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Dr. Doaa Hussien HassenDepartment of Pharmaceutics and Industrial Pharmacy,
College of Pharmacy & Pharmaceutical ManufactureMisr University or Science & Technology
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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..
33--BufferBuffer capacitycapacity ofof bodybody fluidfluid1/28/2012 Dr. Doaa Hussien Hassen 27
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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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