Heat,EnthalpyofdrugForma5on,EnthalpyofReac5on,Cycles,

DrugDissolu5on

Objec5ves:•  LearntolookupEnthalpyofForma5on•  LearntoevaluateEnthalpyofReac5on,Dissolu5on•  Understandthepharmacologicalimplica5onsof

exothermicorendothermicdrugtransi5ons

SpecificHeatCapacity(permass)

•  Enthalpy:H=U+PV•  P=const:ΔH=q•  Calorimetry:ΔH=smΔT

s:specificheatcapacity,swater=4.186j/(g°C)Or1cal/(g°C)incaloriesm:massingrams

Cau$onaboutthesignofheatq:exothermicreac$onmeansNEGATIVEheat.

ΔHbetweentwostateswiththesameelementcomposi5onatconstant

pressure

•  State1,H1(P) •  State2,H2(P)

ΔHshowswhichstatehaslowerinternalenergy(correctedbyPΔV)ΔHdefinesiftheheatisproducedorabsorbedduringthetransi5on

ΔH=H2–H1=q

Reac$onsandTransi$onsForward Reverse State 1 State 2 Comments Examples

Transitions of pure substances Condensation Evaporation (vap) Gas X(g) Liquid X(l)

Crystallization/freezing Melting/Fusion(fus) Liquid X(l) Solid X(s) Depends on crystal Deposition Sublimation Gas X(g) Solid X(s) Iodine, dry ice

Solid phase transition (trs) - CrystalFormA X(sA) CrystalFormB X(sB) Insulin crystal forms Isomerization - Isomer A Isomer B Thalidomide stereo-isomerization

Transitions in mixtures Mixture separation Mixing (mix) Separated pure liquids or gases Mixture Emulsion preparation

Precipitation/Crystallization Dissolution X(aq) X(s) Depends on crystal form/ composition Making/dissolving drug powders; kidney toxicity

“Boiling” Gas dissolution X(aq) X(g) In mixtures: T=f(Concentrations) Inhalers, Dissolution of N2,

O2 or CO2 in blood Solute partition between immiscible liquid phases -

Solute in phase A (e.g. water)

Solute in phase B (e.g. octanol)

Passive membrane permeation, logP

Binding (b) Dissociation (d) P + L PL (complex) Binding of drugs to protein targets or carriers Reduction/Electron gain (eg) Oxidation X + e– X–

Protonation Deprotonation A– or B AH or BH+ Drug (de)ionization Chemical reactions

Generic chemical reaction (r) - Reactants Products Metabolic transformations Formation (f) Atomization (at)* Elements (standard states) X (s,l,g,aq) May be imaginary

Universal currency, tabulated

- Combustion Oxides Substance + O2 A practical method for ΔHf°

determination Activation (‡) Deactivation X in ground state X activated

Chemicalenergyofadrug•  Enthalpygetslowerascovalentbondsareformed

•  Burning(reac5onwithO2)isanoverallincreaseofthenumberofbondsand/orthe‘strengths’ofbonds.Somebondsareformed,somebrokenbuttototalbalanceisformingmorebondsorstrongerbonds.

•  ThereferencestatesfortheΔHfvaluesaresingleelementsinsolidformwithsomenotableexcep5ons:–  Liquid:HgandBr2–  Gas:He,Ne,Ar,Kr,Xe,Rn(inert

gases)anH2,O2,N2,F2,Cl2

Nitroglycerin:drugordynamite?

•  usedtotreatanginaandheartfailuresince1879

•  Mechanism:convertsintoNitricOxide(NO),apotentvasodilator,woundhealing

•  NO-synthaseac5vatedbygarlic,morphine,L-arginineincreasesNO

•  4C3H5(ONO2)3(liq)è12CO2+10H2O+6N2+O2+41.5MJofheat

•  Density=1.6g/mL(MM227.09),4moles->570mL;Products:710L

Ascanio SobreroFirst synthesized NG

Alfred NobelFellow student of SobreroWarning:Nitroglycerinpatchexplosionsduringdefibrilla5onmaybe

duetovoltagebreakdowninvolvingthemetalmeshinsomepatches.

Enthalpyofforma$on•  Imaginaryreac5on:forma5onofasubstance,inagivenstate(s/l/g/

aq),fromitselementalcomponents,intheirstandardstates.(‘aq’meansaqueoussolu5on)

•  Thereac5oncanoccuratdifferentTandPcondi5ons•  ΔHf°isthemolarenthalpyofforma=on•  Thestandardstateofasubstance,mixture,orsolu5onisanarbitrarily

chosenreferencepoint;ooenitsstateatSTP:P=1bar,T=273K).

•  Thestandardstatesofelementsare:–  Liquid:HgandBr2–  Gas:He,Ne,Ar,Kr,Xe,Rn(inertgases)anH2,O2,N2,F2,Cl2–  Moststablesolidallotrope:otherelements(e.g.graphiteforC)

•  ΔHf°foranelementinitsstandardstateis0.•  ΔHf°valuesformanysubstancesaretabulated.•  E.g.hpp://webbook.nist.gov/chemistry/•  Solidallotrope(allo-other,trope–form):eggraphite&diamond

SomeΔHf°valuesat250C[kJ/mol]

Mercury,bromine liquid Hg,Br2 0

Inertgases gas He,Ne,Ar,Kr,Xe,Rn 0

Hydrogen,oxygen,nitrogen,fluorine,chlorine gas H2,O2,N2,F2,Cl2 0

Carbon Solid(graphite) C 0Carbon Solid(diamond) C 1.8Ammonia aqueous NH3 -80.8Ammonia gaseous NH3 -46.1Sodiumcarbonate solid Na2CO3 -1131Sodiumchloride(tablesalt) aqueous NaCl -407Sodiumchloride(tablesalt) solid NaCl -411.12

Sodiumchloride(tablesalt) liquid NaCl -385.92

Sodiumchloride(tablesalt) gaseous NaCl -181.42Sodiumhydroxide aqueous NaOH -469.6Sodiumhydroxide solid NaOH -426.7Sodiumnitrate aqueous NaNO3 -446.2Sodiumnitrate solid NaNO3 -424.8Sulphurdioxide gaseous SO2 -297Sulphuricacid liquid H2SO4 -814Silica solid SiO2 -911Nitrogendioxide gaseous NO2 +33Nitrogenmonoxide gaseous NO +90Water liquid H2O -286Water gaseous H2O -241.8CarbonDioxide gaseous CO2 -393.5

TradingBondEnergiestoReduceHBondEnergy(kJ/mol).Theforma5onenergyisnega=ve. 297 H-I 347 C-C 163 N-N 364 H-Br 611 C=C 418 N=N 368 H-S 837 C:::C 946(315)N:::N 389 H-N 305 C-N 222 N-O 414 H-C 615 C=N 590 N=O 431 H-Cl 891 C:::N 436 H-H 360 C-O 464 H-O 736 C=O 565 H-F 339 C-Cl 151 I-I 142 O-O 159 F-F 498(249)O=O 193 Br-Br 243  Cl-Cl Youneedposi5veenergytobreakabond

Highenergybond

Lowenergybond

Addi$vity,pathindependenceVaporliquidSolid

€

ΔHA→C0 = ΔHA→B

0 + ΔHB→C0

ForwardandReverseProcesses

•  Standardenthalpychangesofforwardandreverseprocessesmustdifferonlyinsign

•  Example:vaporiza5onandcondensa5on(T=373K):

00ABBA HH →→ Δ−=Δ

ΔHwater→vapor0 = 40.68kJ /mol

ΔHvapor→water0 = −40.68kJ /mol

ThermodynamicCycle•  Choosemul5pliersbystoichiometryandorienttransi5ons

•  GoclockwiseandΣΔHXY=0

•  FlipasignofΔHifarrowisintheoppositedirec5on.

B

CD

A

€

ΔHA→B0 + ΔHB→C

0 − ΔHD→C0 − ΔHA→D

0 = 0

Example:4statesand3knowntransi5ons

ΔH?

Cycle:drugbindingexample

DrugConf_A+Protein→DrugConf_B+Protein

[DrugConf_A•Protein]→[DrugConf_B•Protein]

ΔH1-ΔH2-ΔH3+ΔH4=0

ΔH1

ΔH2

ΔH3 ΔH4

Hess’Law•  Fromheatsofforma5ontotheheatofreac5on

•  DirectconsequenceofthefactthatHisastatefunc5on

•  Watchstoichiometrycoefficients(νi).Example:

2H2+O2=>2H2OνΗ2 =2 νΟ2 =1 νΗ2Ο =2

€

ΔHreaction0 = ν p∑ ΔH f ( products)0 − νr∑ ΔH f (react )0

Elements

ProductsReactants

GermainHess(1802-1850)Swiss-bornRussianchemistanddoctor

Use:H(T)=CpΔTtocalculateΔHathighertemperature

ThermochemicalCharacteriza$onofReac$onsandTransi$ons

Ini$alState⇒FinalState•  ΔH=H(finalstate)–H(ini5alstate)•  ΔH ≡heatofreac5onortransi5on

–  ΔH<0means“⇒”isexothermic(producesheat)–  ΔH>0means“⇒”isendothermic(absorbsheat)

CovalentBondforma$onisexothermic•  Coun$ngbonds:Example:burning

2H2(2bonds)+O2(1bond)=>2H2O(4bonds)Balance:+1bondΔHisnega5veNumberofcovalentbondsincreases:exothermic

Reac$onexamples:enthalpy

ΔH – + –TΔS

–

+ Bonds form or get stronger, heat Bonds break, or get weaker, cold

•  Burning(covalentbondsformed)

•  Freezing(noncovalent)•  Condensa5on•  Acid-base

neutraliza5on

•  Mel5ng•  Evapora5on(always)

Example:dissolu$on•  Drug(solid)+H2O⇔Drug(aq)•  Molarheatofreac5onatinfinitedilu5on:

1moleofdrugdissolvedatinfiniteamountofH2O(drugalreadypresentinsolu5onmayaffectdissolu5onenthalpy)

•  Nocovalentbondschangeduringdissolu5on(exceptpH-dependentprotona5on/deprotona5on)

•  Theinterac5onbalanceisdelicate,includesdrug-drugwater-wateranddrug-waterbondstrengths.

•  Ifthereac5oninvolvesstrongnon-covalentbondbreakage,itmaybeendothermic

•  Ifcrystalinterac5onsareweakbutdrug-waterinterac5onsarestrong–dissolu5onisexothermic

•  Q:doesnega5vevaluemeandissolu5on?

DrugDissolu$on:Micro-crystalsizeaffectskine5cs/ratesbutnotequilibrium(iewhetherdissolves)

HClNO2-NH4-NH3KOHCsOHNaClKClO3CH3COOHNaOH

Molarheatofdissolu$onat298K Substance ΔH dissolution

(kJ/mol) HCl (gas) -74.84 no gas interactions, strong water int Ammonia (gas) -30.50 Acetic Acid (liquid) -1.51 NaCl 3.88 Ammonium Nitrate 25.69 Potassium Chlorate 41.38 Lidocaine HCl 43.5 strong crystal int, weaker water int Procaine HCl 30.5

BalanceofΔHcontribu$onsindissolu$on1.  Breakingsoluteaprac5onsforliqorsolids(endothermic)2.  Breakingwater-wateraprac5ons(endothermic)3.  Formingwater-soluteinterac5ons(exothermic)

IcePacks•  Ammoniumnitrateandammoniumchloridedissolveinwaterendothermically

•  Whenbroken:mixing(+NH4)(-NO3)withwater•  Exchangingstrongionicbondsforweakerpolarbonds(lessbonds->posi5veΔH->cold)

•  ForammoniumnitrateΔHdissolu5on=+25.69kJ/mol

HeatPads•  Crystalliza5on:Sodium-acetate:weakerbondsinwatertostrongerionicbonds

•  heatofcrystalliza5onofsodiumacetatetri-hydrateis-35.9to-39.3kJ/mol

•  Dissolu5on:magnesiumsulfate:weakerbondstostrongerbonds

•  anhydrousMgSO4isabout-54.37kJ/mol

•  includesforma5onofahydrateEpsomite(veryexothermic)+itsdissolu5oninwater(slightlyendothermic)

UnderstandingΔH:evapora$on•  Evapora5on:liq→gas•  ΔH=44kJ/mol@300K•  ΔU=44-RT=41.5kJ/mol•  3.7non-covalentbonds(hydrogenbonds)permoleculeinwater,zeroingas

•  Numberofbondsdecreases:systemgetscolder:evapora5onisendothermic.

Example:protein/ligandbinding•  Pforprotein(target),Lforligand(drug)•  Assumesimple1:1stoichiometry:P+L⇔PL•  Molarheatofreac5on:1moleofP+1moleofLform1moleofPL

•  Thereac5onisooen(butnotalways)exothermic•  Apn:Thereac5onis(typically)reversible:

–  notallreactants(P&L)areconvertedtoproducts(PL)–  heatispropor5onaltotheamountofproductthatisformed–  usedindetermina5onofbindingaffini5esbyITC

Generic Name MW

ΔH (kcal/mol)

Nelfinavir 567.8 3.1Indinavir 613.8 1.8

Saquinavir 670.8 1.2Tipranavir 602.7 -0.7Lopinavir 628.8 -3.8

Atazanavir 704.9 -4.2Ritonavir 720.9 -4.3

Amprenavir 505.6 -6.9Darunavir 547.7 -12.7

Enthalpyofbindingofseveralan$-HIVdrugstotheirtargetprotein,

HIVprotease

Molarheatofdrugbindingtobloodplasmaproteins

Drug Protein ΔH binding (kcal/mol) Propranolol α1-acid glycoprotein -11.1

Warfarin human serum albumin -2.44 NormalPlasmaRange (mg/dL) Albumin 3,500-4,500 Prealbumin(Transthyre$n) 10-40 α1-Globulins 300-600

α1AcidGlycoprotein(orosomucoid) 55-140α-Fetoprotein approx. 0.001 Re5nolBindingProtein 3-6 ThyroxineBindingGlobulin 1-2 Transcor5n 3-3.5

α2Globulins(excl.lipoproteins) 400-900 Ceruloplasmin 15-60 HaptoglobinType1-1 100-220 HaptoglobinType2-1 160-300 HaptoglobinType2-2 120-260 α2Macroglobulin 100-280

β-Globulins(excludinglipoproteins)600-1,100 C-Reac5veProtein <1 Hemopexin 50-100β2Microglobulinapprox. 0.2 Transferrin 200-320

γ-Globulins 700-1,500

Willthisdrugbind?

•  Energyandenthalpyofthedruginapocketislowerby2kcal/molethanofthesamedruginwater.

•  Thedruglookslikethis:

Whydoeswaterevaporate?

Astandardenthalpyofvaporiza5on(or“heatofvaporiza5on”):

ΔvapH°=+40.66kJ/molat373K

)O(gH)O(lH 22 →