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ReviewPaperInteractionsandincompatibilitiesofpharmaceuticalexcipientswithactivepharmaceuticalingredients:acomprehensivereview.SonaliS.Bharate,SandipB.BharateandAmritaN.Bajaja*bcP.E.Society’sModernCollegeofPharmacy(ForLadies),Borhadewadi,At/Post-Moshi,Tal-Haweli,Dist-Pune,Maharashtra–a412105,IndiaSTES’sSinhgadCollegeofPharmacy,OffSinhgadRoad,Vadgaon(Budruk),Pune-411041,IndiabC.U.ShahCollegeofPharmacy,S.N.D.T.Women’sUniversity,JuhuTaraRoad,Santacruz(E),Mumbai,Maharashtra-400049,IndiacReceived:05March2010;Accepted:03November2010ABSTRACTStudiesofactivedrug/excipientcompatibilityrepresentanimportantphaseinthepreformulationstageofthedevelopmentofalldosageforms.Thepotentialphysicalandchemicalinteractionsbetweendrugsandexcipientscanaffectthechemicalnature,thestabilityandbioavailabilityofdrugsand,consequently,theirtherapeuticefficacyandsafety.Thepresentreviewcoverstheliteraturereportsofinteractionandincompatibilitiesofcommonlyusedpharmaceuticalexcipientswithdifferentactivepharmaceuticalingredientsinsoliddosageforms.Examplesofactivedrug/excipientinteractions,suchastransacylation,theMaillardbrowningreaction,acidbasereactionsandphysicalchangesarediscussedfordifferentactivepharmaceuticalingredientsbelongingtodifferentthera-peuticcategoriesvizantiviral,anti-inflammatory,antidiabetic,antihypertensive,anti-convulsant,an-tibiotic,bronchodialator,antimalarial,antiemetic,antiamoebic,antipsychotic,antidepressant,anti-cancer,anticoagulantandsedative/hypnoticdrugsandvitamins.Oncethesolid-statereactionsofapharmaceuticalsystemareunderstood,thenecessarystepscanbetakentoavoidreactivityandimp-rovethestabilityofdrugsubstancesandproducts.KEYWORDS:Incompatibility,interaction,activepharmaceuticalingredient,excipients,lactose,magnesiumstearateINTRODUCTIONPreformulationisthefirststepintherationalformulationofanactivepharmaceuticalingredient(API).Itisaninvestigationofthephysical-chemicalpropertiesofthedrugsubs-tance,aloneandincombinationwithexcipients.Assessmentofpossibleincom-patibilitiesbetweenthedruganddifferentexcipientsisanimportantpartofpre-formulation.Theformulationofadrugsubs-tancefrequentlyinvolvesitbeingblendedwithdifferentexcipientstoimprovemanufac-turability,andtomaximizetheproduct’sabilitytoadministerthedrugdoseeffectively.Excipientsareknowntofacilitateadministrationandmodulatereleaseoftheactivecomponent.Theycanalsostabilizeitagainstdegradationfromtheenvironment.Correspondingauthor:Dr.SonaliS.Bharate,AssistantProfessor,P.E.*Society’sModernCollegeofPharmacy(ForLadies),Borhadewadi,At/Post-Moshi,Tal-Haweli,Dist-Pune,Maharashtra–412105,India,Email:sonalibharate@gmail.comThisJournalis©IPEC-AmericasIncJ.ExcipientsandFoodChem.1(3)2010-3ReviewPaperMostexcipientshavenodirectpharmacologicalactionbuttheycanimpartusefulpropertiestotheformulation.However,theycanalsogiverisetoinadvertentand/orunintendedeffectssuchasincreaseddegradationofthedrug.Physicalandchemicalinteractionsbetweendrugsandexcipientscanaffectthechemicalnature,thestabilityandbioavailabilityofdrugproducts,andconsequently,theirtherapeuticefficacyandsafety(1).Therehavebeenseveralapproachesproposedthatsatisfytherequirementsofadrug-excipientchemicalcompatibilityscreen.Themostresourcesparingoftheseapproachesiscomputational,wheredrug-excipientchemicalcompatibilitycanbepredicted.Thisrequiresacomprehensivedatabaseofreactivefunctionalgroupsforbothdrugsandexcipients,com-binedwithanin-depthknowledgeofexcipientsandtheirpotentialimpurities.Suchanapp-roachprovidesarapidanalysisandrequiresnobulksubstance.However,thereareinherentriskswithusingthiscomputationalapproachasthesolesourceofinformation.Binarymixturecompatibilitytestingisanothercommonlyusedmethod.Inthisapproach,binary(1:1orcustomized)mixturesofthedrugandexcipient,withorwithout,addedwaterandsometimescompactedorpreparedasslurries,arestoredunderstressedconditions(alsoknownasisothermalstresstesting(IST))andanalyzedusingastability-indicatingmethod,e.g.highperformanceliquidchromatography(HPLC).ThewaterslurryapproachallowsthepHofthedrug-excipientblendandtheroleofmoisturetobeinvestigated.Alternatively,binarymixturescanbescreenedusingotherthermalmethods,suchasdifferentialscanningcalorimetry(DSC)(2,3).DSCiscurrentlytheleadingtechniqueinthisfield(4).ThemainbenefitofDSC,ratherthanstressedstoragemethods,isitsabilitytoquicklyscreenpotentialexcipientsforincompatibilitiesderivedfromtheappearance,shiftsordisappearancesofpeaksand/orvariationsinthecorrespondingÄH(enthalpyoftransition)(5).Otherfeaturessuchaslowsampleconsumptionalsomakesitanattractivemethod.AlthoughDSCisunquestionablyavaluabletechnique,interpret-nationofthedatamaynotbestraightforward.Inthismethod,thesampleisexposedtohightemperatures(upto300°Cormore),whichinrealityisnotexperiencedbythedosageform.Thus,DSCresultsshouldbeinterpretedcarefully,astheconclusionsbasedonDSCresultsalonecanbeoftenmisleadingandin-conclusive.ThereforeresultsobtainedwithDSCshouldalwaysbeconfirmedwithIST.ISTinvolvesstorageofdrug-excipientblendswith,orwithoutmoisture,atelevatedtem-perturesforaspecificperiodoftime(typical