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    Dr. Doaa Hussien HassenDepartment of Pharmaceutics and Industrial Pharmacy,

    College of Pharmacy & Pharmaceutical ManufactureMisr University or Science & Technology

    Email: [email protected]/28/2012Dr. Doaa Hussien Hassen 1

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    BuffersBuffers areare compoundscompounds oror mixturesmixtures ofof compoundscompounds

    thatthat byby theirtheir presencepresence inin solutionsolution resistresist changeschanges inin pHpH

    uponupon thethe additionaddition ofof smallsmall quantitiesquantities ofof acidacid oror alkalialkali..

    TheThe bufferbuffer actionaction::

    TheThe buffer buffer actionaction isis toto resistresist thethe changechange inin pHpH..

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    BufferBuffer couldcould bebe::

    AA combinationcombination ofof aa weakweak acidacid andand itsits conjugateconjugate

    base base (salt)ee..gg.. aceticacetic acidacid andand sodiumsodium acetateacetate

    oror

    AA combinationcombination ofof aa weakweak basebase andand itsits conjugateconjugateacidacid (salt)(salt)..

    ee..gg.. AmmoniumAmmonium hydroxidehydroxide andand

    ammoniumammonium chloridechloride1/28/2012 Dr. Doaa Hussien Hassen 4

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    IfIf 11 mlml ofof aa 00..11 NN HClHCl isis addedadded toto 100100 mlml ofof purepure waterwater

    (pH=(pH=77)) solution,solution, thethe pHpH isis reducedreduced fromfrom 77 toto 33..

    ButBut ifif 11 mlml ofof aa 00..11 NN HClHCl solutionsolution isis addedadded toto 100100 mlml ofofpurepure waterwater containingcontaining bufferbuffer((equalequal quantitiesquantities ofof aceticacetic acidacid

    andand sodiumsodium acetateacetate 00.. 11 MM solution),solution), thethe pHpH isis changedchanged onlyonly

    00..0909 pHpH units,units, becausebecause thethe basebase AcAc-- tiesties upup thethe hydrogenhydrogen

    ionsions accordingaccording toto thethe reactionreaction::

    AcAc-- +H+H33OO++ HAC +HHAC +H22OO

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    InIn casecase ofof basebase additionaddition::

    IfIf aa strongstrong basebase;; sodiumsodium hydroxide,hydroxide, isis

    addedadded toto thethe bufferbuffer mixture,mixture, aceticacetic acidacid

    willwill neutralizeneutralize thethe hydroxylhydroxyl ionsions

    HAcHAc ++NaOH NaOH HH22O+O+ NaACNaAC

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    TheThe bufferbuffer equationequation oror thethe HendersonHenderson--

    Hasselbalch Hasselbalch equationequation, , for for aa weakweak acidacid

    andand itsits saltsalt::

    pH=pH= pKapKa ++ loglog [Salt]/[acid][Salt]/[acid]

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    ImportanceImportance ofof BufferBuffer EquationEquation::

    1.1. ToTo calculatecalculate thethe pHpH ofof aa bufferbuffer solutionsolution

    TheThe bufferbuffer equationequation isis importantimportant inin thethe preparationpreparation ofof

    bufferedbuffered pharmaceuticalpharmaceutical solutionsolution;; itit isis satisfactorysatisfactory forfor

    calculationscalculations withinwithin thethe pHpH rangerange ofof 44 toto 1010..

    2.2. ToTo calculatecalculate thethe changechange inin pHpH uponupon thethe additionaddition ofof

    anan acidacid oror basebase

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    pH=pH= pKpKww --pKpKbb ++ loglog [base]/[base]/ [salt][salt]

    Buffer Buffer solutions solutions areare notnot ordinarilyordinarily preparedprepared fromfrom

    weakweak basesbases andand theirtheir saltssalts becausebecause ofof::

    ((11)) TheThe volatilityvolatility

    ((22)) InstabilityInstability ofof thethe basesbases

    ((33)) TheThe dependencedependence ofof theirtheir pHpH onon pKpKww,, whichwhich isis

    oftenoften affectedaffected byby temperaturetemperature changeschanges..

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    BufferBuffer capacitycapacity isis thethe magnitudemagnitude ofof thethe resistanceresistance ofof aa bufferbuffer

    toto pHpH changeschanges..

    ItIt isis alsoalso knownknown asas bufferbuffer efficiency,efficiency, buffer buffer index,index, andand

    buffer buffer valuevalue..

    VanVan Slyke Slyke introducedintroduced thethe conceptconcept ofof bufferbuffer capacitycapacity andand

    defineddefined::

    ItIt asas thethe ratioratio ofof thethe incrementincrement ofof strongstrong basebase (or(or acid)acid) addedadded

    toto thethe smallsmall changechange inin pHpH broughtbrought aboutabout byby thisthis additionaddition..

    = B / pH= B / pH

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    = B / pH= B / pH

    delta,delta, hashas itsits usualusual meaning,meaning, aa finitefinite change,change, andand BB isis thethe

    smallsmall incrementincrement inin gramgram equivalentsequivalents perper literliter ofof strongstrong basebase

    addedadded toto thethe bufferbuffer solutionsolution toto produceproduce aa pHpH changechange ofof

    pHpH..

    TheThe bufferbuffer capacitycapacity ofof aa solutionsolution hashas aa valuevalue ofof 11 whenwhen:: thethe

    additionaddition ofof 11 gramgram EqEq ofof strongstrong basebase (or(or acid)acid) toto 11 literliter ofofthethe bufferbuffer solutionsolution resultsresults inin aa changechange ofof 11 pHpH unitunit..

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    ItItmustmust bebe notednoted thatthat::

    ((11)) TheThe bufferbuffer capacitycapacity isis notnot aa fixedfixed valuevalue forfor aa givengiven bufferbuffer system,system, butbut

    ratherrather dependsdepends onon thethe amountamount ofof basebase addedadded..

    ((22)) TheThe bufferbuffer capacitycapacity changeschanges asas thethe ratioratio loglog [salt]/[acid][salt]/[acid] increasesincreases withwith

    addedadded basebase..

    ((33)) TheThe buffer buffer hashas itsits greatestgreatest capacitycapacity whenwhen [salt]/[acid][salt]/[acid] == 11,, and,and,

    therefore,therefore, pHpH == pKapKa..

    ((44)) TheThe bufferbuffer capacitycapacity isis alsoalso influencedinfluenced byby anan increaseincrease inin thethe totaltotal

    concentrationconcentration ofof thethe buffer buffer constituents,constituents, since,since, obviously,obviously, aa greatergreater

    concentrationconcentration ofof saltsalt andand acidacid providesprovides aa greatergreater alkalinealkaline andand acidacid reservereserve..

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    VanVan SlykesSlykes EquationEquation forfor BufferBuffer CapacityCapacity::

    WhereWhere::

    CC isis thethe totaltotal bufferbuffer concentrationconcentration

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    InIn summary,summary, thethe bufferbuffer capacitycapacity dependsdepends onon::

    (a)(a) TheThe valuevalue ofof thethe ratioratio [salt][salt] // [acid],[acid], increasingincreasing asas thethe

    ratioratio approachesapproaches unityunity;; (salt/acid=(salt/acid=11))

    (b)(b) TheThe magnitudemagnitude ofof thethe individualindividual concentrationsconcentrations ofof thethe

    bufferbuffer components,components, thethe bufferbuffer becomingbecoming moremore efficientefficient asas

    thethe saltsalt andand acidacid concentrationsconcentrations areare increasedincreased..

    ThereforeTherefore anan increaseincrease inin thethe concentrationconcentration ofof thethe bufferbuffer

    componentscomponents resultsresults inin aa greatergreater bufferbuffer capacitycapacity oror efficiencyefficiency..

    CC == [salt][salt] ++ [acid],[acid], obviouslyobviously resultsresults inin aa greatergreater valuevalue ofof ..

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    TheThe maximummaximum bufferbuffer capacitycapacity occursoccurs wherewhere pHpH == pKapKa,,

    SubstitutingSubstituting [H[H33OO++]] forfor KaKa inin bothboth numeratornumerator andand denominatordenominator ofof VanVan

    SlykeSlyke equationequation givesgives

    maximummaximum == 00..576576 CC

    InIn whichwhich CC isis thethe totaltotal bufferbuffer concentrationconcentration..

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    Buffer capacity of a weak acid/salt buffer as a function

    of pH, showing maximum buffer capacity at pKa.

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    The

    The componentscomponents ofof variousvarious bufferbuffer systemssystems andand thethe concentrationsconcentrations

    requiredrequired toto produceproduce differentdifferent pHspHs areare listedlisted inin severalseveral referencereference

    books,books, suchsuch asas thethe pharmacopoeiaspharmacopoeias..

    WhenWhen selectingselecting aa suitablesuitable bufferbuffer

    1.1. thethe pKapKa valuevalue ofof thethe acidacid shouldshould bebe closeclose toto thethe requiredrequired pHpH

    2.2. thethe compatibilitycompatibility ofof itsits componentscomponents withwith otherother ingredientsingredients inin

    thethe systemsystem shouldshould bebe consideredconsidered..

    3.3. TheThe toxicitytoxicity ofof bufferbuffer componentscomponents mustmust alsoalso bebe takentaken intointoaccountaccount ifif thethe solutionsolution isis toto bebe usedused forfor medicinalmedicinal purposespurposes

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    AA solutionsolution ofof ephedrineephedrine basebase actact asas aa naturalnatural bufferbuffer

    protectingprotecting againstagainst reductionsreductions inin pHpH..

    WhenWhen HydrochloricHydrochloric acidacid isis addedadded toto thethe ephedrineephedrine

    solution,solution, EphedrineEphedrine hydrochloridehydrochloride isis formed,formed, andand thethe

    buffer buffer systemsystem ephedrineephedrine plus plus ephedrineephedrine

    hydrochloridehydrochloride willwill resistresist largelarge changeschanges inin pHpH untiluntil

    thethe ephedrineephedrine isis depleteddepleted byby reactionreaction withwith thethe acidacid..

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    AA drug,drug, inin solutionsolution maymay oftenoften actact asas itsits ownown bufferbuffer

    overover aa definitedefinite pH pH rangerange.. SuchSuch buffer buffer action,action,

    however,however, isis oftenoften tootoo weakweak toto resistresist pH pH changeschanges

    broughtbrought aboutabout byby thethe carboncarbon dioxidedioxide ofof thethe airair andand thethe

    alkalinityalkalinity ofof thethe bottlebottle.. AdditionalAdditional buffers buffers areare

    thereforetherefore frequentlyfrequently addedadded toto drugdrug solutionssolutions toto

    maintainmaintain thethe SystemSystem withinwithin aa certaincertain pHpH rangerange..

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    TheThe abilityability toto resistresist changechange inin pHpH onon addingadding acidacid oror

    alkalialkali isis possessed possessed alsoalso by by relativelyrelatively concentratedconcentrated

    solutionssolutions ofof strongstrong acidsacids andand strongstrong basesbases..

    InIn general,general, solutionssolutions ofof strongstrong acidsacids ofof pHpH 33 oror less,less,

    andand solutionssolutions ofof strongstrong bases bases ofof pH pH 1111 oror more,more,

    exhibitexhibit thisthis kindkind ofof bufferbuffer actionaction duedue toto thethe relativelyrelativelyhighhigh concentrationconcentration ofof hydroniumhydronium oror hydroxylhydroxyl ionion

    presentpresent..

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    TheThe USPUSP includesincludes amongamong itsits StandardStandard BufferBuffer

    SolutionsSolutions aa seriesseries ofof HydrochloricHydrochloric AcidAcid Buffer,Buffer,

    coveringcovering thethe pHpH rangrang 11..22 toto 22..22,, whichwhich alsoalso containcontain

    potassiumpotassium chloridechloride;; thethe saltsalt doesdoes notnot participateparticipate inin thethe

    bufferingbuffering mechanism,mechanism, asas isis thethe casecase withwith saltssalts ofof weakweak

    acids,acids, insteadinstead itit servesserves asas aa nonnon reactivereactive constituentconstituent

    requiredrequired toto maintainmaintain thethe proper proper electrolyteelectrolyte

    environmentenvironment ofof thethe solutionssolutions..

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    BloodBlood::

    BloodBlood isis maintainedmaintained atat aa pHpH ofof aboutabout 77..44 byby thethe soso--calledcalled primaryprimary buffersbuffers inin

    thethe plasmaplasma andand thethe secondarysecondary buffersbuffers inin thethe erythrocyteserythrocytes..

    TheThe PrimaryPrimary bufferbuffer inin plasmaplasma containscontains::

    CarbonicCarbonic acid/bicarbonateacid/bicarbonate andand

    Acid/alkaliAcid/alkali sodiumsodium saltssalts ofof phosphoricphosphoric acidacid asas buffersbuffers..

    PlasmaPlasma proteins,proteins, whichwhich behavebehave asas acidsacids inin blood,blood, cancan combinecombine withwith basesbases

    andand actact asas buffersbuffers..

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    TheThe secondarysecondary buffersbuffers inin thethe erythrocytes,erythrocytes,

    TheThe twotwo buffer buffer systemssystems consistconsist ofof hemoglobinhemoglobin

    //oxyhemoglobinoxyhemoglobin andand acid/alkaliacid/alkali potassium potassium saltssalts ofof

    phosphoricphosphoric acidacid..

    UsuallyUsually whenwhen thethe pHpH ofof thethe bloodblood goesgoes belowbelow 77..00 oror aboveabove

    77..88,, lifelife isis inin seriousserious dangerdanger..

    TheThe pHpH ofof thethe bloodblood inin diabeticdiabetic comacoma isis allegedalleged toto dropdrop asas

    lowlow asas aboutabout 66..88..

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    LachrymalLachrymal fluid,fluid, oror tearstears lachrymallachrymal fluidfluid

    LachrymalLachrymal fluidfluid hashas beenbeen foundfound toto havehave aa greatgreat degreedegree ofof bufferbuffer

    capacitycapacity:: allowingallowing aa dilutiondilution ofof 11::1515 withwith neutralneutral distilleddistilled waterwater

    beforebefore anan alterationalteration ofof pHpH isis noticednoticed..

    ThisThis wouldwould bebe referredreferred toto asas dilutiondilution valuevalue ratherrather thanthan bufferbuffer

    capacitycapacity..

    TheThe pHpH ofof tearstears isis aboutabout 77..44,, withwith aa rangerange ofof 77 toto 88 oror slightlyslightly

    higherhigher..

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    BufferBuffer solutionssolutions areare usedused frequentlyfrequently inin pharmaceuticalpharmaceuticalpractice,practice,

    particularlyparticularly inin thethe formulationformulation ofof ophthalmicophthalmic solutionssolutions..

    11-- GiffordGifford suggestedsuggested twotwo stockstock solutions,solutions, whenwhen mixedmixed inin variousvarious

    proportions,proportions, yieldyield bufferbuffer solutionssolutions withwith pHpH valuesvalues fromfrom aboutabout 55 toto 99 oneonecontainingcontaining boricboric acidacid andand thethe otherother monohydratemonohydrate sodiumsodium carbonatecarbonate..

    22-- SorensenSorensen PhosphatePhosphate bufferbuffer (mixture(mixture ofof thethe saltssalts ofof sodiumsodium phosphatephosphate

    forfor bufferbuffer solutionssolutions ofof pHpH 66 toto 88..

    SodiumSodium chloridechloride isis addedadded toto eacheach bufferbuffer mixturemixture toto makemake itit isotonicisotonic withwith

    bodybody fluidsfluids.. 33-- BoricBoric acid,acid, sodiumsodium borateborate BufferBuffer..

    ItIt isis usedused forfor ophthalmicophthalmic solutionssolutions inin thethe pHpH rangerange ofof 77 toto 99.. SufficientSufficient

    sodiumsodium chloridechloride toto makemake thethe mixturesmixtures isotonicisotonic

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    SolutionsSolutions toto be be appliedapplied toto tissuestissues oror administeredadministered

    parenterallyparenterally areare liableliable toto causecause irritationirritation ifif theirtheir pHpH isis

    greatlygreatly removedremoved fromfrom thethe normalnormal pHpH ofof thethe relevantrelevant

    bodybody fluidfluid..

    Consequently,Consequently, thethe pharmacistpharmacist mustmust considerconsider thisthis pointpoint

    whenwhen formulatingformulating ophthalmicophthalmic solutions,solutions, parenteralparenteral

    products,products, andand fluidsfluids toto bebe appliedapplied toto abradedabraded surfacessurfaces..

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    PharmacistPharmacistmustmust considerconsider::

    11-- TheThe pHpH ofof thethe formulaformula

    22-- BufferBuffer capacitycapacity andand thethe volumevolume toto be be usedused inin

    relationrelation toto thethe volumevolume ofof bodybody fluidfluid withwith whichwhich thethe

    buffered buffered solutionsolution willwill comecome inin contactcontact.. TheThe bufferbuffer

    capacitycapacity ofof thethe bodybody fluidfluid shouldshould alsoalso bebe consideredconsidered..

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    TissueTissue irritation,irritation, duedue toto largelarge pH pH differencesdifferences between between thethe

    solutionsolution beingbeing administeredadministered andand thethe physiologicalphysiological environmentenvironment

    inin whichwhich itit isis used,used, willwill bebe minimalminimal ifif::

    (a)(a) TheThe lowerlower thethe bufferbuffer capacitycapacity ofof thethe solution,solution, (b)(b) TheThe smallersmaller thethe volumevolume used,used, andand

    (c)(c) TheThe largerlarger thethe volumevolume andand buffer buffer capacitycapacity ofof thethe

    physiologicalphysiological fluidfluid..

    TheThe pHpH ofof solutionssolutions forfor introductionintroduction intointo thethe eyeeye maymay varyvaryfromfrom 44..55 toto 1111 ..55 markedmarked painpain oror damagedamage.. (This(This statementstatement

    evidentlyevidently wouldwould bebe truetrue onlyonly ifif thethe bufferbuffer capacitycapacity waswas keptkept

    low)low)..

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    ItIt waswas foundfound thatthat SorensensSorensens bufferbuffer producedproduced irritationirritation inin thethe eyeseyes

    ofof aa numbernumber ofof subjects,subjects, whereaswhereas aa boricboric acidacid solutionsolution ofof pHpH 55

    producedproduced nono discomfortdiscomfort inin thethe eyeseyes ofof thethe samesame subjectssubjects..

    ThisThis cancan bebe explainedexplainedpartlypartly inin termsterms ofof:: ((11)) TheThe lowlow bufferbuffer capacitycapacity ofof boricboric acidacid asas comparedcompared toto thatthat ofof

    thethe phosphatephosphate bufferbuffer andand

    ((22)) TheThe differencedifference ofof thethe physiological physiological responseresponse toto variousvarious

    speciesspecies..

    ParenteralParenteral solutionssolutions forfor injectioninjection intointo thethe bloodblood areare bufferedbuffered toto aa

    lowlow capacitycapacity soso thatthat thethe buffersbuffers ofof thethe bloodblood maymay readilyreadily bringbring

    themthem withinwithin thethe physiologicphysiologic pHpH rangerange..

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    InIn aqueousaqueous solutionssolutions

    InstabilityInstability maymay arisearise throughthrough thethe catalyticcatalytic effecteffect ofof acidsacids oror basesbases;;

    AcidsAcids:: byby transferringtransferring aa protonproton

    BasesBases byby acceptingaccepting aa protonproton..

    ThisThis instabilityinstability problemproblem couldcould bebe overcomeovercome byby adjustingadjusting pHpH throughthrough thethe

    useuse ofof buffersbuffers

    ItIt mustmust bebe notednoted thatthat pHpH adjustmentadjustment isis importantimportant forfor solutionssolutions thatthat requirerequire

    sterilizationsterilization

    ExamplesExamples::

    MorphineMorphine solutionssolutions::

    IfIf pH

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    SolutionsSolutions ofof thiaminethiamine hydrochloridehydrochloride::

    TheyThey maymay be be sterilizedsterilized by by autoclavingautoclaving withoutwithout

    appreciableappreciable decompositiondecomposition ifif thethe pHpH isis below below 55;;

    aboveabove this,this, thiaminethiamine hydrochloridehydrochloride isis unstableunstable..

    TheThe stabilitystability ofofmanymany dispersedisperse systems,systems,

    TheThe stabilitystability ofof manymany dispersedisperse systemssystems areare especiallyespecially

    ofof certaincertain emulsions,emulsions, isis oftenoften pHpH--dependentdependent..

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    DrugsDrugs areare weakweak acidsacids oror weakweak bases,bases, andand hencehence maymay existexist inin ionizedionized

    oror unionizedunionized formform (or(or aa mixturemixture ofof both),both),

    OftenOften suchsuch drugsdrugs havehave anan optimumoptimum pHpH rangerange forfor maximummaximum activityactivity..

    ((11)) Mandelic Mandelic acid,acid, benzoicbenzoic acid,acid, andand salicylic salicylic acidacid havehave distinctdistinctantibacterialantibacterial activityactivity inin unionizedunionized formform butbut havehave practicallypractically nono suchsuch

    activityactivity inin ionizedionized formform;; accordingly,accordingly, thesethese substancessubstances requirerequire anan

    acidacid environmentenvironment toto functionfunction effectivelyeffectively asas antibacterialantibacterial agentsagents..

    ((22)) SodiumSodium benzoatebenzoate isis effectiveeffective asas aa preservative preservative inin 44%%concentrationconcentration atat pHpH 77..00,, 00..0606 toto 00..11%% concentrationconcentration atat pHpH 33..55 toto 44..00,,

    andand 00..0202 toto 00..0303%% concentrationconcentration atat pHpH 22..33 toto 22..44 (needs(needs acidicacidic pH)pH)..

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    RateRate ofof absorptionabsorption ofof drugsdrugs fromfrom thethe gastrointestinalgastrointestinal andand

    theirtheir passagepassage throughthrough cellularcellular membranesmembranes isis determineddetermined byby::

    ((11)The)The degreedegree ofof ionizationionization andand

    ((22)) LipidLipid solubilitysolubility ofof aa drugdrug

    ((33)) TheThe pH pH ofof thethe physiological physiological mediummedium (gastric(gastric oror

    intestinalintestinal fluid,fluid, plasma,plasma, cerebrospinalcerebrospinal fluid,fluid, etcetc..)) inin whichwhich aa

    drugdrug isis dissolveddissolved..

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    DrugsDrugs thatthat areare weakweak organicorganic acidsacids oror bases,bases,

    andand whichwhich inin nonnon ionizedionized formform areare solublesoluble

    inin lipids,lipids, areare absorbedabsorbed throughthrough cellularcellular

    membranesmembranes byby virtue,virtue, ofof thethe lipidlipid naturenature ofof

    thethe membranesmembranes..

    CompletelyCompletely ionizedionized drugs,drugs, onon thethe otherother

    hand,hand, areare poorlypoorly absorbedabsorbed..1/28/2012 Dr. Doaa Hussien Hassen 34

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    Not Not onlyonly thethe degreedegree ofof thethe acidicacidic oror basicbasic

    charactercharacter ofof aa drugdrug butbut consequentlyconsequently alsoalso thethe pHpH

    ofof thethe physiological physiological mediummedium (gastric(gastric oror

    intestinialintestinial fluid,fluid, plasma,plasma, cerebrospinalcerebrospinal fluid,fluid, etcetc..))

    inin whichwhich aa drugdrug isis dissolveddissolved oror disperseddispersed sincesince

    thisthis pHpH determinesdetermines thethe extentextent toto whichwhich thethe drugdrug

    willwill be be convertedconverted toto ionicionic oror nonionicnonionic formformbecomebecome importantimportant parametersparameters ofof drugdrug absorptionabsorption..

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    StabilityStability versusversus OptimumOptimum TherapeuticTherapeutic ResponseResponse::

    TheThe pHpH forfor maximummaximum stabilitystability ofof aa drugdrug forfor ophthalmicophthalmic useuse

    maymay bebe farfar belowbelow thatthat ofof thethe optimumoptimum physiologicphysiologic effecteffect..

    UnderUnder suchsuch conditionsconditions::

    11-- TheThe solutionsolution ofof thethe drugdrug cancan buffered buffered atat aa lowlow bufferbuffer

    capacitycapacity

    22--AA compromisecompromise pHpH betweenbetween thatthat ofof optimumoptimum stabilitystability andand

    thethe pHpH forfor maximummaximum therapeutictherapeutic actionaction mustmust bebe donedone..

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