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PACKAGING MATERIAL SCIENCE FOR PHARMA PRODUCTS

The document discusses packaging material science and describes the key functions of packaging including protecting pharmaceutical contents from environmental hazards, mechanical hazards, and preventing loss or contamination of contents. It defines primary and secondary packaging and lists common packaging materials like glass, plastics, metals, and papers. Specific plastic materials are described in detail including polyethylene, polypropylene, polystyrene, polyvinyl chloride, and considerations for drug-plastic interactions through permeation, leaching, and sorption. Glass containers like Type I, II, and III are also outlined.

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Packaging Material Science
1.Protectthecontentsfromthefollowingenvironmental hazards: Light- protectthecontentsfromlight Temperature- becapableofwithstandingextremesof temperature. Moisture- becapableofwithstandingextremesofhumidity. Atmospheric gases- protectthecontentsfromtheeffectof atmosphericgases(e.g.aerialoxidation). Particles- protectfromparticulatecontamination. Microorganisms- protectfrommicrobialcontamination. 5
2.Protectsthecontentfromthefollowingmechanicalhazards  Vibration- Usuallyduetotransportation  Compression- thisusuallyincludespressureappliedduringstacking.  Shock- suchasimpact,dropsorrapidretardation.  Puncture- penetrationfromsharpobjectsorduringhandling operations.  Abrasion- thismaycreateelectrostaticeffects. 3.Theymustnotaddorpermitlosstoitscontents:  Protectthecontentsfrombothlossandgainofwater.  Protectthecontentsfromlossofvolatilem aterials  Mustnotshedparticlesintothecontents.  Mustnotleachanythingtothecontents. 6
TYPESOFPACKAGING • Primary Packaging: This is the first packaging envelope which is in touch with the dosage form or equipment (i.e. bottle, cap, cap liner, label etc). The packaging needs to be such that there is no interaction with the drug and will providepropercontainm entofpharmaceuticals. E.g.Blister packages,Strippackages,etc. •The main functions of the primary package are to contain and to restrict any chemical, climatic or biological or occasionally mechanical hazards that may cause or lead to product deterioration. Packaging must also function as a m eansofdrugadministrations. 9
•Secondary Packaging: This is consecutive covering or package which stores pharmaceuticals packages in it for their grouping. E.g.Cartons,boxes, etc. OR •Thepackagingexternaltotheprimarypackageis knownasthe secondarypackaging. •The secondary packaging mainly provides the additional physical protection necessary to endure the safe warehousing andforrefill packaging. 10
 Apart from primary and secondary packaging, two types of special packagingarecurrentlyinuse,asfollows:  •Unit-dose packaging. This packaging guarantees safer medication by reducing medication errors; it is also more practical for the patient. It maybevery useful in improving compliance with treatment andmayalsobeusefulforlessstableproducts.  •“Device” packaging. Packaging with the aid of an administration device is user-friendly and also improves compliance. This type of packaging permits easier administration by means of devices such as prefilled syringes, droppers, transdermal delivery systems, pumpsand aerosol sprays. Such devices ensurethatthemedicinal productis administeredcorrectlyandin therightamount. 12
Types of primary and secondary packaging material Material Type Example of use Glass Primary Metric medical bottle, ampoule, vial Plastic Primary Ampoule, vial, infusion fluid container, dropper bottle Secondary Wrapper to contain primary pack Cardboard Secondary Box to contain primary pack Paper Secondary Labels, patient information leaflet 11
CONTAINER:  Acontainerforapharmacopoeialarticleisintendedtocontainadrug substanceordrugproductwithwhichitis,ormaybeindirectcontact.The closureis apartofthecontainer. QUALITIES OF GOODCONTAINER:  Thecontainermustbeneutraltowardsthematerialwhichis storedinit.  Thecontainer mustnotinteractphysicallyorchemicallywiththesubstance whichitholds.  Itshouldhelpinmaintainingthestabilityofproductagainsttheenvironmental factorswhichcausesitsdeterioration.  Itshouldbemadeofmaterialswhichcanwithstandwearandtearduring normal handling.  Itshouldbemadeofmaterialswhichcanwithstandwearandtearduring normal handling.  Itshouldbeabletowithstandchangesinpressureandtemperature.  Thematerialsusedformakingofthecontainermustbenon-toxic. 13
TYPES OF CONTAINERS: Containersaredividedintofollowingtypesonthebasisof theirutility: Well –closedcontainers: Awell-closedcontainer protectsthecontentsfromlossduringtransportation, handling,storageorsale. Singledosecontainers: Thesecontainersareusedtosupply onlyoneofmedicamentandholdgenerallyparenteral products. E.g.ampoulesandvials 14
Multidosecontainers:Thesecontainersallowthe withdrawalofdoseatvariousintervalswithoutchangingthe strength,qualityorpurityofremainingportion.these containersholdmorethanonedoseandareusedfor injectables. E.g.vials Light-resistant containers: These containers protect the m edicam entfromharmfuleffects oflight.Thesecontainersareused to store those medicaments which arephoto-sensitive. 15
Air-tightcontainers:Thesearealsocalledhermeticcontainers. These containershaveair-tightsealingorclosing.Thesecontainersprotectthe productsfromdust,moistureandair. Whereasair-tight sealedcontainers areusedforinjectables, air-tightclosed containersaremeantforthestorageofother products. Aerosolcontainers:Thesecontainersareusedtoholdaerosolproducts. Thesecontainershaveadequatemechanicalstrengthinordertobearthe pressureofaerosol packing. 16
FACTORS INFLUENCING THE CHOICE OF PACKAGE: 17
Legal and official requirement for containers
Stability aspects of packaging materials
 PACKAGINGMATERIALS Thefollowingmaterialsareusedfortheconstructionofcontainersandclosures Borosilicateglass Treatedsodalimeglass Regularsoda-limeglass General purposesodalimeglass 1.Glass: - (i) Type-I (ii)Type-II (iii)Type-III (iv)Type-NP (v)Colouredglass (ii) Urea (iv) Lead. (i) Phenolics (i)Polyethylene (iii)Polyvinylchloride(PVC) (v)Polycarbonate (vii)Polyethyleneterephthalate 2. Metals:(i) Tin (ii) Iron (iii) Aluminium 3.Plastics: (a)Thermosettingresins: (b)Thermoplastic resins: (ii)Polypropylene (iv) Polystyrene (vi)Polyamide(Nylon) (PET) 4.Rubber: (i) Naturalrubber (ii)Neoprenerubber (iii)Butylrubber. 19
GLASS CONTAINERS: Glassis thepreferredpackagingmaterial. COMPOSITIONOF GLASS  Sand(silicondioxide)Sodaash(sodiumcarbonate) Limestone(calciumcarbonate)Cullet(brokenglass)- aluminium,boron,potassium,magnesium,zinc,barium, Amber:lightyellowishtodeepreddishbrown,carbonand sulphurorironandmanganesedioxide Yellow: Compoundsofcadmiumandsulphur Blue: Variousshadesofblue,cobaltoxideoroccasionally copper(cupric) oxide Green:ironoxide, manganesedioxideandchromiumdioxid2 e 0
MANUFACTURE OF GLASS: Thefourbasicprocessesusedintheproductionof glass are: Blowingusescompressedair formthemoltenglassin thecavityofmetalmold. Indrawing, moltenglassis pulledthroughdiesor rollersthatshapethesoftglass. Inpressingmechanical forceis usedtopressthemolten glassagainstthesideofamold.  Castingusesgravityor centrifugal forcetocause moltenglasstoforminthecavity ofmold. 21
 ADVANTAGES • Theyarehygienicandsuitableforsterilization • Theyarerelativelynonreactive( dependingonthegradechosen) • Itcanacceptavarietyofclosures • Theycanbeusedonhighspeedpackaginglines • Theyaretransparent. • Theyhavegoodprotectionpower. • Theycanbeeasily labeled.  DISADVANTAGES • Itisrelativelyheavy • Glassisfragilesoeasilybroken. • Releasealkali toaqueouspreparation 22
TypeI glass: Composition: Neutralglass, borosilicate glass (silica (silicon dioxide, SiO2) andboron oxide). Advantages:  Itpossessesahighhydrolyticresistance.  Itisthemostinerttypeofpharmaceutical glass.  Ithasthelowestcoefficientof thermalexpansion(and hencesuitable for sterilizationby heat…..forampoulesandvials). Disadvantages:  It hasveryhighglasstransitiontemperaturesoneedscomplicatedprocessing.  Andthereforeexpensive. Uses:  TypeI glassissuitableforpackingall pharmaceutical preparations.  It is widelyusedasglassampoulesandvialstopackagefluidsforinjection.  In contrast to the other types of glass (type II and III), this type has no/little amo2 3 unts of basic oxides, so It is used to package solutions that could dissolve basic oxides in theglass.
TypeII glass Composition:soda-lime-silicaglass. Soda (Na2CO3) is used to decrease the glass transition temperature of silica. However, soda would increase water solubility of silica, so lime (CaO) is used to increasethehydrolyticresistance.Thistypewouldalsocontainotheroxides. Advantages:  This glass hasalowermeltingpointthanTypeI glass. It is thuseasier to produce andconsequentlycheaper.  Highhydrolyticresistanceduetosurfacetreatmentoftheglass. Uses:  TypeII glassusedtopackageaqueouspreparations.  However,asitcontainsbasic oxides,it is notusedtopackageparenteral formulations withapH<7 (i.e.acidic);thiswouldincreasethepHoftheformulation andcouldaffect thedrugstabilityandpotency.  It is theglass used to produce containers for eye preparations and other dropper bottles. 24
Type-III regular sodalimeglass  Containersareuntreatedaremadeofcommercialsodalimeglassof averagearebetterthanaveragechem ical resistance.  Itcontainshighconcentrationofalkalineoxidesandimpartsalkalinityto aqueoussubstances.  Flakesseparateeasily.  Uses:  For all soliddosageforms.  For oilyinjections. TypeNP-general purposesodalimeglass  Containersaremadeofsodalimeglasssuppliedfornonparentalproducts, intendedfororal or topicaluse.  Uses:  For oral use.  Topical purpose. 25
PLASTICS AccordingtoBritishstandardsinstitutesplasticsrepresents; “ Awiderangeofsolidcompositematerials whichare largelyorganic,usuallybaseduponsyntheticresinsor uponmodifiedpolymersofnaturaloriginandpossessing appreciablemechanicalstrength.Atasuitablestagein theirmanufacturing,mostplasticscanbecast,moldedor polymerizeddirectlyintoshape”. 26
 Classesof plastics: Therearetwoclassesofplastics,reflectingthebehaviorwithrespectto individualorrepeatedexposuretoheatingandcooling.  Thermoplastics  Capableofbeingshapedafterinitialheatingandsolidifyingbycooling.  Resistant to breakage and cheap to produce and providing the right plastics are chosen will provide thenecessary protection of theproduct inanattractivecontainers.  E.g.Polystyrene,polyethyleneandpolyvinyl chloride.  Thermosets  They need heat for processing intoa permanent shape. During heating such materials form permanent crosslinks between the linear chains, resultinginsolidification andlossofplasticflow.  E.g. Phenolic,ureaandmelaminearerepresentativeofthermosets. 27
TYPES OF PLASTICS  POLYETHYLENE  Thisis usedashighandlowdensitypolyethylene  Low density polyethylene (LDPE) is preferred plastic for squeezebottles. Properties: Ease of processing , barrier to moisture, strength /toughness,flexibility, easeofsealing.  Highdensitypolyethylene(HDPE) is lesspermeabletogases andmoreresistanttooils, chemicalsandsolvents. Properties:Stiffness,strength/toughness,resistance tochemicals. Itis widelyusedinbottlesforsoliddosageforms. Drawback: pronetostress cracking in thepresenceof surfactant2 s9 orvegetableormineral oils.
 POLYPROPYLENE  Ithasgoodresistancetocrackingwhenflexed.  Goodresistancetoheatsterilization.  It is colorless,odorlessthermoplasticmaterialwithexcellenttensilepropertiesevenat hightem perature.  Excellent resistancetostrongacidsandalkalis.  Lowpermeabilitytowatervapour  Permeability togases is intermediate between polyethylene HD and un-plasticized PVC  Suitableforuseinclosures, tabletcontainersandintravenousbottles.  POLYSTYRENE  Versatility,insulation,clarity,easilyfoamed(“Styrofoam”).  It isalsousedforjarsforointmentsandcreamswithlowwatercontent.  Drawback:Chemicals likeisopropylmyristateproducecrazing(afinenetwo3 r0 kofsurface cracks)followedbyweakeningandeventuallycollapsibleofthecontainer.
 POLYVINYL CHLORIDE  Versatility,easeofblending, strength/toughness, resistancetogrease/oil, resistanceto chemicals,clarity.  Usedasrigidpackagingmaterialandmaincomponentofintravenousbags.  Drawback: Poor impact resistance which can be improved by adding elastomers to theplasticsbutitwillincreaseitspermeability.  POLY VINYLEDENE CHLORIDE: • Excellentbarrierpropertiesagainst:moisture,watervapour,UVlight,aroma, inorganic acids, alkalies, aqueous salt solutions, organic water soluble acids, aliphatic hydrocarbons , esters of long chain fatty acids, detergentbase materials, em ulsifying agentsandwettingagents. • Goodthermoformability. • PVDC is very cost-effective, as coating weight can be customized depending on the requirementsofthebarrierproperties. • Medical gradeandnon-toxic. • Highlevelsoftransparencywhichimprovestheaestheticsoftheproduct. 31
 DRUG-PLASTIC CONSIDERATIONS  Apackagingsystemmustprotectthedrugwithout alteringthecompositionoftheproductuntil thelast doseisremoved.  Drug-plasticconsiderationshavebeendividedintofive categories: 1. Permeation 2. Leaching 3. Sorption 4. Chemical reaction 5. Alteration 32
 Permeation: • Itis thetransmissionofgases,vaporsorliquidsthroughplastic packagingmaterial. • Permeation of watervapor andoxygenthrough plasticwallintothe drugis amajorproblemis thedosageformis sensitivetohydrolysisand oxidation. • Thevolatile ingredientsmightchangewhenstoredin plastic containers andthetasteofthemedicinalproductsmaychangeforthesamereason ofpermeation.  Leaching: • Someplasticcontainershaveoneormoreingredientsaddedtostabilize it, thesemayleachintothedrugproduct. • Problemsmayarisewithplasticswhencoloringagentsareaddedin smallquantitiestotheformula. • Particulardyesmaymigrateintotheparentalsolutionandcauseatoxic effect. 33
 Sorption: • Thisprocessinvolvestheremovableofconstituentsfromthedrugproductbythe packagingmaterial. • Thetherapeuticefficacyoftheproductmaybereducedduetosorption. • Sorptionmaychangethechemicalstructure,pH,solventsystem,concentrationof activeingredientsandtemperatureetc…  Chemical reactivity: • Certainingredientsinplasticformulationsmayreactchemicallywithoneormore componentsofthedrugproduct. • Eveninmicroquantitiesif incompatibilityoccursmayaltertheappearanceofthe plasticorthedrugproduct.  Modification: • Thephysicalandchemicalalterationofthepackagingmaterialbythedrugproductis calledmodification. • Somesolventsystemsfoundtobeconsiderablechangesinthemechanicalpropertiesof theplastics. • For exampleoilshaveasofteningeffectonpolyethylene,hydrocarbonsattack polyethyleneandPVC. 34
METALS  Metal containers are used solely for medicinal products for non- parenteraladministration.  Metal is strong, opaque, impermeable to moisture, gases, odors, light, bacteria, and shatterproof, it is the ideal packaging material forpressurizedcontainers.  Itis resistanttohighandlowtemperatures  They include tubes, packs made from foil or blisters, cans, and aerosol andgascylinders.  Aluminium and stainless steel are the metals of choice for both primaryandsecondarypackagingformedicinalproducts.  Formanexcellenttamperevidentcontainers. 35
 ALUMINIUM • Itis relativelylightyetstrong • Barrier tolightandchemicals • Impermeableandeasytoworkinto avariety offormats,dependingon itsthickness. • Thickest aluminium is used for rigid containers such as aerosol cans andtubesforeffervescenttablets. • Intermediatethickness are whenmechanical integrity is still important butthepack should becapable of being reformed under areasonable force. e.g. Collapsible tubes for semi solid preparations or roll on screw caps. • Thinnest aluminium is used in flexible foil that are usuall3 y6 a componentoflaminatedpackagingmaterial.
 Disadvantagesandtheirovercomesolution • Major disadvantage is its reactivity in raw state, although it rapidly forms a protective film of aluminium oxide it is still liable to corrosion ( when exposed to some liquids and semi solid formulations, particularly at extreme pH or if the product containselectrolytes.  To overcome this problem, Aluminium is lined with epoxide, vinyl orphenolic  resins. • They are work hardening like collapsible tubes are made by impactextrusionwhichtendstomakealuminiumlessflexible.  To overcome, flexibility has to restored by an annealing stage. 37
 TIN  Advantages: • Thismetal is veryresistanttochemicalattack. • Readilycoatsanumberofthemetalse.g.tin-coatedleadtubes combinethesoftnessofleadwiththeinertnessoftinandforthis reasonitwasformerlyusedforpackagingfluoridetoothpaste.  Disadvantages: Tinis themostexpensivemetalamongtin,lead,aluminiumandiron.  Uses: • Tincontainersarepreferredforfoods,likemilkpowdercontainers arecoatedwithtin. • Currently,someeyeointment still packagedinpuretinointment tubes. 38
 IRON  Advantages: Ironassuchisnotusedforpharmaceuticalpackaging,large qualitiesoftin-coatedsteel,popularly called‘tin’, combinesthe strengthofsteelwiththecorrosionresistanceoftin.  Disadvantages: If anaqueousliquid canpenetrateapinholeorotherfaultinthe layeroftin,whichisvirtuallyashort-circuited galvanic cellis setupandtheintensechemicalreactionwhich resultsbrings aboutrapidcorrosionofunderlyingsteel.Asafurther measure thetinsurfaceis lacquered.  Uses: Fabricationofmilkcontainers,screwcapsandaerosolcans. 39
 LEAD  Advantages: • Lowestcostofall them etalsusedinpharmaceutical containers. • Softm etal.  Disadvantages: Leadwhentakeninternallythereisriskofleadpoisoning.So leadcontainersandtubesshouldalwayshaveinternalliningof inertmetalorpolymer.  Uses: Withliningleadtubesareusedforsuchproductasfluoride toothpaste. 58
CLOSURES:  Aclosureis thepartofthepackagewhichpreventthecontents fromescaping andallownosubstancetoenterthecontainer.  Closuresareavailableinfivebasicdesigns: 1. Screwon,threadedorlug 2. Crimpon(crowns) 3. Presson(snap) 4. Roll on and 5. Friction 59
 Threadedscrewcap:  Whenascrewcapis applied,itsthreadsengagedwiththe correspondingthreadsmoldedontheneckofthebottle.  Aliner in thecap,pressedagainsttheopeningofthecontainer, seals theproductin thecontainerandprovide theresistance to chemicalandphysicalreactionwiththeproduct.  Thescrewcapis commonlymadeofmetalorplastics.Themetalis usuallytinplateoraluminumandinplasticisthermoplasticand thermosettingmaterial. 60
Lugcap:  Thelugcapis similartothethreadedscrewcapandoperates onthesameprinciple.  It is simplyaninterruptedthreadontheglassfinish,insteadof acontinuousthread.  Unlikethethreadedclosure,itrequiresonly aquarterturn.  Thelugcapis usedforbothnormalatmospherepressureand vacuumpressureclosing. 61
 Crowncaps:  Thisstylecapis commonlyusedasacrimpedclosureforbeverage bottles.  Roll-onclosures  Thealuminumroll oncapcanbesealsecurely,openedeasilyand resealedeffectively.  Resealable,nonresalableandpilferprooftypesofroll onclosures areavailableforuseonglassorplasticbottles. 62
 Pilfer proof closures  Itis similartoroll onclosurebuthasagreaterskirtlength.  Thisadditionallengthextendsbelowthethreadedportion andfastenedtothebasiccapbytheseriesofnarrow bridges.  Whentheclosureis removedtheextraportionremainsinthe space onneck of thecontainer,thisindicatesthatthe packagehasbeenopened. 63
 CLOSURE LINERS:  Alinermaybedefinedasanymaterialthatinsertedinacaptoeffectaseal betweentheclosureandthecontainer.  Itis oftwotypes: 1. Homogeneousliner  Theseareonepiecelinersavailableasdiskoraringofrubberorplastic.  Itcanbewithstandhightemperaturesterilization. 2. Heterogeneousliners  Thesearecomposedoflayersofdifferentmaterialschosenforspecific requirements.  Itconsistsoffacingandbacking.Facingisincontactwithproductand backingprovidesquestioningeffect. 64
 Factorsinselectingaliner: • Chemicalinertness shouldbechemicallyinert • Appearance,thicknessetc. • Gasandwater-vapourtransmissionrates shouldbelow. • Torquerequiretoremovethecap shouldbeoptimum. • heatresistance e.g.duringautoclavingshouldbe thermostable. • Shelf-life shouldnotchangetheirshapeduringstorage. • Economics shouldbecheap. 65
RUBBERS (Elastomers): • Excellent material for forming seals, used to form closures such as bungs for vials or in similar applications such as gaskets in aerosol cans.  Categoriesof Rubbers: 1) Natural rubbers; • Suitable for multiple use closures for injectable products as rubber resealsafter multipleinsertionofneedle. • Disadvantagesare; i. It doesn't well toleratemultiple autoclaving becomingbrittle and leads to relative degree of extractable material in presence of additives. ii. Riskofproductabsorbingonorintoarubber. iii. It hascertaindegreeofmoisture&gaspermeation. 48
2) Synthetic rubber: • Have fewer additives and thus fewer extractable and tends to experiencelesssorptionofproductingredients. • Are less suitable for repeated insertions of needle because they tend to fragment or core pushing small particles of the rubber intotheproduct. • E.g.Silicone,butyl,bromobutyl,chlorobutyletc. • Silicone is least reactive but it does experience permeability to moistureandgas.  Softer rubbers experience less coring and reseal better, harder rubbersareeasiertoprocessonhighspeedpackaginglines. 49
TYPES OF RUBBER 1.BUTYL RUBBER Thesearecopolymersofisobutylenewith1-3%ofisopreneorbutadiene.  Advantages:- • Aftervulcanization butylrubberpossessesvirtuallynodoublebond,consequentlytheyaremost resistanttoagingandchemical attack. • Permeability towatervapourandair is verylow. • W ater absorptionis verylow. • Theyarerelatively cheapercomparedtoothersyntheticrubbers.  Disadvantages • Slowdecompositiontakesplaceabove1300C. • Oil andsolventresistanceis notverygood. 2.NITRILE RUBBER  Advantages: • Oil resistantduetopolar nitrilegroup. • Heatresistant.  Disadvantage • Absorptionofbactericide andleachingofextractives areconsiderable. 50
3.CHLOROPRENE RUBBERS (NEOPRENE) Thesearepolymers of1:4chloprene.  Advantages • DuetothepresenceofCl group closetothedouble bondsothebondisresistant tooxidationhencetheserubbersagewell. • Thisrubberis morepolarhenceoil resistant. • Heatstabilityis good(upto1500C). • Waterabsorptionandpermeabilityarelessthanfornaturalrubbers. 4.SILICONE RUBBERS  Advantages • Heatresistance(upto2500C). • Extremelylowabsorptionandpermeabilityofwater. • Excellentagingcharacteristicsduetotheirsaturatedchemicalstructures. • Poor tensilestrength.  Disadvantages • Theyareveryexpensive. 51
 FIBROUS MATERIAL  Thefibrousmaterialsaretheimportantpartofpharmaceuticalpackaging.  Fibrousmaterialsinclude:Papers,Labels,Cartons,Bags,Outers, TraysForShrink Wraps,LayerBoardsOnPallets, etc.  TheApplicationsaswell asAdvantagesofCartonsinclude:  Increasesdisplayarea  Providesbetterstackingfordisplayofstockitems  Assemblesleaflets  Providesphysicalprotectionespeciallytoitemslike metalcollapsibletubes.  Fiberboardouterseitherassolidor corrugatedboardalsofindsubstantial applicationfor bulkshipments.  Regeneratedcellulose film, tradenamesCellophane&Rayophane,is usedfor eitherindividual cartonsortoassembleano.ofcartons. 72
 FILMS FOILS AND LAMINATES • Regenerated cellulose film based on viscose ( chemical used for manufacturingofrayon) & laminatingtwoor moretypesoffilms, cellulose coatings, foil and paper play diff roles such as supportive, barrier, heat seal&decorative. • For Exam ple: Aluminumfoil evenin thethinnestgaugesoffersthebestbarrier properties, whicharenotapproachedevenbythemostimpermeableplastics. • “Metallization”: A relatively new process whereby particles of metal are laid down onto a surface under vacuum, can significantly improve the barrier propertiesofamaterialbutthesedonotapproach thepropertiesof apurefoil. • In the newer technology “Co-Extrusion”, a number of plastic plies are extrudedincombinationtoproducecheaperlaminations. 73
• Usesoffilms, foils, laminations:  Strippacks  Blisterpacks  Sachets  Diaphragmsealsfor bottles  Linersforboxeseitherattachedorloosebag-in-boxsystems&bags.  Foil blisters: When sealed with a metal foil-cover, the blister can provide a hermetic pack i.e. an isolated system, which excludes any exchange of gases between the product & surrounding atmosphere.  Alu-alu foil is thebestpharmaceuticalpackagingfilmfortablets,capsules,whichis taking placeofPVC film. ⚫ Applicabletotablets,capsules,pills, etc. ⚫ It'sagoodsubstituteforPVC sheet. ⚫ Nocracking,delaminationorpinholes ⚫ It hasthe quite good blocking properties effectively protecting drugs from water vapor, oxygenandultraviolet. ⚫ It is particularly suitableforpackingmoisture-sensitive drugsorthosesoldin thehotand humidareas. 54
 TAMPER RESISTANT PACKAGING:  Therequirementfortamperresistantpackagingis nowoneofthe majorconsiderationsinthedevelopmentofpackagingfor pharmaceutical products.  Atamperresistantpackageisprovidedwithanindicatoror barrierbeforeenteringthepackage, sothatif thisindicatoror barrier is broken,thebuyerimmediatelygetstheevidencethat theproducthasbeenopenedortampered.  Especiallyoverthecounterproductsrequiretamperresistant packaging. 75
ThefollowingpackagesareapprovedbyFDAas tamperresistantpackagingsystems: Film wrappers Blisterpackage Strippackage Bubblepack Shrinksealsandbands Foils, paperorplasticpouches 76 Bottleseals Tapeseals Breakablecaps Sealedtubes Aerosol containers Sealedcartons.
 Filmwrappers  Atransparentfilmwithdistinctivedesigniswrappedsecurelyaroundthe entireproductcontainer.Thefilmmustbecutortorntoremovetheproduct. Thewrappermusthaveanidentifyingcharacteristic(e.g.apattern,name, registeredtrademark,logo,orpicture)thatcannotbereadilyduplicated. Tintedwrappersarenotacceptable as anidentifyingcharacteristicbecause ofthepossibilitythattheirmaterialmaybeavailabletothepublic.A reasonablytight"fit"ofthefilmaroundthecontainermustbeachieved,e.g. byaheatshrinktypeprocess.  Sealingofafilmwrapperwithoverlappingendflaps is acceptable only if theendscannotbeopenedand resealedwithoutleavingvisibleevidenceoftampering. Theuseofcellophanewithoverlappingendflapsisnot acceptablebecauseofthepossibilitythattheendscan beopenedandresealedwithoutleavingvisible evidence thattam peringhasoccurred. 57
 Althoughfilmcanbeaccomplishedinseveralwaysandvariesin configurationfrompackagingequipmenttopackagingequipment,it canbegenerallycategorizedintofollowingtypes:  Fin sealwrapper  End-foldedwrapper  Shrinkwrapper  Finseal wrapper: Thesesealsareformedbycrimpingthefilmtogetherandsealing togetherthetwoinsidesurfacesof thefilm,producing a“fin” seal. Theoverwrapcanberemovedoropenedonlybytearingthewrapper. Materials:PolyethyleneorSurlyn(DuPont’sIonomerresin) 58
 End-foldedwrapper:Thiswrapperisformedbypushing theproduct into sheetofoverlappingfilm,whichformsthefilmaroundtheproductandfoldthe edgesingiftwrapfashion.Filmusedmustbeheat-sealable onbothsurfaces. Tobetamper-resistant,theoverwrapmustbewellsealedmustbeprintedor uniquelydecoratedtoexcludethepossibilityofhavinganalternateoverwrap substitutedinitsplace.Theprintedsurfaceofthecarton being wrappedmay alsobecoatedwithheatsensitivevarnish,whichcausesoverwraptobond permanentlytothepaperboard carton duringsealingof overwrap. The removal oftheoverwrapwoulddefacethecarton, makingthecarton unsuitableforreuse. Materials: •Cellophanecoatedinbothsidebyheatsealable polyvinylidenechloride(PDVC) ornitrocellulose-PDVC providesdurablemoisturebarrier. •Polypropylenecoatedwithheatsealableacrylic coating orpolypropyleneis addedwithheatsealablemodifiers. 59
 Shrinkwrapper: Theshrinkwrapconceptinvolvesthepackaging ofaproductinthermoplasticfilmthathasbeenstretchedand orientedduringitsmanufactureandthathasthepropertyof revertingback toitsunstretcheddimensions as thefilmunwinds ontheoverwrappingmachine,apocketis formedinthefoldofthe sheet,intowhichtheproductis inserted.AnL shapedsealerseals theremainderof overwrapandtrimsoff theexcessfilm.The looselywrappedproductisthenmovedthrough heatedtunnel whichshrinkstheoverwrapintoatightlywrappedunit. Materials:Heatshrinkablegradesofpolypropylene,polyethylene andpolyvinylchloride(PVC). 60
 Blister packs:  It is apackaging configuration capable of providing excellent environmental protection,coupledwithanestheticallypleasinganefficacious appearance.it alsoprovides user functionalityin terms of convenience, child resistance, and nowtemperresistance.  Theblisterpackageisformedbyheat-softeningasheetofthermoplastic resin andvacuumdrawingthesoftenedsheetofplasticintoacontouredmold.After cooling,thesheetisreleasedfromthemoldandproceeds tothefillingstation ofthepackaging machine. The semi-rigidblisterpreviouslyformedisfilled withproductandliddedwithaheat-sealablebackingmaterial.Thebacking material,orlidding,canbeofeitherapushthroughorpeelabletype. Dosageunits(forexample,capsulesortablets)are individuallysealedinplasticorfoil.Theindividual compartmentmustbetornor brokentoobtainthe product.Thebackingmaterialscannotbereadily separatedfromtheblistersoreasily replacedwithout leavingevidenceoftampering. 61
 Strippackage  Astrippackageis aformofunitdosepackagingoftabletor capsules.Astrippackageisformedbyfeedingtwowebsofheat sealableflexiblefilmthrougheitheraheatedcrimpingrollerora heatedreciprocatingplaten.Theproductisdroppedinto the pocketformedpriortoformingthefinalsetofseals.Sincethe sealingisusuallyaccomplishedbetweenpressurerollers,ahigh degreeofseal integrityis possible. 82
 Bubblepacks  Thebubblepackcan bemadeinseveralwaysbutisusually formedbysandwichingtheproductbetweenathermoformable, extensible,orheat-shrinkableplasticfilmandarigidbacking material,thisis passedthroughaheatedtunnel,whichshrinksthe filmintobubbleorskinovertheproduct,firmlyattachingittothe backingcard.  Theproductandcontaineraresealed inplasticandmountedinor onadisplaycard.Theplasticmustbetornorbrokentoremovethe product.The backing material cannotbereadilyseparated from thebubble oreasilyreplaced withoutleaving evidence of tampering 83
 Heatshrinkbandsor w rappers  Theshrinkbandconceptmakesuseoftheheat-shrinkingcharacteristicofa stretchorientedpolymerusuallyPVC. Thepolymerismanufacturedasan extruded,orientedtubeinadiameterslightlylargerthanthecap andneck ringofthebottletobesealed.Bandsorwrapperswithadistinctivedesign (e.g.,apattern,name,registeredtrademark,logo,orpicture)areshrunkby heattosealtheunionofthecapandcontainer.Thesealmustbecutortorn torem ovetheproduct.  Thebandorwrappercannoteasily beworkedoffandreappliedwithout visibledamagetotheband.Useofaperforatedtearstripcanenhance tamperevidence.Cellulosewetshrinksealsarenotacceptableasthe knowledgeofhowtoremoveandreapplythesesealswithoutevidenceof tam peringis widespread. 84
 Foil, paper,orplasticpouches  Theflexiblepouchispackagingconceptcapableofprovidingnotonlya packagethatistamperresistant,butalso,bytheproperselectionof material,apackagewithahighdegreeofenvironmentalprotection.A flexiblepouchisusuallyformedduringtheproductfillingoperationby eithervertical orhorizontalforming,filling,sealing(f/f/s) equipment.  Theproductisenclosedinanindividualpouchthatmustbetornor brokentoobtain theproduct. Thepouchshouldhaveadistinctive design(e.g.,apattern, name,registeredtrademark,logo,or picture).Theendsealsofthepouchescannotbeseparatedandresealed withoutshowingvisibleevidenceofentry. 85
 Bottlemouthinner seals  Abottlemaybemadetamper-resistantbybondinganinnersealtotherimofthe bottleinsuchawaythataccesstotheproductcanonlybeattainedbyirreparable destroyingtheseal.  Variousinnersealcompositionsmaybeusedlike: • Glassineandfoillaminations. • Gluem ounted. • Pressuresensitiveadhesive. • Heatsensitiveadhesive.  Paper,thermalplastic,polystyrenefoam(exceptthoseappliedwithpressure sensitiveadhesive),plasticfilm,foil,orcombinationsthereof,withadistinctive design(e.g.,apattern,name,registeredtrademark,logoorpicture)is sealedtothe mouthofacontainerunderthecap.Thesealmustbetornorbrokentoopenthe containerandremovetheproduct.Sealsappliedbyheatinductiontocontainers appeartoofferahigherdegreeoftamperevidencethanthosethatdependonan adhesivetocreatethebond.  Tomeettamper-resistantcriteria,theinnersealmustbeprintedordecoratedwith uniquedesign.Thesealmustalsobebondedsufficientlytoensurethatitsremoval wouldresultindestructionoftheseal. 66
 Tapeseals  Tapeinvolvestheapplicationofagluedorpressuresensitivetape orlabelaroundorovertheclosureofthepackage,whichmustbe destroyedtogainaccesstothepackagedproduct.Thepaperused mostoftenishighdensitylightweightpaperswithpoor tear strength.  Paperorfoilwithadistinctive design issealed over allcarton flapsorabottlecap.Thesealmustbetornorbrokentoremovethe productTapesealsareacceptableonlyiftheycontainaunique featurethatmakesitapparentifthesealshavebeenremovedand reapplied, e.g., apermanentadhesive. 87
 Breakablecaps  Breakableclosurescomeinmanydifferentdesigns.The rolloncap design usedinthepastforcarbonatedbeveragesusesanaluminumsheet,which placedoverbottleneckduringcapping operation. The cap blank isheld on thebottleunderpressurewhilerollerscrimpandcontourthebottletreadinto thecapblank.Thebottomportionof cap isrolledaroundandunderthe lockingringonthebottleneckfinish.Thislowerportionofthecapblankis usuallyperforatedsothatitbreaksawaywhenthecapisunscrewed,which servesasvisiblesignofprioropening.  Aratchet-styleplasticcapisalsocommonlyusedforanumberofdifferent products.Inthisdesignthebottomportionofclosurehasatear-awaystrip, whichengagesaratchetonthebottleneck.Toremovetheclosure,thebottom portionoftheclosuremustbetornawaytodisengagetheratchet andallow theremoval ofthecap. 88
 Sealedmetaltubesorplasticblind-endheatsealedtubes  Collapsibletubesusedforpackagingareconstructedofmetal,plastic,or laminationoffoil,paper,andplastic.Metaltubesarestillusedforthose productsthatrequirehighdegreeofbarrierprotectionaffordedbymetal. Punctureinserts,whichareusuallymadeofaluminum3to5milthick,are usedtosealthetubeopeningfortamperresistance.  Bothendsofthetubearesealed.Themouthorblind-endmustbepuncturedto obtaintheproduct.Atubewithacrimpedendis acceptableif thecrimpedend cannotbebreachedbyunfoldingandrefoldingwithoutshowingvisible evidenceoftam pering. Directprintingofthelabel onthecontainer is preferredtousingalabelthatcouldberemovedandsubstituted. 89
 Cardboardcartons  Folding paperboardcartonshavebeenusedassecondarypackage for OTC productsfor manyyears. Seal endcartonsusesexternally appliedglueor hotmelttoprovidecartonsealing.  CardboardCartonsspecificallydesignedtoensurethatinorderto obtaintheproduct,thecartonsealmustbecutormustbenon- resealablewithoutshowingvisibleevidence of entorntoremove theproductandmustnotbeabletobeeasilyworkedopenand resealedwithoutobviousdamagetothecarton. 90
 Aerosol containers  Theaerosolcontainerusedforpharmaceuticalproductsisusuallymadeof drawnaluminium.Theinsideofthecontainercanbespeciallycoatedif productcompatibilityis aproblem.  Ahydrocarbonpropellantinitscooledliquidphaseisaddedtothecontainer alongwiththeproduct,andaspraynozzlecontainedinagasketedmetal ferruleiscrimpedovertheopeningoftheaerosolcontainer.Alengthof polyethylenetube,calledadip-tube,isattachedtotheinsideof thespray nozzleanddipsintotheproduct,drawingproductintothespraynozzlewhen thesprayer is activated.  Thespraynozzlesareusuallymeteredtoallowaspecificdosetobedispersed witheachspray. 91
QUALITY CONTROL TESTS FOR GLASSES 1) CHEMICAL RESISTANT OF GLASS CONTAINERS A)POWDEREDGLASS TEST: Itisdonetoestimatetheamountofalkali leachedfromthepowderedglasswhichusuallyhappensattheelevated temperatures.Whentheglassis powdered,leachingofalkaliis enhanced, whichcanbetitratedwith0.02Nsulphuricacidusingmethylredasan indicator  Step-1:Preparationofglassspecimen:Fewcontainersarerinsed thoroughly withpurified wateranddried withstreamof cleanair. Grind thecontainers in amortartoafinepowderandpassthroughsieveno.20and50.  Step-2: W ashingthespecimen: 10gmoftheabovespecimenis takeninto250 mlconicalflaskandwashitwith30mlacetone.Repeatthewashing, decant theacetoneanddriedafterwhichitis usedwithin48hr.  Procedure: 10gmsampleisaddedwith50mlof high puritywaterina250mlflask.Placeit inanautoclaveat121⁰C±2⁰Cfor30min.Coolitunderrunning water.Decant thesolutionintoanotherflask,washagainwith15mlhigh purity waterand againdecant.Titrateimmediatelywith0.02N sulphuricacidusingmethylr7 e2 d asanindicator andrecordthevolume.
 PREPARATION OF SPECIMEN FOR POWDERED GLASS TEST 93
POWDEREDGLASS TEST (AccordingtoUSP volume27) 94
B) W ATER ATTACK TEST:  Thisisonlyfortreatedsodalimeglasscontainersunderthecontrolled humidityconditionswhichneutralizethesurfacealkaliandglasswillbecome chem ically moreresistant.  Principleinvolvedis whetherthealkalileachedornotfromthesurfaceofthe container.  Procedure:Rinsethoroughlywithhighpuritywater.Fill eachcontainerto 90%ofitsoverflowcapacitywithwaterandisautoclavedat121⁰Cfor30min thenitiscooledandtheliquidisdecantedwhichistitratedwith0.02N sulphuricacidusingmethylredasanindicator.Thevolumeofsulfuricacid consumedisthemeasureoftheamountofalkalineoxidespresentintheglass containers. TESTS CONTAINER VOL.OF 0.02N H2SO4 Powdered glass test Type I Type II Type III 1.0 8.5 15.0 Water attack test Type II(100ml or below) Type II(above 0.07 0.02 95
WATER ATTACK TEST (USP) 96
2)HYDROLYTIC RESISTANCE OF GLASS CONTAINERS:  Rinse eachcontainer atleast 3timeswithCO2 free waterandfill withthesameto their filling volume. Also fill & Cover thevials andbottles and keepin autoclave. Heatto100⁰C for 10minandallow thesteamtoissue fromtheventcork. Rise the tempfrom 100⁰C to121⁰C over 20min. Maintain thetempat121⁰C to122⁰C for 60min.Lowerthetempfrom121⁰Cto100Cover40minventingtopreventvacuum.  Removethecontainerfromautoclave,coolandcombinetheliquidsbeingexamined. Measurethevolumeoftestsolutionintoaconicalflaskandtitratewith0.01MHCl usingmethylredasanindicator.Perform blankwithwaterandthedifference betweenthetitrationrepresentsthevolumeofHCl consumedbythetestsolution. Nominal capacity of container (ml) Number of containers to be used Volume of test solution to be used or titration (ml) Up to 3 at least 20 25.0 5 or less at least 10 50.0 6 to 30 at least 5 50.0 More than 30 at least 3 100.0 97
3)ARSENIC TEST:  Thistestis forglasscontainersintendedforaqueousparenterals.Wash theinnerandoutersurfaceofcontainerwithfreshdistilledwaterfor 5min.Preptestasdescribedinthetestforhydrolyticresistanceforan adequateno.ofsamplestoproduce50ml.pipetteout10mlsolutionfrom combinedcontentsofallampoulestotheflask.Add10mlofHNO3to drynessonthewaterbath,drytheresidueinanovenat130⁰Cfor 30mincool andadd10mlhydrogenmolybdatereagent.Swirlto dissolveandheatunderwaterbathandrefluxfor25min.Cooltoroom tempanddeterminetheabsorbanceat840nm.Dotheblankwith10ml hydrogenmolybdate.  Theabsorbanceofthetestsolutionshouldnotexceedtheabsorbance obtainedbyrepeatingthedeterminationusing0.1mlofarsenic standardsolution(10ppm)inplaceoftestsoln. 79
4)THERMAL SHOCK TEST:  Placethesamplesinuprightpositioninatray.Immersethetrayintoahot waterforagiventimeandtransferstocoldwaterbath,tempofbothare closelycontrolled.Examinecracksorbreaksbeforeandafterthetest.The amountofthermalshockabottlecanwithstanddependsonitssize,design andglassdistribution.Smallbottleswithstandatempdifferentialof60to 80⁰Cand1pintbottle30to40⁰C.Atypicaltestuses45Ctempdifference betweenhotandcoldwater. 5)INTERNAL BURSTINGPRESSURE TEST:  ThemostcommoninstrumentusedisAmericanglassresearchincrement pressuretester.Thetestbottle isfilledwithwaterandplacedinsidethe testchamber.Ascalingheadisappliedandtheinternalpressure automaticallyraisedbyaseriesofincrementseachof which isheldfora setoftime.Thebottlecanbecheckedtoapreselectedpressureleveland8 0 thetestcontinuesuntilthecontainerfinallybursts.