Containers and Closure

Sterile preparation formulation

• Ampoules• Vials• Bottles• Bags• Syringes• Cartridges• Devices

Types of Sterile Container/Closure Systems

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:

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:

• Carbon and sulfur or iron and manganese Amber• Compounds of cadmium and sulfur Yellow• Cobalt oxide or cupric oxide Blue• Iron oxide , Manganese dioxide , and chromium dioxide 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 .

 

 

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.

Some common plastic mateials used in medical devices are listed

below :

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.

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 Y-

site, a polyvinyl chloride tube, and a polypropylene clamp.

 

Plastic devices used for parenteral medical practice include:

1. Disposable syringes (polyethylene, polypropylene, polycar-

bonate)

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)

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;

vapor transmission, sterilization qualities,

texture, clarity, weight, aging, ease of production,

ease of destruction, ultimate method of use,

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 closuresThe 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 to insert the needle through the closure is an

important physical characteristic. Injections which are normally administered

with thin 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, obtained under

accelerated storage conditions, using various solvents, pH conditions.