Transcript Lecture 3 hana.ppt

Sterile preparation
formulation
Containers and Closure
Types of Sterile
Container/Closure Systems
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Ampoules
Vials
Bottles
Bags
Syringes
Cartridges
Devices
The container And Container Components
 Container components for parenteral products must be considered an
integral part of the product because they can dramatically effect
product stability, potency, toxicity and safety.
 Parenteral dosage forms, especially solutions, usually require more
evaluation of packaging components as to product compatibility and
stability.
 Common container components in direct contact with the product
include various types of glass, rubber, plastic, and stainless steel
(needles), all of which may react with the drug.
1. GIass:
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Glass is a readily available economical material which is
Relatively inert, thus giving excellent product/pack compatibility,
and provides good
product presentation
(clarity, sparkle, design)
together with good product identification.
 Glass earlier suffered some limitations associated with the production
process and difficulties in finding a satisfactory closure.
 Today blown glass containers can be made at speeds of over 200
per minute with range of neck finishes that are suitable for many
types of closure.
 In spite of their weight and fragility, glass containers can be
handled at high speed on production lines.
The various pharmacopoeia define the types of glass used for packaging
pharmaceutical preparation as follows:
• Type I
Neutral or borosilicate
• Type II Soda glass with a surface treatment
• Type III Soda glass of limited alkalinity
• NP
Soda glass (nonparenteral usage)
 Neutral glass is more expensive and is more difficult to process. It is harder,
more resistant to thermal shock, and durable, hence any likelihood of surface
erosion is considerably reduced.
 Types I, II and III are intended for parenteral preparations and type N.P. for
oral, topical products and other commercial purposes.
 Type I is used for most injections and for water for injection.
 Types I and II may be used for infusion fluids, blood and plasma. Because
these preparations require large volume containers, treated soda lime glass is
allowed as a less costly alternative to boro-silicate.
 Types I and III may be used for most of the oily injections. Type III is
specified for thiopentone sodium.
To avoid the deleterious effect of light, coloured glass containers could be
used. Glass can be coloured as follows:
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Carbon and sulfur or iron and manganese
Compounds of cadmium and sulfur
Cobalt oxide or cupric oxide
Iron oxide , Manganese dioxide , and chromium dioxide
Amber
Yellow
Blue
Green
2- Plastics
"Plastic" is a term used generally to describe a variety of compounds of
high molecular weight that can be molded to shape , hardness , and clarity
.
Some common plastic mateials used in medical devices are listed
below :
1. Polyethylene. Various densities are available (low,
medium,
high). It is relatively inert, opaque material containing no
plasticizer, constituting a common ingredient of plastic syringes
2. Polypropylene. Similar to polyethylene, being relatively inert,
available in many grades, and autoclavable. It is a common
ingredient of plastic syringes.
3. Polyvinyl chloride. Available in a variety of formulation to
produce relatively clear, autoclavable container. When 30% to
40% of a phthalate ester is added to formula, this product can be
flexible, Polyvinyl chloride formulations are used to manufacture
plastic I.V. bags. All l.V. tubing administration sets are polyvinyl
chloride formulations.
4. Polystyrene. An inexpensive, rigid clear type of plastic material;
however, being not very inert, wilt react with paraldehyde and other
materials. It has a low melting temperature and cannot be heat sterilized.
5. Nylon. A stable inert and generally opaque material, can be made and
used where hardness is necessary (e.g.. I. v sets, filters in blood sets).
6. Polymethylmethacrylate (Lucite). A relatively expensive, stable,
hard material used to make needle adaptors on l. v. sets.
7. Polyolefins (polyethylene and polypropylene).
A mixture of two compounds produces a rigid or semi-rigid formulation
containing no plasticizer.
Plastic devices used for parenteral medical practice include:
1. Disposable syringes (polyethylene, polypropylene, polycarbonate)
2. l.V. solution administration sets (polyvinyl chloride (PVC))
3. Plastic 1:V. catheters (Teflon, polypropylene)
4. Blood containers (polyvinyl chloride)
5. l.V. solution containers (polyvinyl chloride)
6. Irrigating solutions (polyolefins, polyethylene, polypropylene)
 A common l.V. administration set may combine a variety of plastic
components tailored to suit a particular need.
 For example, an administration set contains a nylon spike, a Lucite Ysite, a polyvinyl chloride tube, and a polypropylene clamp.
 Plastic components may contain a variety of additives to enhance
the quality desired for their use.
1. Plasticizers to give flexibility to the package.
2. Antioxidants are added to prevent discoloration.
3. Plastic devices are produced with heat and pressure which
may result in the need for stabilizing agents.
4. Fillers may be added to enhance the formulation.
5. Anti static agents are sometimes needed to prevent clinging
of the material.
6. Colorants may be necessary for some devices.
7. Lubricants are added to facilitate removal from the
production molds.
Numerous factors are involved in considering plastic material for
parenteral use;
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vapor transmission, sterilization qualities,
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texture, clarity, weight, aging, ease of production,
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ease of destruction, ultimate method of use,
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inertness, chemical reactivity of plastic material with drug,
binding, leaching and.
Probably most important, biologic safety.
Soft, flexible plastic bags have some advantages over the
traditional glass containers:-
1. The most outstanding feature of this type of container is its ability to
respond to normal outside atmospheric pressure.
2. The possibility of air embolism is significantly reduced in the use of
flexible plastic containers.
3. Flexible containers are non-breakable.
4. Studies have shown that plastic I.V. containers have less particulate
matter than do glass containers.
3. Rubber closures
The basic types of polymers in rubber formulations are saturated and
unsaturated elastomers or a combination of the two. The following
classification lists most of the polymers utilized as parenteral closures:
Unsaturated elastomers
1. Polyisoprene-natural or synthetic.
2. Polybutadiene
3. Styrene butadiene rubber.
4. Nitrile butadiene rubber.
5. Polychloroprene.
Saturated elastomers
1. Copolymer of polyisobutylene and polyisoprene (butyl).
2. Ethylene propylene rubber.
3. Ethylene propylene diene rubber.
4. Silicone rubber.
Rubber components are usually formulated from many ingredients.
In addition to the basic polymer, ingredients used might include:
 Accelerators: Amines, thiol and thiuram compounds, sulfamides,
ureas
 Activators: Stearic acid, Zinc oxide. Zinc stearate. Amines, paraffin
waxes.
 Vulcanizing agents: Sulfur, organic peroxides, phenolic resnis.
 Pigments: Carbon black, chromium oxide, iron oxide
 Plasticizers and lubricants {Processing aids): Paraffin, mineral oils,
fatty oils, organic phosphates, phthalates.
 Reinforcing agents (filters}: Aluminum and calcium silicates.
.titanium dioxide, carbon black, silica, barium sulfate.
 Production variations which may occur during the manufacture of
stoppers can affect the quality and the properties of the stopper.
 In order to maintain batch-to- batch uniformity of particular formulation
the following control tests are necessary:
A. Physical properties:
A number of physical properties of stoppers are important:-
1. Durometer:
This is a measure of the hardness of rubber. In general, a value of 30-35 is a
soft rubber; 35-45, average; and above 45 , hard rubber. Higher durometer
values usually mean increased coring, reduced resealability, and increased
resistance to puncturing. However, a high durometer value is needed for syringe
plunger-heads.
2. Coring:
Coring is a phenomenon in which a small plug or particle of rubber is cut
out of the stopper as the needle is inserted. The rubber type, formulation,
and stopper design (including thickness of target area) will influence the coring
rate.
3. Resealability:
The resealability will vary with rubber stocks. Since the stoppers must
reseal to prevent contamination and leakage it is obviously quite important that
the resealability be evaluated.
4. Puncture resistance:
The pressure required
important
with thin
to insert the needle through the closure is an
physical characteristic. Injections which are normally administered
needles (23-25 gauge)must have lower puncture
resistance
than
those administered with needles having a larger diameter.
5. Compression set:
Some rubber deforms permanently when held under pressure. It is desirable
that closure materials have good recovery after compression to assure good
sealing characteristics with the glass finish.
6. Moisture vapor Transmission (MVT):
MVT
is
an
important
consideration
when
selecting a closure for
hygroscopic powders, lyophilized products, and for products in which an inert
gas is overlaid. MVT is inversely proportional to the thickness of the barrier.
Generally, increasing the filler will decrease MVT.
A number of materials such as lacquer, plastic, or teflon have been applied
to stoppers in an attempt to reduce MVT, to retain an inert gas, or to minimize
sorption and leaching. Although some of these materials are apparently being
used satisfactorily, their main disadvantage is the sloughing of the coating on
aging and With needle penetration.
7. Tackiness:
For ease of handling it is desirable that stoppers should not stick together
or clump during processing and handling. This usually occurs when stoppers are
heated during sterilization.
B. Compatibility with preparation:
Normally if enough tests are run it will be possible.
to find a closure that is compatible with the parenteral product.
The most common compatibility problem which occurs with stoppers:-
(1) the leaching of ingredients from the stopper and the reaction of
these ingredients with the product. For instance, waxes may migrate to
the surface of the stopper, resulting in particulate contamination of the
product.
(2) Another problem is the sorption by the closure of preservatives or other
ingredients in solution.
Due to the large variety of ingredients in most rubber formulations, it is
usually quite difficult to determine which ingredient or ingredients might
be leached into the product, possibly resulting in turbidity, precipitation,
etc.
Methods of evaluation include:
(1) microscopic examination of the particulate contaminant
(2) evaluation of the solution or other extracts
of
the
closure
by
ultraviolet or infrared spectroscopy, thin layer chromatography,
nuclear magnetic
resonance,
gas
chromatography
and
mass
spectroscopy.
(3) Qualitative and quantitative determinations of closure ingredients
from extracts of various stopper formulations,
accelerated
conditions.
storage
conditions,
using
obtained under
various solvents, pH