Lecture 4.ppt

biopharmaceutics

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ةـــــــــــــيلكلا ةــــــــــــيؤر
ةــــــــــــيلكلا ةلاـــــــــــــــسر
ةدايرلاً ايلحمً ايميلقاوً ايلودوءاقترلالةحصبناسنلاانمللاخمادختسابلااتاراكتىف
لاجمميلعتلاثوحبلاوةيملعلاتاسرامملاوةيقيبطتلا.
ريفوتلضفأتاسرامملايفلاجمميلعتلاملعتلاوبيردتلاوةيرارمتسإوقلخفصربلاطلل
نيجيرخلاوراكتبإبرشنوقيبطتوةفرعملاةثيدحلاةزكترملاىلعثوحبلالاوتاقيبطتيف
مولعلاةيلديصلاةيكينيلكلإاوةيعامتجلإاوضوهنللةحصلاب

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Upon successful completion of this course the student
should be able to;
Describe the physicochemical and physiological factors that
influence the absorption of drugs from extra and intravascular
routs of administration, their distribution within the body, and
the irroutesand mechanisms of elimination.

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ThepH-partitiontheoryexplainstheinfluenceofGI
pHanddrugpKaontheextentofdrugabsorption.
A.pH -Partition Theory
Asmostdrugsareweakelectrolytes,theunionized
formofweaklyacidicorbasicdrugs(i.e.thelipid-
solubleform)willpassacrossthegastrointestinal
epithelia,whereasthegastrointestinalepitheliais
impermeabletotheionized(i.e.poorlylipid-soluble)
formofsuchdrugs.

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AccordingtothepH-partitionhypothesis,the
absorptionofaweakelectrolytewillbedetermined
chieflybytheextenttowhichthedrugexistsinits
unionizedformatthesiteofabsorption.

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Theextenttowhichaweaklyacidicorbasicdrugionizes
insolutioninthegastrointestinalfluidisdeterminedby:
itspKa&thepHattheabsorptionsiteandmaybe
calculatedusingtheappropriateformoftheHenderson-
Hasselbachequation

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Whatisacid?
acidisasubstancethatliberateshydrogenions[H
+
]in
solution.
Whatisabase?
AbaseisasubstancethatcanbindH
+
andremovethem
fromsolution.
pH=-log[H
+
]
Strongacids,strongbases,aswellasstrongelectrolytes
areessentiallycompletelyionizedinaqueoussolution.
Weakacidsandweakbasesareonlypartiallyionizedin
aqueous solutionandyieldamixtureofthe
undissociatedcompoundandions.

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HA H
+
+ A
-
Ka =
[H
+
] [A
-
]
[HA]
Insolutionsofweakacids
equilibria exist between
undissociatedmoleculesand
theirions.
TheionizationconstantKaofa
weakacidcanbeobtainedby
applyingtheLawofMassAction:

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pKa = pH -log
[A
-
]
[HA]
log
[A
-
]
[HA]
= pH -pKa
Henderson -Hasselbalch
Equation
pK
a
= the negative logarithm
of K
a
FromthepKa,onecan
calculatetheproportionsof
druginthechargedand
unchargedformsatanypH:
For acidic drugs, the lower
the pKa the stronger the acid

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Some Typical pKa Values for Weak Acids at 25 °C
pKaWeak Acid
4.76Acetic
3.49Acetylsalicyclic
9.24Boric
2.73Penicillin V
8.1Phenytoin
2.97Salicyclic
7.12Sulfathiazole

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Insolutionsofweakbasesequilibria
exist between undissociated
moleculesandtheirions.
TheionizationconstantKaofa
protonatedweakbasecanbe
obtainedbyapplyingtheLawof
MassAction:
B + H
+
BH
+
Ka =
[H
+
] [B]
[BH
+
]

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pK
a
= the negative logarithm of K
a
FromthepKa,onecan
calculatetheproportionsof
druginthechargedand
unchargedformsatanypH:
pKa = pH -log
[B]
[BH
+
]
Henderson -Hasselbalch
Equation
log
[B]
[BH
+
]
= pH -pKa
Forbasicdrugs,thehigherthe
pKathestrongerthebase

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Therefore,accordingtotheseequations:
aweaklyacidicdrug,pKa3.0,willbe:
predominantlyunionizedingastricfluidatpH1.2
(98.4%)andalmosttotallyionizedinintestinalfluidat
pH6.8(99.98%),
aweaklybasicdrug,pKa5,willbe:
almostentirelyionized(99.98%)atgastricpHof1.2
andpredominantlyunionizedatintestinalpHof6.8
(98.4%).

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Thismeansthat,accordingtothepH-partition
hypothesis,aweaklyacidicdrugismorelikelytobe
absorbedfromthestomachwhereitisunionized,
andaweaklybasicdrugfromtheintestinewhereitis
predominantlyunionized.
However,inpractice,otherfactorsneedtobetakeninto
consideration.

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Lipid solubility :weak acids and weak bases
HA <==> H
+
+ A
-
B + HCl <==> BH
+
+ Cl
-
[ UI ] [ I ] [ UI ] [ I ]
pKa=pH + log (HA/A
-
) pKa= pH + log(BH
+
/B)
ASPIRIN pKa = 4.5 (weak acid)
100mg orally
99.9 = [ UI ] [ UI ]
Stomach
pH = 2
Blood
pH = 7.4
0.1 = [ I ]
Aspirin is reasonably absorbed Strychnine not absorbed until
from stomach (fast action) enters duodenum
0.1 = [ UI ] [ UI]
Blood
pH = 7.4
99.9 = [ I ]
STRYCHNINE pKa = 9.5 (weak base)
100mg orally
Stomach
pH = 2

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LimitationsofthepH-partitionhypothesis
Weakacidsarealsoabsorbedfromthesmallintestine
dueto:
Thesignificantlylargersurfaceareathatis
availableforabsorptioninthesmallintestinein
contrasttostomach
Thelongersmallintestinalresidencetime
ThemicroclimatepH,thatexistsatthesurface
oftheintestinalmucosaandislowerthanthat
oftheluminalpHofthesmallintestine

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ThepH-partitionhypothesiscannotexplainthefact
thatcertaindrugs(e.g.tetracyclines)arereadily
absorbeddespitebeingionizedovertheentirepH
rangeofthegastrointestinaltract.Onesuggestionfor
thisisthatsuchdrugsinteractwithendogenous
organicionsofoppositechargetoformanabsorbable
neutralspecies-anionpair-whichiscapableof
partitioningintothelipoidalGITbarrierandbe
absorbedviapassivediffusion.

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Barbitoneandthiopentone,havesimilardissociation
constants-pKa7.8and7.6,respectively-and
thereforesimilardegreesofionizationatintestinalpH.
However,thiopentoneisabsorbedmuchbetterthan
barbitone.WHY?theabsorptionofdrugsisalso
affectedbythelipidsolubilityofthedrug.
Thiopentone,beingmorelipidsolublethanbarbitone,
exhibitsagreateraffinityforthegastrointestinal
membraneandisthusfarbetterabsorbed.
B. Lipid Solubility of Drugs

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Anindicationofthelipidsolubilityofadrug,and(its
absorption)isgivenbyitsabilitytopartitionbetweena
lipid-likesolvent(usuallyoctanol)andwater.
Thisisknownasthedrug'spartitioncoefficient,andisa
measureofitslipophilicity.
How can we measure lipid solubility??

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ThepartitioncoefficientPistheratioofthedrug
concentrationintheorganicphasetoitsconcentration
intheaqueousphase
Partitioncoefficient(p)=[L]conc/[W]conc
[L]concistheconcentrationofthedruginlipidphase,
[W]concistheconcentrationofthedruginaqueous
phase.
Thehigherpvalue,themoreabsorptionisobserved.
Polarmolecules,i.e.thosethatarepoorlylipidsoluble
andrelativelylarge,suchasheparinarepoorly
absorbedafteroraladministrationandthereforehave
tobegivenbyinjection.

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Aprodrugisachemicalmodification,
frequentlyanesterofanexistingdrug.
The esterlinkageincreasesthe
lipophilicityofthecompound thus
enhancestheabsorption.
Aprodrughasnopharmocologicalactivity
itselfbutitconvertsbacktotheparent
compoundasaresultofmetabolismby
thebody.(e.g.Rivampicillinaprodrugfor
ampicillin)
The drug is too hydrophilic, what can be done??
Prodrugisoneoftheoptionsthatcanbeusedto
enhancepvalueandabsorptionassequence.

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Sofarwehavelookedatthetransferofdrugsin
solutionintheG-Itract,throughamembrane,into
solutionintheblood.
However,manydrugsaregiveninsoliddosageforms
andthereforemustdissolvebeforeabsorptioncantake
place.
C. Drug Dissolution

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TherateofsolutionmaybeexplainedusingFick’sFirst
LowofDiffusion:Itistherateatwhichadissolved
soluteparticlediffusesthroughthestagnantlayertothe
bulksolution
Ifabsorptionisslowrelativetodissolutionthenallwe
areconcernedwithisabsorption.However,ifdissolution
istheslow,ratedeterminingstep(thestepcontrolling
theoverallrate)thenfactorsaffectingdissolutionwill
controltheoverallprocess.

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Fick's first law
By Fick's first law of diffusion:
D diffusion coefficient,
A surface area,
C
ssolubility of the drug,
C
bconcentration of drug in the bulk solution,
h thickness of the stagnant layer.
As Cb is much smaller than Cs
the equation reduces to :
Solid
Stagnant
Layer
C
s C
bh
Bulk Solution

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Thereareanumberoffactorswhichaffectdrugdissolution:
Surfacearea,A
Thesurfaceareapergram(orperdose)ofasoliddrug
canbechangedbyalteringtheparticlesize.
e.g.acube3cmoneachsidehasasurfaceareaof54
cm
2
.Ifthiscubeisbrokenintocubeswithsidesof1cm,
thetotalsurfaceareais162cm
2
.

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GenerallyasAincreasesthedissolutionratewillalso
increase.Improvedbioavailabilityhasbeenobserved
withgriseofulvin,digoxin,etc.
Methodsofparticlesizereductionincludemortarand
pestle,mechanicalgrinders,fluidenergymills,solid
dispersionsinreadilysolublematerials(PEG's).

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Diffusionlayerthickness,h
Thisthicknessisaffectedbytheagitationinthebulk
solution.
Invivoweusuallyhaveverylittlecontroloverthis
parameter.
Itisimportantthoughwhenweperforminvitro
dissolutionstudiesbecausewehavetocontrolthe
agitationratesothatwegetsimilarresultsinvitroas
wewouldinvivo.

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Diffusioncoefficient,D
ThevalueofDdependsonthesizeofthemoleculeand
theviscosityofthedissolutionmedium.
Increasingtheviscositywilldecreasethediffusion
coefficientandthusthedissolutionrate.
Thiscouldbeusedtoproduceasustainedrelease
effectbyincludingalargerproportionofsomething
likesucroseoracaciainatabletformulation.

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Drugsolubility,Cs
Solubilityisanotherdeterminantofdissolutionrate.
AsCsincreasessodoesthedissolutionrate.
Wecanlookatwaysofchangingthesolubilityofadrug:

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base,thereforeifthedrug
canbegivenasasaltthe
solubilitycanbeincreased
and we should have
improveddissolution.One
exampleisPenicillinV.
D. (1)Salt Form
Ifwelookatthedissolutionprofileofvarioussalts.
Saltsofweakacidsandweakbasesgenerallyhave
muchhigheraqueoussolubilitythanthefreeacidor

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Somedrugsexistinanumberofcrystalformsor
polymorphs.
Thesedifferentformsmaywellhavedifferentsolubility
propertiesandthusdifferentdissolutioncharacteristics.
Chloramphenicolpalmitateisoneexamplewhichexists
inatleasttwopolymorphs.
E. (2)Crystal Form

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PlotofCpversusTimefor
Three Formulations of
ChloramphenicolPalmitate
TheBformisapparentlymorebioavailable.Thisis
attributedtothemorerapidinvivorateofdissolution.
The recommendation
might be that
manufacturers should
usepolymorph Bfor
maximum solubilityand
absorption.

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Inadditiontodifferentpolymorphiccrystallineforms,a
drugmayexistinanamorphousform.
Becausetheamorphousformusuallydissolvesmore
rapidlythanthecorrespondingcrystallineformsthere
willbesignificantdifferencesinthebioavailabilities.
e.g.antibioticnovobiocin.Themoresolubleandrapidly
dissolvingamorphousformofnovobiocinwasreadily
absorbed.
However,thelesssolubleandslower-dissolving
crystallineformofnovobiocinwasnotabsorbedtoany
significantextentthustherapeuticallyineffective.

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AcidandenzymatichydrolysisofdrugsinGITisoneof
thereasonsforpoorbioavailability.
PenicillinG(halflifeofdegradation=1minatpH=1)
RapiddissolutionleadstopoorbioavailabilityWHY?(due
toreleaselargeportionofthedruginthestomach,pH=
1.2)
Howtoprotectthedrugfromthegastricjuice?
1.Entericcoatingthetabletcontainingthedrug.
2.Prodrugthatexhibitslimitedsolubilityingastricfluid
butliberatestheparentdruginintestinetobeabsorbed.
F. Drug Stability and Hydrolysis in GIT

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G. Adsorption
Certain insoluble substances may adsorb
co-administrated drugs leading to poor
absorption.
Charcoal (antidote in drug intoxication).

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ComplexationofadrugintheGITfluidsmayalterrate
andextentofdrugabsorption.
1.GITcomponent-druginteraction:
Intestinalmucosa+Streptomycin=poorlyabsorbed
complex
2.Food-druginteraction:
Calcium+Tetracycline=poorlyabsorbedcomplex
3.Tabletadditive–druginteraction:
Carboxylmethylcellulose(CMC)+Amphetamine =
poorlyabsorbedcomplex
H. Complexation

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4. Complexing agent + polar drugs:
Dialkylamides + prednisone = well-absorbed lipid
soluble complex
5. Lipid soluble drug + water soluble complexing agent
Miconazole + cyclodextrine = water soluble complex

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