PLASTICS AS PACKAGING MATERIAL
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 can be changed. 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:
3. Polyvinyl chloride,
4. Polystyrene, and
5. To a lesser extent, poly ethyl methacrylate, polyethylene terephthalate, polytetrafluoroethylene, the amino formaldehyde, and polyamides.
Plastic containers consist of one or more polymers together with certain additives. 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, opact modifiers, lubricants, plasticizers, and stabilizers.
There are two types of plastics:
(i) Thermosets (screw caps) and
Advantages of Plastics:
The advantages of plastics for packaging are as follows:
1. Release few particles into the product.
2. Flexible and not easily broken.
3. Are of low density and thus light in weight.
4. Can be heat sealed.
5. Are easily mounded into various shapes.
6. Suitable for use as a container, closure, and as secondary packaging.
Disadvantages of Plastics:
The disadvantages of plastics are:
1. They are not as chemically inert as Type-I glass.
2. Some plastics undergo stress cracking and distortion from contact with some chemicals.
3. Some plastics are very heat sensitive.
4. They are not as impermeable to gas and vapor as glass.
5. They may possess an electrostatic charge which will attract particles.
6. Additives in the plastic are easily leached into the product.
7. Substances such as the active drug and preservatives may be taken up from the product.
The Principal Plastic Materials used in Pharmaceutical Packaging
|Soft, flexible, and easily stretched.||Squeeze bottles as eye
|• Disadvantages. of PE (LDPE and HDPE):
• Softened by flavoring agent and aromatic oils,
• Unsuitable for packaging oxygen-sensitive products.• Adsorb antimicrobial preservative agents,
• Crack on contact with organic solvents.
|Strong, stiff, less permeable to gases than LDPE.||Bottles for solid dosage forms.|
|Polypropylene||Strong and stiff,
good resistance to
|Used for closures with
hinges. Used also for
tablet containers and
|Rigid||Laminate (for blisters)
and the main
constituent of IV bags.
|Polystyrene (PS)||Clear, hard, brittle
with low impact
|Used for tubes and
It is also used for jars
for ointments and
creams with low water
|• Its use in drug packaging is limited due to its high permeability to water vapor|
Types of Plastic Containers
2. Collapsible tubes
3. Unit dose packaging (blister, strip)
Storage and Stability of Medicines
Medicines cannot be kept indefinitely. Some can be kept for only a short time. There are six general causes for the limited time for which medicines can be kept and these are:
1. Loss of drug (such as hydrolysis or oxidation).
2. Loss of vehicle (such as evaporation of water or other volatile ingredients).
3. Loss of uniformity (such as caking of a suspension or creaming of an emulsion).
4. Change in bioavailability (particularly with tablets where aging van reduces availability).
5. Change of appearance (such as colour changes).
6. Appearance of toxic or irritant products (as a result of a chemical change General notes for storage and expiry date Storing in a cool place means 8-15°C, in a refrigerator means at 2-8°C.
• Expiry date is the date after which the medicine should not be used. The expiry date is calculated from the shelf life at the time of preparation.
• Shelf life is normally the time that a medicine can be kept before the potency has fallen to 90% of the original.
• Shelf life for manufactured products is based on accelerated stability studies (Arrhenius plot).
• The shelf for extemporaneous preparation may be found in an appropriate monograph, if available. If no monograph is available, the product is labeled with as short an expiry date as possible.
• Freshly prepared is defined as prepared not more than 24 hours before issue.
• Recently prepared is defined as discarded after 4 weeks
At present, a great number of plastic resins are available for the packaging of drug products. A general description of the more popular ones is presented here.
Plastics used for Packaging
The density of polyethylene, which ranges from 0.91 to 0.96, directly determines the following basic physical characteristics of the blow-molded container:
• Moisture-vapor transmission,
• Stress cracking,
• Clarity or translucency.
Since these polymers are generally susceptible to oxidative degradation during processing and subsequent exposure the addition of some antioxidant is necessary in the level of hundreds of parts per million are used. Antioxidants generally used are butylated hydroxy toluene or dilauryl thiodipropionate and antistatic additives are often used in bottle grade polyethylenes. They 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% concentrations in HDPE.
• It is a good barrier against moisture but a relatively poor one against oxygen and other gases.
• Most solvents do not attack polyethylene, and it remains unaffected by strong acids and alkalies.
• Polyethylene in all its variations offers the best all-around protection to the greatest number of products at the lowest cost.
• Lack of clarity.
• Relatively high rate of permeation of essential odors, flavors, and oxygen militate against the use of polyethylene as a container material for certain pharmaceutical preparations.
2. Polypropylene (PP):
Polypropylene (PP) has recently become popular because it has many of the good features.
• 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.
• Polypropylene is an excellent gas and vapor barrier.
• Its resistance to permeation is slightly better than that of HDPE.
• It is superior to low-density or branched polyethylene (LDPE).
• Lack of clarity.
• It is brittle at low temperature.
• In its purest form, it is quite fragile at 0°F and must be blended with polyethylene or other materials to give it the impact resistance required for packaging.
3. Poly-Vinyl Chloride (PVC):
• They can be produced with crystal clarity, provide a fairly good oxygen barrier, and have greater stiffness.
• It is an inexpensive, tough, clear material that is relatively easily processed.
• PVC is an excellent barrier for oil, both volatile and fixed alcohols, and petroleum solvents.
• It retains odour and is a good barrier for oxygen, moisture and gases.
• PVC is not affected by acids or alkalies except for some oxidizing acids.
• It may also be used as a skin coating on glass bottles. This is accomplished by dipping the bottle in a polyvinyl chloride plastisol and curing the coating, which produces a shatter-resistant coating over the glass bottle.
• It is impermeable to moisture and gas.
• It is inexpensive and versatile which has led to the widespread use in blister packs.
• In its natural state, polyvinyl chloride has poor impact resistance.
• PVC is seldom used in its purest form.
• If overheated it starts to degrade at 280°F and the degradation products are extremely corrosive.
• The colour of PVC becomes yellow when exposed to heat or ultraviolet light, unless a stabilizer is included by the resin supplier.
• It is virtually impossible to process vinyls at elevated temperatures without a stabilizing agent.
• In the formulation of PVC compounds with calcium-zinc stabilization materials, all ingredients are used in concentrations below their maximum extractable concentrations.
• It is possible to incriminate in the development of cancer of the liver (angiosarcoma) in some persons exposed to vinyl chloride monomer and polyvinyl chloride during manufacture.
4. Polymonochloro-Trifluoroethylene (PCTFE):
PCTFE comes under the trade name Aclar.
• It is one of the most inert plastics
• It has low permeability to moisture.
• It is the most expensive plastic and has so far only been
used in packaging as a thin layer (laminated to PVC) for blister packing. Three
copolymers are in use: 22A, 33C and 88A. 33 C is the cheapest and has a similar
permeability at approximately half the thickness.
• New homopolymers Rx 160, ultRx 2000 and 3000, SupRx 900 offer certain advantages
over the copolymers, including lower costs.
• The basic monomer chlorotrifluoroethylene C, C1/73, is associated with toxicity.
• PCTFE is a good barrier against moisture, but a poor one against O2, N2 and CO2 relatively to PVdC.
• It is a rigid, crystal clear plastic.
• It is relatively low in cost.
• The plastic has a high water vapor transmission (in comparison to high-density polyethylene) as well as high oxygen permeability.
• It is resistant to acids, except strong oxidizing acids, and to alkalies.
• Polystyrene is not useful for solid dosage products.
• Depending on the methods of manufacture and other factors, polystyrene containers are easily scratched and often crack when dropped.
• It easily builds up a static charge; it has a low melting point (190°F) and therefore cannot be used for hot items or other high-temperature applications.
• It is attacked by many chemicals, which cause it to craze and crack so it is used for packaging dry products only.
• To improve impact strength and brittleness (both of which are sometimes referred to as practical toughness), general-purpose polystyrene may be combined with various concentrations of rubber and acrylic compounds which diminishes certain properties with impact polystyrene e.g. clarity and hardness.
• The shock resistance or toughness of impact polystyrene may be varied by increasing the content of rubber in the material.
6. Nylon (Polyamide):
• Nylon is made from a dibasic acid combined with a diamine. So there is a -great variety of nylons. The type of acid and amine that is used is indicated by an identifying number: nylon 6/10 has 6 carbon atoms in the diamine and 10 in the acid.
• Nylon and similar polyamide materials can be fabricated into thin-wall containers.
• Nylon can be autoclaved.
• It is extremely strong and quite difficult to destroy by mechanical means.
• The widespread acceptance of nylon is due to its resistance to a wide range of organic and inorganic chemicals.
• It 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.
Polycarbonate can be made into a clear transparent container. This relatively expensive material has many advantages.
• It has ability to be sterilized repeatedly.
• The container is rigid like glass thus has been considered a possible replacement for glass vials and syringes.
• Polycarbonate is resistant to dilute acids, oxidizing or reducing agents, salts, oils (fixed and volatile), greases, and aliphatic hydrocarbons.
• 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.
• Polycarbonate articles can be subjected to repeated sterilization in steam or water without undergoing significant degradation.
• It is only moderately chemically resistant and only a fair moisture barrier.
• It is FDA-approved, although its drug-plastic problems have not been investigated adequately.
• It is attacked by alkalies, amines, ketones, esters, aromatic hydrocarbons, and some alcohols.
• Polycarbonate resins are expensive and consequently are used in specialty containers.
8. Acrylic Multipolymers (Nitrile Polymers):
• These polymers represent the acrylonitrile or methacrylonitrile monomer.
• They have unique properties such as gas barriers, good chemical resistance, excellent strength properties, and safe disposability.
• They are advantageous in food packaging due to the oil and grease resistance as well as minimal taste transfer effects which is regulated to standards set by the Food and Drug Administration.
• This medium cost material produces a fairly clear container (not as brilliant as styrene).
• 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.
9. Polyethylene Terephthalate (PET):
Polyethylene terephthalate is generally called as PET which is a condensation polymer typically formed by the reaction of terephthalic acid or dimethyl terephthalate with ethylene glycol in the presence of a catalyst.
• It is used as a packaging film since late 1950s, its growth has recently escalated with its use in the fabrication of plastic bottles for the carbonated beverage industry.
• The development of the biaxially oriented PET bottle has a major impact on the bottling of carbonated beverages, accounting for an estimated annual resin usage of approximately 350 million pounds.
• Its excellent impact strength and barrier properties make it attractive for use in cosmetics, mouth washes as well as in other products in which strength, toughness,and barrier are important considerations.
• The resin has been sanctioned for over 25 years by the FDA for food contact applications and has been the recipient of a favorable environmental impact statement.
10. Acetal Polyoxymethylene (POM):
POM is available under trade name Delrin and Kemetal. It is obtained from the polymerization of formaldehyde.
• It is basically an engineering plastic with high tensile strength, stiffness, and good fatigue endurance.
• Its Usage usually lies with devices, aerosol valves and similar engineering components. The density of POM is approximately 1.41.
• POM less hygroscopic than nylons, and if correctly stored it does not require pre-drying.
• Being a polymerization product of formaldehyde, residues may have to be checked.
11. Regenerated Cellulose:
Although it is a derivative of wood pulp comes under plastics.
• Uncoated regenerated cellulose film is very hygroscopic.
• Highly permeable to water.
• Has poor dimensional stability.
• Coated film is strong, flexible and transparent with good grease resistance.
• Coated films are mainly used as transparent overwraps, strip packs and as an outer ply in laminations which comes under trade names such as cellophane and rayophane.
12. Other Plastics:
• Coextruded resins are being used to fabricate bottles and thermoformed blisters with barrier characteristics.
• Coextrusion technology allows the use of high-barrier resins such as ethylene-vinyl alcohol which could not be used alone because of either high cost or physical/ dimensional instability.
• The resins used in the coextrusion can be selected to provide optimum performance characteristics for the particular product needs.
• A coextrusion such as polypropylene/ethylene-vinyl-alcohol/ polypropylene provides the moisture barrier of polypropylene coupled with the enhanced gas barrier of ethylene vinyl alcohol.
• It also provides packaging alternatives for products that previously were packaged only in glass.
• high-barrier plastics that might compete with glass and metal containers may be available through a new processing technology developed by Du Pont Co which involves dispersing nylon in a polyolefin resin so that the final polymer matrix
contains unique laminar arrangement of nylon platelets, which provide a series of overlapping barrier walls.
• It is reported that this technique produces a plastic which when compared with the polyolefins demonstrates a 140-fold increase as a barrier against certain hydrocarbons and an 8 fold increase as a barrier for oxygen.
The chief disadvantage of plastic containers when compared with glass is the problem of permeation in two directions:
• From the solution into the container,
• From the ambient environment through the plastic into the preparation.
Materials can be leached from the plastic container/adsorbed/absorbed into the liquid
preparation and in certain instances; the contents of the container can chemically or
physically react with the plastic components of the container causing container deformation.
Drug-plastic considerations have been divided into following:
4. Chemical reaction and
5. Alteration in the physical properties of plastics or products.
The transmission of gases, vapors, or Liquids through plastic packaging materials can
have adverse effects on the shelf-life of a drug.
(i) For example Penicillin tablets were found to degrade in polystyrene containers leading to permeation of water vapor.
(ii) A change in colour and taste of tetracycline suspension was observed owing to permeation of air through the walls of a polyethylene container.
Factors Influencing Permeability:
• 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.
Whereas molecules do not permeate through crystalline zone as a result increase in crystalline of the material should decrease permeability.
• Ex: hydrophilic material such as nylon is poor barriers to water vapor whereas hydrophobic materials such as polyethylene provide much better barriers.
• Whereas formulations containing volatile ingredients might change when stored in plastic containers and 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.
Most of the plastic contains some small amount of ingredients to stabilize or impart a specific property to the plastic, the prospect of leaching or migration from the container to the drug product is present. Problems can arise with plastics when dyes are added to the formula in relatively small amounts. Special dyes can migrate to a
parenteral solution and cause a toxic effect. Emissions of a component from the plastic container to the drug product can lead to drug contamination and necessitate removal of the product from the market.
This process involves the removal of agents from the pharmaceutical composition by means of the packaging material. Sorption can have serious consequences for pharmaceutical compositions containing important ingredients in solution. Since highpotency drugs are administered in low doses, sorption losses may significantly affect the
therapeutic effectiveness of the formulation. In practice, the loss of preservatives is often a problem. These agents act at low concentrations, and their sorption caused by sorption can be high enough to prevent the product from being protected from microbial growth.
Factors Influencing Characteristics of Sorption from Product:
• Chemical structure
• Solvent system
• Concentration of active ingredients
• Length of contact and
• Area of contact.
4. Chemical Reactivity:
Other ingredients used in plastic structure can respond to chemicals in one or more drug products. Sometimes the ingredients in formulation can be touched by plastic. Even small items of non-chemical substances can change the appearance of plastic or drug products.
5. Alteration in the Physical Properties of Plastics or Products:
Physical and chemical changes in packaging materials due to pharmaceuticals are called a correction. Phenomena such as penetration, sorption, and leaching play the role of changing the properties of plastics and may also lead to its degradation.
Deformation of polyethylene containers is often caused by the penetration of gases and vapors from the environment, or the loss of contents from the walls of the container.
For example Isteris has been found to be responsible for the considerable change in the mechanical properties of the plastic. Fluorinated hydrocarbons attack polyethylene and polyvinyl chloride. Changes in polyethylene caused by some agents have been noted.
• In other cases, the contents may extract plasticizers, antioxidants, or stabilizers, which change the flexibility of the package. Polyvinyl chloride is an excellent barrier to petroleum solvents, but the plasticizer in polyvinyl chloride is extracted by the solvent. This action usually leaves the plastic hard and hard. In some cases, this effect may not be immediately recognized as the solvent softens the plastic or substitutes for the plasticizer.
• Plastic containers used for emulsion preparations must be thoroughly evaluated for physical and chemical changes. Certain materials in an emulsion have a tendency to migrate toward the polyethylene wall, causing either a change in the emulsion or a collapse in the container. Since polyethylene has a tendency toward elastic recovery,
air is continuously drawn into the plastic container, increasing the chance of oxidation and drying out of the preparation. The air can cause the emulsion to break down, owing to dehydration or oxidation of the oil phase. This phenomenon is known as “breathing”. It can also be responsible for the loss of flavor and perfume ingredients from products packaged in plastic containers.
Guideline for Hold-Time Studies of Tablets
reference :Industrial Pharmacy -I (Formulative Pharmacy) by Dr. B Prakash Rao, S Rajarajan and Dr. Beny Beby
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube