules thus improving its strength and reducing its susceptibility to temperature
changes.
Accelerators- reduces the time and amount of sulphur required, e.g. thiazoles.
Activators- increase the activity of accelerators, e.g. stearic acid.
Fillers- they are of two types:
 Reinforcing fillers: improves physical property, e.g. carbon black which increases
tensile strength.
 Extending fillers: added mainly as diluents to reduce cost and partly to facilitate

Softeners- facilitate the incorporation of fillers, make the compound
easier and cheaper to manipulate, and influence the hardness of finished
product, e.g. mineral oil.
Anti-oxidants- prevents oxidation of rubber, e.g. aromatic amines and
phenols.
Pigments- originally mineral pigments such as oxides of iron and
sulphides of cadmium and antimony were used but these are being
displaced by coal tar dyes.
Special ingredients- examples include:
• Paraffin wax: migrates to the surface and produces a protective barrier
to oxygen attack and water absorption.
• Rosin: increases tackiness.
Lubricants- assists the removal of closures from their moulds after
preparation, e.g. zinc stearate, talc.

Synthetic rubbers are superior to natural rubbers in one or more respects
but inferior in others. In general they are:
 More resistant to high and less resistant to low temperatures.
 More resistant to the agents that accelerate ageing (light, oxidation and
its catalyst, copper and manganese).
 More difficult to process.
 More expensive.
The method of compounding differs in two major respects:
Because synthetic rubber are harder, more softening is required and
thus, esters are used to facilitate this and improve the resilience of the
final article.
Because they are more inert, higher concentrations of accelerators and
longer vulcanisation times are needed.

SYNTHETIC RUBBER
BUTYL RUBBER
1. Co-polymers of
isobutylene with 1-3%
of isoprene or
butadiene.
2. Resistant to aging and
chemical attack.
3. Air and water vapour
permeability is very
low.
4. Relatively cheap.
NITRILE RUBBERS
1. Butadiene-
acrylonitrile co-
polymers.
2. Oil and heat
resistant.
3. Absorption of
bactericide and
leaching of extractives
are considerable.
CHLOROPRENE
RUBBERS
1. Polymers of 1:4
chloroprene.
2. More polar and
resistant to oils.
3. Less easily attacked
by oxygen.
4. Heat stability is good.
SILICONE RUBBERS
1. Made by
polymerisation of
methyl silicon fluids
using an inorganic
halide as a catalyst and
then vulcanisation with
an organic peroxide.
2. Exceptional heat
resistance and poor
tensile strength.
3. Very expensive.

SINGLE DOSE INJECTIONS OF SMALL VOLUMES
Each dose is in a separate container from which it is given to the patient with a syringe. Usual
volumes are from 0.5-10mL. They may be packed in ampoules, cartridges or injection units.
AMPOULES
• Most common
• Made entirely of glass in a size
range of 0.5-50mL.
• Glass may be neutral or lime soda
but former is preferred.
• Can be used only once and
consequently need not be very
strong.
• Their walls can be thin with the
advantages of lightness, greater
thermal resistance and more rapid
heat conduction to the contents
during sterilisation.
• After filling, ampoules are sealed
by fusion of glass, so there is no
cartridges
• Cylindrical glass tubes with a
capacity of slightly more than 1mL.
• They are closed at one end with a
rubber stopper and the other end by
a rubber plunger.
• Compared with ampoules, they are
quicker and easier to use. They are
safer as accidental contact with
potent drug preparations in the
injection is minimised as well as
there is no possibility of injecting
glass spicules.
• More suitable for suspensions.
• Syringe is unbreakable and only the
needle mount need to be sterilised
Injectionunits
• Disposable injection units combining container
and syringe which eliminates the need to
transport sterile syringes or facilities for
sterilisation.
• Early development was a soft metal tube with a
needle attached. It has two major disadvantages
viz-a-viz contents are invisible and it is
necessary to guard against the solution
corroding the container as well as container
affecting the solution.
• Automatic injector was developed which is
packed in a neutral glass ampoule containing an
inert gas under pressure. Advantage is that the
user has nothing to sterilise or assemble,
therefore time saved and safety are even greater.
• Plastic syringes consists of the injection in small

SINGLE DOSE INJECTIONS OF LARGE VOLUME
Infusion fluids usually given IV, are slowly dripped into the patient’s body and 3-4L may be given in
24 hours. Containers must be large and strong enough to withstand frequent cleaning, sterilisation,
transport and handling. Bactericides are not permitted in large volume intravenous injections,
therefore infusion fluids must always be regarded as single dose injections. These may be classified as:
 British standard transfusion bottle:
• It is often called a blood bottle because it is used for giving and taking blood.
• It is most popular for IV fluids.
• The graduated capacity is 540mL, volume being the sum of anticoagulants(120mL) and blood
when the bottle is used for taking blood(added 500mL, normally).
• There are two scales moulded on the outside, one reading from the base when the bottle is
upright and the other from neck when the bottle is inverted.
 Other containers:
• There are alternatives to blood bottles which includes the use of plastic containers.
• Another is the use of large container that can be fitted to the normal giving sets, discussed later.

It is used for transferring IV injections
from the bottle to the patients. Disposable
giving sets consists of a piece of tubing
about 1.5m long with a needle at one end
for insertion into vein and a means of
piercing the bottle closure at the other.
Near to the bottle is a drip chamber from
which speed of administration can be
estimated. The unit must have a filter to
prevent the transfusion of clots from blood.
These have replaced the non-disposable
types.
These are being increasingly used for
infusion and dialysing fluid and for
blood as they are unbreakable, light,
disposable and occupy less storage
space. However, they have some
disadvantages like labels printed on
the plastic are more difficult to read,
less transparent than glass and can be
punctured by the needles of giving
sets. Commonly used plastics are PVC,
polythene and polypropylene.
DISPOSABLE PLASTIC/GLASS SYRINGES:
They are not a type of single dose large volume injections but are
commonly used for injecting, withdrawing or instilling fluids. It
consists of a glass or plastic barrel with a tight fitting plunger at
one end and a small opening at the other end which
accommodates the head of a needle. Needle gauge is the outside
diameter of needle shaft.

MULTIPLE DOSE INJECTIONS
With this it is more difficult to comply with the official requirement that an injection must be
dispensed in a container sealed to exclude microorganisms. Hence there have been various
improvements in its design.
RUBBERCAPPEDVIAL
• Earlier they consist of glass bottles(5-
30mL) with a fairly wide mouth
covered by rubber cap wired tightly.
• Its disadvantages include: (a) the cap
was constantly exposed to dust, light
and air, (b) difficulty to sterilise finally
packed injection due to ballooning and
further bursting on cap during
sterilisation as the contents expand on
heating.
• Several methods were developed to
overcome this difficulty.
CLINBRITICBOTTLE
• A bottle of neutral glass either clear or
amber and in 4 sizes (10,25,50,100mL).
• An inner rubber cap consisting of thick
walled plug with a thin central diaphragm
and a comparatively thin walled skirt
above.
• Has an outer bakelite screw cap which
protects the surface of the cap from dust
and hold it securely.
• The disadvantage of closure is that it is
easily removable without being able to
detect this. (MARK I).
• A new pattern in which skirted cap is
replaced by a plug of antibiotic vial type is
ANTIBIOTICVIAL
• It consists of a small glass vial (few mm
capacity), a small rubber plug with a
short hollow shank and a larger flat top,
and is sealed by aluminium sealing ring
with a small hole at the centre of plug for
needle penetration.
• This type of seal serves the advantages
like, (a) not easily damaged, (b) difficult
removal which cannot be achieved
without tearing the ring, (c) cannot be
replaced.

On the whole, multiple dose containers are more
popular than ampoules with the medical and nursing
professions. Possible reasons are:
1. More convenient when the dose has to be varied.
2. Ampoules are more difficult to manipulate and
require a greater degree of aseptic techniques.
The official sources should discourage the use of multi dose
containers unless the number of dosed is small and the contents are
used quickly, the reason being:
1. The contents may become contaminated each time the container is
used and, although a bactericide must be present it would be rash to
assume that it will control every possible contaminant.
2. Closures are less efficient than fusion of glass at excluding
microorganisms, air and moisture.
3. Rubber is essential for easy penetrability but provides problems
such as extractives and absorption.
4. Wrong dose measurement may occur.
5. Can be more wasteful as they would have to be discarded even
before used completely due to stability or other reasons.
SINGLE DOSE v. MULTI DOSE

Powder glass test
Water attack test
Others

Rinse 6 or more containers and dry them.
Crushed into fragments.
Divide 100g of coarsely crushed glass into 3 equal parts.
Place one portion in a mortar.
Crush further by striking 3 or 4 blows with hammer.
Nest the sieves (#20, 40 at least)
POWDERED GLASS TEST
Preparation of specimen:

Empty the mortar into sieve 20.
Shake the sieves and remove the glass particles from #20 and #40.
Crush them again and sieve them.
Transfer the retained portion on #50.
Spread the specimen on a glazed paper and remove iron particles with the
help of magnet.
Wash with 6 portions of 30mL acetone.
Dry the contents for 20 min. at 140o C.
Transfer to weighing bottle and cool in a desiccator.
Final specimen to be used further in the test.

Powdered glass test: Transfer 10g of prepared specimen in a 250ml conical
flask digested previously with high purity water in a bath at 90oC.
Add to conical flask containing 50mL high purity water.
Cap all the flasks and autoclave.
Adjust temperature to 150oC.
Reduce the temperature to 121oC. for 30 minutes.
Cool the flask under running water.
Wash the residue powder glass (4 times with 15mL purity water).

Add the decanted washings to main portions.
Add 5 drops of methyl red solution.
Titrate immediately with 0.02N sulphuric acid.
Record the volume of 0.02N sulphuric acid.
Volume does not exceed that is indicated in the USP as per the type of glass
concerned.

WATER ATTACK TEST
Rinse 3 or more containers with high purity water.
Fill each container to 90% of its over flow capacity.
Cap all the flasks and autoclave for 60 mins.
Empty all the contents and cool the contents in 250 ml conical flasks to volume
of 100ml.
Add 5 drops of methyl red solution.
Titrate with 0.02N sulphuric acid while warm.

Record the volume of 0.02N sulphuric acid consumed.
Volume should not exceed as indicated in USP as for type of glass.

Leakage test
Water vapour
permeation test
Others

LEAKAGE TEST
Fill 10 plastic containers with water and fit the closure.
Keep them inverted at room temperature for 24 hours.
No sign of leakage should be there from any container.

WATER VAPOUR PERMEATION TEST
Fill 5 containers with nominal volume of water.
Heat seal the bottles with an aluminium foil- polyethylene laminate or other
suitable seal.
Weigh accurately each container and allow to stand for 14 days at a relative
humidity of around 60% and a temperature between 20-25oC.
Reweigh the containers.
The loss in weight in each container is not more than 0.2%.

FEATURES ENSURING QUALITY
 Biological toxicity: The test is performed in vitro by placing the extract in contact with mammalian
cells to check its toxicity. In vivo procedures are performed in mice and rabbits for systemic and
intracutaneous injections respectively.
 Protection: A container intended to provide protection from light must meet the requirement of the
USP light transmission test.
 Compatibility: Container component should not interact with the dosage form and may not show
leaching. Other changes such as pH shift, precipitation and discoloration should be evaluated.

REFERENCES
 Indian Pharmacopoeia; Volume I, 2014, The
Indian Pharmacopoeia Commission,
Ghaziabad, pp. 889-899
 Carter, S.J.(ed.); Cooper and Gunn’s dispensing
for pharmaceutical students, CBS publishers,
12th edition, pp. 357-391
 Jain, N; Anwar, M; Avis, KE (ed.); Sterile
products, In, Lachman/Lieberman’s ‘The theory
and practice of industrial pharmacy’; 4th
edition; CBS Publishers; pp. 842-845

Containers and closure system of parenterals

Containers and closure system of parenterals

More Related Content

What's hot

Similar to Containers and closure system of parenterals

Recently uploaded

Containers and closure system of parenterals