DrugSalts,Pro-Drugs

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,RoPgoPneVilazodone,Naphazoline

SulfuricAcid SO42- Dextroamphetamine,Hydroxychloroquine

AcePcAcid(acetate) CH3COO- Leuprolide,Goserelin,Desmopressin,…

cocainehydrochloride

+

DrugSalts:AcidsBaseB,e.g.NaOH

AcidicDrugAH

e.g.R-COOH - +Drug

ion,[A-] CaPon

CaPonicSaltoftheDrug

plus

OH-Base Ca5on Examples

Sodium Na+ Ecabet,Diclofenac,Indomethacin,Benzoate,Salicylate

Calcium Ca++ AtorvastaPn,CalciumGluceptate

Potassium K+ PenicillinVPotassium,Losartan

Ca++needstwonegaPvecharges

CalciumGluceptate

Warning:donotforgettousecorrectmolecularweightofthesalt

Salts:summary•  Stoichiometry:makesure

thatthetotalformalchargeiszero(e.g.[D-]2Me2+)

•  AmbiguityofchemicalrepresentaPon:[DH+][Cl-]vs[D][HCL],MolWeight.

•  Solubilityofcrystals:usuallybe\erthannon-salt,butdiffersbetweendifferentsalts.

•  Iden8calinSolu8on:OncethesaltisdissolveditbecomesidenPcaltothenon-saltformofthedruginsoluPon

•  Resonance:Example,sulfate:perfecttetrahedronwithtotalnegaPvechargeof-2distributedbetween4negaPveoxygenatomsandoneposiPvessulfur.

Saltswithbe\ersolubility: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−(acePcacid)•  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:•  SolubilityisgoodforchargedcompoundswithmulPplepolargroups(e.g.pepPdes)

•  Permeabilityisgoodforhydrophobicandapolarcompounds

TwosoluPons:•  Beexactlyinthemiddlewiththesamechemicalstructure(minority)

•  BeabletochangeviaenzymaPcacPvaPon(prodrug)oradoptalternaPvechargedforms

Solubility,LogP,andLogD

•  Notallunchargedcompoundsareinsoluble

•  Notallpolarorchargedcompoundscannotpermeateamembrane

•  Itisaquan8ta8vema\er•  ThreemeasurablequanPPesareusedtocharacterizeadrugsubstance:LogSw,LogPandLogD

water

membrane

DrugSolubility:definiPon•  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(solvaPon,differententropyterms)

•  Theentropy-of-mixingcontribuPontodissoluPon(andrigidbodyrotaPon/translaPon)doesnotdependonchemicaltypeandinteracPons.Themaindifference:–  thenumberoffreedrotatablebonds,hydrophobicsurface,(ΔS);

–  intermolecularinteracPonsinthecrystalvswater,ΔH

water

µ 0aq + RT lnSW = µ 0s

DrugandProteinCrystals•  HighlyorderedarraysofmoleculesheldtogetherbyNONCOVALENTinteracPons

•  Crystallanceisa3Drepeatofthesameunit.Itisdefinedbythesidesandtheanglesofaparallelepipeda,b,c,α,β,γ

Crystalhabitsofdrugs•  Thesamesymmetrygroupmayleadto

differentsizeandshapeofacrystal•  Crystalhabits(andsize)mayinfluence

–  injecPon(plates:easy,needles:difficult),–  tablenng(easyforcompression)–  rateofdissoluPon

•  Habits:–  Acicular(needle-like)–  PrismaPc,pyramidal,tabular, equant,

columnaranlamellartypes•  Habitdeterminants:

–  Solvent–  Temperature–  ConcentraPonofimpuriPes

Snowflakes&drugcrystals

•  Snowflakesareaverywellknownexample,wheresubtledifferencesincrystalgrowthcondiPonsresultindifferentgeometries.

ParPclesizeandtherateofdissoluPon

•  ConsiderthesurfaceofthefixedamountofcompoundasthefuncPonoflinearmicro-crystalsize,d,andthetotalvolumeV

•  Fornon-cubicshapes,calculatetheAreaasafuncPonoftotalvolumeandshape.

dVd

dVA 66 23 ==

d

ForsimplecubicshapethetotalareaofmicrocrystalsurfaceisinverselyproporPonaltothecrystalsize

LogDandMembranepermeaPon

•  Togetinsidethecelladrugneedtogetinsidethemembranefirst

•  Par88oningbetweenwaterandamembraneischaracterizedbyLogPforharddrugsand

LogDforionizabledrugs•  NegaPveLogD:toopolar•  LargeposiPveLogD:–toohydrophobic

ThequanPtaPveoctanol/watermodel.MoleculeDoesnotChange:LogP

wat

oct

CCP loglog =

OH

O

OH

Owater octanol

•  PmeansParPPon•  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

Thewater/octamolmodel:LogD

wat

oct

AHAHP][][loglog =

OH

O

OH

Owater octanol

watwat

octoct

AAHAAHD][][][][loglog

−

−

+

+=

O

O

O

O

LogDistheapparentparPPoncoefficient

LogDdependsonLogPoftheneutralformandpH-pKa

wat

oct

AHAHP][][loglog =

OH

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 + (pH – pKa) (for pH < pKa-1, charged form dominates)

LogDisapparentLogP

logP=1.87;pKa=4.2;LogD(pH=7.2)≈1.87-3=-1.13

OurbodyiswatchingthelipophilicityofxenobioPcs

KidneystakecareofthepolarLivertakescareofthehydrophobs

•  Polarandchargedmolecules–renalclearance(fast).*Probenecid(OATinh.)increasesexcrePonofuricacidbutblocksrenalexcrePonofandotherdrugs.

•  BBBblocksthepolarandchargedcompounds

•  Hydrophobiccompoundsaremadeintopolaronesbymetabolism.Cyp450smodifyhydrophobiccompounds,

Lipophilicity–adeterminantofpharmacokinePcs

•  LogD,pH=7.4(fromShalaeva,““NewTechnologiestoIncreaseDrugCandidateSurvivability”,Philadelphia,2002)

•  <0 Toopolar.IntesPnalandCNSpermeabilityproblems.SuscepPbletorenalclearance

•  0to1 Agoodbalancebetweenpermeabilityandsolubility.Atlowvalues,(morepolar),CNSpermeabilitymaysuffer

•  1to3 Op5mumrangeforCNSandnon-CNSorallybioavailabledrugs.Lowmetabolicliabili5es,generallygoodCNSpenetra5on

•  3to5 Solubilitytendstobecomelower.MetabolicliabiliPes.

•  Above5Lowsolubilityandpoororalbioavailability.ErraPcabsorpPon.Highmetabolicliability,althoughpotencymaysPllbehigh.

0

1

2

3

4

5

LogD

CytochromeP450•  R-H+O2+2e=>R-OH+H2O(usesNADPH)•  AddingOneOxygen:monooxygenase•  R-OHisfurthermodifiedbysolubilizingsulfateorsugars•  bergamonn,dihydroxybergamonn,andparadicin-Ain

grapefruitjuice(andotherjuices)havebeenfoundtoinhibitCYP3A4,-overdose

•  Saint-John'sWortinducesCYP3A4,butalsoinhibitsCYP1A1,CYP1B1,andCYP2D6,-noacPon

•  TobaccosmokinginducesCYP1A2,..

4-hydroxy-tamoxifenintheestrogenreceptorpocket

CytochromeP4502B4withparoxePne

ProblemaPcpermeability

•  Naturalproducts(bigandpolar)– permeabilityamajorproblem

•  PepPdomimePcs(longandpolar)– permeabilityamajorproblem

•  RNAi•  CNStargets(Pghtbarrier)– Blood-brainpermeabilityamajorproblem

Solubility/Permeabilitygate•  Permeability– PSA>140-200Å2isproblemaPcforsystemicdistr.– PSA>75Å2isproblemaPcforCNSdelivery

•  Solubility– Solubility<5-20µg/mLisproblemaPc

•  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– difficultextrapolaPonfromanimaltoman

•  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-enzimaPcally

Alipophilictail

Prodrugtofixpermeability

•  Enapril(ACEinhibitor,hypertension)ishydrolyzedtoEnaprilatbyesterase.Byproduct:ethanol

•  Aspartame/NutraSweetByproduct:methanol

Bewareofmethylesters

Enapril+H2OtoEnaprilat+ethanol

+H2O

Prodrug:howtotricktheBrain

•  Pretendtobeanaminoacid•  Valaciclovirtoaciclovir(herpesanPviral)byesterase:transport

•  LevodopatoDopaminebydecarboxylase–  BrainhasaspecifictransportsystemforL-aminoacids

Dopamine

Prodrug:IncreasedBBpermeability

NH2 OH

O

GABA (gamma-amino butyric acid)

Drug:

N

Cl

F NH2

OOH

Progabid

Prodrug:

• anP-convulsiveneurotransmi\er• orallyinacPve• nopenetraPonofblood-brainbarrier

• orallyacPve• rapidpenetraPonofblood-brainbarrier