Physicochemical Properties of Drugs Affecting Bioavailability · –Dissociation of the drug...

Biopharmaceutics

PhysicochemicalPropertiesofDrugsAffectingBioavailability

Lec:4

Assist.LecturerAliYaseen AliBScPharmacy

MScIndustrialPharmaceuticalSciencesDept.ofPharmaceuticsSchoolofPharmacy

UniversityofSulaimani1

Biopharmaceutics

Physicochemicalproperties

DosageformRouteof

Administration

Bioavailability(Rate&Extent)

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Overview• PhysicochemicalFactors– Dissolutionrate• DissolutionrateandNoyes-Whitneyequation• PhysiologicalFactorsaffectingDissolutionRate• DrugFactorsaffectingdissolutionrate• FactorsaffectingConcentrationintheGIT afterdissolving• Poorlysolubledrugs

– Dissociationofthedrugmolecules(pKa)• pH-partitionhypothesis

– Lipidsolubility–Molecularsizeandhydrogenbonding3

DissolutionRate

• Theprocessofdissolvingisdissolution• Thisprocesshasacertainrateovertimecalleddissolutionrate

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Dissolutionrate:Noyes-Whitney equation

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• dm/dt:rateofdissolutionofdrugparticles• D:diffusioncoefficientofdruginsolutioninGITfluids• A:effectivesurfaceareaofthedrugparticlesincontact

withGITfluids• h: thicknessofthediffusionlayeraroundeachdrugparticle• Cs:isthesaturationsolubilityofthedruginsolutioninthe

GITfluids• C:theconcentrationofthedruginthegastrointestinal

fluids.

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Overview• PhysicochemicalFactors

– Dissolutionrate• DissolutionrateandNoyes-Whitneyequation• PhysiologicalFactorsaffectingDissolutionRate• DrugFactorsaffectingdissolutionrate• FactorsaffectingConcentrationintheGIT afterdissolving• Poorlysolubledrugs


– Lipidsolubility– Molecularsizeandhydrogenbonding

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PhysiologicalFactorsaffectingDissolutionRate

• TheenvironmentofthegastrointestinaltractcanaffecttheparametersoftheNoyes-Whitneyequationandhencethedissolutionrateofadrug.

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PhysiologicalFactorsaffectingDissolutionRate

• Thediffusioncoefficient,D,ofthedruginthegastrointestinalfluidsmaybedecreased bythepresenceofsubstancesthatincreasetheviscosityofthefluids.

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FoodintheGIT

• Foodmaycauseadecreaseindissolutionrateofadrugbyreducingtherateofdiffusion ofthedrugmoleculesawayfromthediffusionlayersurroundingeachundissolved drugparticle.

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Surfactants

• Surfactantsingastricjuiceandbilesalts–Wettability ofthedrug,andhencetheeffectivesurfacearea,A,exposedtogastrointestinalfluids

– solubilityofthedruginthegastrointestinalfluidsviamicellisation.

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Motility

• Thethicknessofthediffusionlayer,h,willbeinfluencedbythedegreeofagitationexperiencedbyeachdrugparticleintheGIT.

– ThisiscanbeseenbytheGImotilitybothgastricandintestine.

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Overview

• PhysicochemicalFactors– Dissolutionrate• DissolutionrateandNoyes-Whitneyequation• PhysiologicalFactorsaffectingDissolutionRate• DrugFactorsaffectingdissolutionrate• FactorsaffectingConcentrationintheGIT afterdissolving

– Dissociationofthedrugmolecules(pKa)– Lipidsolubility– Chemicalstabilityandcomplexationpotential

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DrugFactorsaffectingdissolutionrate

1. Particlesize&wettability2. Solubility3. Formofthedrug

a) Saltorfreeb) Crystallineoramorphous

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1.ParticlesizeandWetability• Surfaceareaisincreasedbyparticlesizereduction(micronisation )

• Increaseinthesurfaceareawillincreasetherateofdissolution• ProvidedthatalltheparticlesareintimatelywettedbyGITfluids

• Dissolutionratelimiteddrugs,particlesizereduction(increaseA)islikelytoincreasebioavailabilityofthedrug.

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Example

• Griseofulvin:classicexampleofwhichparticlessizereductionincreasesitsbioavailability.

• Manypoorlysolubledrugsorslowlydissolvingdrugsarepresentedinmicronised formtoimprovetheirdissolutionprofile.

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OtherExamples

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Doesmicronisationhasproblems?

I. Hydrophobicdrugs(poorlywatersoluble)

II. UnstabledrugsintheGIT

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I.Hydrophobicdrugs:

• Micronisationmightresultinaggregationofparticlestoformbiggerparticleshencereducesurfacearea.

– E.g.Aspirin,Phenobarbitals

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Solvingtheproblem

• Theproblemofaggregationcanbesolvedby:A. Micronisation inthepresenceofwetting

agentorhydrophiliccarrierA. E.g.danazol,bioavailabilityincreasedby400%

B. Additionofwettingagenttotheformulation– E.g.Polysorbate 80addedtoaqueous

suspensionofphenacetin,improvedrateandextentofabsorption.

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II.Chemicaldegradation

Somedrugsareunstableinstomachacid.

– ErythromycinandPenG

• Particlesizereductionwillincreasetheirdissolutionrate

• Alsoincreases destructionofdrugs

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IntrinsicSolubilityCs• UndersinkconditionsaccordingtotheNoyes-Whitneyequation,thedissolutionrate∝thesolubilityCs.

• Solubility– Molecularinteractionbetweenmoleculesofthesolidparticle– Intermolecularinteractionbetweenthemoleculesofthesolventandthesolidsubstance

– Entropychanges

Fordrugs(weakelecrtolytes)pHisalsoimportant.

dm/dt=DA(Cs-C)/h

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sIntrinsicSolubilityC

• DissolutionratedependsonthepKa ofthedrugandthesolubilityinthediffusionlayer.

• pHofthediffusionlayerdependsonthepKa ofthedrugandsolubility,pKaandsolubilityofbuffersintheGIT

• DifferenceinthedissolutionrateisexpectedfromdifferentGITregions.

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sIntrinsicSolubilityC

• Weakacids:solubilityincreaseswithincreasingpHdowntheGIT

• Weakbases:solubilitydecreaseswithincreasingpH– Thesesdrugsneedstobedissolvedinthestomachpriortothetransittotheintestine

– Ketoconazole given2hoursafterH2 antagonistcimetidine,resultsinthereductionintherateandextentofabsorption

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Salts

• Thedissolutionofweakaciddrugsinthestomachisrelativelylow?

• Dissolutionofthesedrugscanbeincreased bychangingchemicalnatureofthedrugandmaketheminthesaltform,sodiumNa+ orpotassiumK+salts.

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Salts

• ThisincreaseinthepHisduetoneutralisingeffectsoftheionsofthesalt

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Precipitation

• HoweverwhenthedrugdiffusestothebulkpHprecipitation mightoccurwhentheconcentrationofthedrugishigherthanthesaturationconcentrationofthesolventtodissolveit.

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Doestheprecipitationmatter?

• Theprecipitatesredissloveeasily– Veryfineparticlesandhighlywetted– Theconcentrationofthedruginthelumenreduces• Absorptionintothecirculation• Secretionandavailabilityofotherfluids• Emptyingintotheintestine

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AcidicDrugs

• Strongbasicsaltsofweakacidsdrugs

• Tolbutamide sodium:hasdissolutionrate500timesfasterthanoffreeform,theabsorptionisfaster

• NaproxenNa

• BarbituratesaredesignedintheformofNasalttoproducefasteronsetofaction

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Basicdrugs

• Drugstobedeliveredtotheabsorptionsiteinsolution

• Inordertoensurethatcompleteandfastdissolutionoccursinthestomach,drugismadeinthesaltform.

• Chorpromazine Cl dissolvesfaster inbothgastricandintestinalfluids

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Crystalform• Whenadrugisfoundinmorethanonecrystallineformthisiscalledpolymorphism andeachofthecrystallineformsarecalledpolymorph.

• Tetracycline,chloramphencol palmitate

• Metastable formhasfasterdissolutionratethanmorestableforms.

• Fordissolutionlimiteddrugs,thismightaffectthebioavailabilityproducedbythedrug

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Chloramphenicol

• Chloramphenicol palmitate:– A:stable– B:metastable– C:unstable

• Cistoounstabletobeusedindosageforms

• BhasfasterdissolutionratethanA,andhencetheextentofabsorptionishigher.

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Solvates• Itistheabilitytoassociatewithsolventmoleculestomakecrystals.

• Solventiswater itiscalledhydrate.

• Thegreaterthesolvation ofthecrystalthe lowerthesolubilityanddissolutionrate inthesolventidenticaltothesolvation molecules.

• Thisdifferenceindissolutionmightreflectdifferencesinbioavailabilityofdissolutionlimiteddrugs.

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Amorphoussolids• Dissolvesrapidly• Differencemightoccurinbioavailabilityofadrugthatisdissolutionratelimited.

• Stabilityissues

• OralsuspensionofNovobiocin:amorphousformiseffectivewhilethecrystallineformisineffective.

• Thisisbecauseofhedissolutionprofilebetweenthe2forms

• Theamorphousischangingtothecrystalline??

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Amorphoussolids

• Theamorphousformofampicillinisfasterdissolving andhasgreaterextentofabsorptionthanampicillintrihydrate,inbothhardgelatinecapsulesandsuspensions.

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Overview

• PhysicochemicalFactors– Dissolutionrate• DissolutionrateandNoyes-Whitneyequation• PhysiologicalFactorsaffectingDissolutionRate• DrugFactorsaffectingdissolutionrate• FactorsaffectingConcentrationintheGIT afterdissolving

– Dissociationofthedrugmolecules(pKa)– Lipidsolubility– Chemicalstabilityandcomplexationpotential

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FactorsaffectingconcentrationofdruginsolutionintheGIT

PhysicochemicalpropertiesA. ComplexationB. Micellar solubilisationC. AdsorptionD. Chemicalstability

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A.Complexation

• Beneficialordetrimental

• DosageformorGIT

• GITcomplexation :Tetracyclinewithfoodcomponents• Dosageforms:commoninliquiddosageforms– Presenceofcalciumasdiluent (dicalcium phosphate)inthedosageformsoftetracyclines reducesitsbioavailability

– PhenobarbitalandPEG4000

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Beneficial

• Increasedrugsolubility,poorlywatersolubledrugs

• Cyclodextrinfamily:enzymaticallymodifiedstarch

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b-cyclodextrin:hostplusguest

• Sevenunits• Outersurface–hydrophilic

• Innersurface–hydrophobic

• Increasesolubilityandhencebioavailability

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• Miconazole :poorbioavailabilitybecauseofpoorwatersolubility

• Complexationenhancesitssolubilityanddissolutionrate

• Doublinginitsbioavailability• Itraconazole(Sporanox)thefirstdrugintheUK,piroxicamandindomethacin

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B.Micellarsolubilisation

• Itcanincreasethesolubilityofdrugs

• Bilesalts

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C.Adsorption• Adsorbentscaninterfere withabsorptionofdrugsfromGIT.

• Foundasdrugsorintheformulationofdrugsandmedicines

• Kaolin,charcoal

• Reducetherateandextentofabsorptionthroughreducingtheeffectiveconcentrationofthedrugavailableforabsorption.

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Reductionintherateorextent

• Dependsonthenatureofinteractionbetweenthedrugandadsorbent

• Reversible• Irreversible

e.g.lincomycin-kaopectate,promazine-charcoal

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D.ChemicalstabilityofthedrugintheGIT

• Unstabledrugs

• Stability:– Chemical(acidic)– Enzymatic

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Stabilityissues

• Peptidedrugs

Solution1. Delayingthedissolutionofthedrug:enteric

coatingoftablets– Omeprazole,erythromycin

2. Prodrug:erythromycinstearate

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ErythromycinStearatevsErythromycinpelletsentereic

coated

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Poorlysolubledrugs(DissolutionRateLimited)

1. Nanosizeion2. Formulationassolutionor,suspension3. Stabilisingdrugsinamorphousform4. Formulationwithcyclodextrin

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– Lipidsolubility– Chemicalstabilityandcomplexationpotential53

DrugAbsorption

• Druginsolutionisreadyforabsorption

• Physicochemicalpropertiesaffectingabsorption:1. DissociationconstantpKa2. Lipophilicity(LogP)3. Molecularweight

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Drugdissociationandlipidsolubility

1. Dissociationconstant2. Lipidsolubility3. pHoftheenvironmentintheGIT– alwaysaffectsabsorption

• TheinterrelationshipbetweendegreeofionisationofweakelectrolytedrugsintheGITandtheextentofabsorptionisexplainedbypH-partitionhypothesis.

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pH-partitionhypotheis

• GITepitheliumactsasalipidbarrier todrugswhichareabsorbedbypassivediffusion.

• Lipidsoluble drugscanpassthemembrane.

• Mostdrugsareweakacidsandbases,theunionised offormofthedrugwillpassacrossthemembrane.

• However,themembraneisimpermeable totheionisedformofthedrugs.

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• Absorption canbedeterminedbytheextentintowhichthedrugisfoundintheunionisedform.

• ThisisdeterminedbyHanderson-Hasselbalchequation.

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Handerson-Hasselbalch• Weakacids:

𝑝𝐻 = 𝑝𝐾𝑎 + log[𝑖𝑜𝑛𝑖𝑠𝑒𝑑][𝑢𝑛𝑖𝑜𝑛𝑖𝑠𝑒𝑑]

– Weaklyacidicdrugs(pKa=3)willbepredominantlyunionisedatthestomachpH,andalmosttotallyionisedatintestinalpH.

• Weakbases

𝑝𝐻 = 𝑝𝐾𝑎 + log[𝑢𝑛𝑖𝑜𝑛𝑖𝑠𝑒𝑑][𝑖𝑜𝑛𝑖𝑠𝑒𝑑]

o Weaklybasic,pKa 5,almostentirelyionisedatgastricpH,andpredominantlyunionisedatintestinalpH.

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Limitationsofhypothesis1. Degreeofionisationisnottheonlyfactorin

determiningabsorption.– Weakacidsalthoughareionisedintheintestine,theyarewellabsorbed.

– Therateofabsorptionintheintestineishigherthaninthestomach.• Largesurfacearea• Longresidencetime• MicroclimatepHontheepitheliumwhichislowerthanthelumen

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2.Unstirredwaterlayerisnotaccountedfor3.Itcannotexplaintheabsorptionofsome

drugsthatareionisedacrosstheGIT.e.g.Quaternaryammoniumcompounds– Themembraneisnotcompletelyimpermeabletoioniseddrugs

– Itinteractswithendogenousoppositechargeionstoformabsorbableneutralspecies

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– Lipidsolubility– Chemicalstabilityandcomplexationpotential61

Lipidsolubility

• TwodrugsmighthavesimilarpKa,accordingtothepH-partitionhypothesistheymustbeabsorbedinsimilarmanner.

• E.g.– Thiopentene (pKa:7.6)– Barbitone (pKa:7.8)– thiopentene isabsorbedbetter.• Becausethiopentene ismorelipophilic

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Measurement

• Itiscalculatebymeasurementofitspartitionbetweenlipophilicsolventandwater,partitioncoefficient

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Partitioncoefficient =[𝑐𝑜𝑛𝑐. 𝑖𝑛𝑜𝑟𝑔𝑎𝑛𝑖𝑐𝑝ℎ𝑎𝑠𝑒][𝑐𝑜𝑛𝑐. 𝑖𝑛𝑎𝑞𝑢𝑒𝑠𝑜𝑢𝑠𝑝ℎ𝑎𝑠𝑒]

Polarmolecules

• Polar(LogP <0)andlargemoleculescannotbeabsorbedandneedstobetakenbyotherroutes.– E.g.gentamicin,ceftriaxoneandheparin

• Polarmoleculeswithsmallersizecanbeabsorbedviaparacellular pathway.– E.g.Betablocker,Atenolol

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• Lipid-solubledrugs(LogP>0)arewellabsorbedafteroraladministration.

• VeryLipid-solubledrugs(LogP>3)arewellabsorbed,buttheyaremorelikelytobemetabolisedandexcretedbybiliaryclearance.

• Althoughitisnotappliedtoalldrugs,butincreaseinlipophilicitywithinhomologousgroupimprovesabsorption– Beta-blockers

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Poorlipidsolubility?

• Prodrugdesign

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Molecularsizeandhydrogenbonding

• Paracelullarpathway.:– ideallymolecularweightshouldbe<200Dalton(therearealsoexamplesoflargermolecules)

• Transcellular(passivediffusion):–Molecularweightof<500ispreferable– Biggerthan500isabsorbedlessefficiently– Fewdrugsabsorbed>700

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• Toomanyhydrogenbondsaredetrimental– Hydrogenbonddonors<5– Hydrogenbondacceptors<10

– the sum of nitrogen and oxygen atoms in the molecule is often taken as a rough measure of hydrogen bond acceptors

– Peptides

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Conclusion

• Physicohcemicalpropertiesofthedrugaremajordeterminantofthedissolutionandabsorptionofdrugs.

• Therefore,rateandextentofabsorptionisinfluencedtolargeextent.

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FurtherReadings

• Aulton'sPharmaceutics:TheDesignandManufactureofMedicines,M.E.Aulton,ChurchillLivingstone,2007.

• ShargelL,YuAB,(Eds.),AppliedBiopharmaceuticsandPharmacokinetics.

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Physicochemical Properties of Drugs Affecting Bioavailability · –Dissociation of the drug...

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