Capsules;

 definitionofcapsules,
 typesofcapsules,
 sizesandshapesofcapsules,
 natureandtypesofgelatin,
 compositionofgelatin,
 capsuleformulation,
 activepharmaceuticalingredients,excipients,
 designofhardgelatincapsuleforpowderfill,
 fillingofhardgelatincapsules,storage,packagingandstabilityconsideration,
 softgelatincapsule,manufactureofsoftgelatincapsules,comparisonofhardsoftgelatincapsules.

Capsulesarethedosageformsinwhichthedrugformulationinapowder,semisolid,orliquidformisenclosedinas
hell.Thisshellisgenerallymadefromgelatin,butcanbemadefromotherpolymerssuchashydroxypropylmethyl
cellulose(HPMC),polyvinylalcohol(PVA),seaweed,orstarch.

Typesofcapsules

Dependingonthecompositionofthegelatinshell,thecapsulescanbe;

a)Hardcapsules,suchashardgelatinorHPMCcapsules,aretypicallyusedforpowderorsolidfills.Lately,hardcap
suleshavealsobeenusedforliquidorsemisolidfills.

b)softgelatincapsules,usedforsemisolidorliquidfills.

Softgelatincapsules(alsoknownas softgels)aremadefromarelativelymoreflexible,plasticizedgelatinfilmtha
nhardgelatincapsules.Mostsoftandhardcapsulesareintendedtobeswallowedasawhole.Somesoftgelatinca
psulesareintendedforrectalorvaginalinsertionassuppositories.Somesoftgelatincapsulesareintendedtobec
utopenbythepatienttoremoveandexternallyapplythecontainedmedicament,for example,ophthalmically. 
Figure21.1 showsthecommonshapesofsoftgelatincapsules. Table21.1 showstheexamplesofcommonlyuse
dcapsuledosageforms.
Figure21.1  Schematicdiagramsillustratingdifferentshapesofsoftgelatincapsules.Therangeoffillvolumesisa
lsoindicated.

Thecapsuleshelldissolvesrapidlyoncontactwithgastrointestinal(GI)fluids,thusreleasingthecapsule’sconten
ts.Drug’sbioavailabilityfromcapsulesisusuallyhighandsimilartothoseofimmediate-
release(IR)tablets.Coatingofcapsuleshellordrugparticles(withinthecapsule)withsustained-
release(SR)polymerscanprolongdrugreleaseandaffectbioavailability.

Hardgelatincapsuleshaveasignificantamountofboundwater.Thesecapsulesaregenerallynotphysicallystabl
einlowhumidityconditions,suchasinthepresenceofdesiccantinthepackageddrugproduct.Theytendtobeco
mefragileandcrackatlowhumidity.Ontheotherhand,HPMCcapsuleshavelowerequilibriummoisturecontent
sthangelatincapsulesandhavebetterphysicalstability(i.e.,donotbecomefragileandcrack)onexposuretolow
humidity.Themajorityofcapsuleproductsmanufacturedtodayarehardgelatincapsules.

GELATIN

Gelatinisacolorless,almosttasteless,translucentproteinaceoussubstancethatisbrittlewhendryandelasticw
henmixedwithcontrolledamountofmoisture.Itisproducedbyirreversible,partialhydrolysisofcollagen,which
isobtainedfromanimalskinandbones.I

Gelatinpossessesfivebasicpropertiesthatmakeitsuitableforthemanufactureofcapsules:
1.Itisnon-toxic,widelyusedinfoodstuffs,andisacceptableforuseworldwide.
2.Itisreadilysolubleinbiologicalfluidsatbodytemperature.
3.Itisagoodfilm-formingmaterial,producingastrongflexiblefilm.Thewallthicknessofahard
gelatincapsuleisabout100µm.
4.Solutionsofhighconcentration,e.g.40%w/v,aremobileat50°C.Otherbiologicalpolymers,
suchasagar,arenot.
5.Asolutioninwaterundergoesareversiblechangefromasoltoagelattemperaturesonly
afewdegreesaboveambient.

Hardgelatincapsules

Ahardgelatincapsuleshellconsistsoftwopieces:acapandabody.Thebodyhasslightlylowerdiameterthanthec
apandfitsinsidethecap.Theyareproducedemptyandarethenfilledinaseparateoperation.Duringthecapsulefi
llingunitoperation,thebodyisfilledwiththemedicament,followedbytheinsertionofthecapoverthebody.

Theshapesandinterlockingarrangementofthebodyandthecaphaveevolvedtomeetthemanufacturingandus
erequirementsofhardgelatincapsulesasshownin Figure21.2.

Figure21.2Schematicdiagrams(a–
c)ofhardgelatincapsulesillustratingtheirdesignfeatures.Thelarger,narrowerpartofthecapsulesisthebodyan
dthesmaller,widerpartisthecap.

·           Conventionally,thebodyandthecaphadsmoothedgeswithadiameterofthecapbeingslightlyhighertha
nthatofthebody.Thetwocomponentscouldslideovereachother(Figure21.2a).

·           Tominimizedefectsduringtheproductionprocess,thedesignoftheedgeofthebodywastaperedtoallow
smoothpenetrationintothecapwithminimumdefectsduringhigh-speedproductionoperation(Figure21.2b).

·           Thecapsulesweremodifiedtohaveanencirclinggrooveeachonthecapandthebody(Figure21.2c)and/
oranotchtoallowfirmlockingofthecaponthebody(Figure21.2b and c).

·           Toaccommodatetheneedforafirmsealinthecaseofliquidandsemisolid-
filledhardgelatincapsules,raisedcircularbands(dimples)wereintroducedonthebodyandthecapalongtheseal
ingzone(Figure21.2c).
·           Fortheuseofhardgelatincapsulesindouble-
blindclinicaltrials,itwasnecessarytohavehardgelatincapsulesthatcouldnotbereopenedafterclosing.Tomee
tthisobjective,capsuleswiththecapthatcoversmostofthebodyweredeveloped.

Forhumanuse,emptygelatincapsulesaremanufacturedineightsizes,rangingfrom000(thelargest,fillvolume1
.37ml)to5(thesmallest,fillvolume0.13ml),asshownin Table21.1.Thepowder-
fillingcapacityofthesecapsulesvariesdependingonthepackeddensityoftheformulation.Modernhigh-
speedcapsule-
fillingmachinesarecapableoffillingupto200,000capsulesperhour,matchingtheproductioncapacityoftablets
.Theformulationfilledweightinthecapsulescanrangefrom30to1400mg,dependingonthepowder’sbulkandc
ompactdensities.

Table21.1  Typicalsizesofhardgelatincapsules

Hardgelatincapsulescanbefilledwithpowders,granules,pellets,microtablets,tablets,capsules,liquids,orsem
isolids.Mostofthemarketedproductscontainpowdersorgranules.Recently,theliquid-orsemisolid-
filledhardgelatincapsuleshavegainedpopularity.

Afteringestion,thegelatinshellimbibeswater,softens,swells,anddissolvesintheGItract.Encapsulateddrugsa
rereleasedrapidlyanddispersedeasily,leadingtorapidabsorption.

Advantagesanddisadvantagesofhardgelatincapsules

Advantages

Comparisonwithtablets

1. Hardgelatincapsulesoftenprovideformulationcapabilityforuniquelychallengingdrugmolecules.For
example,adrugcandidatewithalowmeltingpointorthatisliquidatroomtemperatureusuallyhaspoor
 manufacturabilityasatablet,especiallyifitrequiresahighdose.Suchacompoundcanbeencapsulatedi
naliquid-orsemisolid-filledhardgelatincapsule.
2. Inaddition,verylow-dosedrugs(in μg)canhavecontentuniformitychallengeswhenformulatedasata
blet.Thedistributionofthesedrugscanbesignificantlybetterwhenencapsulatedasasolutioninaliquid
orsemisolidmatrixinahardgelatincapsule.
3. Hardgelatincapsulesgenerallyrequirelessformulationcomponentsandplacelessstringentrequirem
entonthepowderpropertiesoftheformulation.Theycanalsoallowflexibilityinformulationwiththepo
ssibilityoffillingoneormoreofdiversesystemsincludingpowders,granules,pellets,andsmalltablets.I
naddition,hardgelatincapsulescanbeusedforblind-inginclinicalstudies.

Thedisadvantagesofhardgelatincapsules

Inherenthighmoisturecontentrequirementofgelatin.Forexample,highlysolublesalts,suchasiodides,bromid
es,andchlorides,ofdrugsaregenerallynotformulatedinhardgelatincapsulesbecausethesecandrawmoisture
fromtheshell,thusmakingtheshellbrittle.Storageunderlowhumidityconditions,suchaswiththeuseofdesicca
ntinpackaging,canalsomaketheshellbrittle.Inaddition,gelatinispronetocross-
linkinginthepresenceofverylow(inpartspermillionrange)concentrationsofformaldehyde,whichmaybepres
entincertainpharmaceuticalexcipientssuchaspolyethyleneglycol(PEG).

Comparisonwithsoftgelatincapsules

Incomparisontosoftgelatincapsules,themanufacturingprocessofhardgelatincapsulesislessdemanding,tedi
ous,andcostly.Thisisbecausethesoftgelatincapsulemanufacturerequirestheformationofgelatinribbonsduri
ngtheencapsulationprocessitself,whereasthehardgelatincapsulesusepremanufacturedcapsuleshells.Theh
ardgelatincapsulemanufacturealsodoesnotrequireacuringormoisture-
lossstepafterencapsulationofthedrugformulation.

Theresidualwaterinthecapsuleshellsislower(~10–16%w/
w)forhardgelatincapsulesthanforsoftgelatincapsules(~30%w/
w).Thiscanaffectthestabilityoftheencapsulatedformulationdirectlybychemicaldegrada-
tion(e.g.,hydrolysis)ofwater-
sensitivecompoundsorplasticizationofthereactionmediumwithwater,thusincreasingtherateofdegradation
.Inaddition,softgelatincapsuleshellshaveahighoxygenpermeationrate,whichcancontributetotheoxidation
ofsensitivedrugs.

Solid-filledhardgelatincapsules

Mainapplications

Hardgelatincapsulesareoftenpreferredovertabletsasthedosageformforinitial(PhaseIandPhaseIIA)clinicalst
udiesofnewmolecularentities(NMEs).Thisisbecausetheeffectoflimitedavailabilityoftheactivepharmaceutic
alingredient(API)toconductnecessaryscreeningforthedevelopmentoftablets.Manyinitialclinicalstudiessim
plyuseadrug-in-
capsule(DIC)product,whichistheonlydrugmanuallyencapsulatedinthehardgelatinorHPMCcapsules.
Hardcapsulesarealsopreferredforthecomparatorandblindedclinicalstudies.Theseclinicalstudiesrequiretha
tthepatientand/
orthedoctorshouldnotbeabletoidentifytheactualdrugproductbeingadministeredtothepatient.Inthesestud
ies,twoormoredrugproductsareadministeredafterencapsulatingtheminhardgelatincapsulesofthesamespe
cificationsandsuchthatthecapsulescannotbeopened.

Formulationconsiderations

Hardgelatincapsule-
manufacturingprocessplacesarelativelylessstringentrequirementonthepowderpropertiesofthefillformula
tionthantablets.Theimportantformulationconsiderationsincludethefollowing:

1.        Flow:Adequateflowthroughthehopperandintothedosingdevice  (dosator)forreproduciblefillingofth
ecapsules.

2.        Density:Reproducibledensityofthepowderisimportantforfill  weightuniformityofcapsulesbecauseth
edosingdevicesinhigh-speedcapsule-
fillingmachinesarefilledbasedonthevolumeofthepowderforatargetweight.

3.        Lubricity:Magnesiumstearateistypicallyaddedtomostpowder  formulations.Whenmixedwithotherp
articles,magnesiumstearatecoatstheirsurfaceandactsasalubricant.Lubricantsfacilitatethelackofadhesiont
ometallicmachineparts,especiallythedosingdeviceusedtoformapluginhigh-
speedmachines,andadequateflowoftheformulation.Otherlubricantscommonlyusedarestearicacidandsodi
umstearylfumarate.

4.        Compactibility:Somehigh-speedcapsule-fillingmachinesforma  plugofthepowderbeforefillingintoth
ecapsule.Incaseswhereplugformationisrequiredforencapsulation,somelevelofcompactibilityofthepowder
isneeded.

5.        Noninteractionwithcapsuleshell:Lackofinteractionbetweenthe  drugsubstanceand/
orformulationcomponentswiththecapsuleshell,eithergelatinorHPMC.Thisinteractioncouldbeintheformof
solubilizationorchangingthewatercontentoftheshell.Hygroscopicandvolatilecomponentsareusuallyunsuit
able.Thefillshouldnotcontainmorethan5%w/wofwater.Inaddition,chemicalinterac-
tionsbetweenthecomponentscanleadtobioavailabilityorstabilityproblems.Forexample,theuseofPEGindru
gformulationcanleadtocross-
linkingofgelatinonstorageduetotheunintendedpresenceofformaldehydeinPEG,whichcandiffuseintothesh
ellandreactwithgelatin.Similarproblemshavebeenobservedduetothepresenceofresidualperoxidesinexcipi
ents.

6.        Dose:Doseanddrugloading(i.e.,  %w/woftheformulation,thatis  theAPI)influencesdrugcontentunifor

mitybetweenthecapsules,theextenttowhichthepowderpropertiesoftheformulationareaffectedbythephysi
cochemicalcharacteristicsofthedrugsubstance,andmanufacturabilityofthecapsuledosageform.Forexampl
e,itmaybedifficulttoassureadequateuniformityofthecontentoftheAPIfordrugswithextremelylowdoses(e.g.
,in μg),anditmaynotbepossibletofillacapsuleofacceptablesizeforextremelyhigh-
dosedrugs(e.g.,morethan600mg).Forintermediatedoses,thepercentdrugloadingintheformulationcanrang
ewidely.Drugpropertiespredominantlygovernthepowderpropertiesoftheformulationforhighdrug-
loadingformulations(e.g.,morethan60%w/w).
7.        Particlesize,shape,anddensity:Particlesizeandshapeinfluence  theflow,uniformity,andthuscontento
ftheactiveinaformulation.Adrugsubstancewithirregularorspherical-
likecrystalsismorelikelytoflowwellthantheneedle-
shapedcrystals.Drugcontentuniformityisalsoaffectedbyparticledensity,ifitissignificantlydifferentthanthed
ensityoftheexcipients.

8.        Moisturesorption–desorptionisotherm:Moisturesorptionand  retentionpropertiesofthedrugandexci
pients,indicatedbyahysteresisinthesorption–
desorptionisotherm,canaffectthephysicalstabilityofgelatinduringstorageandthechemicalstability.

9.        Solubilityandwettability:Solubilityandwettabilityofthedrug  substanceaffectitsdissolutioncharacteri
stics.Alow-
solubilitydrugsubstancemightrequiretheadditionofawettingagent(e.g.,surfactantsuchaspolysorbate80)int
heformulation.

Excpients

Thepowderformulationsforencapsulationintohardgelatincapsulesrequireacarefulconsiderationofthefillin
gprocessrequirements,suchaslubricity,compactibility,andflow.Additivespresentincapsuleformula-
tions,suchastheamountandchoiceoffillers,lubricant,disintegrant,andsurfactant,andthedegreeofplugcomp
action,caninfluencedrugreleasefromthecapsule.Thefunctionalcategoriesofformulationcomponentsareasf
ollows:

1.Fillers  (ordiluents):Activeingredientismixedwithasufficientvolumeofadiluent,usuallymicrocrystallinecell
ulose,lactose,mannitol,starch,ordicalciumphosphate,toincreasethebulkoftheformulation.

2.Glidants:Glidantsarefinelydivideddrypowdersaddedtotheformulationinsmallquantitiestoimprovetheirfl
owratefromthehopperandintothebodyofthecapsuleduringthefillingprocess.Glidants,suchascolloidalsilico
ndioxide,powderedsilicagel,starch,talc,andmagnesiumstearate,improveflowby

a.Reducingtheroughnessbyfillingsurfaceirregularities.

b.Reducingattractiveforces.

c.Reducingelectrostaticrepulsion.

Theoptimalconcentrationoftheglidantusedtoimprovetheflowofapowdermixtureisgenerallylessthan1%w/
w.

3.Lubricants:Capsuleformulationsusuallyrequirealubricantjustas  thetabletformulationstoreducepowdera
dhesiontothemachineparts,especiallyduringplugformation.Lubricantseasetheejectionofplugsbyreducingt
headhesionofpowdertometalsurfacesandfrictionbetweentheslidingsurfacesincontactwiththepowder.The
mostcommonlubricantsforcapsuleformulationsarehydrophobicstearates,suchasmagnesiumstearate,calci
umstearate,andstearicacid.

4.Surfactantsandwettingagents:Surfactantsmaybeincludedincapsuleformulationsofpoorlywater-
solubledrugstoreducethecontactangle,increasethewettabilityofdrugparticles,andenhancedrugdissolution
.Themostcommonlyusedsurfactantsincapsuleformulationsaresodiumlaurylsulfateandsodiumdocusate(so
diumdioctylsulfosuccinate).
Inaddition,ahydrophilicpolymer,suchasHPMC,issometimesusedasawettingagentintheformulationsofpoor
lysolubledrugs.Powderwettabilityanddissolutionrateofseveraldrugs,suchashexo-
barbitalandphenytoin,wereenhancedwiththeinclusionofmethyl-
celluloseorhydroxyethylcelluloseintheircapsuleformulations.

5.Disintegrants:Adisintegrantisfrequentlyincludedtoaidrapiddisintegrationanddissolutionofthecontents.
Commondisintegrantsusedinhardgelatincapsuleformulationsincludecroscarmellosesodium,crospovidone
,andsodiumstarchglycolate.

Controlled-
releasebeadsandminitabletsareoftenfilledintogelatincapsulesforconvenientadministrationofanoralcontr
olled-
release(CR)dosageform.Forexample,SRantihistamines,antitussives,andanalgesicsarefirstmanufacturedint
oextended-release(XR)micro-
capsulesormicrospheres,andthenplacedinsideagelatincapsule.Anotherexampleisenteric-
coatedlipaseminitabletsthatareplacedinagelatincapsuleformoreeffectiveprotectionoftheseenzymesfromt
heacidicenvironment.

Manufacturingprocess

Verysmall-
scaleandexperimentalfillingofthehardgelatincapsulescansimplybecarriedoutmanually,thatis,byremovingt
hecapfromthebodyofanemptycapsuleshell,fillingthebodywithapreweighedamountofAPIorformulation,an
dattachingthecap.Thiscanbecarriedoutinearlyclinicalstudiesbythesponsororbythepharmacist.Compoundi
ngby
Figure21.3  Hand-fillingmachineusedtofillhardgelatincapsules.

thepharmacistispreferredwhenthestabilityofthedruginthecapsuleisunknownandiscalledon-
sitecompounding.

Capsulefilling
Capsulesizes
Hardcapsulesaremadeinarangeofsizes;thestandardindustrialonesinusetodayforhuman
medicinesrangefromsize0to4.Toestimatethefillweightforapowder,thesimplest
wayistomultiplythebodyvolumebyitstappedbulkdensity.Thefillweightforliquidsiscalculated
bymultiplyingthespecificgravityoftheliquidbythecapsulebodyvolumemultipliedby0.9.Toaccommodatespe
cialneedssomeintermediatesizesareproduced,termed‘elongatedsizes’,that
typicallyhaveanextra10%offillvolumecomparedtothestandardsizes,e.g.for500mgdosesofantibiotics,elong
atedsize0capsulesarecommonlyused.

Large-scalefillingofhardgelatincapsulesfollowsthesameprinciplesusingahigh-speedcapsule-
fillingmachine,withtwosignificantimprovements:

·           Capsulealignmentandseparationaredrivenbyvacuum,insteadofmechanicalinterlocking.

·           Powderfillingmayrequireasoftcompact(plug)formationdependingontheformulationweightandcaps
ulefillvolume.Thiscompactisusuallymuchsofterthanatypicaltablet.Thecompactionforce usedforplugforma
tionistypically20–30N,comparedto10–30kNtypicallyusedfortableting.
·           Thehigh-speedpowderfillingisaccomplishedbyeitherofthetwodosingdevices:
(a)dosatordeviceor(b)dosingdisk/tampingdevice.

1.The dosatordevice usesanemptytubethatdipsintopowderbed,whichismaintainedataheightapproximate
lytwo-
foldgreaterthanthedesiredlengthoftheplug.Thedosatorpiston’sforwardmovementhelpsformtheplug,whic
histhentransferredtothebodyofthecapsule,andreleased.

2.The tampingdevice operatesbyfillingthecavitiesboredintothedosingdisk,similartothedie-
fillingoperationduringtableting.Atampingpunchslightlycompressesthefilledpowderbyrepeatedaction,whi
chisfollowedbytheejectionoftheplugintothecapsulebody.

Automaticmachinescanbeeithercontinuousinmotion,likearotarytabletpress,orintermittent,wherethemac
hinestopstoperformafunctionandthenindexesroundtothenextpositiontorepeattheoperationonafurtherse
tofcapsules.
Thedosingsystemscanbedividedintotwogroups:
•Dependent–dosingsystemsthatusethecapsulebodydirectlytomeasurethepowder.
Uniformityoffillweightcanonlybeachievedifthecapsuleiscompletelyfilled.
•Independent–dosingsystemswherebythepowderismeasuredindependentlyofthebody
inaspecialmeasuringdevice.Weightuniformityisnotdependentonfillingthebodycompletely.
Withthissystemcapsulescanbepartfilled.

Liquid-andsemisolid-filledhardgelatincapsules

Mainapplications

Liquid-andsemisolid-
filledhardgelatincapsulesaresometimesusedtoimprovethebioavailabilityofdrugsubstanceswithlowsolubili
tyandwet-tability.Lipidsintheformulationtendtoincreasethebileflow invivo andpromotedrugabsorption.F
orexample,mixturesofmono-,di-,andtri-glyceridesofmono-
ordicarboxylateestersofPEGs,commerciallyavailableasGelucire®,areavailableinvariousmeltingpointandhy
drophilic–
lipophilicbalance(HLB)ranges.OralavailabilityofdrugsolutioninGelucire®orinPEGisfrequentlyhigherthanth
atofpowderdrugformulation.Inaddition,self-emulsifyingandself-
microemulsifyingdrugdeliverysystems(SEDDSandSMEDDS,respectively)cansignificantlyimprovedrug’sbio
availability,forexample,inthecaseofcyclosporineAandfenofibrate.

Liquidfillingofhardgelatincapsulesmayalsobeindicatedinthecaseofdrugswithextremelylowdose(e.g.,in μg)
anddrugloading(e.g.,lessthan5%w/
w)intheformulationtoassureuniformityofcontent.Uniformityofdrugdistributionbetweendifferentdosageu
nitscanbehigherwithadrugsolutioninaliquidorsemisolidbasethanablendedpowder.

Drugswithmanufacturabilityissuesinatabletdosageformmayalsobeformulatedasaliquid-
filledhardgelatincapsules.Forexample,drugswithlowmeltingpointscanshowsignificantstickingissuesinboth
tablet-andpowder-
filledcapsuledosageforms.Certaindrugswithsignificantinstabilitytolightormoisturecanshowbetterstabilityi
nliquidorsemisolidfilled,comparedtoapowder-
filled,hardgelatincapsule.Thepresenceofanopaquewaxybaseandamolecularmixtureoftheantioxidantwitht
hedrugcanincreasetheeffectivenessofenvironmentalprotectioninthecapsuledosageform.

Examplesofdrugsubstancesformulatedasliquid-filledhardgelatincapsulesarelistedin Table21.2.

Table21.2 Examplesofcommonlyusedcapsuledosageforms

Formulationconsiderations

Themainformulationconsiderationsforliquid-
filledhardgelatincapsulearesimilartothoseforsoftgelatincapsules:

1.Noninteractionwithcapsuleshell:Physicochemicalcompatibility  betweenthedrug/
formulationexcipientsandthecapsuleshellarerequiredforanycapsuleformulation.Asdescribedearlier,know
ndrug–
gelatininteractionsincludepHeffectongelatinhydrolysisortanning,hygroscopicityorwatereffectonshellinte
grity,andtheroleofdiffusiblealdehydesincross-linkinggelatinshell.

2.Dose:Thecapsulesizeimposesalimitonthemaximumamountof  formulationthatcanbefilledintoahardgela
tincapsule.

3.Hygroscopicity:Theformulationcomponentsshouldnotsignificantly  affectthemoistureleveloftheshell.For
example,highlyhygroscopicexcipientssuchasglycerol,sorbitol,andpropyleneglycolarenotsuit-
ableforliquid-
filledhardgelatincapsulesinhighconcentrations,althoughtheymaybeusedforsoftgelatincapsules.Thisisbeca
useofthelowerinherentmoisturecontentofthehardgelatinshell.

Formulationcomponents

Drugsolutioninanappropriatebaseformulationcanbefilledintohardgelatincapsulesatroomorslightlyhighert
emperature.Thefunctionalcategoriesofformulationcomponentsareasfollows:

1.Triglycerides  forsolubilizationofthedrugsubstance.Theseinclude  eitherthemediumchaintriglycerides,su

chasMiglyol®810and812,orthelongchaintriglycerides,suchassoybeanoil,oliveoil,andcornoil.
2.Surfactants  canbeincludedintheformulationassolubility,dissolution,and/
orabsorptionenhancers,suchasCremophor®,Gelucire®,Labrafil®,andTween®.

3.Cosolvents  canbeusedinlowconcentrations,especiallyforSEDDS  andSMEDDS,suchasethanol,propyleneg

lycol,andPEG.

Manufacturingprocess

Themainconsiderationandprocessriskinthemanufactureofliquid-
filledhardgelatincapsulesistheirtendencytoleakatthejointbetweenthebodyandthecap.Thisconcernhasbee
naddressedinoneofthetwoways:

1.Applyingazoneofgelatinfilmonthejoiningregionofthebodyandthecap.Thisisknownas banding,becauseab
andofgelatinisformedontheoutsideofthecapsule.

2.Sprayingasolutionofethanolandwaterontheoverlappingareasofthebodyandthecapalongwiththeapplica
tionofheat(e.g.,40°C–60°Cforseveralseconds).Thisprocessisknownas sealin
g.Thelowsurfacetensionofthesolventmixtureallowsittodiffuseintoanddissolvegelatin,whichalsomeltsduri
ngheating,toallowthefusionofgelatinfromthecapwiththatfromthebody.

SOFTGELATINCAPSULES

Softgelatincapsulesconsistofahermeticallysealedoutershellofgelatinthatenclosesaliquidorsemisolidmedic
amentintheunitdosage.Softgelatincapsulesareacompletelysealeddosageformandcannotbeopenedwithou
tdestroyingthecapsules.Drugsthatarecommerciallypreparedinsoftcapsulesincludecyclosporine,declomyci
n,chlorotrianisene,digoxin,vitaminA,vitaminE,andchloralhydrate.

Figure21.1 showsdifferentshapesofsoftgelatincapsules.
Figure21.1  Schematicdiagramsillustratingdifferentshapesofsoftgelatincapsules.Therangeoffillvolumesisa
lsoindicated.

Softgelscanbeformulatedandmanufacturedtoproduceanumberofdifferentdrugdeliverysystems:
•Orallyadministeredsoftgelscontainingsolutionsorsuspensionsthatreleasetheircontentsinthe
stomachinaneasy-to-swallow,convenientunit
doseform.
•Chewablesoftgels,whereahighlyflavouredshellischewedtoreleasethedrugliquidfillmatrix.
Thedrug(s)maybepresentinboththeshellandfillmatrix
•Suckablesoftgels,whichconsistofagelatinshellcontainingtheflavouredmedicamenttobe
suckedandaliquidmatrixorjustairinsidethecapsule
•Twist-offsoftgels,whicharedesignedwithatagtobetwistedorsnippedoff,therebyallowing
accesstothefillmaterial.Thistypeofsoftgelcanbeusedforunitdosingoftopical
medication,inhalationsorfororaldosingofapaediatricproduct.
•Meltablesoftgelsdesignedforuseaspessariesorsuppositories.

Advantagesanddisadvantagesofsoftgelatincapsules

Softgelatincapsulesprovideapatient-friendlydosageformforperoraladministrationofnonpalatableand/
oroilyliquids.Solutionsorsuspensionswithanunpleasantodorortastecanbeeasilyingestedinasoftgelatincap-
suledosageform,whichofferstidyappearanceandconvenientingestion.

Thisdosageformcanbeparticularlyadvantageousforlowdosedrugsthatarelipidsolublebecauseitcanallowgr
eateruniformityofcontentbetweendosageunitsthantheconventionaltabletdosageform.Itcanalsobemores
uitablethanatabletdosageformfortheencapsulationofliquid,water-
insolubledrugs.Thecapsulescanbeformulatedtobeimmediaterelease(IR),sloworsustainedrelease(SR),oren
tericcoated.

Theuseofsoftgelatincapsuleshellimposessignificantlimitationsonthedrugformulationsthatcanbeencapsula
tedinthisdosageform,thatis,restrictedtoliquidsandsemisolids.Themanufacturingprocessisrela-
tivelytediousanddifficulttooptimize(e.g.,ribbonthickness,fillweight,andweightvariation).Inaddition,thebre
akageofevenonecapsuleduringthemanufacturingcanleadtothecoatingofdrugformulationontheoutersurfa
ceofseveralothercapsules.Thiscanalsohappenduringstorageinmultipleusecontainers,suchashigh-
densitypolyethylene(HDPE)bottles.

Softgelatincapsuleshavecertaindisadvantagescomparedtoliquid-
filledhardgelatincapsules.Duetotherelativelyhigherwatercontentinsoftgela-tinshell(20–30%w/
w)comparedtohardgelatincapsules(13–16%w/w)moisture-
sensitivedrugsmaynotbestableinsoftgelatincapsules.Inaddi-
tion,themaximumtemperatureoftheformulationthatcanbefilledintosoftgelatincapsulewithoutdeformatio
noftheshellandotherproductionissuesisabout35°C,whereasaformulationcanbefilledatupto70°Cinhardgela
tincapsuleswithoutshelldeformation.ExtremeacidicandbasicpHmustalsobeavoidedbecauseapHbelow2.5
hydrolyzesgelatin,whereasapHabove9hasatanningeffectonthegelatin.

Reasonsfordevelopmentofsoftgelatincapsules

Softgelatincapsulesareoftendevelopedforoneormoreofthefollowingreasons:

1.Lineextension  productsforstrategicmarketingadvantageinathera-
peuticareawithintensecompetition.Forexample,coughandcoldmedicinesavailableasasoftgelatincapsuleca
nofferpatientbenefit,suchasingestionwithoutwaterandportability.

2.Technologicaladvantage  suchasgoodcontentuniformityofalow  dosedrugorformulationofawater-

insolubledrugthatisliquidatroomtemperature.

3.Safety  reasonsduringproductmanufacturing,dispensing,andusage.  Forexample,mostoftheproductman

ufacturingunitoperationsoftabletsandhardgelatincapsulesinvolvehandlingoffinepowders.Inthecaseofsoft
gelatincapsules,thepowderhandlingisrestrictedtodrugdissolutionordispersioninaliquidmedium.Powdersi
nher-entlyhavegreaterexposurehazardsthanliquids.Therefore,softgel-
atincapsulesprovidegreateroperatorsafetyduringmanufacturing.Inaddition,asthedrugformulationisherm
eticallysealedinashell,theexposuretothemedicationisminimizedduringdispensingaswellasuse.

4.Improvedoralbioavailability:Theuseofcertainlipidscanbeasso-
ciatedwithincreasedoralbioavailabilityandreducedintra-
andinterpatientvariabilitybymodificationofGIdigestiveprocesses.Inaddition,presentationofthedruginapre
dissolvedstatecanleadtoshorterdurationtotheonsetofaction.Byformulatingnifedipineoribuprofenintosoft
gelatincapsulesafterbeingdissolvedinPEG,thebioavailabilityofthesedrugscanbeimproved.
ExcipientsusedinFormulationofsoftgelatincapsuleshell

Thecompositionofthesoftcapsuleshellconsistsofthreemainingredi-ents:(1)gelatin,
(2)plasticizer,and(3)water.Incontrasttohardgelatincapsules,arelativelylargeamount(~30%w/
w)ofplasticizersisaddedinsoftgelatincapsuleshellformulationtoensureadequateflexibility.Waterisusedtof
ormthecapsule,andotheradditivesareoftenaddedasneeded.

Table21.3  Typicalcompositionofasoftgelatincapsuleshell

Atypicalcompositionofthesoftgelatincapsuleshellislistedin Table21.3 andthefunctionalcomponentsaredes
cribedasfollows:

1.Gelatin:Similartohardgelatinshells,thebasiccomponentofsoft  gelatinshellisgelatin.Thepropertiesofgela
tinshellsarecontrolledbythechoiceofgelatingradeandbyadjustingtheconcentrationofplasticizerintheshell.
Thephysicochemicalpropertiesofgelatinarecontrolledtoallow

·           Adequateflowatdesiredtemperaturestoformribbonsofdefinedthickness,texture,mechanicalstrengt
h,andelasticity.

·           Ribbonstobeeasilyremovedfromthedrums,stretchduringfill-
ing,sealthetemperaturebelowthemeltingpointofthefilm,anddryquicklyunderambientconditionstoanadeq
uateandarepro-duciblestrength.

Physicochemicalpropertiesofgelatinimportanttocapsuleformationincludegelstrength,viscosity,changeinvi
scositywithtemperatureandshear,meltingpoint,settlingpoint(temperature),settlingtime,particlesize(affec
tstimetodissolve),andmolecularweightdistribu-tion(affectsviscosityandstrength).

2.Plasticizer:Aplasticizerinteractswithgelatinchainstoreducethe  glasstransitiontemperature(Tg)ofthegela
tinshelland/orpromotestheretentionofmoisture(hygroscopicity).Themostcommonplasti-
cizerusedforsoftgelatincapsulesisglycerol.Sorbitol,maltitol,andpolypropyleneglycolcanalsobeusedincomb
inationwithglycerol.Glycerolderivesitsplasticizingabilityprimarilyfromitsdirectinter-
actionswithgelatin.Incontrast,sorbitolisanindirectplasticizerbecauseitprimarilyactsasamoistureretentivea
gent.Comparedtohardgelatincapsulesandtabletfilmcoatings,arelativelylargeamount(~30%w/
w)ofplasticizersareaddedinasoftgelatincapsuleformulationtoensureadequateflexibility.

3.Water:Thedesirablewatercontentofthegelatinsolutionusedtopro-
duceasoftgelatincapsuleshelldependsontheviscosityofthespecificgradeofgelatinused.Itusuallyrangesbetw
een0.7and1.3partsofwatertoeachpartofdrygelatin.Afterthecapsuleisformed,mostofthewaterisremovedb
ydrying.Thefinishedsoftgelatincapsulescontain13–16%w/wwater.

4.Preservative:Preservativesareoftenaddedtopreventthegrowthof  bacteriaandmoldinthegelatinsolution
duringstorage.Potassiumsorbate,andmethyl,ethyl,andpropylhydroxybenzoatearecom-
monlyusedaspreservatives.

5.Colorantand/oropacifier:Acolorantand/oropacifier(e.g.,titanium  dioxide)maybeaddedtotheshellforvisu
alappealand/
orreducingthepenetrationoflightfortheencapsulationofaphotosensitivedrug.Thecolorofthecapsuleshellis
generallychosentobedarkerthanthatofitscontents.

6.Otherexcipients:Other,infrequently,usedexcipientscanincludeflavorsandsweetenerstoimprovepalatabil
ityandacid-
resistantpolymerstoimpartentericreleasecharacteristics.Theycanalsobeusedtoformulatechewablesoftgel
atincapsules,forexample,ChildLife’sPureDHAchewable250mgsoftgelcaps.Achelatingagent,suchasethylen
ediaminetetraceticacid(EDTA),canbeaddedtopreventchemicaldegradationofoxidationsensitivedrugscatal
yzedbyfreemetalsingelatin,suchasiron.

Drugformulationforencapsulationinsoftgelatincapsules

Softgelatincapsulesmaycontainaliquidorsemisolidsolution,suspension,orpreconcentrateofaself-
emulsifyingorself-
microemulsifyingsystem.Forexample,Accutane®isasuspensionofisotretinoininoil,Sandimmune®isaself-
emulsifyingpreconcentrate,andNeoral®isaself-microemulsifyingpreconcentrate.

Formulationconsiderationsforthecontentsofthesoftgelatincapsulesincludethefollowing:

·           Noninteractionwithgelatin:Thecontentsofthesoftgelatincapsule  shouldnotinteractwiththegelatins
hell.

·           Nonmoisturesensitivity:Themoisturecontentofsoftgelatincap-
sulesplasticizedwithglycerolisconsiderablyhigherthanthatofhardgelatincapsules.Therefore,toensurechem
icalstabilityofthedrug,moisture-sensitivedrugsshouldnotbeformulatedinsoftgelatincapsules.

·           Nontemperaturesensitivity:Themoltengelatinmassusuallyhasa  pourableviscosityat60°C–
70°C.Therefore,thesealingoperationisusuallycarriedoutatahigherthanambienttemperature.Hence,highlyt
hermolabiledrugsmaynotbeencapsulatedinsoftgelatincapsules.

·           pH:ExtremeacidicandbasicpHshouldbeavoidedbecauseapH  below2.5hydrolyzesgelatin(leadingtol
eakage),whereasapHabove 9hasatanningeffectonthegelatin.Tanningprocessinvolvescross-
linkingofgelatin,whichresultsinhardeningoftheshell.Theshellbecomesinsolubleinwaterandresistanttodige
stionbyGIenzymes:trypsinandchymotrypsin.

Drugsforencapsulationinasoftgelatincapsuleareusuallydissolvedorsuspendedinasuitablecarrier.Insoluble
drugsareoftendispersedorsus-
pendedinanagentsuchasbeeswax,soybeanoil,orparaffin.Surfactantsareoftenaddedtopromotewettingofth
eingredients.Theuseofwaterorethanolinthefillcompositionisonlypossiblewithspecialmodifica-
tionsofthecapsuleshell.DrugscanbedispersedinethylcelluloseforanSReffect.

Manufacturingprocess

Softgelatincapsulesarefilledwithsolutionsorsuspensionsofdrugsinliquids,andsealedinasingleoperation.Th
eyarepreparedfromamoreflexibleplasticizedgelatinbyarotary-dieprocess.Asshownin Figure21.4,thisproce
ssinvolvesthefollowingsequentialoperations:

1.        Twoheatedsheetsofgelatinofsimilarthicknessareproducedbythecontrolledflowofthefluidgelatinfro
mitsheatedstoragecontainer(gelatintank)byusingacontrolledporeopeningandfillina spreader box.

2.        Thegelatinfilmflowsthroughaseriesof oilrolls thatstretchthesheetsanddirectthemappropriatelytow
ard dierollers.

3.        Thetwosheetsofgelatinmergeonthemetallicrollersthatcontaindiesofappropriateshapeandsizeandm
oveintheoppositedirec-
tiontowardeachother.Theapplicationofvacuuminsidetherollerscombinedwithpressurizedfillingofthecomp
onentsenablesthefor-
mationofacavity.Theapplicationofheatandmechanicalpressureenablessealingoftheshellsastheypassthrou
ghtherollers.

4.        Asthegelatinsheetsarebeingannealed,acalibratedamountofthedrugformulationispumpedintoeachc
avitybythe productpump throughan injectionwedge.

5.        Theconcurrentprocessofdrugproductinjectionintothediecavityandsealingofthecavityiseitheraccom
paniedbythecuttingandreleaseofindividualsoftgelatincapsules(iftherollersaresuitablydesigned)or,asshow
nin Figure21.4,thecapsulesmaybecutfromthesheetsinaseparate,subsequentoperation.

6.        Thefilledcapsulesaredriedatambientconditionstoremovemoisturefromtheoutersurfaceandmaybet
raydriedforanextendedperiodoftime(e.g.,upto48hours).

7.        Finishedcapsulesarepassedonaconveyorbeltforthenextunitoperationsofpackagingandlabeling.
Figure21.4  Manufacturingprocessofsoftgelatincapsules.(Adaptedfrom  http://  www.sunkingpm.com/
htm/PM/SCP/5.html)

Nongelatinsoftcapsules

Theuseofalternatepolymersfortheformationofsoftcapsulesisdrivenbymarketingorformulationrequiremen
ts.Forexample,Vegicaps®areanimal-free.Theirshellismadefromseaweedextractandgluten-
freestarch.Formoisturesensitivedrugs,HPMCcapsulesmaybepreferred,whichgenerallyhavelowerequilibri
ummoisturecontentthangelatincap-
sules.HPMCcapsulesalsohavebetterphysicalstabilityonexposuretolowhumidity.

Assignment:WritenotesonStorage,PackagingandStabilityofcapsules