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