PACKAGING OF PHARMACEUTICAL DOSAGE FORMS
INTRODUCTION:- Packaging is the process by which the pharmaceuticals are suitably placed so that they should retain their therapeutic effectiveness from the time of their packaging till they are consumed.
Definition: Packing is the art and science which involves preparing the articles for transport, storage, display and use.
The ideal container or package should:
- Protect the contents from the following environmental hazards:
- Light – protect the contents from light
- Temperature – be capable of withstanding extremes of temperature.
- Moisture – be capable of withstanding extremes of humidity.
- Atmospheric gases – protect the contents from the effect of atmospheric gases (e.g. aerial oxidation).
- Particles – protect from particulate contamination.
- Microorganisms – protect from microbial contamination.
- Protects the content from the following mechanical hazards
- Vibration – Usually due to transportation
- Compression – this usually includes pressure applied during stacking.
- Shock – such as impact, drops or rapid retardation.
- Puncture – penetration from sharp objects or during handling operations.
- Abrasion – this may create electrostatic effects.
- They must not add or permit loss to its contents:
- Protect the contents from both loss and gain of water.
- Protect the contents from loss of volatile materials
- Must not shed particles into the contents.
- Must not leach anything to the contents.
- Must have a pharmaceutically elegant appearance:
- In a competitive market the appearance of a package first draws the attraction of the consumers than its contents.
- Must be easy to label and thus to identify the product.
- Must be convenient and easy to use by the patient.
- Must be cheap and economical.
- Must not react with the content.
- Must be biodegradable.
SELECTION OF PACKAGING MATERIAL
The materials selected for packaging must have the following characteristics:
- They must protect the preparation from environmental conditions.
- They must not be reactive with the product,
- They must not impart tastes or odors to the products,
- They must be non-toxic,
- They must be FDA (Food & Drug Administration) approved,
- They must meet applicable tamper-resistance requirements
- They must be adaptable to commonly employed high-speed packaging equipment. and
- They must have reasonable cost in relation to the cost of the product.
The following materials are used for the construction of containers and closures
- Glass: – (i) Type-I Borosilicate glass
(ii)Type-II Treated soda lime glass
(iii)Type-III Regular soda-lime glass
(iv)Type-NP General purpose soda lime glass
- Metals (i) Tin (ii) Iron (iii) Aluminum (iv) Lead.
- Plastics (a) Thermosetting resins : (i) Phenolics
(b) Thermoplastic resins: (i)Polyethylene
(viii)Polyethylene terephthalate (PET)
- Rubber (i) Natural rubber
(ii) Neoprene rubber
(iii) Butyl rubber.
|Type of glass||Main Constituents||Properties||Uses|
e.g. Pyrex, Borosil
|SiO2 – 80%
B2O3 – 12
Al2O3 – 2%
Na2O+CaO – 6%
|· Has high melting point so can withstand high temperature
· Resistant to chemical substances
· Reduced leaching action
|· Laboratory glass apparatus
· For injections and
· for water for injection.
Treated soda-lime glass
|Made of soda lime glass. The surface of which is treated with acidic gas like SO2 (i.e. dealkalised) at elevated temperature (5000C) and moisture.||· The surface of the glass is fairly resistant to attack by water for a period of time.
· Sulfur treatment neutralizes the alkaline oxides on the surface, thereby rendering the glass more chemically resistant.
|· Used for alkali sensitive products
· Infusion fluids, blood & plasma.
· large volume container
Regular soda-lime glass
|· It contains high concentration of alkaline oxides and imparts alkalinity to aqueous substances
· Flakes separate easily.
· May crack due to sudden change of temperature.
|· For all solid dosage forms (e.g. tablets, powders)
· For oily injections
· Not to be used for aqueous injection
· Not to be used for alkali-sensitive drugs.
Non-parenteral glass or General purpose soda-lime glass.
|· For oral and
· Topical purpose
· Not for ampoules.
|Neutral Glass||SiO2 – 72-75%
B2O3 – 7-10%
Al2O3 – 6%
Na2O – 6-8%
K2O – 0.5 – 2%
BaO – 2-4%
|· They are softer and can easily be moulded
· Good resistance to autoclaving
· Resistant to alkali-preparations (with pH upto 8)
· Lower cost than borosilicate
|· Small vials (<25 ml)
· Large transfusion bottles
|Neutral Tubing for Ampoules||SiO2 – 67%
B2O3 – 7.5%
Al2O3 – 8.5%
Na2O – 8.7%
K2O – 4%
CaO – 4%
MgO – 0.3%
|· In comparison to neutral glass its melting point is less. After filling the glass ampoules are sealed by fusion and therefore the glass must be easy to melt.||· Ampoules for injection.|
|Coloured glass||Glass + iron oxide||· Produce amber color glass
· Can resist radiation from
290 400 450nm
|· For photosensitive products.|
Advantages of glass container:-
- They are quite strong and rigid.
- They are transparent which allows the visual inspection of the contents; especially in ampoules and vials.
- They are available in various shapes and sizes. A visually elegant container attracts the patients.
- Borosilicate (Type-I) and Neutral glasses are resistant to heat so they can be readily sterilized by heat.
- Glass containers can be easily cleaned without any damage to its surface e.g. scratching or bruising.
- Borosilicate type of glass is chemically inert. Treated soda lime glass has a chemically inert surface.
- As the composition of glass may be varied by changing the ratio of various glass constituents the proper container according to desired qualities can be produced.
- They do not deteriorate with age, if provided with proper closures
- Photosensitive drugs may be saved from UV-rays by using amber colour glass.
- They are cheaper than other packaging materials.
- They are brittle and break easily.
- They may crack when subject to sudden changes of temperatures.
- They are heavier in comparison to plastic containers.
- A transparent glass gives passage to UV-light which may damage the photosensitive drugs inside the container.
- Flaking:– From simple soda-lime glass the alkali is extracted from the surface of the container and a silicate rich layer is formed which sometimes gets detached from the surface and can be seen in the contents in the form of shining plates – known as ‘flakes’ and in the form of needles – they are known as ‘spicules’. This is a serious problem, especially in parenteral preparations.
- Weathering:- Sometimes moisture is condensed on the surface of glass container which can extract some weakly bound alkali leaving behind a white deposit of alkali carbonate to remain over there, further condensation of moisture will lead to the formation of an alkaline solution which will dissolve some silica resulting in loss of brilliance from the surface of glass – called weathering.
To prevent weathering, the deposited white layer of alkali carbonates should be removed as early as possible by washing the containers with dilute solution of acid and then washing thoroughly with water.
- This metal is very resistant to chemical attack.
- Readily coats a number of the metals e.g. tin-coated lead tubes combine the softness of lead with the inertness of tin and for this reason it was formerly used for packaging fluoride toothpaste.
Tin is the most expensive metal among tin, lead, Aluminium and iron.
- Tin containers are preferred for foods, like milk powder containers are coated with tin.
- Currently, some eye ointment still packaged in pure tin ointment tubes.
- Aluminium is a light metal – hence the shipment cost of the product is less.
- They provide attractiveness of tin at some what lower cost.
- The surface of aluminium reacts with atmospheric oxygen to form a thin, tough, coherent, transparent coating of oxide, of atomic thickness, which protects the metal from further oxidation.
- Any substance that reacts with the oxide coating can cause corrosion e.g. products with the oxide coating can cause corrosion e.g. products of high or low pH, some complexing agents etc.
- As a result of corrosion process H2 may evolve.
- Aluminium ointment tubes.
- Screw caps
- Aluminium strips for strip-packaging of tablet, capsules etc. Some times internally lacquered aluminium containers are used to stop the reaction with the content.
Advantages:- Iron as such is not used for pharmaceutical packaging, large qualities of tin-coated steel, popularly called ‘tin’, combines the strength of steel with the corrosion resistance of tin.
Disadvantages:- If an aqueous liquid can penetrate a pinhole or other fault in the layer of tin, which is virtually a short-circuited galvanic cell is set up and the intense chemical reaction which results brings about rapid corrosion of underlying steel. As a further measure the tin surface is lacquered.
Uses:- Fabrication of milk containers, screw caps and aerosol cans.
- Lowest cost of all the metals used in pharmaceutical containers.
- Soft metal.
Disadvantages:- Lead when taken internally there is risk of lead poisoning. So lead containers and tubes should always have internal lining of inert metal or polymer.
Uses:- With lining lead tubes are used for such product as fluoride tooth paste.
General properties of plastics
- Plastics are synthetic polymers of high molecular weight.
- They are sensitive to heat, and many may melt or soften at or below 1000 Nevertheless, several plastics can be autoclaved e.g. nylon, polycarbonate, polypropylene, high density polyethylene (HDPE) etc.
- Plastic containers are light in weight, they are easier to handle.
- Mechanically they are almost as strong as metals and, therefore, containers can have thinner walls than glass containers.
- They are poor conductors of heat, a disadvantage if the content is to be autoclaved.
- Generally, they are resistant to inorganic chemicals but are often attacked by organic chemicals but are often attacked by organic solvents and oils.
- Plastic contain some additives (e.g. antioxidants, lubricants, plasticizers, stabilizers, and filler) which may contaminate the content.
- Very few types of plastics completely prevent the entry of water vapour and some are permeable to gases like oxygen, carbon-di-oxide.
TYPE OF PLASTICS:- Plastics are classified into two groups according to their behavior when heated:
- Thermoplastic type:- On heating, they soften to a viscous fluid which hardens again on cooling.
e.g. Polyethylene, polypropylene, polyvinylchloride, polystyrene, nylon (polyamide), polycarbonate, acrylic multipolymers, polyethylene terephthalate etc.
- Thermosetting type:- When heated, they may become flexible but they do not become liquid; usually their shape is retained right up to the temperature of decomposition. Because of a high degree of cross-linking they are usually hard and brittle at room temperature.
e.g. phenol-formaldehyde, urea formaldehyde, melamine formaldehyde.
|High density polyethylene (HDPE)
r = 0.955 g/cc
|Inert, low cost, low water vapour transmission, tough.||Semi-opaque, transfer of taste ingredients, absorbs dilute solutions.||Detergents, bleaches, milk, foods, cleansing powders, drugs & cosmetics.|
|Low density polyethylene (LDPE)
r = 0.920 g/cc.
|Squeeze property, inertness, low cost.||Relatively poor barrier to non-polar molecules and high water vapour transmission.||Cosmetics, personal products, foods.|
r = 1.05 g/cc.
|Clarity, stiffness, low cost.||High water vapor transmission, susceptibility to cracking, poor impact.||Dry drugs, petroleum jelly.|
|Rigid polyvinylchloride (PVC)
r = 1.35 g/cc.
|Clarity, stiffness, O2-barrier, retention of non-polar molecules.||10-12 additives may be present, difficult to process, susceptible to organic solvent.||Shampoo, bath oil, detergent.|
r = 0.90 g/cc.
|Inert, low cost.||Low temperature brittleness, high concentration of stabilizer is present.||Drugs, cosmetics, syrups, juices.|
r= = 1.10 g/cc.
|Good barrier for non-polar molecules, tough, good O2-barrier, sterilizable.||High cost, water absorption||Foods, drugs, cosmetics, aerosols|
r = 1.20 g/cc.
|Very tough, clear, sterilizable||Cost, susceptibility to solvent cracking, poor barrier for water and O2.||Drugs, cosmetics.|
|Acrylic polymers (PMMA =Polymethyl methacrylate)
r = 1.10 g/cc.
|Clarity, good for oils||Poor water vapor transmission, poor barrier for O2.||Drug cosmetics.|
|Polyethylene terephthlate (PET)||Excellent strength, good barrier for gas and aroma.||Bottle for carbonated waters, mineral waters, mouth washes, cosmetics.|
DRUG-PLASTIC CONSIDERATION:- A packaging must protect the drug without altering the composition of the product until the last dose is removed.
Drug plastic consideration has been divided into five separate categories:-
(4) Chemical reaction, and
(5) Alteration in the physical properties of plastics or products.
- PERMEATION:- The transmission of gases, vapours or liquids through plastic packaging materials can have an adverse effect on the shelf-life of a drug.
- Permeation of water vapor and O2 through the plastic wall into the drug can cause a problem if the dosage form is sensitive to hydrolysis and oxidation. Temperature and humidity influences the permeability of oxygen and water. e.g. Nylons are hydrophilic in nature, and are poor barrier for water while hydrophobic materials as polyethylene provide much better barriers.
- Formulations containing volatile ingredients may change when stored in plastic containers due to the permeation of one or two ingredients through the walls of the containers. Often, the aroma of cosmetic products become objectionable and the taste of medicinal products changes.
- Certain w/o 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.
- LEACHING:- Additives those are added in the plastics may leach into the content. 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, may catalyse some reaction in the solution – decomposing the drug.
- SORPTION:- This process involves the removal of constituents from the drug product by the packaging material. Drug substances of high potency are administered in small doses. In this case losses due to sorption may significantly affect the therapeutic efficacy of the preparation.
A common problem is the loss of 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 influencing the characteristics of sorption from products are:
- chemical structure of the solute,
- solvent system,
- concentration of solute,
- time of contact and
- area of contact.
- CHEMICAL REACTIVITY:- Certain ingredients that are used in plastic formulations may react chemically with one or more components of a drug. 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.
- MODIFICATION:- The physical and chemical alteration of the packaging material by the drug product is called modification. Deformation in polyethylene containers is often caused by permeation of gases and vapours from the environment or by loss of content through the container walls.
- Oils have a softening effect on polyethylene and PVC.
- Fluorinated hydrocarbons attack polyethylene and PVC. In some cases, the content may extract the plasticizers, antioxidant or stabilizer, thus changing the flexibility of the package.
- Plasticizer when extracted by some solvents renders the wall stiff.
- CONTAINERS:- The container is the device that holds the drug. The immediate container is that which is in direct contact with the drug at all times. According to the method of closure and use, the containers are of following types;-
- Well closed containers:- A well closed container is used to protect the preparation from contamination by extraneous solids, to prevent the loss of contents during transport, storage and handling.
- Air tight container:- Air tight containers are used to protect the container from atmospheric contamination of liquids, solids or vapors. They prevent loss of drugs due to efflorescence, deliquescence or evaporation or oxidation.
- Hermetically sealed containers:- Hermetically sealed containers is that which does not allow the air and other gases to pass through it. E.g. glass ampoules are sealed by fusion.
- Light resistant containers:- They are used to protect the drugs which undergo decomposition in the presence of light. Such drugs may be enclosed in amber colored bottle or opaque container.
- Single dose container:– They are used to supply only one dose of the medicament. e.g. ampoules.
- Multi dose container:- A multidose container holds a number of doses e.g. multidose vials.
- Aerosol containers:- Containers for aerosol must be strong enough to withstand the pressure evolved inside the container at the time of use of the preparation.
- Classification of containers according to their shapes:
- Glass / polyethylene bottles.
(i) Narrow mouth
(ii) Wide mouth
- Dropper bottles/ droptainers
- Collapsible tubes
- Polythene packets for i.v. fluid.
- Polythene / glass bottle for i.v. fluids
- Aerosol containers
- Glass / Polyethylene bottles:-
(i) Wide mouthed bottles are used for containing solid dosage forms like powder, capsules, and tablets. To absorb the moisture sometimes silica-gel bags are given inside the bottle.
(ii) For low viscosity liquids e.g. gargle, mouth washes, mixtures, elixirs narrow mouthed bottle is used. For high viscosity liquids or for suspensions wide-mouthed bottles are used.
(iii) Liquid preparations for external uses like lotion, liniments, paints etc. are supplied in coloured fluted bottles in order to distinguish them from preparations meant for internal use.
- Dropper bottles or droptainers:- Eye drops, ear drops, nasal drops etc. should be dispensed in amber colour glass bottles fitted with a dropper. Now-a-days manufacturers prefer plastic droptainers. It is a single piece of squeezable container having an in built dropper.
- Collapsible tubes:- Ointments, pastes, gels are packed in plastic or metal tubes.
- Ampoules:- Ampoules are made of special type of neutral glass having low m.p. so that it can be heat sealed at low temperature.
- Vials:- Used for storing multidose indictable preparation. The needle is passed through the rubber closure, the drug is drawn out. The rubber plug automatically seals the hole. Thus contamination of bacteria is checked.
- Polyethene packets for infusion fluid:- These flexible bags or packets are made of PVC, polyethylene or polypropylene.
- Glass bottles for i.v. fluids:- Previously glass bottles with big rubber stoppers were used.
- Aerosol containers:- Gases are made liquid under high pressure. So this type of containers should ensure that pressure.
CLOSURE AND CLOSURE LINERS:- A closure is that part of a package which prevent the contents from escaping and allow no substance to enter the container. Closures are available in five basic designs:
(1) Screw-on, threaded or lug,
(2) Crimp-on (Crowns)
(3) Press-on (snap)
(4) Roll-on and
Many variations of these basic types exist, including vacuum, tamper-proof, safety, child-resistant and linerless types and dispenser application.
Threaded Screw Cap:- When the screw-cap is placed on the neck of the container, its threads engage with the corresponding threads molded on the neck of the bottle. A liner in the cap seals the opening of the container. Screw-caps are commonly made of metals (tinplate or aluminium) and plastics (thermoplastics and thermosetting). Metal caps are usually coated on the inside with an enamel or lacquer for resistance against corrosion.
Lug-cap:- It is similar to screw-cap in principle. It is simply an interrupted thread on the glass Finnish, instead of continuous thread. It requires only a quarter turn.
Uses: It is used for both normal atmospheric pressure and vacuum-pressure closing. This type of caps is widely used in food industry.
Crown caps:- This style of cap is commonly used as a crimped closure for beverage bottles and remains unchanged for more than 50 years. Crown-caps are made of metals.
Roll-on closures:- Roll-on closures are obtained as threadless shell. These shells are placed on glass bottles having threaded neck. The shell is placed and then pressed so that a thread is automatically formed. Roll-on type of closures is extremely suitable for glass-containers, since these closures allow for dimensional changes in the glass container.
Pilfer-proof closures:- It is similar to roll-on closures except that it has a greater skirt length. This additional length extends below the threaded portion to form a bank, which is fastened to the basic cap of a series of narrow metal “bridges”. When the pilfer-proof closure is removed, the bridges break, and the bank remains in place on the neck of the container.
Non-reusable Roll-on Closures:- In some packaging applications a reusable cap is not desired. Vials for ophthalmic products are good example of this type. The aluminium roll-on closures have to be torn-off the tabs.
CLOSURE LINERS:- A liner may be defined as any material that is inserted in a cap to effect a seal between the closure and the container.
Liners are classified into two types:
(a) Homogeneous liner:- These are one-piece liner available either as a disk or as a ring. They are widely used for pharmaceuticals because their properties are uniform and can withstand high-temperature sterilization.
(b) Heterogeneous or Composite liners:- These are composed of layers of different materials chosen for specific requirements, In general the composite liner consists of two parts: a facing and a backing. Usually, the facing is in contact with the product, and the backing provides the cushioning and sealing properties required.
TAMPER RESISTANT PACKAGINGS:- A tamper resistant package is provided with an indicator or barrier before entering the package, so that if this indicator or barrier is broken, the buyer immediately gets the evidence that the product has been opened or tampered. Especially over the counter products require tamper resistant packaging. The following packages are approved by FDA as tamper resistant packaging systems:
- Film wrappers
- Blister package
- Strip package
- Bubble pack
- Shrink seals and bands
- Foils, paper or plastic pouches
- Bottle seals
- Tape seals
- Breakable caps
- Sealed tubes
- Aerosol containers
- Sealed cartons.
Film wrapper:- Film wrapper can be categorized into:
(i) End-folded wrapper:- This is formed by passing the product into a sheet of overwrapping film, which forms the film around the product and folds the edges in a gift-wrap fashion. The folded areas are heat sealed by passing against a heated bar.
(ii) Fin seal wrapper:- The seals are formed by crimping the film together and sealing together the two inside surfaces of the film, producing a ‘fin’-seal.
In this case heated bars never comes in contact with the package, hence much greater and more consistent sealing pressure can be applied and consequently better sealing integrity can be accomplished.
(iii) Shrink wrapper:- In this type of packaging the product is packed within a thermoplastic film that has been stretched and oriented during its manufacture and that has the property of reverting back to its unstretched dimensions once the molecular structure is ‘unfrozen’ by application of heat.
As the film unwinds on the over-wrapping machine, a pocket is formed in the center fold of the sheet, into which the product is inserted. An L-shaped sealer seals the remainder of the overwrap and trims off the excess film.
(iv) Blister package:- The blister package is formed by heat-softening a sheet of thermoplastic resin and vacuum drawing the soften sheet into a contoured mold. After cooling, the sheet is released from the mold and proceeds to the filling station of the packaging machine. The semi-rigid blister previously formed is filled with product and lidded with a heat-sealable backing material. The backing material may be of two types:
(i) a push-through type or (ii) peelable type.
For commercial reason and for machine performance the blisters on most unit dose packages are made of PVC. For moisture protection PVC may be laminated with polyvinylidene chloride (saran) or polychlorotrifluoroethylene (Aclar) films. Under extremely humid condition Aclar coated PVC is preferred.
For push through type backing material aluminium foil coated with heat sealable coating is used.
For peelable type backing material polyester or paper is used as a component of the backing lamination. This peelable type backing material is tamper proof and child resistant.
(v) Strip package:- A strip package is a form of unit dose packaging that is commonly used for package is formed by feeding two webs of a heat-sealable flexible film through either a heated crimping roller or heated reciprocating plates. The product is dropped into the pocket formed prior to forming the final set of seals.
A continuous strip is formed, generally several packets wide. The strip packets are cut to the desired number of packets in length.
The product usually has a seal around each tablet. The seal can be rectangular, or “picture-frame format” or can be contoured to the shape of the product.
Since the sealing is usually accomplished between pressure rollers, a high degree of seal integrity is possible.
(vi) Aerosol containers:- The aerosol container used for pharmaceutical products is usually made of drawn aluminium. The inside of the container can be specially coated if product compatibility is a problem. A hydrocarbon propellant in its cooled liquid phase is added to the container along with the product, and a spray nozzle contained in a gasketed metal ferrule is crimped over the opening of the aerosol container. A length of polyethylene tube, called a dip-tube, is attached to the inside of the spray nozzle and dips into the product, drawing product into the spray nozzle when the sprayer is activated.
The spray nozzles are usually metered to allow a specific dose to be dispersed with each spray.
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