drug salts, pro-drugs - ruben.ucsd.eduruben.ucsd.edu/19/r16.pdf · hydrochloride (hcl) cl-...
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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