Heat, Enthalpy of drug Formaon, Enthalpy of Reac5on ...ruben.ucsd.edu/19/r04.pdf · Chemical energy...

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Heat, Enthalpy of drug Forma5on, Enthalpy of Reac5on, Cycles, Drug Dissolu5on Objec5ves: Learn to look up Enthalpy of Forma5on Learn to evaluate Enthalpy of Reac5on, Dissolu5on Understand the pharmacological implica5ons of exothermic or endothermic drug transi5ons

Transcript of Heat, Enthalpy of drug Formaon, Enthalpy of Reac5on ...ruben.ucsd.edu/19/r04.pdf · Chemical energy...

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+4�1.5MJofheat

•  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 →