1. George Wild Science of Medicines
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Packaging Products
The primarypackagingof a pharmaceutical preparationisthe packagingthatisinintimate contact
withthe medicine i.e.the blisterpack,strippack,glassampoule,whilstthe secondarypackaging
referstothe packagingthatcontainsthe medicine inits primarypackagingalongwithotherancillary
productslike oral syringe/spoonandthe patientinformationleaflet(PIL).The primarypackagingwill
be chosenwithroute of administration,dosage form, patientpopulation/adherence anddrug
physicochemical propertiesinmind,whilstthe secondarypackagingwill seektobe aesthetically
pleasing,informative andpractical initsprotectionof the primaryproduct.
Glasspackaginghas many benefitsoverother,lessrobustformslike plasticorpaper,butalso comes
withsome disadvantageslike potential fragilityandleachingof glassconstituentsintothe product.
Due to the waysinwhichglasscan be manufactured,there are fourdistincttypesof glassthatcan
be usedinpharmaceutical packaging;typesI,II,IIIand NP. Type I glassis borosilicate(boronoxide is
added),whichisthe mostinertglasstype andtherefore usedforparenteral productslike ampoules
and vials.Itisalsousedto package slightlyacidicpreparationsandisthe mostexpensivetoproduce.
Type II glassisdealkalysedsodalimeglass,the nextlowergrade aftertype I,whichhasbeenwashed
withsulphurdioxide toremove ionsonthe glasssurface.Itisusedto holdsolutionsbufferedto
belowpH7. Type IIIis standardsoda lime glassusedinfoodpackagingandusedtopackage large
volumes>100mL. NP isnon-parenteral use glassof the lowestgrade,usedfortopical applications
like mouthwashes.
Chemical Degradation
Hydrolysisoccurswithmanydrugsand involvesthe additionof awatermolecule acrossabond
withinamolecule thatcausescleavage of saidbond.Thisoccursfrequentlywithamidesandesters
due to the electrondeficientcarbonbeingatargetfor nucleophilicattack,andis more commonin
some drugsthan others,suchas chloramphenicol where the deficiencyisincreasedthroughthe
presence of chlorine groups;thisiswhyeye dropsmustbe storedinthe fridge.Beta-lactamrings
foundinsome penicillindrugsandare againparticularlysusceptibledue tothe strainappliedon
carbons inthe 4-memberedring.
Oxidationisthe increase of C-Obondsina molecule and/orthe reductionof C-Hbonds.Whenthis
occurs at ambienttemperatureswithmolecularoxygen,it’scalledautoxidationandisusually
because of radicals inthe liquidinitiating,propagatingandterminatingincycles.
Dimerand polymerisationmayalsooccur betweenmoleculesof the same drugto cause degradation
throughthe formationof newmolecules.Thishappenswithglutaraldehydesatalkaline pHvalues
throughketoenol tautomerism,andwithamoxicillinthroughbeta-lactamringhydrolysis. Isomeric
change may alsooccur underacid or basiccatalysis,toproduce enantiomerswhichmayleadto
racemisationof Rand S enantiomersandequilibrium.Thiscan be bad due to poorertherapeutic
effectortoxicityissues.Racemisationata chiral centre ina multi-chiral-centredmolecule is
epimerisation.GeometricisomersaroundC=Cbonds,andstructural isomerswhichhave the same
molecularformulamay alsooccur duringdegradation.
2. George Wild Science of Medicines
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Photodegradationismore of anissue with300 – 400nm wavelengthsfoundinsunandartificial light,
and withgroupssuchas; nitro,alkene,aryl chloride,phenolandcarbonyl groups.The absorptionof
wavelengthsof lightcommonly leadstooxidationof some kindbutmayalsocause isomerisation,as
isthe case withretinol.
Transacetylationisanexample of achemical modificationthatcanoccur indrugs, examplesof which
are foundbetweenaspirinandparacetamol,aspirinandPEGs and aspirinandphenylephrine.
Transacetylationmayalsooccurwhenan acetyl groupis relocatedwithinamolecule,changingits
structure,as isthe case withhydroxybenzoate estersandsugars/sugaralcohols.The Maillard
reactionisanotherexample of chemical modificationthatoccursthistime betweenreducingsugars
and an amine,whichreactwhenthe reducingsugarringstautomerise andopenup.Sodium
metabisulphate isanantioxidantthatcommonlyreactswithadrenaline insolutiontoform
adrenaline sulphonate,withreducedtherapeuticaction.
The stabilityof proteinsisdue toa large extentonthe physical andchemical stabilitythatthey
possess.A proteinisrequiredtohave aspecifictertiarystructure contributedtobythe primaryand
secondarystructuresof foldingandaminoacidorderrespectively.Inthe body,proteinscommonly
arrange withhydrophobicgroupsfacinginwardssothatthe more hydrophilicgroupsare facingthe
aqueousenvironment,whichismore energeticallyfavourable. The formationof aggregatescan
occur whenthisno longerholdstrue andhydrophobicgroupsbecome outwardsfacingandinteract
withotherhydrophobicelementsof otherself-molecules.Thisresultsinlossof proteinfromsolution
as adsorptionof the molecules toeachotheroccurs.Partiallyunfoldedproteinsmayfoldbackbut
aggregationisgenerallyirreversible,meaningthatitisto be avoidedindrugdevelopment.Factors
that increase the aggregationincidence include;heat(preventinguse of heatsterilisationtherefore),
freezing(nofreeze-drying),shearstress(stirringandpumping) aswell aschemical degradation.
Factors influencingthe chemical degradationof proteinsinclude;aminoacidsassome are more
prone than otherstodegradation;position of aminoacidsassome sequencesare more prone than
others;and locationwithinthe tertiarystructure asthose thatare deeperare protectedfrom
oxygen,waterandlight.The mostcommonchemical reactionsare oxidation, deamidation,
disulphide bridgeinterchange,hydrolysisandracemisation. Oxidationmayoccurwithaminoacidsin
solutionorinfreeze-driedformulations,withmethionine andcysteinebeingespeciallysusceptible.
Cysteine moleculesmayinteracttoformdisulphide bridgesleadingtochange inshape,or
aggregationif it’sbetweenmolecules.Hydrolysisoccursmostcommonlyatasparagine-proline
bondsand resultsinscissionof amolecule.Glutamateandasparagine residuesreactthroughtheir
side chainmoleculesthroughdeamidation,whichcanleadtosubstantial change toconformation
and bioactivity.
By substitutingdifferent,more stable aminoacidsinforlesserstableones,the stabilitycanbe
improvedbothchemically,throughbetterbonding,andphysicallythroughstrongerintermolecular
bondsor more intermolecularbondsi.e.substituteasparagineforserine.
