World Journal of Pharmaceutical Research
`Praveen
`World Journal of Pharmaceutical Research
` SJIF Impact Factor 5.045
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`Volume 3, Issue 5, 344-368.
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` Review Article
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` ISSN 2277 – 7105
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`A REVIEW ON PHARMACEUTICAL PACKAGING MATERIAL
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`Praveen Nasa*
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`Department of Pharmaceutical Education & Research, Bhagat Phool Singh Mahila
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`Vishwavidyalaya, Bhainswal Kalan (Sonipat), India.
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`Article Received on
`22 May 2014,
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`Revised on 16 June 2014,
`Accepted on 10 July 2014
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`ABSTRACT
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`Pharmaceutical package is an integral part of Pharmaceutical product.
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`An ideal package protects the product from harmful effects of
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`environmental gases, moisture, microbes etc. Primary package is in
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`direct control with the product and secondary package is the package
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`*Correspondence for
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`which surrounds the primary package. Tertiary package is the package
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`Author
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`Praveen Nasa
`
` Department of Pharmaceutical
`
`Education & Research, Bhagat
`
`Phool Singh Mahila
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`used for transportation purpose.Pharmaceutical package provides the
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`hermetic seal which do not contaminate the Pharmaceutical product.
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`Glass, Plastic, Metal and rubber are the important component of
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`container closure system. Various types of glass, plastic, metal
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`Vishwavidyalaya, Bhainswal
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`packaging material are used for construction of containers and
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`Kalan (Sonipat), India..
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`closures. The selection of these material depends upon the products
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`which is to be stored in the container. Closure is also an important part
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`of Pharmaceutical packaging and it is direct contact with the pharmaceutical preparation. So
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`container and closure material should be carefully selected which do not affect the
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`therapeutic efficacy of
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`the products. This review article mainly focused on
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`the
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`Pharmaceutical packaging material properties, their use and their limitations.
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`KEY WORDS: Blister package, Closures, Primary package, Glass, Plastic.
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`What is a Pharmaceutical Package?
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`A Pharmaceutical Package container
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`is an article or device which contains
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`the
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`Pharmaceutical Product and the container may or may not in direct contact with the product.
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`The container which is designed for pharmaceutical purpose must be stable. [1]
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`Ideal Qualities of a Pharmaceutical Package
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`1. It should have sufficient mechanical strength so as to withstand handling, filling, closing
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`and transportation.
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`2. It should not react with the contents stored in it.
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`3. It should be of such shape that can be elegant and also the contents can be easily drawn
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`from it.
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`4. It should not leach alkali in the contents.
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`5. The container should not support mould growth.
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`6. The container must bear the heat when it is to be sterilized.
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`7. The contents of container should not be absorbed by the container.
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`8. The material used for making the container should be neutral or inert.
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`9. Any part of the container or closure should not react with each other.
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`10. Closure should be of non toxic nature and chemically stable with container contents.
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`11. It should provide desired degree of protection from environmental hazards. [2, 3]
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`Function of Package
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`1. Protective Function
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`A good package protects the container from static and dynamic force during transportation
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`and storage. Vibration is mainly responsible for cracking of emulsion which can be inhibited
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`by using good package. It also protects the contents from biological hazards. It protect the
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`container from moisture ,temp, environmental gases, humidity etc. light sensitive material
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`can be protected from light by using primary packing of amber colored bottles.
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`2. Identification Function
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`A packaging provide information regarding product such as date of manufacturing, expiry
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`date, use, batch no., warnings if any etc. It also provide an ease of identify the product for e.g
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`colored flutted bottles are used for packaging external preparation.
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`3. Storage and transport Function
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`Packaging plays an important role in storage and transportation of product. Package shape
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`should be such that it can be handled easily. It must be so designed that they can be stored in
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`efficient manner i.e safely one above the other. The dimensions of package should be
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`according to the pellets.
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`4. Other Functions
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`Other functions of package includes protection from theft, compression, impact etc., patient
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`compliance, effective tool for marketing. [3-6]
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`Types of Package
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`1. Primary Package
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`Primary package are those package which are in direct contact with the Pharmaceutical
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`formulation. The main aim of primary package is to protect the formulation from
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`environmental, chemical, mechanical and/or other hazards.
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`2. Secondary Package
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`The package external to Primary package is known as secondary package. This package
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`provide additional protection during warehousing and also provide information about drug
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`product for e.g Leaflets.
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`3. Tertiary Package
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` It is used for warehouse storage and transport shipping. The most common form is a
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`palletized unit load that packs tightly into the container.
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`Table 1: Types of Primary and secondary packaging material
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`Images of Examples
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`Metal
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`Primary
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`Ointment tubes, pastes
`etc.
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`Cardboard
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`Secondary
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`Box to contain primary
`pack
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`Paper
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`Secondary
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`Labels, patient
`information leaflet
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`Types of primary and secondary packaging material
`Material
`Type
`Example of use
`Glass
`Primary
`Ampoule, vial etc.
`Ampoule, vial, infusion
`fluid container, dropper
`bottle
`Tray, Wrapper to contain
`primary pack
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`Primary
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`Secondary
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`Plastic
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`Cardboard,
`Plastic
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`Tertiary
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`Shippers, Pellets.
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`Types of containers which are used as primary package are as follows
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`Primary Package for liquid orals is
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`1. Well closed containers
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`These type of containers provide the protection from foreign particles and loss during
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`transportation, sale etc.
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`Fig.1: Well closed containers
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`2. Air tight containers
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`These types of containers protect the container from environmental hazards. If these
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`containers are intended to be opened on more than one occasions then they remains airtight
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`after reclosure. These are also known as hermetic sealed containers.
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` Fig.2: Air tight containers
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`3. Single Dose Containers
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`This type of container contain single dose of medicament example are: Glass ampoules,Vials
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`etc.
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`Fig.3: Single dose containers
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`4. Multi Dose Containers
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`As the name indicates these type of containers holds more than single dose and their contents
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`are withdrawn at various intervals. For e.g Vials etc.
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`Fig.4: Multi dose containers
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`5. Light Resistant Containers
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`These containers protect the contents from light (UV light). These are made up of the
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`materials which do not allow the UV light to pass from them to contents. For e.g : Amber
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`colored glass containers.
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`Fig.5: Light resistant containers
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`Primary Package for solid dosage forms
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`1. Strip Package
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`In this the contents are sealed in a packet. The Package is made up of two layers of film. A
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`strip containing many pockets and each pocket contains single dose of medicament.
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`Fig.6: Strip Package
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`2. Blister Package
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`It is made up of base layer (PVC layer) with cavities which contain Pharmaceutical product.
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`This type of Package provides greater protection than strip package. The lid is made up of
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`aluminium or paper foil. The package is sealed by combining lid and base with the
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`application of heat and pressure.
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`Fig.7: Blister Package
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`3. Primary Package for semi solid dosage forms
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`Semi- Solid dosage forms include creams, pastes, ointments etc. the containers used for
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`semi-solid dosage forms includes collapsible tubes etc. Plastic Containers are also very
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`popular now a days. Another type of products are also available in market for e.g Pressurized
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`products. For these types of products the package made up of stainless steel, aluminium etc.
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`is used. The package used must be strong enough to withstand pressure built up in the
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`container. [3, 7-9]
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`Fig.8: Collapsible Tubes
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`Materials used for Packaging Glass
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`Glass containers are very commonly used for storing pharmaceutical products. These
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`containers are intended to come into direct contact with pharmaceutical products. Glass
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`containers are used because of their following advantages.
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`1. They are impermeable to water vapors, air etc.
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`2. They are available in various sizes and shapes.
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`3. They have efficient mechanical strength and rigidity.
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`4. They are transparent so the contents can be easily seen from outside for e.g in case of
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`parental products.
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`5. They can be converted into light resistant glass by mixing with metal oxides.
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`6. They have elegant appearance than the plastic containers.
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`7. They are able to withstand temperature and pressure during sterilization.
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`8. They can be easily labeled.
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`9. They can be easily sealed which can provide hermetic sealing.
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`Disadvantages
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`1. They have heavy weight which increases their transportation cost.
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`2. They are breakable.
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`3. They can easily leach alkali to aqueous solutions if not properly treated with chemical.
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`Composition of Glass
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`Glass is made up of silica with varying degree of metal oxides, limestone and cullet. Cullet is
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`mainly the broken glass which acts as fusing agent. The common cations which are found in
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`pharmaceutical glassware are silicon, zinc, boron, alumina, sodium, potassium, zinc etc. the
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`only anion present is oxygen.
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`Manufacturing Process of glass
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`It includes mainly three steps.
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`1. Blowing
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`It uses compressed air to form the molten glass in the cavity of a mold.
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`2. Drawing
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`In this molten glass is pulled through dies that shape the soft glass. The containers
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`manufactured by this process includes ampoules, vials etc.
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`3. Pressing
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`In this mechanical force is used to press or force the molten glass against the ride of a mold.
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`4. Casting
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`This includes use of gravity or centrifugal force to initiate the formation of molten glass in
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`the cavity.
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`Types of Glass
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`Type I Glass: Borosilicate Glass (Pyrex)
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`This type of glass is composed of boric oxide, aluminium oxide and alkali and/or alkaline
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`earth oxides. Except for type I glass containers, glass containers for pharmaceutical
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`preparations are not to be re-used. It has a high hydrolytic and thermal shock resistance.
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`It is chemically more inert than soda lime glass. It is mainly used in preparation of laboratory
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`glass apparatus and containers for injection and water for injection.
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`Fig.9: Borosilicate Glass
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`Type II Glass: De alkalized soda lime glass
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`It has higher level of sodium and calcium oxide. It is less resistant to leaching property as
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`compare to type I glass but more resistant than type III. It is used to store infusion fluids,
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`plasma and alkali sensitive products.
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`Fig.10: De alkalized soda lime glass
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`Type III: Regular soda lime glass
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`This type of glass contains metal oxides, sodium oxides, aluminium, earth oxides mainly
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`calcium oxides. The main disadvantage is that it can leach alkali in the preparation. So it is
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`used to store liquid formulations which are not alkali sensitive. It is also used to store all
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`types of solid dosage forms.
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` Fig.11: Regular soda lime glass
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`USP type NP Glass: Non-Parentral
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`As the name indicated this type of glass is used to store non parentral formulations where
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`heat shock are not a factors. These formulations are used to store capsules, tablets, topical
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`products. This type of glass is not used for autoclaved products because autoclaving will
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`accelerate the glass erosion reaction. Dry heat sterilization arise not a problem for type III
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`containers. [10,11,22]
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` Fig.12: NP Glass: Non-Parentral
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`Plastics
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`Plastics are very commonly used for packaging Pharmaceutical products. These constitute
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`about 20% of weight of all pharmaceutical packaging. Plastics can be easily molded to
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`required shape.
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`Fig.13: Plastic containers
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`Advantages
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`1. They are unbreakable.
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`2. They have less wt. than glass and so their transport cost is also very less.
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`3. They are available in various size and shapes.
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`4. They can be easily molded into desired shape.
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`5. They provide good protection power against chemical hazards.
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`6. They do not have alkali leaching property as in glass containers.
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`7. They also have suck back feature.
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` Disadvantages
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`1. The main disadvantage is permeation. The atmospheric gases, vapors or liquid from
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`surrounding environment can easily migrate into plastic container.
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`2. Permeation causes problem of oxidation and/or hydrolysis and can degrade the product
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`which is sensitive to hydrolysis and/or oxidation.
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`3. They also have leaching problem, for e.g dyes which are used as coloring agent may
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`migrate into product from the container.
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`4. Another problem is sorption; sorption is the process of removal of one or more constituents
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`from the product by packaging material. This can affect the therapeutic efficacy of the
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`product.
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`5. Preservative can also be absorbed by the container material. This may change the
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`flexibility of the container. [10,12,13]
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`Materials used for making Plastic containers
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`1. Polyethylene
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`Polyethylene is very commonly used polymer. It is available in high density, medium density
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`and low density grades. Mainly high density polyethylene is used for pharmaceuticals. It
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`provides protection against moisture but poor protection against oxygen & other
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`environmental gases. The containers prepared from polyethylene cannot be sterilized by heat
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`but can be easily sterilized by autoclave. Polyethylene’s have melting point range of 120-
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`150ºc. It has an excellent chemical resistance, it means it provide protection against strong
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`acid & alkali. It is used to prepare plastic bag, plastic films, bottles etc.
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`Fig.14- Polyethylene Plastic containers
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`2. Polypropylene
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`It is very popularly used in Pharmaceutical container. It has many qualities of polyethylene. It
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`has mpt. Of 170ºc which is higher than polyethylene and make it suitable for sterilization at
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`high temp. It has very good resistance power to almost all types of chemicals. It is superior to
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`low density polyethylene. The main drawback of polypropylene is its less clarity which can
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`be improved by making thin walls containers. Other drawback is its brittleness at low temp.
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`which can also be improved by mixing it with some proportion of polyethylene.
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` Fig.15: Polypropylene Plastic containers
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`3. Polyvinylchloride (PVC)
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`It has high clarity and good oxygen barrier. It is third most widely produced polymer after
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`polyethylene & polypropylene. It can be made softer & flexible by incorporation of
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`plasticizers. The heat stability of PVC is very poor and its mpt. is 160ºc. It has good
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`insulation properties but inferior than polyethylene & polypropylene. PVC can be used for
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`making containers used for blood & blood components, catheters, bypass sets, hemodialysis
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`sets etc. The main advantages of PVC include its transparency, light wt., softness, suitability
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`for sterilization and biocompatibility.
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` Fig.16: PVC Plastic containers
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`4. Polyamide (Nylon)
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`It is macromolecules having repeated units linked by amide bonds. Nylon is mainly
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`artificially made. It can be produced by interaction of a diamine and a dicarboxylic acid. It
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`has main advantage of good chemical resistance, high strength, good toughness, high heat
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`resistance, good water resistance etc. it can be autoclaved easily. The main disadvantage is
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`high moisture absorbtivity, attacked by oxidizing agent, strong acids & alkalis etc.
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` Fig.17: Polyamide Plastic containers
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`Various grades are available and approved by FDA. Some of these are as follows.
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`Table 2: - Various grades of Polyamides with their structur
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`Polyamide (nylon)
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`Repeating unit
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`6,10
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`5. Polystyrene
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`It is made from petroleum. It is non biodegradable, light and rigid. Its main advantages are
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`that it is inexpensive, resistant to acids, strong alkalies & strong oxidizing agents, high heat
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`resistance, expandable etc. The main disadvantage is that it can leach styrene & benzene
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`when come in contact with warm food, oils, alcohols etc. which causes contamination of
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`product.
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`Fig.18: Polystyrene Plastic containers
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`6. Polycarbonate
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`Polycarbonate is resistant to dilute acids, oxidizing or reducing agents, salts, oils (fixed and
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`volatile), greases, and aliphatic hydrocarbons. It is attacked by strong acids, reducing agents,
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`amines, ketones, aromatic hydrocarbons, and some alcohols. It has highest impact strength
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`and inexpensive. It is clear and very good heat resistance power. It is mainly used for
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`manufacturing of surgical equipments. [14-18]
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`Fig.19: Polycarbonate Plastic containers
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`Metal containers
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`Metals are very commonly used as packaging material for pharmaceutical
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`containers. Examples of metals used for this purpose include mainly
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`aluminium, lead, tin etc.
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`Advantages of metals
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`1. They are light in weight than glass.
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`2. They are strong.
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`3. They are resistant to light, moisture and gases.
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`4. They are elegant in appearance.
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`5. Labels are not required to be pasted because labels can be printed directly on the surface.
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`Disadvantages
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`1. They may leach metal particles into product.
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`2. They may react with certain drugs or chemicals and produce toxic product.
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`3. They are costlier than plastic.
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`Material used for making metal containers
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`Aluminium
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`Aluminium is very commonly used because of its light weight and elegant appearance. They
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`are less expensive than tin. The transparent coating of oxide formed on surface of aluminium
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`on reaction with oxygen protect the metal from further oxidation but some complexing agent
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`& product of high or low pH can cause corrosion on reaction with oxide coating. Aluminium
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`is used for preparation of ointment tube, tablets & capsule strips, screw caps etc.
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`Tin
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`It is expensive than amongst other metals used for pharmaceutical containers preparation. It is
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`resistant to chemical attack. It offers a good appearance and it is chemically inert. It is used
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`for preparation for food containers.
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`Fig.21: Tin Container
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`Lead
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`It is inexpensive than amongst all other metals. It is soft in nature. so usually 3% antimony is
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`added in lead to increase its hardness. The main disadvantage of lead is that there is
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`possibility of lead poisoning if taken internally. So, before its use it should be coated with
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`inner lining of inert metal or polymer. It is used for non food products such as paints, inks,
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`lubricants etc.
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`Fig.22: Lead containers
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`Types of metal containers
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`Collapsible Tubes
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`These are made up of aluminium, tin or lead. They are used to pack semisolid preparation.
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`Aluminium tubes are used for dispensing of tooth paste & creams. Lead is not used for
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`pharmaceutical purpose because of risk of lead poisoning. In case of aluminum collapsible
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`tubes there are chances of minimum contamination of the remaining portion of tube content
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`because of absence of suck back mechanism.
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` Fig.23: Collapsible Tubes
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`Metal containers for solid dosage forms
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`Aluminium is mainly used for this purpose. So the containers for tablets & capsules are light
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`in weight & also strong enough.
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`Fig.24: Containers for solid dosage forms
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`Metal Foil
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`These foils are used for wrapping of individual suppositories or pessaries. Mainly aluminium
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`foil is used for this purpose. Metal foil is also used for strip & blister packing of tablets &
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`capsules. [3,19]
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` Fig.25:Aluminium Foil (suppositories wrapping)
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`Secondary Package
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`Paper and paperboards
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`Secondary package are used
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`to store primary package containing Pharmaceutical
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`Preparations. Secondary package are directly in contact with the primary package but not
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`with Pharmaceutical preparations. Secondary package mainly contains shippers or cartons
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`which give the physical protection to the primary package. These are prepared of cellulose
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`fibers obtained from wood. Paperboards are also used as secondary package which are thicker
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`than paper and heavy in weight. Examples of paperboards are white board, solid board,
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`chipboard, fiberboard. These boards are mainly laminated using polyethylene or waxes.
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`chipboard is obtained from recycled paper. Bleached sulphate boards are the example of
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`solidboards which are laminated with polyethylene. [4,20]
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`Closures
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`This is the most critical component of a container. An effective closure system prevents the
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`loss of material from the container, prevents the environmental contamination of the product,
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`prevents the microbs to enter inside he container.
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`Ideal properties of a closure
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`1. It should be inert.
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`2. It should be compatible with product & container.
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`3. It should have the property of re sealable.
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`4. It should be economical.
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`5. It should provide an effective seal.
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`6. It should be easily handable.
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`Design of closures
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`Closures are available in five main designs. Their details are as follows.
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`1. Threaded Screw Type:
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`These are made up of aluminium, tin or plastic. As the name indicates they contain threads
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`which get engaged with the threads present on the neck of container. These types of closures
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`provide the effective seal which protect the product from physical and chemical reaction.
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`Plastic caps are more popular than metal because plastic are resistant to corrosion.
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`Fig.26: Threaded Screw Type closure
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`2. Lug Cap
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`The difference in lug cap and thread cap is that in thread cap, continuous threads are present
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`but in lug cap threads are present in intermittent fashion. Another difference is that lug cap
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`requires only a quarter turn. Lug caps are mainly used in storage of food products.
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`Fig.27: Lug Cap
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`3. Crown Caps
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`These caps are made up of metal and commonly used for beverages bottles. These also
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`provides an effective seal and cannot be open with hands. These cannot be seal again.
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`Fig.28: Lug Cap
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`4. Roll on closures
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`Roll on closure contains the aluminium roll on cap which can be easily sealed, opened and
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`closed. These are available in re sealable, non- sealable & pilfer proof type forms. These are
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`available for use on glass or plastic bottles & jars for food, beverages, chemicals and
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`Pharmaceuticals.
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` Fig.29: Roll on closures
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`5. Pilfer Proof Closures
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`In this additional length extends below to threaded portion which forms a bridge. When the
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`closure is removed then the bridge break and the additional portion remains in place on neck
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`of container which show its opening. [3, 11, 21]
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` Fig.30: Pilfer Proof Closures
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`Material used for construction of closures
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`Rubber
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`It is used for construction of closures for vials, transfusion bottle fluids etc. Many types of
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`rubbers are used for this purpose for e.g butyl rubber, nitrile rubber, silicon rubber etc. Butyl
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`rubber is very commonly used because of its low absorption property and also they are
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`cheaper than other synthetic rubber but it decompose above 130ºC. Nitrile rubber has oil
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`resistant and heat resistant property but it can absorb the preservative from the preparation.
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`Silicon rubbers have very low absorption & permeability of water and are stable for a long
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`time. But they are very expensive.
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`A rubber is prepared by mixing a base polymer with additives. The selection of base polymer
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`& additives depends upon the type of rubber properties to be desired. The resultant rubber is
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`non vulcanized compound.
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`Fig.31: Rubber Closures
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`Additives used in preparation of rubber
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`1. Fillers
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`Two types of fillers are used. Reinforce for e.g Carbon black and other is non reinforce for
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`e.g Calcium carbonate. Carbon black is mostly used due to this most of the rubbers are black.
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`2. Plasticizers
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`They are used to improve the flow of rubber during their processing for e.g Oils & Paraffin’s.
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`3. Vulcanizing agent
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`Vulcanization is a process of conversion of rubber molecule into a network by formation of
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`crosslinks. Vulcanizing agents are used for introducing crosslinking. e.g of vulcanizing
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`agents are: Sulphur etc.
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`4. Accelerators
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`They are used to increase the rate of crosslinking reaction and optimize the vulcanizate
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`properties by reducing sulphur content. For e.g Thiazoles.
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`5. Activators
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`They activate the vulcanizing process. Examples are: Zinc oxide, Stearic acid.
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`6. Pigments
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`These are used as coloring agent to color rubber compounds. Examples are: Cadmium, iron
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`etc. [22]
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`Plastic
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`Two types of plastics are used for construction of closure. These are as follows:
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`Thermoplatics
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`This type of plastic gets softened to a viscose fluid on heating and then get hard on cooling.
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`Example includes: Polyethylene, Polypropylene, Polystyrene etc.
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`Thermosetting
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` They are firstly softened under heat and then curved before harden to final state. The shape
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`should be required to be achieve during softening because after softening shaping cannot be
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`done. Thermosetting plastics cannot be remelt so the closure which are imperfect or improper
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`in shape must be discarded. Example includes Phenolic compounds and Urea.
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`1. Phenolic compounds
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`Fig.32: Plastic Closures
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` These provides the sturdy and hard product.Phenolic closures provide a tight seal over a
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`prolong period of time. They are rigid, chemically resistant to dilute acids and alkalies.
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`2. Urea
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` Closures made from urea have elegant in appearance and chemically inert. They are
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`expensive than Phenolic. They cannot be autoclaved but can withstand high temperature
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`without softening. [10, 11,23]
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`CONCLUSION
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`Packaging plays an important role in Pharmaceutical Industries. The pharmaceutical
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`packaging market is constantly i