液體制劑(英文)課件

Liquidpharmaceutical

PreparationsDr.MuratKizaibek(木拉提·克扎衣別克博士）TraditionalKazakhMedicineResearchInstituteofIliKazakhAutonomousPrefectureXinjiangMedicalUniversity

Apr22,2012Asolutionisahomogenousone-phasesystemconsistingoftwoormorecomponents.→solvent+soluteThesolventisthatphaseinwhichthedispersionoccursandthesoluteisthatcomponentwhichisdispersedassmallmoleculesorionsinthesolvent.Liquidpreparations:theformulationpreparedbydispersingdrugsubstanceintheappropriatesolventsandusedinternallyorexternally.Attention:injectionsandextractionsarenotincludedinthischapterIntroductionClassificationofliquidpreparations(I)AccordingtodispersionsystemHomogeneoussystem:thermodynamicstable

Lowmolecularsolutions:solute<1nmHighmolecularsolutions:solute1~100nmNon-homogeneoussystem:unstablesystem

Sol(lypophobiccolloid):molecularaggregate(1~100nm)Emulsion:>100nmSuspensions:>500nmemulsionsuspensioncolloidsolutionClassificationofliquidpreparations(Ⅱ)Accordingtoadministrationroute–oral:

drops,syrups,emulsions,suspensions,mixture–External:?Dermal:lotion,liniment?ForENT(ears,nose,throat):nasaldrops,auristillae?Forophthalmicadministration:eyedrops,collyria?Forrectal,vaginalandurethraladministration:enema,irrigationsAdvantagesofliquidformulationsAdrugadministeredintheformofasolutionisimmediatelyavailableforabsorption.Irritationisreducedbyadministrationbecauseoftheimmediatedilutionofdrugsbythegastriccontents.Liquidsareeasiertoswallowthansolidsandthereforeparticularlyacceptableforpediatricandgeriatricuse.Especiallysuitableforoildrugs(emulsion)AbroadadministrationrouteDisadvantagesofliquiddosageformChemicalstability:hydrolysis,oxidation…Physicalstability:emulsion,suspensionLiquidsarebulkyandthereforeinconvenienttotransportandstore.Solutionsoftenprovidesuitablemediaforthegrowthofmicro-organismandmaythereforerequiretheadditionofapreservative.QualitycontrolofliquiddosageformsHomogeneousformulations:shouldbeclearsolution.Non-homogeneousformulations:particlesshouldbesmallwithanarrowparticlesizedistribution.Liquidformulationsfororalshouldbepalatable.Forallliquidformulations:withaccuratecontentstableconservativeconvenientpackageSolventsforliquidpreparationsAqueoussolvent–DistilledwaterNon-aqueoussolvents–Alcohol–Glycerin–Propyleneglycol–Polyethyleneglycol(PEG)–Dimethylsulfoxide(DMSO)–FattyoilswaterWaterWateristhemostwidelyusedsolventforuseasavehicleforpharmaceuticalproductsbecauseoflackoftoxicity,physiologicalcompatibilityanditsabilitytodissolveawiderangeofmaterialsDistilledwaterFreeofsaltFreeofpyrogenFreefromcarbondioxideorfreefromairEthanol(ethylalcohol)Ethanol(ethylalcohol)Nexttowater,itisthemostusefulsolventinPharmacy.InChinesePharmacopoeia:95%(V/V)primarysolventformanyorganiccompounds.Togetherwithwateritformsahydroalcoholicmixturethatdissolvesbothalcohol-solubleandwater-solublesubstances.particularlyforexternalapplication.particularusefulfortheextractionofcrudedrugsbeingmoreselectivethanwater.Glycerin(USP:glycerol)Glycerin(USP:glycerol)Glycerinisaclearsyrupyliquidwithasweettaste.misciblewithbothwaterandalcohol.widelyusedparticularlyasaauxiliarysolventinconjugationwithwateroralcohol.usedinmanyinternalpreparations.10%water-containingglycerinnoirritation>30%glycerinhaspreservativequalities.PropyleneglycolPropyleneglycolForpharmaceuticaluse:1,2-propyleneglycol.usefulsolventwithawiderangeofapplicationsandismisciblewithwaterandalcohol.frequentlysubstitutedforglycerininmodernpharmaceuticalformulations.Mixtureofpropyleneglycolandwatercandecreasethehydrolysisofdrugsubstanceandincreasestability.Polyethyleneglycol(PEG)TypeAppearance(25℃)Molecular

WeightpHPEG200Colorlessliquid180~2205.0~7.0PEG300Colorlessliquid270~3305.0~7.0PEG400Colorlessliquid360~4405.0~7.0PEG600Colorlessliquid540~6605.0~7.0PEG800Whitepaste720~8805.0~7.0PEG1000Whitepaste900~11005.0~7.0PEG1500Whitesolid1350~16505.0~7.0PEG2000Whitesolid1800~22005.0~7.0PEG3000Whitesolid2700~33005.0~7.0PEG4000Whitesolid3600~44005.0~7.0PEG6000Whitesolid5400~70005.0~7.0PEG8000Whitesolid7200~88005.0~7.0Polyethyleneglycol(PEG)Generalformula:MW<1000,liquidstate,suchasPEG200,300,400,600.Commonlyusedinliquidformulation:PEG300~600.BecauseofstrongH-bondingbetweenPEGsandwater,theyarefreelysolubleinwaterandinmanyorganicsolvents,oftenusedinconjunctionwithwaterorglycerolasacosolvent.Usedintheformulationofwater-miscibleointmentbases.Dimethylsulfoxide(DMSO)isahighlypolarcompoundandincreasestherateofabsorptionofdrugsthroughtheskin,itcanbeusedasadrugdeliverysystem

Dissolvesabroadrangeofsubstance,thereforecalledalcahest(universalsolvent).FattyoilsIncludingsesameoil,castoroil,cottonseedoil,soyaoil,maizeoil,oliveoilDissolveshormones,volatileoil,freealkaloids,agreatdealofaromaticcompounds.Commonlyforexternaluse:nasaldrops,lotion,linimentForinternal:VAandVDsolutions.Isopropylmyristateoilysubstanceusedassolventsforexternaluseparticularlyincosmeticswherelowviscosity,lackofgreasinessandgoodabsorptionthroughtheskinaredesired.ExcipientsinliquidformulationsSolubilizersurfactantHydrotropyagentCosolventPreservativesFlavoursColoursSurfactantsDefinition

Surfacetension:Themoleculesatthesurfacedonothaveothermoleculesonallsidesofthemandthereforearepulledinwards.Thiscreatessomeinternalpressureandforcesliquidsurfacestocontracttotheminimalarea.Surfactants:aresubstancesthatabsorbtosurfacesorinterfaces,causingamarkeddecreaseinthesurfacetension.SurfactantstructureAllsurfactantsarecharacterizedbyhavingtworegionsintheirmolecularstructure:A)ahydrophobicgroup,suchasahydrocarbonchain,thathasnoaffinityforaqueoussolventsB)ahydrophilicgroupthathasanaffinityforwater.Amolecularorionthatpossessesthistypeofstructureistermedamphipathic(amphiphilic).ClassificationofSurfactantsDependentonthemolecularcompositionandthenatureofdissociationoftheirpolarheadgroupsthesurfactantsareclassifiedasionic(cationic,anionic,amphiphilic)ornonionic.Ionicsurfactants:Cationicsurfactants

1.quaternaryammoniumcompound:[R1R2N+R3R4]X-，suchasBenzalkoniumchlorideandBenzalkoniumbromide.2.aminesalt:[RNH3+]X-

，[R2NH2+]X-Notes:1.toxic,usedonlyasantiseptics;2.incompatiblewithanionicsurfactantsandpolyvalentanions;3.unstableathighpHAnionicsurfactants

Saltsofhigherfattyacids(soaps)Sodiumdodecylsulfate(SDS)(Sodiumlaurylsulphate(SLS))(widelyusedtoproduceo/wemulsions).SodiumglycocholateSodiumtaurocholateAlkylbenzenesulfonates(detergents)Notes:1.Toxic,usedonlyforexternallyappliedpreparations;2.Incompatiblewithpolyvalentcationsanddeionizedwaterbeusedfortheirpreparations.Amphiphilicsurfactants?ThistypeofsurfactantpossessesbothpositivelyandnegativelychargedgroupsdependingonthepHofthesystem.TheyarecationicatlowpHandanionicathighpH.?Generalformula:?Lecithin:isusedtostabilizeintravenousfatemulsions.Structureofaphosphatidylcholine,atypeofphospholipidinlecithinNon-ionicsurfactantsAdvantages:Lowtoxicityandirritancy.Canbeusedfororallyandparenterallyadministeredpreparations.Agreaterdegreeofcompatibility.LesssensitivetochangesinpHortotheadditionofelectrolytes.Non-ionicsurfactantsPolyhydricalcohol:Tween,SpanPolyoxyethylenePluronic(Poloxamer)Sucroseesters(SE)

TweensSpans

858060

858060Spans(fattyacidestersofsorbitan)Producedbytheesterificationofoneormoreofthehydroxylgroupsofsorbitanwitheitherlauric,palmiticorstearicacid.Thegeneralformulaspan20(Sorbitanmonolaurate)span40(Sorbitanmonopalmate)span60(Sorbitanmonostearate)span65(Sorbitantristearate)span80(Sorbitanmono-oleate)span85(Sorbitantrioleate)Application:Thisrangeofsurfactantsexhibitslipophilicpropertiesandtendstoformw/oemulsions.Tweens(Polysorbates)

R-representsafattyacidchainVariationsinthetypeoffattyacidusedandinthenumberofoxyethylenegroupsinthepolyethyleneglycolchainsproducesarangeofproductsofdifferingoilandwatersolubility.Tween20，Tween40，Tween60,Tween80，Tween85(o/w)Polyoxyethylenetypepolyoxyethylenefattyacidesters:Thegeneralformula：RCOOCH2(CH2OCH2)nCH2OH,belongstoMyrijsurfactants.e.g.Polyoxyethylene40stearate(Myrij52)isawater-solublematerialoftenusedwithstearylalcoholtogiveo/wemulsions.polyoxyethylenefattyethers:Thegeneralformula：RO(CH2OCH2)nH，arecondensationproductsofpolyethyleneglycolandfattyalcohols,usuallycetylorcetostearyl,whereRisafattyalcoholchain.ItbelongstoBrijsurfactants.Poloxamer(Pluronic)polyoxyethylene/polyoxypropylenecopolymerswiththegeneralformulaHO(C2H4O)a-(CHCH2(CH3)O)b-(C2H4O)aH

Poloxamer188(F68):usedasemulsifyingagentsforintravenousfatemulsions.ItcomprisesaverylargegroupofcompoundswithMw1000-14000,HLBvalueis0.5~30;PropertiesofsurfactantsCriticalmicelleconcentration(CMC)HLBCriticalmicelleconcentration(CMC)

Micell:Thesurfactantsconsistoflongmoleculeswithtwoverydifferenttypesofends.Oneendlikeswater,andiscalledhydrophilic,theotherendlikesoilanddislikeswater,andiscalledhydrophobic.Whenthesesurfactantsareplacedinwater,thehydrophobicendsattracteachotherandrepelwater.Theyarrangethemselvesintoasphericalstructurewiththehydrophobicendsinsidethespherewiththehydrophilicendsontheoutersurfaceofthesphere,whichiscalledamicelle.micellCriticalmicelleconcentration(CMC)CMC:concentrationofsurfactantsatwhichitbegintoformmicelles.IncreasingconcentrationofsurfactantinwaterslowlyformingalayeronthesurfaceandeventuallyformingmicellesatorabovetheCMCHydrophile-lipophilebalance(HLB)

Hydrophile-lipophilebalance：surfactantscontainbothhydrophilicgroupsandlipophilicgroupswithoneortheotherbeingmorepredominant,thehydrophile-lipophilebalance(HLB)numberisusedasameasureoftheratioofthesegroups.Itisavaluebetween0-40definingtheaffinityofasurfactantforwateroroil.HLBvalueofnonionicsurfactantsrangesfrom0-20.HLBnumbers>10haveanaffinityforwater(hydrophilic)andnumber<10haveanaffinityofoil(lipophilic)..

HLB01020

hydrophiliclipophilicTheHLBvaluecanalsobeusedtopredicttheotherpropertiesofasurfactant:Avaluefrom3to6indicatesaW/O(waterinoil)emulsifierAvaluefrom8to18indicatesaO/W(oilinwater)emulsifierAvaluefrom7to9indicatesawettingagentAvalueof13to18indicatesasolubiliserSolubilizationAbovethesurfactants'CMC,thesolubilityofpoorly-solubledrugsincreasesdramaticallyduetotheformationofsurfactantmicelles.theabilityofsurfactantsiscalledsolubilization,thesurfactantsarecalledsolubilizerandthesolutesarecalledsolubilizates.SurfactantswithHLBvalues15~18arethebestsolubilizingagents.Thecommonlyusedsolubilizers:TweensThemechanismforsolubilizationSolubilizationistheprocessofincorporationofthesolubilizateintoorontothemicelles.HydrotropyDefinition:Theapparentsolubilityofasparely-solublesoluteinaparticularliquidmaybeincreasedbytheadditionofathirdsubstancewhichformsanintermolecularcomplex,doublesaltormolecularassociationwiththesolute.Thethirdsubstanceiscalledhydrotropyagent.?Hydrotropyagentsaresmallmolecularcompoundsinsteadofsurfactants.?Forexample,I2+KI→KI3–Iodinesolubility:1g:2950ml(~0.03%)–In10%KIorNaI,5%HydrotropyClassificationofhydrotropyagentsOrganicacidsandtheirsodiumsaltssodiumbenzoateSodiumsalicylatepara-aminobenzoicacid(PABA)AmidecompoundsurethaneUreanicotinamideacetamideCosolvencyDefinition:Thesolubilityofweakelectrolytesandnonpolarmoleculescanbeincreasedbytheadditionofwater-misciblesolvents.Thisprocessisknownascosolvencyorsolventblending,andthesolventsusedincombinationtoincreasethesolubilityofthesolutearecalledcosolvents.Cosolvents:ethanol,propyleneglycol,glycerin,sorbitolandpolyethyleneglycol.Mechanism:1)changethedielectricconstant.DCofagoodcosolvent:25~80.2)hydrogenbondingintwosolventsCosolvencySolubilityofphenobarbitalindifferentconcentratedalcoholsPreservativesApreservativeisasubstancethatisaddedtoproductssuchasfoods,pharmaceuticals,cosmetics,etc.topreventmicrobialcontamination.Thepreservativemustbenonirritating,non-sensitizingandnon-toxicintheamountadministered.mustbesolubleenoughinwatertoachieveadequateconcentrationsintheaqueousphaseofasystemmusthaveadequatestability.mustbecompletelycompatiblewithallotherformulativeingredients.mustnotinteractwithacontainer,suchasaplasticmedicationbottle….Commonlyusedpreservatives

Estersofparahydroxybenzoicacid(Parabens)(0.1-0.2%)Benzoicacidandsodiumbenzoate(0.1-0.2%)SorbicacidBenzalkoniumbromide(0.002-0.01%）Chlorhexideacetate（0.02~0.05%）Alcohol(15-20%)ChlorobutanolPhenol(0.1-0.5%)Cresol(0.1-0.5%)Phenylmercuricnitrateandacetate(0.002-0.01%)ParabensThemethyl,ethyl,propylandbutylestersandtheirsodiumsaltsareprobablythemostwidelyusedgroupofpreservatives.TheyaremosteffectiveatapH7~9.Concentrationsof0.1~0.2%arenormallyusedandtheyaresuitableforbothexternalandinternaluse.Theyareusuallyusedincombination,suchasethyl:propylester(1:1)orethyl:butylester(4:1).BenzoicacidandsodiumbenzoateagoodantifungalandantibacterialpreservativeusedatapHoflessthan4.Aconcentrationof0.03~0.1%isrecommended.Sodiumbenzoate:0.1~0.25%.Onlytheundissociatedfractionormolecularformofapreservativepossessespreservativecapacitybecausetheionizedportionisincapableofpenetratingthemicroorganism.Sorbicacidanditssalts(sorbates)Sorbicacidhassimilarpropertiestobenzoicacid.Itisalsoonlyeffectiveinacidicconditions(pH4.5).Concentrationsof0.05~0.3%areused.Suitablefororaluse.Ingeneralthesaltsarepreferredovertheacidformbecausetheyaremoresolubleinwater,butitistheacidformthatisactive

OthersChlorhexideacetate,alsocalledhibitane（0.02%~0.05%);glycerin(>30%)spearmintoil(0.05%)cinnamylaldehyde(0.01%)eucalyptusoil(0.01%~0.05%)SweetenersSucroseDextroseLiquidglucosehoneyGlycerinSorbitolMannitolStevioside:300timesofsucrose,0.025~0.05%,usedtogetherwithsucroseandsaccharin.Saccharin/Saccharinsodium:200~700timesofsucrose,0.03%.Aspartame：150~200timesofsucrose,nobitterne