Home>TacklingMoistureChallengesinSolidDosageManufacturing

TacklingMoistureChallengesinSolidDosage
Manufacturing
ArminGerhardt,associateprofessorofPharmaceuticalScience,Concordia
UniversityWisconsinSchoolofPharmacy,discussestheeffectsofmoistureon
productqualityandhowtoachievegoodcontrolofmoistureduringpharmaceutical
manufacturingoperations.
May02,2016
ByAdelineSiew,PhD[1]
PharmaceuticalTechnology
Volume40,Issue5,pg34
ArminGerhardt,associateprofessorofPharmaceuticalScience,Concordia
UniversityWisconsinSchoolofPharmacy,discussestheeffectsofmoistureon
productqualityandhowtoachievegoodcontrolofmoistureduringpharmaceutical
manufacturingoperations.
PharmTech:Whatarethedifferentsourcesofmoistureinasoliddosageform?
Gerhardt:Themostcommonsourcesofwaterinasoliddosageformare
atmosphericmoisturevaporthemanufacturingprocessandtheexcipients.Many
pharmaceuticalfacilitiesarelocatedingeographicallocationswhereperiodsofhigh
heatandrelativehumidityarefound.Withatmosphericmoisturevapor,itispossible
forexposedsolidphasematerialstosorbgasphasewaterontheirsurfaceorwithin
theparticles.Whilethemanufacturingandstorageenvironmentmaybetightly
controlled,therecanbedisruptionsduetomechanicalorhumanfactorsforinstance,
amaintenanceeventoftheairhandlingsystem,oranoperatorerror,thatproducesa
temporarysurgeinatmosphericwatercontent.
Duringthemanufacturingprocess,themostobvioussourcesofwaterincreaseare
whenliquidphasewaterisaddedduringagranulationorcoatingunitoperation.
Whileboththeseoperationsareassociatedwithasubsequentdryingstep,itis
importanttoconductanaccuratewatercontentassessmentoftheproduct.
Granulationsamplestakenfromthedryingunitoperationneedtoensurethesample
particlesizedistributionisidenticaltothebulkmaterial.
Rifflingorconeandquarteringaretwooptionsforpreparingsamplesofappropriate
size,butpouringfromacontainerfrequentlyenrichesthesamplewithlarger
particles,thusproducinganinaccuratemoistureassayresult.Milling,anoperation
carriedouttoincreasesolidparticlesurfacearea,alsoincreasesthepotentialfor
sorptiontooccur.Thekineticsofsorptioncanbequiterapidafewminutesof
uncontrolledexposuremayproducesignificantincreasesofmoisture.Alsohold
timesbetweenunitoperationsmayincreasethequantityofmoisturesorption.
Excipientsareapotentialsourceofmoisture.Manypharmaceuticalmaterialsarrive
withvariousquantitiesofwaterdistributedinthem.Polymericmaterialsareprime
examples:microcrystallinecellulosetypicallyhas4.55.0%watercontent,hard
gelatincapsulestypicallyhave1316%watercontent,andthiswatermayequilibrate
withinthedosageformandinfluenceprocessingandperformance.
PharmTech:Whataretheeffectsofmoistureonthephysicalandchemical
propertiesofadrugproductandthemanufacturingprocess?
Gerhardt:Moisturecontentofthepowderblendduringcompressioniscrucialtothis
unitoperationandtoproductstabilityhowever,moisturehas
oppositeeffectsinthesetwofacets.Duringcompression,itisgenerallypreferredto
havearelativelyhighermoisturecontentsothathighertablethardnesscanbe
producedatlowercompressionforce.Thereisalimitthough,becausehigher
moisturecontenttendstoproducetwodetrimentalresults:
Areductioninpowderflowrateincreasesmoisture,whichthenincreasespowder
particleadhesion,leadingtoerratictabletweightuniformity
Anincreaseinstickingdefects,whichcanbeparticularlychallengingwithembossed
compressiontoolingbecausetherearemorepocketswherepowdermayadhere.
Regardingchemicalstability,arelativelylowermoisturecontentispreferredto
reducetheextentofdrugdegradationandmakeitmoredifficultformicrobialgrowth
tooccur.Effervescenttablets,forexample,areextremelysensitivetomoisture
content.Thechemicalreactionbetweentheorganicacidandinorganicbaseis
autocatalyticandityieldsgaseouscarbondioxideandwater.Averylowmoisture
contentis,therefore,requiredtopreventthe
reactionfromstarting,butoncestarted,thewaterproducedbyitfurtherpromotesthe
reactionuntilthecomponentsareexhausted.
Onefurthercautionwitheffervescenttabletsisthatthehighsaltcontentnecessaryto
achieveeffervescencemaybeahealthchallengetothoseonarestrictedsaltdiet.
Thechallengeduringthedevelopmentphaseistobalancethecontrastingwater
preferencesofprocessingandstability,anddefineamoisturerangewhere
reasonabletablethardness,weightuniformity,andchemicalstabilityareachieved,
andthispartrequiresconsiderableeffortanddatageneration.
PharmTech:Howdoyouachievegoodcontrolofmoistureduringthemanufacturing
ofsoliddosageforms?
Gerhardt:Startwiththeprinciplesofqualitybydesign.Selectexcipientsaftera
thoroughreviewoftheirproperties,includingmoisturelevelandimpurities.

Characterizethedrugsubstanceforitspotentialtosorbmoistureandsensitivityto
degradation.Thedrugsubstanceneednotdecomposebyhydrolysistobesensitive
tomoisture.Watercanmovewithinadosageformfromonematerialtoanother.
Ratherthanforminganevendistributionacrossallsurfacesorwithinparticles,water
mayaccumulateinmicroscopicpockets.Andwhenitdoes,thesolidphasematerial
atitsperipherymaybecomemoremobileastheglasstransitiontemperatureinthese
zonesislowered,whichmaythenleadtoincreasedchemicalreactivityanddrug
degradation.
Anticipatetherisksofallactivities,equipment,andprocesses.Buildon
priorexperienceofallproductsandunitoperations.Considernotjustwhathappens
withintheconfinesofthemanufacturingfacility,butexpandthescopetoinclude
excipientvendoractivities/upgrades/modificationsandequipmentvendorexpertise.
Probethetechnicalservicepersonnelofequipmentvendorsfortheirperspectiveon
recentchallengesandsolutionsthatotherswithinourindustryhavegenerated.Be
particularlysensitivetoqueriesfromregulatorsastheyhaveaninsideperspectiveof
allthecompanieswithinourindustry.Whiletheycannotdivulgethesourceordetails
ofthesequestions,itisreasonabletoinferanotherfirmhadchallengesthatspurred
thequestion,anditmayprovideanopportunitytobeproactivepriortohavinga
similarchallenge.
PharmTech:Whataboutthepackagingofthedrugproduct?Whatmaterialsare
typicallyusedformoisturesensitiveformulations?
Gerhardt:Typicallytheunitdosecontainerclosuresystemsarethemost
challengingforstability.Compositeswithalayerofaluminumfoilareroutinely
consideredaveryrobustoptionformoisturesensitivedrugproducts.
Aquicksurveyoftheoverthecountereffervescentproductsinacommunity
pharmacycanbehelpfulduringthedevelopmentprocess.Dataareavailableto
comparethemoisturevaportransmissionrateofawiderangeofmaterials.In
addition,thesealbetweenlayersisanimportantconsiderationbecausethisaspect
isafrequentsourceforbarrierfailure.Alsowithunitdosematerials,theshapeofthe
cavitycontainingthetabletorcapsuleisafactor.Duringtheprocessofheatingthe
flatsheetstocktoformthecavities,thereissignificantstretchingandthinningofthe
polymericmaterial.Thethicknessreductioncanbeasmuchas50%ormorewhere
therearebends,anditisthesethinportionswherethemostriskoccursformoisture
ingress.Withmultipledosageunitcontainers,comparisonofthemoisturevapor
transmissionrateforpackagingresinsisrecommended.Theheadspaceandthe
quantityofpotentialmoisturethatcouldbeaddedtothedrugproductneeds
inclusion,hencetherequirementforcontrollingairqualityduringpackaging.One
additionaloptionistoincludeadesiccantpacketorcanister.
Duringearlystagesofdevelopment,itshouldbeatopprioritytoinitiatestability
studiesusingarangeofpotentialcontainerclosuresystems.Datafrom12,18,24
month,orlongerstorageatthefinalstoragetemperature/relativehumidity
combinationareveryvaluable.
ArticleDetails
PharmaceuticalTechnology

Vol.40,No.5
Pages:34
Citation:
Whenreferringtothisarticle,pleaseciteitasA.Siew,"TacklingMoistureChallenges
inSolidDosageManufacturing,"Sidebarto"AQbDMethodDevelopmentApproach
foraGenericpMDI"PharmaceuticalTechnology40(5)2016.
2016AdvanstarCommunications,Inc.Allrightsreserved.Reproductioninwholeorinpartisprohibited.Pleasesendanytechnicalcommentsorquestionstoourwebmasters.

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Links:
[1]http://www.pharmtech.com/adelinesiewphd