《药剂学》课程双语教学方法建设的工作进展

Chapter3Powdersandgranules

2007.1.14第一页，共五十八页。1DefinitionofpowdersConnotation(涵义)1,thephysicalformofamaterialadrysubstancecomposedoffinelydividedparticles

Theuseofpowderedsubstancesinthepreparationofotherdosageformsisextensive.Forexample,a.tabletsandcapsules;b.liquiddosageforms(solutionsorsuspensions);c.ointmentsandcreams.Connotation2,atypeofpharmaceuticalpreparation

amedicatedpowderintendedforinternal(i.e.,oralpowder)orexternal(i.e.,topicalpowder)use

Theuseofmedicatedpowdersperseintherapeuticsislimited第二页，共五十八页。2DefinitionofgranulesGranulesarepreparedagglomeratesofpowderedmaterials,andmaybeusedperseforthemedicinalvalueoftheircontentortheymaybeusedforpharmaceuticalpurposes,asintableting.第三页，共五十八页。3Thechemicalandphysicalfeaturesofsolidmaterialsusedinthepreparationofpharmaceuticalproducts1.morphology(形态学)2.purity(纯度)3.solubility(溶解度)4.stability(稳定性)5.particlesize(粒径)6.uniformity(均一性)7.compatibility(相容性)withanyotherformulationcomponentschemicalandpharmaceuticalprocessingefficientproductionofafinisheddosageformandoptimumtherapeuticefficacyTherequirementsforthematerialofsoliddosageformMixingthoroughlyFlowabilityFillingproperty

第四页，共五十八页。4ParticlesizeandanalysisTheparticlesizegradationinUSPVerycoarse（最粗粉）Coarse（粗粉）Moderatelycoarse（中粉）Fine（细粉）Veryfine（最细粉）Thisgradationsystemisbasedonsievingmethod（筛分法）,andisrelatedtotheproportionofpowderthatiscapableofpassingthroughtheopeningofstandardizedsievesofvaryingdimensionsinaspecifiedtimeperiodundershaking.第五页，共五十八页。5Particlesizeandanalysistypicalparticlesizeofgranules:4-to12-sieveGranulesfallwithintherangeof12-to20-sievearesometimesusedintabletmaking.Thepurposeofparticlesizeanalysisinpharmacyistoobtainquantitativedataonthesize,sizedistribution,andshapesofdrugandnondrugcomponentstobeusedinpharmaceuticalformulations第六页，共五十八页。6ParticlesizeandanalysisParticlesizecaninfluenceavarietyofimportantfactors:Dissolutionrate(particlesize↓→surfacearea↑)Suspendability(混悬性)(suspensions;0.5-10μm)Uniformdistributiontoensuredose-to-dosecontentuniformity(powders,granulesandtablets)Penetrability(inhalers;1-5μm,depositiondeepintherespiratorytract)Nongrittiness(无砂砾感)(dermalointments,creams,andophthalmic(眼科)preparations;50-100μm)第七页，共五十八页。7ParticlesizeandanalysisThemethodsusedforthedeterminationofparticlesizeSieving40to9500μmMicroscopy0.2to100μmprovideinformationofshapeSedimentationrate0.8to300μmLightenergydiffractionorlightscattering0.2to500μmlaserscattering0.02to2000μmphotoncorrelationspectrumLaserHolography1.4to100μmprovideinformationofshapeCascadeimpaction(级联撞击)Acombinationoftheabovemethodsandothersisoftenpreferredtoprovidegreaterassuranceofsizeandshapeparameters.第八页，共五十八页。8ParticlesizeandanalysisStokes’law/relationv:velocityofthesedimentationincm/secr:particleradiusincmD:particlediameterincmd1:densityoftheparticleing/mld2:densityoftheliquiding/mlg=gravitationalconstant=980.7cm·sec-2η＝theviscosityofthemediuminpoises,i.e.,g·cm-1·sec-1(poise)incgsunitsIncidentally,thewaterat20℃hasaviscosityofapproximatelyonecentipoises(0.01poise).1g·cm-1·sec-1

=1p=100cp=0.1Pa·s1cp=1mPa·s第九页，共五十八页。9Onmicromeritics(微粒学,粉粒学)Micromeriticsisthescienceofsmallparticles;aparticleisanyunitofmatterhavingdefinedphysicaldimensions.Micromeriticsincludesanumberofcharacteristicsincludingparticlesize,particlesizedistribution,particleshape,angleofrepose(休止角),porosity(空隙率),truevolume(真实体积),bulkvolume(总体积、松容积),apparentdensity(松密度)andbulkiness(膨松度)

.Areductioninapowder’sparticlesizeincreasesthenumberofparticlesandthepowder’stotalsurfacearea.第十页，共五十八页。10particlesizedeterminedbymicroscopicmethodsizegroupofcountedparticles/μmMiddlevalueμm“d”Numberofparticlespergroup“n”“nd”40-60501575060-807025175080-10090958550100-12011014015400120-1401308010400∑n=355∑nd=36850第十一页，共五十八页。11particlesizedeterminedbysievingmethodSeivenumberArithmeticmeanopening(mm)Weightretained(G)%Retained%Retained×Meanopening20/400.63015.514.39.00940/600.33525.823.77.93960/800.21448.344.49.50280/1000.16315.614.32.330100/1200.1352108.7100.029.232第十二页，共五十八页。12Angleofrepose（休止角）Theangleofreposeisaparameterusedtoestimatetheflowabilityofapowder.hrθPowderswithlowanglesofreposewillflowfreelyandpowderswithhighanglesofreposewillflowpoorly.Anumberoffactors,includingshapeandsize,determinetheflowabilityofpowders.Shape:Sphericalparticlesflowbetterthanneedles.Size:Veryfineparticlesdonotflowasfreelyaslargeparticles.a)250-2000μm:flowfreelyiftheshapeisamenableb)75-250μm:mayflowfreelyorcauseproblems,dependingonshapeandotherfactorsc)lessthan100μm:Flowisproblemwithmostsubstances.第十三页，共五十八页。13Othercharacteristicsofmicromeritics第十四页，共五十八页。14Comminution(粉碎)ofdrugsDefinitionComminutionistheprocessofreducingtheparticlesizeofasolidsubstancetoafinerstateofsubdivisions.Itisusedtoa)facilitatecrudedrugextraction,b)increasethedissolutionratesofadrug,c)aidintheformulationofpharmaceuticallyacceptabledosageforms,andd)enhancetheabsorptionofdrugs.第十五页，共五十八页。15Comminution(粉碎)ofdrugsMechanismofcomminutionisovercomingtheinternaladheringforce(内聚力)withmechanicalactionincluding:a)impaction(冲击力)

b)compression(压缩力)

c)cuttiing/shearing(剪切力)

d)bending(弯曲力)

e)rubbing(研磨力)

第十六页，共五十八页。16Comminution(粉碎)ofdrugsTrituration（研磨）:theprocessofgrinding(磨碎)adruginamortartoreduceitsparticlesize.Tools:mortar(研钵)andpestle(研杵)Application:onasmallscaleOnalargescaleTools:ballmills(球磨机),colloidmills(胶体磨),impactmills(冲击式粉碎机)andfluid-energymills(流能磨)

第十七页，共五十八页。17Comminution(粉碎)ofdrugs第十八页，共五十八页。18Comminution(粉碎)ofdrugs流能磨的优点：1、能耗低；2、同时完成微粉碎和微粉分选；3、磨损小，由于主要粉碎作用是粒子相互冲击碰撞，高速粒子与壁面很少碰撞，可适用粉碎硬度较大的物料；4、粉碎粒度小，在d≤5μm；5、物料在气流带动下自身碰撞粉碎，不带入介质,无污染;6、不用停机即可控制产品的细度，且细粉能全部回收，不污染环境；7、不升温，由于物料是在气体膨胀状态下粉碎，所以粉碎腔体温度控制在常温状态，温度不会升高；8、对易燃、易爆物料可用惰性气体作介质粉碎。第十九页，共五十八页。19Comminution(粉碎)ofdrugsLevigation（水飞,液中研磨）:combiningthepowdermaterialandasmallamountofliquid（thelevigatingagent:mineraloilandglycerin）inwhichthepowderisinsoluble,thentrituratingthemixturetoreducetheparticlesizeandgrittinessofaddedpowders(apasteisproduced),thisprocessistermedlevigation.Tools:mortar,pestleoranointmenttileApplication:thesmall-scalepreparationofointments第二十页，共五十八页。20Comminution(粉碎)ofdrugsWhatisointmenttile,andhowtouseit?Itisaflatrectangularorsquareslabofglassorporcelain.Itisalsoanexcellentworksurfacefor

triturating

and

levitating

small

amounts

ofointmentsandsuppositorymasses.Theointmenttile

should

never

be

scratched

and

should

becleaned

and

stored

when

not

in

use.第二十一页，共五十八页。21BlendingpowdersThemechanismofblendingconvectivemixing;shearmixing;diffusivemixingThemethodsofblending:Spatulation(调拌)Trituration(研磨)Sifting(过筛)Tumbling(翻转)Stirring(搅拌)第二十二页，共五十八页。22BlendingpowdersThemethodsofblending——1.Spatulation(调拌)Spatulationisamethodbywhichsmallamountsofpowdersmaybeblendedbythemovementofaspatulathroughthepowdersonasheetofpaperoranointmenttile.Features:littlecompressionorcompactingofthepowderNotsuitablefor:largequantitiesofpowdersorforpowderscontainingpotentsubstances.Suitablefor:themixingofsolidsubstancesthatformeutecticmixtures(beingdampenedorliquify)whenincloseandprolongedcontactwithoneanother.第二十三页，共五十八页。23BlendingpowdersHowtoavoidformingeutecticmixtures(低共熔混合物)?mixinginthepresenceofaninertdiluentsuchaslightmagnesiumoxideormagnesiumcarbonateSubstancesthatformeutecticmixtureswhencombinedincludechloralhydrate(水合氯醛),

phenol,camphor(樟脑),menthol,thymol(麝香草酚),aspirin(乙酰水杨酸),phenylsalicylate(苯基水杨酸)andothersimilarchemicals.第二十四页，共五十八页。24BlendingpowdersHowtoblendmaterialscontainingeutecticmixtures?Method1:avoidformingeutecticmixturesMethod2:byformingeutecticmixturesTaketheeffectofeutecticmixturesonthepharmacologicalactionintoaccount:a)pharmacologicalaction↑:method2b)pharmacologicalaction↓:method1c)pharmacologicalaction→:method1or2第二十五页，共五十八页。25BlendingpowdersThemethodsofblending——2.Trituration(研磨)Features:maybeemployedbothtocomminuteandtomixpowdersGeometricdilutionmethod:Thepotentdrugisplacedonanapproximatelyequalvolumeofthediluentinamortarandmixedthoroughlybytrituration.Thenasecondportionofdiluentequalinvolumetothemixtureisadded,andthetriturationrepeated.Thisprocessiscontinuedbyaddingequalvolumesofdiluenttothepowdermixtureandrepeatinguntilallofthediluentisincorporated.Suitableforthemixingofasmallamountofapotentdrugwithalargeamountofdiluent,inparticular,thepotentandthenonpotentingredientsbeingofthesamecolor.第二十六页，共五十八页。26BlendingpowdersThemethodsofblending——3.Sifting(过筛)Features:resultinginalightfluffyproduct;notacceptablefortheincorporationofpotentdrugsintoadiluentpowder第二十七页，共五十八页。27BlendingpowdersThemethodsofblending——4.tumbling(翻转)Features:tumblingthepowderenclosedinarotatingcontainer(V-shape,cube,cylinderetc.);motorizedpowderblenders(large-scale)→widelyemployedinindustryMixingisthorough,althoughtime-consumingThemethodsofblending——5.stirring(搅拌)alsofrequentlyusedonlargescale.第二十八页，共五十八页。28MedicatedpowdersApplicationinternally(withbluelabel)a.takenorallyaftermixingwithwaterb.inhaledintothelungsc.packagedwithaliquidsolventorvehicleforconstitution(orally,asaninjection,asavaginaldouche:Astreamofwater,oftencontainingmedicinalorcleansingagents,thatisappliedtoabodypartorcavityforhygienicortherapeuticpurposes.)eg.antibioticsforpediatricuseexternally(withredlabel,externallyuseonlyortopical)a.sifter-type(筛罐)

containerb.apowderaerosol第二十九页，共五十八页。29Medicatedpowderstheadvantageanddisadvantageofmedicatedpowderadvantagesa.suitableforpatientswhohavedifficultyswallowingsoliddosageformsb.fasterratesofdissolutionandabsorptionthansoliddosageforms(oralpowdersforsystemicuse)disadvantagea.theundesirabletasteofthedrug第三十页，共五十八页。30AerosolizedpowdersVariousapplicationformPressurizedaerosolsTomakethepowderdepositdeepintothelungs,theparticlesizeofthemicronizedmedicationispreparedintherangeof1μmto6μmindiameter.Mechanicaldevices(SPINHALER)forthedeliveryofpowdersinacapsulesPowderblowersorinsufflators第三十一页，共五十八页。31Thedefinitionofaerosols(气雾剂)DefinitionAnaerosolisdefinedasasystemthatdependonthepowerofacompressed

orliquefiedgastoexpelthecontents

fromthecontainerwithspecialvalvesystem.Anaerosolproductconsistsofthefollowingcomponentparts:

pellants(抛射剂)

b.container

c.valve

(阀门)andactuator(推动钮)

d.therapeuticagentandpharmaceuticalexcipients(辅料)第三十二页，共五十八页。32AdvantagesofaerosolsAdvantagesoverotherdosageformsa.contaminationb.

Stabilityc.Sterilityd.deliveredina

desiredforme.

Irritationf.easeandconvenienceofapplicationg.applicationofmedicationinathinlayer

第三十三页，共五十八页。33Theclassificationofaerosols1.accordingtoadministrationroute1)inhalationaerosols(吸入气雾剂):2)non-inhalationaerosols(非吸入气雾剂):3)topicalaerosols(外用气雾剂):2.accordingtotheworkingwayofvalve1)metereddoseaerosols(定量气雾剂)2)non-metereddoseaerosols(非定量气雾剂)第三十四页，共五十八页。34Theclassificationofaerosols

(continued)3.accordingtodispersionsystem1)solutionaerosols(溶液型气雾剂):2)emulsionaerosols(乳剂型气雾剂):3)suspensionaerosols(混悬型气雾剂):4.accordingtothenumberofphases1)twophasesaerosols(二相气雾剂)2)threephasesaerosols(三相气雾剂)

第三十五页，共五十八页。35ThecomponentsofaerosolsAnaerosolproductconsistsofthefollowingcomponentparts:

pellants(抛射剂)(Thefluorinatedhydrocarbonsfindwidespreaduseinmostaerosols.Otherpropellantsincludeshydrocarbonsincludingpropane,butane,andisobutane,andcompressedgasessuchasnitrogen,carbondioxide,andnitrousoxide(N2O).)

b.container(tinplate(镀锡铁皮),aluminum,stainlesssteel,glass)

c.valve(阀门)

andactuator(推动钮)

d.therapeuticagentandpharmaceuticalexcipients(辅料)includingdiluents,antioxidantsandsuspendingagents第三十六页，共五十八页。36c.valveandactuatorc1.continuoussprayvalvesc2.meteringvalvesThevalvesconsistofthefollowingparts:1)ferrule(套圈)ormountingcup(固定杯)2)stem(阀门杆)3)valvebody(阀体)orhousing(小室)

4)gasket(垫圈、封圈)

5)spring(弹簧)6)diptube(浸入管)

Actuator(推动钮)Thecomponentsofaerosols

(continued)第三十七页，共五十八页。37Theformulation(处方)ofaerosolsTypesofpharmaceuticalaerosolsSolutionsystem(two-phasesystem)SuspensionsystemsFoam/emulsionsystemsa.aqueousstablefoamsb.nonaqueousstablefoamsc.quick-breakingfoamsd.thermalfoams第三十八页，共五十八页。38Typesofpharmaceuticalaerosols——Solutionsystem(two-phasesystem:consistsofavaporandliquidphase)Example1:weight/%isoproterenol(异丙肾上腺素)HCl0.25ascorbicacid(Vc)0.10ethanol35.75propellant1263.90Inordertoreducethepressure,theadditionofpropellant114isrecommended.Ethanolisacosolvent.Ascorbicacidisantioxidant.Theformulation(处方)ofaerosols第三十九页，共五十八页。39Typesofpharmaceuticalaerosols——SolutionsystemExample2:weight/%activeingredientsupto10-15solvents(ethanoletc.)upto10-15distilledwater10-15hydrocarbonpropellantA-4655-70Hydrocarbonsareoftenusedintopicalaerosol.Dependingontheamountofwaterpresent,thefinalproductmaybeasolutionorathree-phasesystem.Theformulation(处方)ofaerosols第四十页，共五十八页。40Typesofpharmaceuticalaerosols——SuspensionsystemsExample3weight/%epinephrine(肾上腺素)bitartrate(within1to5microns)0.50sorbitantrioleate(spans-85)0.50propellant11449.50propellant1249.50sorbitantrioleate:surfactants/suspendingagents,todecreasetherateofsettlingofthedispersedparticles.Theepinephrinebitartratehasaminimumsolubilityinthepropellantsystem,butissufficientlysolubleinthefluidsinthelungstoexertatherapeuticactivity.Theformulation(处方)ofaerosols第四十一页，共五十八页。41Typesofpharmaceuticalaerosols——SuspensionsystemsThephysicalstabilityofanaerosoldispersioncanbeincreasedbya)controlofmoisturecontent,b)useofderivativesofactiveingredientshavingminimumsolubilityinpropellantsystem,c)reductionofinitialparticlesizetolessthan5microns,d)adjustmentofdensityofpropellantand/orsuspensoid(悬胶体)sothattheyareequalized,ande)useofdispersingagents.Theformulation(处方)ofaerosols第四十二页，共五十八页。42Typesofpharmaceuticalaerosols——Foam/emulsionsystemsa.aqueousstablefoamsb.nonaqueousstablefoams(usingvariousglycols,suchasPEG)c.quick-breakingfoamsd.thermalfoamsTheformulation(处方)ofaerosols第四十三页，共五十八页。43a.aqueousstablefoamscanbeformulatedasfollows:%w/w

ActiveingredientsOil-waxeso/wsurfactantWaterHydrocarbonpropellant95.0-96.53.5-5.01)Oil-waxes:myristicacid,stearicacid,cetylalcohol,lanolin,etc.2)Hydrocarbonpropellantcanbereplacedbycompressedgas.3)Astheamountofpropellantincreases,astifferanddryerfoamisproduced.Lowerpropellantconcentrationsyieldwetterfoams.4)Surfactantsthatshowedsomesolubilityinthepropellantsarepreferable.Theformulation(处方)ofaerosols第四十四页，共五十八页。44a.nonaqueousstablefoamscanbeformulatedasfollows:%w/w

Glycol91.0~92.5Emulsifyingagent4.0Hydrocarbonpropellant3.5~5.01)Themosteffectiveemulsifyingagentsareglycolesters,namely,myrijs.Theformulation(处方)ofaerosols第四十五页，共五十八页。45ManufactureofpharmaceuticalaerosolsStep1:manufactureofconcentrate(generalprocedureandcondition)Step2:additionofpropellantThefillingmethods:

coldfilling:-40。F;restrictedtononaqueousproductsandtothoseproductsnotadverselyaffectedbylowtemperatures

pressurefilling:preferableforsolution,emulsions,suspensions;lessdangerofcontaminationoftheproductwithmoisture;highproductionspeeds;lesspropellantloss.第四十六页，共五十八页。46TestingofpharmaceuticalaerosolsA.Flammability(可燃性)andcombustibility(燃烧性)1.Flashpoint(闪点)oflimitedvalue2.Flameextension(火焰延长),includingflashback(闪回)B.Physicochemicalcharacteristics1.vaporpressure:pressuregauge(压力计),waterbath,pressurevariationfromcontainertocontainer;2.density:hydrometer(液体比重计)3.moisturecontent:KarlFishermethod,GC4.identificationofpropellants:GC,IR5.concentrate-propellantratio:GC第四十七页，共五十八页。47Testingofpharmaceuticalaerosols

(continued)C.Performance(性能)1.Aerosolvalvedischargerate(排空率):W1-W0g/s2.spraypattern(喷雾模式):sprayonapapertreatedwithadye-talcmixture3.dosagewithmeteredvalves:1)reproducibilityofdosageeachtimethevalveisdepressed:a)oneortwodosesofdischarge;b)leftamount.2)amountofmedicationactuallyreceivedbythepatient:a)hardtodetermine;b)contents(净含量):Wtotal-Wcontainer5.foamstability:visualevaluation,rotationalviscometer,rodfalling,masspenetration第四十八页，共五十八页。48Testingofpharmaceuticalaerosols

(continued)6.particlesizedetermination:cascadeimpactor(级联撞击器):0.1~30micronslightscatterdecay:Tyndallbeam7.leakageD.biologiccharacteristics1.therapeuticeffect2.toxicity第四十九页，共五十八页。49PackagingofpowdersBulkpowderslimitedtononpotentsubstancessuchasa)antacidpowdersandlaxativepowdersb)douchepowdersc)medicatedpowdersforexternalapplicationantiinfectivesorantifungalsd)powdercontainingnutritionalsupplementsDividedpowdersa)weigheachportionseparatelyforpotentdrugb)block-and-dividemethodfornonpotentdrugapproximateeachportion第五十页，共五十八页。50granulesPreparationofgranules1.wetmethods1)basicwetmethoda)moisteningthepowdermixture(paste-likemass)b)granulationbyscreening(wetgranules)c)drying(drygranules)d)sizingthegranulesbyscreening(finishedgranules)

2)fluid-bedprocessingParticlesarevigorouslydispersedandsuspendedwhilealiquidexcipientissprayedonthemandthefluidizedproductdried,formingg