6.2-Plastic container:
Plastics in packaging have proved useful for a number of reasons, including the ease with which they can be formed, their high quality, and the freedom of design to which they lend themselves. Plastic containers are extremely resistant to breakage and thus offer safety to consumers along with reduction of breakage losses at all levels of distribution and use. Plastic containers for pharmaceutical products are primarily made from the following polymers: polyethylene, polypropylene, polyvinyl chloride, polystyrene, and to a lesser extent, polymethyl methacrylate, polyethylene terephthalate, polytrifluoroethylene, the amino formaldehydes, and polyamides.Plastic containers consist of one or more polymers together with certain additives. Those manufactured for pharmaceutical purposes must be free of substances that can be extracted in significant quantities by the product contained. Thus, the hazards of toxicity or physical and chemical instability are avoided. The amount and nature of the additives are determined by the nature of the polymer, the process used to convert the plastic into the containers, and the service expected from the container. For plastic containers in general, additives may consist of antioxidants, antistatic agents, colors, impact modifiers, lubricants, plasticizers, and stabilizers. Mold release agents are not usually used unless they are required for a specific purpose.10

6.2.1-Advantages of Plastic Containers:
Plastic containers have a number of inherent practical advantages over other containers or dispenses. They are:
•    Low in cost
•    Light in weight
•    Durable
•    Pleasant to touch
•    Flexible facilitating product dispensing
•    Odorless and inert to most chemicals
•    Unbreakable
•    Leak proof
•    Able to retain their shape throughout their use.
•    They have a unique 'suck-back' feature, which prevents product doze.
If the quantity of the drug dispensed with one squeeze is more , relaxation of hard pressure permits the product to be sucked back into the tube. If this feature is undesirable for fear of contamination, plastic tubes designed to avoid suck back are available. Thus the suck back feature of plastic tubes can be an advantage or disadvantage. When the tube is partly empty, however, this feature is a nuisance, because the air must be expelled before the product can be dispensed.

6.2.2-Disadvantages :
Plastics appear to have certain disadvantage like interaction, adsorption, absorption lightness and hence poor physical stability. All are permeable to some degree to moisture, oxygen, carbon dioxide etc and most exhibit electrostatic attraction, allow penetration of light rays unless pigmented, black etc. Other negative features include:
•    Stress cracking , a phenomenon related to low density polythene and certain stress cracking agents such as wetting agents, detergents and some volatile oils.
•    Paneling or cavitation, where by a container shows in ward distortion or partial collapse owing to absorption causing swelling of the plastic or dimpling following a steam autoclaving operation.
•    Crazing, a surface reticulation which can occur particularly with polystyrene and chemical substances (e.g. isopropyl myristate which first cause crazing and ultimately reaches of total embitterment and disintegration).
•    Poor key of print -certain plastics, such as the poly olefins need pre treating before ink will key. Additives that migrate to the surface of the plastic may also cause printing problem.
•    Poor impact resistance – both polystyrene and PVC have poor resistance. This can be improved by the inclusion of impact modifiers such as rubber in case of polystyrene and methyl methacrylate butadiene styrene for PVC.11
Majority of these effects can be either minimized or can be overcome by one or another means. For example, it was required to pack a nasal spray formulation in a plastic squeeze bottle which was available worldwide. This immediately called for a lowdensity polyethylene (LDPE) pack. The product however, contained a volatile preservative system, which both dissolved in LPPE and was lost from it by volatilization, thereby immediately suggesting that a conventional squeeze pack was unsuitable. The LDPE bottle was enclosed in a PVC blister impermeable to the volatile preservative and fitted with a peelable foil lid (also impermeable). As a result of this combination the loss of preservative was restricted to less than 5% of the total i.e. preservative soluble in the LDPE and preservative in the air space of the PVC blister reached a point where equilibrium was achieved between product, LDPE and the surrounding air space.

At present, a great number of plastic resins are available for the packaging of drug products. The more popular ones are:
High-density polyethylene is the material most widely used for containers by the pharmaceutical industry and will probably continue to be for the next several years. Polyethylene is a good barrier against moisture, but a relatively poor one against oxygen and other gases. Most solvents do not attack polyethylene, and it is unaffected by strong acids and alkalies.Polyethylene has certain disadvantages that it lack clarity and a relatively high rate of permeation of essential odors, flavors, and oxygen. Despite these problems, polyethylene in all its variations offers the best all-around protection to the greatest number of products at the lowest cost.
The density of polyethylene, which ranges from 0.91 to 0.96, directly determines the four basic physical characteristics of the blow-molded container: (1) stiffness, (2) moisture-vapor transmission, (3) stress cracking, and (4) clarity or translucency. As the density increases, the material becomes stiffer, has a higher distortion and melting temperature, becomes less permeable to gases and vapors, and becomes less resistant to stress cracking. The molecular structure of high-density material is essentially the, same as that of low-density material, the main difference being fewer side branches.
Since these polymers are generally susceptible to oxidative degradation during processing and subsequent exposure, the addition of some antioxidant is necessary. Usually levels of hundreds of parts per million are used. Antioxidants generally used are butylated hydroxy toluene or dilauryl thiodipropionate.
Antistatic additives are often used in bottle grade polyethylenes. Their purpose is to minimize airborne dust accumulation at the surface bottle during handling, filling, and storage. These antistatic additives are usually polyethylene glycols or long chain fatty amides and are often used at 0.1 to 0.2% concentration in high-density polyethylene.
Polypropylene has recently became popular because it has many good features of polyethylene, with one major disadvantage either eliminated or minimized. Polypropylene does not stress-crack under any conditions. Except for hot aromatic or halogenated solvents, which soften it, this polymer has good resistance to almost all types of chemicals, including strong acids, alkalies, and most organic materials. Its high melting point makes it suitable for boilable packages and for sterilizable products. Lack of clarity is still a drawback, but improvement is possible with the construction of thinner walls.
Polypropylene is an excellent gas and vapor barrier. Its resistance to permeation is equivalent to or slightly better than that of high-density or linear polyethylene, and it is superior to low-density or branched polyethylene. One of the biggest disadvantages of polypropylene is its brittleness at low temperatures. In its purest form, it is quite fragile at 0°F and must be blended with polyethylene or other material to give it the impact resistance required for packaging.
Polyvinyl Chloride (PVC):
Clear rigid poly-vinyl chloride bottles overcome some of the deficiencies of polyethylene. PVC can be produced with crystal clarity, provide a fairly good oxygen barrier, and have greater stiffness. In its natural state, polyvinyl chloride is crystal clear and stiff, but has poor impact resistance. PVC can be softened with plasticizers. Various stabilizers, antioxidants, lubricants, or colorants may be incorporated. Polyvinyl chloride is seldom used in its purest form. PVC is an inexpensive, tough, clear material that is relatively easy to manufacture.PVC must not be overheated because it starts to degrade at 280°F, and the degradation products are extremely corrosive. Polyvinyl chloride yellows when exposed to heat or ultraviolet light, unless a stabilizer is included by the resin supplier. From the standpoint of clarity, the best stabilizers are the tin compounds, but the majority cannot be used for food or drug products. Dioctyl-tin mer-captoacetate and maleate compounds have been approved by the FDA, but these have a slight odor, which is noticeable in freshly blown bottles. Polyvinyl chloride is an excellent barrier for oil, both volatile and fixed alcohols, and petroleum solvents. It retains odor and flavors quite well and is a good barrier for oxygen. Rigid polyvinyl chloride is a fairly good barrier for moisture and gases in general, but plasticizers reduce these properties. Polyvinyl chloride is not affected by acids or alkalies except for some oxidizing acids. Its impact resistance is poor, especially at low temperatures.
General-purpose polystyrene is a rigid, crystal clear plastic. Polystyrene has been used by dispensing pharmacists for years for containers for solid dosage forms because it is relatively low in cost. At present, polystyrene is not useful for liquid products. The plastic has a high water vapor transmission (in comparison to high-density polyethylene) as well as high oxygen permeability. Depending on the methods of manufacture and other factors, polystyrene containers are easily scratched and often crack when dropped. Polystyrene will build up static charge. Polystyrene has a low melting point (190°F) and therefore cannot be used for hot items or other high-temperature applications. Polystyrene is resistant to acids, except strong oxidizing acids, and to alkalies. Polystyrene is attacked by many chemicals, which cause it to craze and crack, and so it is generally used for packaging dry products only. To improve impact strength and brittleness, general-purpose polystyrene may be combined with various concentrations of rubber and acrylic compounds. Certain desired properties like clarity and hardness diminish with impact polystyrene. The shock resistance or toughness of impact polystyrene may be varied by increasing the content of rubber in the material, and often these materials are further classified as intermediate-impact, high-impact, and super-impact polystyrene.
Nylon (Polyamide):
Nylon is made from a dibasic acid combined with a di-amine. Variety of nylons can be made with different dibasic acids and amines. The type of acid and amine that is used is characteristic and denotes the type of acid and amine used.e.g. nylon 6/10 has six carbon atoms in the diamine and ten in the acid. Nylon and similar polyamide materials can be fabricated into thin-wall containers. Nylon can be autoclaved and is extremely strong and quite difficult to destroy by mechanical means. Important to the widespread acceptance of nylon is its resistance to a wide range of organic and inorganic chemicals. As a barrier material, nylon is highly impermeable to oxygen. It is not a good barrier to water vapor, but when this characteristic is required, nylon film can be laminated to polyethylene or to various other materials.Its relative high-water transmission rate and the possibility of drug-plastic interaction have reduced the potential of nylon for long-term storage of drugs. Some of the nylon approved by FDA are Nylon 6, Nylon 6/6, Nylon 6/10, Nylon 11, and certain copolymers.
Polycarbonate can be made into a clear transparent container. Polycarbonate is expensive and offers some advantage that it can be sterilized repeatedly. The containers are rigid, as is glass, and thus has been considered a possible replacement for glass vials and syringes. It is FDA-approved, although its drug-plastic problems have not been investigated adequately. It is only moderately chemically resistant and only a fair moisture barrier. The plastic is known for its dimensional stability, high impact strength, resistance to strain, low water absorption, transparency, and resistance to heat and flame.
Polycarbonate is resistant to dilute acids, oxidizing or reducing agents, salts, oils (fixed and volatile), greases, and aliphatic hydrocarbons. It is attacked by alkalies, amines, ketones, esters, aromatic hydrocarbons, and some alcohols. Polycarbonate resins are expensive and consequently are used in specialty containers. Since the impact strength of polycarbonate is almost five times greater than other common packaging plastics, components can be designed with thinner walls to help reduce cost.
Acrylic Multipolymers (Nitrile Polymers):
These polymers represent the acrylonitrile or methacrylonitrile monomer. Their unique properties of high gas barrier, good chemical resistance, excellent strength properties, and safe disposability by incineration make them effective containers for products that are difficult to package in other plastic containers. Their oil and grease resistance and minimal taste transfer effects are particularly advantageous in food packaging. These type of polymers produce clear container and are les costly. The use of nitrile polymers for food and pharmaceutical packaging is regulated to standards set by the Food and Drug Administration. The present safety standard is less than 11 ppm residual acrylonitrile monomer, with allowable migration at less than 0.3 ppm for all food products.
Polyethylene terephthalate (PET):
Polyethylene terephthalate, generally called PET, is a condensation polymer typically formed by the reaction of terephthalic acid or dimethyl terephthalate with ethylene glycol in the presence of a catalyst. Although used as a packaging film since the late 1950s, its growth has recently escalated with its use in the fabrication of plastic bottles for the carbonated beverage industry. Its excellent impact strength and gas and aroma barrier make it attractive for use in cosmetics and mouth washes as well as in other products in which strength, toughness, and barrier are important considerations. Polyethylene terephthalate is used in food packaging and offers favourable environmental impact system.

6.2.4-Product-Plastic interactions:
Product-Plastic interactions have been divided into five separate categories: (1) permeation, (2) leaching, (3) sorption, (4) chemical reaction, and (5) alteration in the physical properties of plastics or products.12
1) Permeation:
The transmission of gases, vapors, or liquids through plastic packaging materials can have an adverse effect on the shelf-life of a drug. Permeation of water vapor and oxygen through the plastic wall into the drug can present a problem if the dosage form is sensitive to hydrolysis and oxidation. Temperature and humidity are important factors influencing the permeability of oxygen and water through plastic. An increase in temperature reflects an increase in the permeability of the gas.Great differences in permeability are possible, depending on the gas and the plastic used. Molecules do not permeate through crystalline zones; thus, an increase in crystallinity of the material should decrease permeability. Two polyethylene materials may therefore give different permeability values at various temperatures.Materials such as nylon, which are hydrophillic in nature, are poor barriers to water vapor, while such hydrophobic materials as polyethylene provide much better barriers. Studies have also revealed that formulations containing volatile ingredients might change when stored in plastic containers because one or more of the ingredients are passing through the walls of the containers. Often, the aroma of cosmetic products becomes objectionable, owing to transmission of one of the ingredients, and the taste of medicinal products changes for the same reason.The physical system making up the product also may have an influence on the plastic container. For example, certain water-in-oil emulsions cannot be stored in a hydrophobic plastic bottle, since there is a tendency for the oil phase to migrate and diffuse into the plastic.
2) Leaching:
Most plastic containers have one or more ingredients added in small quantities to stabilize or impart a specific property to the plastic and the prospect of leaching, or migration from the container to the drug product is present. Problems may arise with plastics when coloring agents in relatively small quantities are added to the formula. Particular dyes may migrate into a parenteral solution and cause a toxic effect. Release of a constituent from the plastic container to the drug product may lead to drug contamination and necessitate removal of the product from the market.
This process involves the removal of drug content from the product by the packaging material. Sorption may lead to serious consequences active ingredients are in solution. Since drug substances of high potency are administered in small doses, losses due to sorption may significantly affect the therapeutic efficacy of the preparation. Sorption is seen mainly with preservatives. These agents exert their activity at low concentration, and their loss through sorption may be great enough to leave a product unprotected against microbial growth. Factors that influence characteristics of sorption from product are chemical structure, pH, solvent system, concentration of active ingredients, temperature, length of contact, and area of contact.
4) Chemical Reactivity:

Certain ingredients that are used in plastic formulations may react chemically with one or more components of a drug product. At times, ingredients in the formulation may react with the plastic. Even micro-quantities of chemically incompatible substances can alter the appearance of the plastic or the drug product.
5) Modification:

The changes in physical and chemical properties of the packaging material by the pharmaceutical product is called modification. Such phenomena as permeation, sorption, and leaching play a role in altering the properties of the plastic and may also lead to its degradation. Deformation in polyethylene containers is often caused by permeation of gases and vapors from the environment or by loss of content through the container walls. Some solvent systems have been found to be responsible for considerable changes in the mechanical properties of plastics. Oils, for example, have a softening effect on polyethylene; fluorinated hydrocarbons attack polyethylene and polyvinyl chloride. In some cases, the content may extract the plasticizer, antioxidant, or stabilizer, thus changing the flexibility of the package. Polyvinyl chloride is an excellent barrier for petroleum solvents, but the plasticizer in polyvinyl chloride is extracted by solvents. This action usually leaves the plastic hard and stiff. Sometimes, this effect is not immediately perceptible because the solvent either softens the plastic or replaces the plasticizer; later, when the solvent evaporates, the full stiffening effect becomes apparent.

6.2.5-Constituents of plastic containers:
The residues, additives and processing aids that may be used, and therefore possibly extracted from, plastic include:13
•    Monomer residues
•    Catalysts
•    Accelerators
•    Solvents
•    Extenders
•    Fillers
•    Slip additives
•    Anti slip additives
•    Antistatic agents
•    Anti blocking agents                  
•    Release agents
Most plastics include only a few of these constituents. Depending upon the additives used, other properties of the plastic can be changed, e.g. fillers such as chalk or talc are likely to increase moisture permeation.

6.3-Metal container:
The collapsible metal tube is an attractive container that permits controlled amounts to be dispensed easily, with good re closure and adequate environmental protection to the product. The risk of contamination of the portion remaining in the tube is minimal, because the tube does not "suck back." It is light in weight and unbreakable, and it lends itself to high-speed automatic filling operations.The ductile metals used for collapsible tubes are tin (15%), aluminum (60%), and lead (25%). Tin is the more expensive than lead. Tin is the most ductile of these metals. Laminates of tin-coated lead provide better appearance and will be resistant to oxidation.They are also cheaper compared to tin alone. The tin that is used for this purpose is alloyed with about 0.5% copper for stiffening. When lead is used, about 3% antimony is added to increase hardness. Aluminum work hardens when it is formed into a tube, and must be annealed to give it the necessary pliability. Aluminum also hardens in use, sometimes causing tubes to develop leaks.
Tin: Tin containers are preferred for foods, pharmaceuticals, or any product for which purity is an important consideration. Tin is chemically inert of all collapsible tube metals. It offers a good appearance and compatibility with a wide range of products.
Aluminum: Aluminum tubes offer significant savings in product shipping costs because of their light weight. They provide good appearance.
Lead has the lowest cost of all tube metals and is widely used for nonfood products such as adhesives, inks, paints, and lubricants. Lead should never be used alone for anything taken internally because of the risk of lead poisoning. The inner surface of the lead tubes are coated and are used for products like fluoride toothpaste.
Linings: If the product is not compatible with bare metal, the interior can be flushed with wax-type formulations or with resin solutions, although the resins or lacquers are usually sprayed on. A tube with an epoxy lining costs about 25% more than the same tube uncoated. Wax linings are most often used with water-base products in tin tubes, and phenolics, epoxides, and vinyls are used with aluminum tubes, giving better protection than wax, but at a higher cost. When acidic products are packed, phenolics are used and for alkaline products , epoxides are used.

The closure is normally the most vulnerable and critical component of a container in so far as stability and compatibility with the product are concerned. An effective closure must prevent the contents from escaping and allow no substance to enter the container. The adequacy of the seal depends on a number of things, such as the resiliency of the liner, the flatness of the sealing surface on the container, and most important, the tightness or torque with which it is applied. In evaluating an effective closure system, the major considerations are the type of container, the physical and chemical properties of the product, and the stability-compatibility requirements for a given period under certain conditions.14



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