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Absorp'onisquan'ta'vetoo
• Permea'onrate,RP=PAreaΔC• Amountabsorbed=RP•Time
– Pismembranepar''oncoefficient(relatedtoLogP)
– Areaiseffec'vesurfaceareaofmembrane
– ΔCisconcentra'ondifferencefortheneutralformofthedrug
• Astomach/Aileumdiffer1000'mes.Thatmeansthatevenifthefrac'onofneutralspeciesinstomachis100'mesgreater,s'll10'mesmorecompoundwillbeabsorbedinthegut.Theeffectof'mecomesontop.
Cout
Cin
A=120m2
A=0.1m2
DrugSalts:Bases
Note:HydrochlorideinDrug.HClmaybemisleading,itshouldbejustchloride(Drug+.[Cl-]),samewithH2SO4
Acid[AH]
BasicDrug[B] + -
Drug,BH+Anion
AnionicSaltoftheDrug
plus
Acid Anion Examples
Hydrochloride(HCl) Cl- PyridoxineHCl,PramipexoleHClChlorpromazineHCl,Demeclocycline..DemethylchlortetracyclineNalbuphine,ChlorhexidinePropafenone,MitoxantroneLincomycin,Ro'go'neVilazodone,Naphazoline
SulfuricAcid SO42- Dextroamphetamine,Hydroxychloroquine
Ace'cAcid(acetate) CH3COO- Leuprolide,Goserelin,Desmopressin,…
cocainehydrochloride
+
DrugSalts:AcidsBaseB,e.g.NaOH
AcidicDrugAH
e.g.R-COOH - +Drug
ion,[A-] Ca'on
Ca'onicSaltoftheDrug
plus
OH-Base Ca;on Examples
Sodium Na+ Ecabet,Diclofenac,Indomethacin,Benzoate,Salicylate
Calcium Ca++ Atorvasta'n,CalciumGluceptate
Potassium K+ PenicillinVPotassium,Losartan
Ca++needstwonega'vecharges
CalciumGluceptate
Warning:donotforgettousecorrectmolecularweightofthesalt
Salts:summary• Stoichiometry:makesure
thatthetotalformalchargeiszero(e.g.[D-]2Me2+)
• Ambiguityofchemicalrepresenta'on:[DH+][Cl-]vs[D][HCL],MolWeight.
• Solubilityofcrystals:usuallybecerthannon-salt,butdiffersbetweendifferentsalts.
• Iden8calinSolu8on:Oncethesaltisdissolveditbecomesiden'caltothenon-saltformofthedruginsolu'on
• Resonance:Example,sulfate:perfecttetrahedronwithtotalnega'vechargeof-2distributedbetween4nega'veoxygensandoneposi'vessulfur.
Saltswithbecersolubility:example• Example:
– Phenobarbital,awhitepowder,isaweakacidwithlimitedsolubilityinwater,
– thesodiumsaltofPhenobarbital,alsoawhitepowder,thesaltoftheweakacid,nowwatersoluble
• pKa=7.41
• pH(satur.sol)5~10.• Solubility:1g/L1g/10mL
Epoprostenol.Na+ProstacyclinI.V.vasodilatorinischemia&PH
Na+
Moreexamples:Naproxen NaproxenSodiumFenoprofen FenoprofenCalciumPenicillinG PenicillinGPotassium
Moreanionsforbasicdrugs• Base Salt/ConjugateAcid• Diphenhydramine DiphenhydramineHCL• Glucosamine Glucosaminesulfate• Epinephrine Epinephrinesulfate• Ephedrine EphedrineHCl• Atropine Atropinesulfate• Tetracycline TetracyclineHCl
• Mostofthesedrugs,asyoucantellbytheirname,are"amines",whichmeanstheyareweakbases
• AcetateCH3COO−(ace'cacid)• CarbonateCO3
2−,carbonicacid)• ChlorideCl−(hydrochloricacid)• CitrateHOC(COO−)(CH2COO−)2(citricacid)• CyanideC≡N−(hydrocyanicacid)(toxic)• NitrateNO3
−(nitricacid)• NitriteNO2
−(nitrousacid)• PhosphatePO4
3−(phosphoricacid)• SulfateSO4
2−(sulfuricacid)Sodium-nitroprusside,-vasodilator
SolubilityandPermeability
Twooppositerequirements:• Solubilityisgoodforchargedcompoundswithmul'plepolargroups(e.g.pep'des)
• Permeabilityisgoodforhydrophobicandapolarcompounds
Twosolu'ons:• Beexactlyinthemiddlewiththesamechemicalstructure(minority)
• Beabletochangeviaenzyma'cac'va'on(prodrug)oradoptalterna'vechargedforms
Solubility,LogP,andLogD
• Notallunchargedcompoundsareinsoluble
• Notallpolarorchargedcompoundscannotpermeateamembrane
• Itisaquan8ta8vemacer• Threemeasurablequan''esareusedtocharacterizeadrugsubstance:LogSw,LogPandLogD
water
membrane
DrugSolubility:defini'on• Water(aqueous)solubility(SW)isthemaximumamountofasubstancethatcandissolveinwater.SWdependsonP,T.
• Swisinmoles/L(M).Watchformg/Lormg/dL!
• LogSw(orLogS)=Log(Sw)
Sucrose
Succinylcholine>10M!Butnotfatsoluble Mitotane:0.1mg/L
SolubilityandGibbsenergy
• Solubilityisdefinedbyadifferencebetweenthefreeenergyinthecrystalform(primarilyenthalpy)andthedissolvedform(solva'on,differententropyterms)
• Theentropy-of-mixingcontribu'ontodissolu'on(andrigidbodyrota'on/transla'on)doesnotdependonchemicaltypeandinterac'ons.Themaindifference:– thenumberoffreedrotatablebonds,hydrophobicsurface,(ΔS);
– intermolecularinterac'onsinthecrystalvswater,ΔH
water
µ 0aq + RT lnSW = µ 0s
DrugandProteinCrystals• HighlyorderedarraysofmoleculesheldtogetherbyNONCOVALENTinterac'ons
• Crystallaoceisa3Drepeatofthesameunit.Itisdefinedbythesidesandtheanglesofaparallelepipeda,b,c,α,β,γ
Polymorphism• Compoundscancrystallizeasdifferentpolymorphs(differentmolecularconforma'onandpacking,cell)
• Polymorphscanhavedrama'callydifferentsolubility,mel'ngpoint,'meofdissolu'on,habits
A
AA
AA
AAA
A
AA
A
A
A
AA
AA
AAA
A
AA
A
A
A
A
A
A
A
AA
A A
AA A
A AA
AAA A
AA A AA
A
A
A
A
A
AA
A A
AA A
A AA
AAA A
AA A AA
G
AA
AAA
AAA
G
G
G
GGG
A
A
A
GG
AG
G
AA
AAA
AAA
G
G
G
GGG
A
A
A
GG
AG
C-A+
C- C-C-
C- C-C-C-
A+
A+
A+A+
A+
A+A+
A+C-
A+C- C-C-
C- C-C-C-
A+
A+
A+A+
A+
A+A+
A+
Salts
Co-crystals??
PolymorphsSameAPISameAc;veMoiety
DifferentAPI
WhereDoCo-CrystalsFit?
IsaNewRegulatoryClassofSolidsNeeded?
Adoptedfromthepresenta'onofFDA-Div-DirectorDr.AndreS.Raw
API:Ac'vePharmaceu'calIngridients
Crystalhabitsofdrugs• Thesamesymmetrygroupmayleadto
differentsizeandshapeofacrystal• Crystalhabits(andsize)mayinfluence
– injec'on(plates:easy,needles:difficult),– tableong(easyforcompression)– rateofdissolu'on
• Habits:– Acicular(needle-like)– Prisma'c,pyramidal,tabular, equant,
columnaranlamellartypes• Habitdeterminants:
– Solvent– Temperature– Concentra'onofimpuri'es
Snowflakes&drugcrystals
• Snowflakesareaverywellknownexample,wheresubtledifferencesincrystalgrowthcondi'onsresultindifferentgeometries.
Par'clesizeandtherateofdissolu'on
• Considerthesurfaceofthefixedamountofcompoundasthefunc'onoflinearmicro-crystalsize,d,andthetotalvolumeV
• Fornon-cubicshapes,calculatetheAreaasafunc'onoftotalvolumeandshape.
dVd
dVA 66 23 ==
d
Forsimplecubicshapethetotalareaofmicrocrystalsurfaceisinverselypropor'onaltothecrystalsize
LogDandMembranepermea'on
• Togetinsidethecelladrugneedtogetinsidethemembranefirst
• Par88oningbetweenwaterandamembraneischaracterizedbyLogPforharddrugsandLogDforionizabledrugs
• Nega'veLogD:toopolar• Largeposi'veLogD:–toohydrophobic
Thequan'ta'veoctanol/watermodel.MoleculeDoesnotChange:LogP
wat
oct
CCP loglog =
OH
O
OH
Owater octanol
• PmeansPar''on• Octanol~membrane• Freeenergydifference
HOH
RTCCP
CRTCRT
ow
w
o
ooww
3.2loglog
lnln00
00
µµ
µµ
−==
+=+
oo
ww
CC,
,0
0
µ
µ druginwaterdruginoctanol
BenzoicAcid:LogP=1.87
Theoctanol/watermodel:LogD
wat
oct
AHAHP][][loglog =
OH
O
OH
Owater octanol
watwat
octoct
AAHAAHD][][][][loglog
−
−
+
+=
O
O
O
O
LogDistheapparentpar''oncoefficient
LogDdependsonLogPoftheneutralformandpH-pKa
logP ≡ log [AH ]oct[AH ]watOH
O
OH
O
logD = logP – log(1 + 10pH-pKa) for acids ≈ logP – (pH – pKa) (for pH> pKa+1, charged form dominates)
water octanol
watwat
octoct
AAHAAHD][][][][loglog
−
−
+
+=
O
O
O
O
logD = logP – log(1 + 10-(pH-pKa)) for bases ≈ logP – (pKa–pH) (for pH < pKa-1, charged form dominates)
LogDisapparentLogP
pKa=4.2;LogD(pH=7.2)≈1.87-3=-1.13
AtpHvalueswhereneutralformsdominatesinwater:LogD ≈ LogP
AtpHvalueswherechargedformsdominatesinwater:LogD is smaller than LogP:
Ourbodyiswatchingthelipophilicityofxenobio'cs
KidneystakecareofthepolarLivertakescareofthehydrophobs
• Polarandchargedmolecules–renalclearance(fast).*Probenecid(OATinh.)increasesexcre'onofuricacidbutblocksrenalexcre'onofandotherdrugs.
• BBBblocksthepolarandchargedcompounds
• Hydrophobiccompoundsaremadeintopolaronesbymetabolism.Cyp450smodifyhydrophobiccompounds,
Lipophilicity–adeterminantofpharmacokine'cs
• LogD,pH=7.4(fromShalaeva,““NewTechnologiestoIncreaseDrugCandidateSurvivability”,Philadelphia,2002)
• <0 Toopolar.Intes'nalandCNSpermeabilityproblems.Suscep'bletorenalclearance
• 0to1 Agoodbalancebetweenpermeabilityandsolubility.Atlowvalues,(morepolar),CNSpermeabilitymaysuffer
• 1to3 Op;mumrangeforCNSandnon-CNSorallybioavailabledrugs.Lowmetabolicliabili;es,generallygoodCNSpenetra;on
• 3to5 Solubilitytendstobecomelower.Metabolicliabili'es.
• Above5Lowsolubilityandpoororalbioavailability.Erra'cabsorp'on.Highmetabolicliability,althoughpotencymays'llbehigh.
0
1
2
3
4
5
LogD
CytochromeP450• R-H+O2+2e=>R-OH+H2O(usesNADPH)• AddingOneOxygen:monooxygenase• R-OHisfurthermodifiedbysolubilizingsulfateorsugars• bergamoon,dihydroxybergamoon,andparadicin-Ain
grapefruitjuice(andotherjuices)havebeenfoundtoinhibitCYP3A4,-overdose
• Saint-John'swortinducesCYP3A4,butalsoinhibitsCYP1A1,CYP1B1,andCYP2D6,-noac'on
• TobaccosmokinginducesCYP1A2,..
4-hydroxy-tamoxifenintheestrogenreceptorpocket
CytochromeP4502B4withparoxe'ne
Problema'cpermeability
• Naturalproducts(bigandpolar)– permeabilityamajorproblem
• Pep'domime'cs(longandpolar)– permeabilityamajorproblem
• RNAi• CNStargets('ghtbarrier)– Blood-brainpermeabilityamajorproblem
Predic'ngLogP/LogD• LogPisrelatedtothePOLARSURFACEAREA(PSA):thetotalsolventaccessibleareaofpolaratoms
• Moresophis'catedmethodstopredictLogPandLogD(cLogP,MolLogP,etc.)
Compound LogP
Methane(CH4) 1.1
Propane(C3H8) 2.24
Pentane(C5H12) 3.26
Hexane(C6H10) 3.76
�1-Pentanol�(C5H12O) 1.35
1-Hexanol(C6H13OH) 1.86
Solubility/Permeabilitygate• Permeability– PSA>140-200Å2isproblema'cforsystemicdistr.– PSA>75Å2isproblema'cforCNSdelivery
• Solubility– Solubility<5-20µg/mLisproblema'c
• Poorpermeabilityisworsethanpoorsolubility-noeasyformula8onfixexists
• Intra-molecularH-bondsimprovepermeabilitywithminimalaffectonsolubility.
Prodrugstoimprovesolubility
NH
Cl
OO
O-Na+O
O
ClOH
O2N
NH
Cl
OH
O
ClOH
O2N
O-Na+O
O
OH
Esterase
or Water
Chloramphenicol Succinate
Chloramphenicol
Sodium succinate
Howtofixpermeability• Pro-drug–addahydrophobicgroupthancanbecleavedoffinsideacell– difficultextrapola'onfromanimaltoman
• Changethestructure– e.g.introduceintramolecularH-bond
Prodrug
Drug OPromoiety
OOH Promoiety
Promoiety ODrug
O
Drug OH
O
Promoiety OH
OOH Drug
or
+
+
Ethylestersandalkalinehydrolysis
• Ethylestersarefrequentlyusedasapro-moiety
• Theycanalso(atsomelevel)behydrolizednon-enzima'cally
Alipophilictail
Prodrugtofixpermeability
• Enapril(ACEinhibitor,hypertension)ishydrolyzedtoEnaprilatbyesterase.Byproduct:ethanol
• Aspartame/NutraSweetByproduct:methanol
Bewareofmethylesters
Enapril+H2OtoEnaprilat+ethanol
+H2O
Prodrug:howtotricktheBrain
• Pretendtobeanaminoacid• Valaciclovirtoaciclovir(herpesan'viral)byesterase:transport
• LevodopatoDopaminebydecarboxylase– BrainhasaspecifictransportsystemforL-aminoacids
Dopamine
Prodrug:IncreasedBBpermeability
NH2 OH
O
GABA (gamma-amino butyric acid)
Drug:
N
Cl
F NH2
OOH
Progabid
Prodrug:
• an'-convulsiveneurotransmicer• orallyinac've• nopenetra'onofblood-brainbarrier
• orallyac've• rapidpenetra'onofblood-brainbarrier
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