A look at several aspects associated with preformulation sciences including molecular dissociation and salt selection.

1. George Wild Science of Medicines
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Concept and Assay Development
Preformulationisthe investigativestage thatoccursbefore formulation-propertodetermine viable
drug candidatesbasedontheirphysicochemical,intrinsicandderived characteristics. Thisprevents
moneybeinginvestedindrugsthatare potentiallyeffective butphysicallyimpractical orunviable. In
orderto assessthe propertiesof drugcandidates,assaysmustbe undertakenthatprovide
preformulationscientistswithexperimental data.Because onlyasmall amountof drug,like 50mg
will existatthispointintime,samplesmaybe reusedwhenappropriateandassaysshouldseekto
minimise wastageof drug.Also,because there issolittledrugproduct,it’sthe intrinsicproperties
that are investigatedfirstasthere canbe insufficientmasstoinvestigate bulkpropertiesfullyatthis
stage.Withthese assays,it’sokayjustto determine approximate valuesasthese willjustbe usedto
decide if it’sago/no-gosituationandsothe precisionandrigourisnot neededyet.Assaysshouldbe
able to be carriedout usingjustHPLC, DSC,XRPD (x-raypowderdiffraction),UV specandDVS
(dynamicvapoursorption);TLCandthermogravimetricanalysesmayalsobe usedbutare less
importantthisearlyon.
Nature Property Assay/technique Sample needs
Intrinsic Solubility(aqueous+non) UV Chromophore
pKa UV Acid/base part
logP(partition) UV, TLC, HPLC Chromophore
Hygroscopicity DVS,TGA None
Stability,hydrolysis,oxidation,
photolysis etc
HPLC None
Derived Meltingpoint DSC None
Enthalpyof fusion DSC
Physical forms DSC, XRPD,
microscopy
Particle shape,size,
morphology,habit,rugosity
Microscopy,particle
sizing
Density(bulk,tapped,true) Tapping
densitometer
Flow Angle of repose
Compresability Carr’s index,Hausner
ratio
Excipientcompatability HPLC, DSC
Intrinsic Solubility
Solubilityisveryimportantinpreformulationasall drugswill needtogointosolutionatsome point
before theyare absorbedandtheywill needtobe inliquidformtobe administeredtoanimalsin
development,eitherorallyorintravenously.Inearly studiesasolubilityof 1mg/ml isacceptable,but
by the time the drug isreadyto be licensed,itshouldbe atleast10mg/ml.The original solubility
may be improvedforuse inpreformulationbysaltingorthroughnovel dosage forms.
Whena soliddissolvesinexcessinsolution,the solutionissaturatedwithanequilibrium
concentrationthatisthe solubilityof the drug. If the drug isionisable thenthe solubilityof the
unionisedformisthe intrinsicsolubility,whichisimportantlydifferenttothe observedsolubilityas
the latterwill be affectedbythe pHof the environment.

2. George Wild Science of Medicines
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The processof dissolutioncanbe seenthermodynamicallyasthe sumof the energychangesof
fusion(ΔHF) and of mixing(ΔHMIX).The energychange of fusionisthe energyrequiredtobreakthe
solute-solutebonds,whilstthe energyof mixingreferstothe sumof the energiesrequiredtobreak
solvent-solventbondsandtoform solvent-solute bonds. Thisrelationshipbetweensolubilityand
bondenergyisuseful asitcan be usedto make predictionaboutsolubilitybasedonthermal energy
changes.
∆HSOL = ∆HF + ∆HMIX KSOL = x2
Sometimesthe energyrequiredtobreaksolvent-solventbondsisequal tothe energyreleasedwhen
solute-solventbondsformwhichmeansthatΔHMIX = 0 and the solutionissaidtobe ideal asit
exhibitsideal solubility.Inthese instances,the enthalpychange of fusionisequal tothe enthalpy
change of dissolution,whichmeansthatbothvaluesare positive asenthalpychange of dissolutionis
positive forideal solutions.Forsomethingtooccurspontaneously,there mustbe areductionin
Gibbsfree energy,whichmeansthatthe drivingforce therefore isentropy.The above “KSOL”
equationisreminiscentof anequilibriumconstantwhichmeansthe van’tHoff equationcanbe
appliedtogive the secondof the belowequations. Thisequationisuseful asitallowsthe calculation
of ideal solubilityataparticulartemperature if the enthalpychange of fusionandthe melting
temperature are known.
∆GSOL = ∆HSOL - T∆SSOL lnx2 =
-∆HF
RT
+
∆HF
RTM
Meltingpointandenthalpyof fusionare thereforethe nextfactorsthatare determinedin
preformulationasthese canprovide informationonthe concentrationof anideal solution.Theseare
calculatedusingdifferentialscanningcalorimetry(DSC) where asample isheateduntil melted,with
the enthalpyof fusionbeingseenasanendothermicpeakonthe trace of poweragainsttime.The
heatingrate (β) can be linearormodulatedbythe program, butthe areaunderthe endothermic
peakisalwaysthe enthalpychange of fusionandrepresentsenergyrequiredtobreakall solute-
solute bonds.The temperature of meltingcanbe foundbyusingthe peakmaximum(Tm) or
extrapolatedfromthe onsetusingaline (To).Inrealitysolutionsdon’treallyshow ideal behaviour
because the assumptionthatthe fusionisindependentof temperature andΔHMIX = 0 isnot the case;
exothermicmixingenthalpiesincreasethe solubilitywhilstendothermicenthalpiesreduce it.
The extentof intermolecularbondingbetweensolventmoleculesisthe cause of the non-idealityof
manysystems,whichisbasedondielectricconstants,the abilitytoformhydrogenbondsandthe
dipole momentof the solvent.Dipolesincrease the strengthof interactionswithinthe solventand
alsohelpto dissolveionicandotherpolarsolutesthroughfavourable enthalpychanges.The
dielectricconstantisameasure of the solvent’sabilitytoabsorbcharge fromdissolvingmolecules;
those withhigherdielectricconstantsare more suitedtodissolve ionicandpolarmolecules(but
definitelynotnon-polarmolecules).Hydrogenbondsoccurwhenelectronegative atomsinteract
withhydrogenatomsbondedtootherelectronegative atomsi.e.O-H,N-H,S-H;those drugswith
these groupsthatare capable of hydrogenbondingwill have increasedaqueoussolubility.
It’sknownthat increasingthe temperatureoftenincreasessolubilitybutthisisnotalwaysthe case
because anassumptionmade inderivingthe formof the van’tHoff equationshownabove wasthat
ΔHF = ΔHSOL whichisn’tthe case a lot of the time.

3. George Wild Science of Medicines
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The relationshipbetweensolidstate andsolubilitycentresonpolymorphismandamorphous
structures.Where polymorphsexist,the metastable formswill be lessstable,have weaker
intermolecularforcesof attraction,require lessenergytomeltandsohave lowerΔHF valuesand
greatersolubilitiesthanthe more stable form(s).However,there isanatural tendencytorevertto
the more stable form from the metastable one,meaningthatformulatingametastable drugcould
be riskyas the reversionwill reducebioavailability.Havingsaidthis,if the metastable formtakes3
yearsto revertby10%, itwouldstill likelybe used,butthe expirydate andstorage instructions
wouldneedtoaccommodate thisfeature of the medicine. Amorphousformsof solidsdonot
possessaregularstructure as such and so have nomeltingpointandtherefore the greatest
solubility.
The solubilityof drugsisroutinelymeasuredin0.1MHCl,0.1M NaOH andwater whichprovide
crude informationasto whetherornotthe drugis acidic,basicor non-ionicinnature.UV
spectroscopyisusedtoobtainvaluesforconcentrationbecause of the small volumethat’sneeded,
familiarity,costandthe fact that most drugshave at leastone group capable of absorbingUV light.
Whenthe moleculesabsorblight,the absorbedfractionof the original light(IO) passingthroughand
reachingthe detector(I) will be less.The amountabsorbedis afunctionof concentration anddepth
of solution thatisexpressedinthe Beer-Lambertequation,asseenbelow.Here,εrepresentsthe
molarextinctioncoefficient,whichisdefinedformanychromophoresand auxochromes (additive
electronsystemsinfluencingdelocalisaton),andl representsthe pathlength.
absorbance =log
I
IO
= εCl
Measurementsshouldbe takenuntilthe concentrationreachesamaximum, andcare shouldbe
takento ensure thatdegradationdoesnotoccur if the molecule isprone tohydrolysisorphotolysis.
The temperature shouldalsobe preventedfromfluctuatingwhenitismeasuredatthe mainthree
temperatures;4°C(minimisesrate of hydrolysisbutmakeswatermore viscous),25°C(roomtemp)
and 37°C (invitrotemperature). Althoughthe mainthree testswill show whetherthe drugisacidic
(more soluble inNaOH),basic(more solubleinHCl) orneither(equallysoluble overall three media),
it maybe of use to testthe solubilityinothertypical media the drugmayencounteronvarious
routesof administration.Forexample with oral administration;simulatedgastricfluid(SGF),fed
simulatedintestinal fluid(FeSSIF) andfastedsimulatedintestinalfluid(FaSSIF) canbe usedtoassess
viabilityof the drugwhenadministeredorally.
Impuritiescanbe testedforandshouldbe especiallyconsideredininstanceswhere the drugis
knownto be metastable oramorphous,asunderthese circumstancesthe chancesof gettingalittle
bitof somethingelseinthe mix ismore likely.DSCandXRPDcan be usedto obtaininformationon
the structure of the solidleftinexcessfromsolutionsasdifferentformwill have different
properties.Chemicallyimpure samplescanalsobe identifiedthroughplottingphase-solubility
diagrams,where impure compoundsexhibitmultiplegradientsof the ascendinglimbof the line.
Whenthe compoundispure,the concentrationat the plateauistakenas the solubility(indicatedby
blackarrow on the belowdiagram,howeverforimpure compounds,the solubilitiesare takenby
extrapolatingthe gradientfromthe secondportionof the line (solubilityof one of the constituents)
and thenbysubtractingthisfromthe total concentrationreachedtogetthe solubilityof the other
chemical.

4. George Wild Science of Medicines
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Alternatively,fourdifferentformulationswithdifferentdrugtosolventphase-ratioscanbe prepared
and have theirsolubilitymeasuredandextrapolated toa theoretical phase-ratioof zero.Positive
gradientsindicate impuritiesactingtoimprove solubility,whilstnegativegradientsshow decreased
solubility.LinesextrapolatingtoC0 representnoimpurityandtrue solubility.
DSC can alsobe usedtoassessimpuritiesbecause evenasmall amountof impuritywill cause a
difference inthe endothermicpeakof fusion.Qualitatively,if the meltingendothermrecordedis
broad thenthe sample islikelytobe impure.Butif the meltingpointandenthalpyof fusionare
knownforthe drugcompoundthenthe impurityisquantifiedbyassessingthe fractionmeltedata
giventemperature.Integratingthe peakareaona DSC thermogramcan give the total heat of
melting(Q) andpartial integrationgivesthe smallerheat(q).
FT =
q
Q
Molecular Dissociation and Partitioning
Many drugs ionise betweenpH2 and 12 and so determiningthe pKa valuesof drugsisimportantin
determiningtheirsolubilities,asthese will be pHdependent.Thisisof particularimportance for
perorallyadministereddrugswhichwillexperience arange of pH valuesfrom1 – 8 in the GI tract,
therefore the solubilitieswillneedtobe known.Havinginformationonthe degreestowhichdrugs
ionise incertainpHvaluesalsoallowsscientiststoeffectivelyformulate saltsforgreatersolubility.
pH and pKa relationship For weakacids For weakbases
pH < pKa by 2 pH units Completelyunionised Completelyionised
pH > pKa by 2 pH units Completelyionised Completelyunionised
pH = pKa 50% ionised 50% ionised
pH >> pKa Infinite solubilityincrease Infinite solubilitydecrease
The above holdstrue because ionisedspeciesare more soluble inwaterthanunionisedspecies due
to polar/ionicinteractionsandwe canuse the Henderson-Hasselbachequationtofindoutthe
solubility.Thismeansrecognisingthatthe [A-
] meansthe saturatedionisedconcentration/solubility
(SI) and that [HA] representsthe intrinsicsolubility(SO),givingusthe modifiedequationseenhere.
0
0.2
0.4
0.6
0.8
1
0 0.2 0.4 0.6 0.8 1
Measuredconcentration(mgmL-1)
Weight of soluteper volume solvent (mg mL-1)
Phase-solubilities of chemically pureand impure compounds
Pure Impure

5. George Wild Science of Medicines
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Knowingalsothatthe total solubility(ST) isthe sumof the intrinsicandionisedsolubilities,we can
rearrange the Henderson-Hasselbachequationtofindthe total solubility.
pKa= pH + log
SO
SI
(ST = SI + SO) pKa= pH + log
SO
ST- SO
ST = SO[1 + antilog(pH - pKa)
The above equationsare true for a weakacidsand can be easilymodifiedforweakbases. Forweak
acidsthough,total solubilitywillbe equal tointrinsicsolubilityatpH valuesbelow pKa andwill be
significantlyhigheratvaluesabove it.Forthisthe pKa may be calculatedusingpotentiometricpH
titrationandplottingvolume of titrant againstpHgraphically. Itmayalsobe calculatedfromthe
Henderson-Hasselbachequationif the intrinsicsolubilityisknown.
The extenttowhicha drug partitionsbetweenaqueousandorganicphasesinthe bodyisan
importantfactorto determine inpreformulationasthiswill indicate how well the drugmaybe
absorbedi.e.lipophilicity.Inthe body,all drugspartitiontosome extentbetweenthe twophases
and so an equilibriumisreachedthatcan be expressedinthe below forms.Inpreformulation
however,itwouldbe impractical toemulate the exactconditionsinthe bodyasmany biological
membranesexistandsothe drug partitionsbetweenmanyorganicphasesandthe aqueousphase
so insteadscientistsuse waterforthe aqueousphase and(mostcommonly) n-octanol forthe
organicphase.
PW
O
=
CO
CW
DW
O
=
CO
CW(ionised) + CW(unionised)
DW
O
= Funionised PW
O
Valuesof P(partitioncoefficient) thatare above 1 indicate alipophilicdrug,whilstthose below 1
indicate hydrophilicdrugs.Giventhatthe valuesforhydrophilicdrugscanoftenbe verysmall,a log
scale may be used,givingvaluesof logPthatare negative forhydrophilesandpositiveforlipophiles.
Alsorepresentedabove isthe equationforthe distributioncoefficient,whichisusedtocalculate the
distributionof ionisable species.Thisisbecause the partitioncoefficientonlyappliesif adrug cannot
ionise orisin a pH inwhichit isfullyunionised,therefore formanydrugsthatcan partiallyionise,
the distributioncoefficient(D) mustbe usedinstead.The relationshipbetweenDandP islinkedby
the fractionof solute unionised(funionised),alsoabove.
The shake-flaskmethodcanbe usedto determine valuesof logPbymixingtwosolventsof n-octanol
and waterand determiningthe concentrationsineachphase afterequilibriumisreached.
- First,the solventsare allowed tomix toassessthe small solubilityof one inthe other.
- Drug is allowedtodissolve inaqueoussolventandthenismixedinaseparatingfunnelwith
the n-octanol byshakingfor30 minutes.
- Afterthispartitioning,the phasesseparate (for5 minutes) andthe concentrationinthe
aqueousphase ismeasuredagain.The concentrationinn-octanol bydefaultisthe
concentrationdifference betweenthe initial andfinal aqueousconcentrations.
WhenP favoursthe organicphase,lessmaybe usedto increase accuracy,whichwouldrequire the
equationtothenincorporate thisratio,i.e.1:x n-octanol:waterratio.
PW
O
=
(x+1)CO
CW
Drawbacksto thismethodinclude the large volumesusedandthe time neededforequilibriumtobe
reached.Howeverdifferentsolventscanbe usedtomimicdifferentmembranesinthe body.

6. George Wild Science of Medicines
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Chromatographicmethodslikereversephase liquidchromatographyandHPLCcan be usedto
measure experimentallythe valueof logP.The interactionof soluteswiththe liquid(mobile) phase
inreverse liquidchromatographymeasureshow hydrophilicorlipophilicadrug is.Reverse TLCcan
be usedto compare the progressionof solventandsolute fromastartingpoint,providingavalue for
the resolutionfactor(Rf),whichcanbe convertedtoa retentionfactor(Rm) whichisproportional to
logP. The higherthe resolutionfactor,the closertothe solventfrontthe drughasmoved. InTLC n-
octanol isnot usedas much as silicaimpregnatedwithsiliconeoil forthe stationaryphase,whilst
wateris notreallyusedforthe mobile phase eitherasitpreventsthe adequate movingof lipophiles
up the plate;insteadcosolventsmaybe usedtoincrease the solubilityof these drugs.When
cosolventsare used,theireffectislinearmodulation,whichmeansthatextrapolatingto0 cosolvent
givesthe retentionfactorforwater.
In reverse HPLC,the stationaryphase isusuallyanon-polarpolarmolecule (i.e.C18 hydrocarbon)
boundto a chemicallyinertsolidsupportlikesilica.The mobilephase here canbe watersaturated
withn-octanol butas before,there are disadvantagestothisregardinglipophilesasthe eluding
powerisnot good.Because the hydrocarbonsare boundto a solidsupport,there’sambiguity
surroundingwhetherthe interactionissurface adsorptionortrue partitioning,withthe latterbeing
unlikelyinthismethod.
Good aqueoussolubilitiesdonotnecessarilymeanhighratesof dissolutionassolubilityismore of
an equilibriumpositionandthereforedoesnotinfluencethe rate at whichdissolutionisobtained.
Absorptioncanbe assumedtobe unimpededhowever,isthe IDRis greaterthan1mg cm-2
min-1
but
the IDR is notthe dissolutionrate ascalculatedbythe Noyes-Whitneyequationasthisassumesthat
the diffusioncoefficient,surface areaanddiffusionboundarylayerthicknessall remainconstant
whenthisdoesnotoccur. Thisis because the specificsurface will increase significantlyasasolid
dosage formbreaksup,before itlessensagainandbecomes0;i.e.itismost definitelynotaconstant
value.The IDR therefore isameasure of the dissolutionrate of a solidwhenA iskeptconstant,
whichcan be achievedthroughcompactingadrug (300mg) withpre-lubricatedmetal surfacesof
chloroform(5%w/v) before attachingtothe holderof a rotatingbasketwithparaffinwax onall but
the side facingthe medium.Thismediumwill be 1Lof 37°C dissolutionmediuminaflat-bottomed
vessel,inwhichthe discisrotated20mm fromthe bottomat 100rpm.
- If these conditionsare met,i.e.thatA remainsconstantandsinkconditionsare maintained,
thenthe measuredrate isindeedthe IDR,where IDR= KST
Consideringthe IDRof drugsincombinationwithpHand the commonioneffectare importantto
obtainan insightintomechanismof release.Asafunctionof pH, the equationbelow isuseful to
determine the IDRwhenthe pHand pKais known,andvaryingthe pH microenvironmentcanbe
optimisedbyexperimentallyinvestigatingthe IDRindifferentmedialike 0.1MHCl and simulated
gastrointestinal fluids. The self-bufferingeffectof acidsandbasesmustalso be considered,asthis
altersthe boundarylayerpH andconcentrations,whichcause deviationsfromideal behaviour.The
commonioneffectalsonecessitatesthe investigationof the effectof differentHCl concentrations
on the IDR.

7. George Wild Science of Medicines
7
Salt Selection and Screening
Changingthe saltformof drugscan be usedto improve aqueoussolubilityduringpreformulation
and shouldbe done before toxicitytestingaseachformis treatedasa new entitybyregulatory
authorities. The decisiononwhichsalttouse won’tbe basedon solubilityalonebutthe factthat so
manyexistonthe marketmeansthat theirbenefitsoftenoutweighthe drawbacks.
Advantagesof salts Disadvantagesof salts
Increasedsolubility Corrosiveness
Fasterdissolution Increasedtoxicity
Betterstability Increasednumberof polymorphs
Increaseddissolutionrate Decreasedpercentage of active drug
Bettertaste Decreasedchemical stability
Improvedphotostability Possible disproportionation
Lowerhygroscopicity Additional manufacturingstep
Highermeltingpoint Reduceddissolutionin gastricmedia
Higherbioavailability
Betterprocessability
A saltis simplyanionicinteractionbetweenionisedacidandbase species.Generallyif the pHof the
base is low,thenthe saltwill be unstable atphysiological pHvaluesasthere isless of a tendencyfor
the base to existinitsionisedform;it’ssaidthata pKa value of lessthan5 isindicative of
formulationbeinglesslikely.Sometimesdrugsare namedtosoundas if theyare salts/electrolytes,
like fluticasone propionate,butitmayactuallybe a single compoundwithcovalentbonds.
Description
pKa
Acid Base
Verystrong <0 >14
Strong 0 – 4.5 9.5 – 14
Weak 4.5 – 9.5 4.5 – 9.5
Veryweak 9.5 – 14 0 – 4.5
Extremelyweak >14 <0
Neutralisationoccursbetweenastrongacid anda strongbase,where bothspeciesare fullyionised
and the reactiongoesto completion.Excessacidorbase leadsto the formationof a precipitate as
the concentrationrisesabove the solubilitybutmostweakacidsandbasesdo notreactionto
completion inthiswayandare insteadconsideredintermsof the BrønsteadandLowryprinciples.
These state that an acidis a protondonator anda base isa protonacceptor,whichdoesnot
necessitate the presence of OHwithinthe molecule,onlythe abilitytoaccepta proton.Removinga
protonfrom a B/L acid createsthe conjugate base (A-
) of the acid,whilstaddingaprotonto a B/L
base createsthe conjugate acidof the base (BH+
).
A weakbase anda strongacid may reactto form a salt fromthe conjugate acid and base.Basicsalts
containthe conjugate acidof the drug and will donate itsH+
to waterupondissolutiontoformthe
H3O+
ionas well asthe free base.Thisfree base isthenpresentinamicroenvironmentwithavery
lowpH, inwhichit ismuch more soluble.Thisisattributedtothe increase insolubilitythatsalt
formationbringtopreformulation;the creationof apH suitable microenvironmentinwhichthe
drug ismore soluble. Fora solutionof dissolvedacid,pH= ½(pKa - log[BH+
]).

8. George Wild Science of Medicines
8
A weakacidand strongbase mayreact to forma saltof the conjugate acidand base.Acidicsalts
containthe conjugate base of the drug, whichcan thenaccept a protonfrom a watermolecule to
formthe free acidand OH-
ionswhichincrease the pH.The free acidismore soluble inthe higherpH
values,whichincreasesthe solubilityof the drug.The pH of a solutionof dissolvedbase isgivenas
pH = ½(pKa + pKw + log[A-
]) where the “w”elementisthe ionisationpotential of water.
Formingsaltisn’talwaysnecessarilybestachievedinaqueoussolutionaswatertendstocause
formationof the free acidor base,and the change in solubilityoverthe free acidorbase onlyresults
fromthe change of pH on dissolution,soif the saltisdissolvedinabufferedsolutionthere will be no
increase insolubility.
In orderfor a saltto successfullyform,there shouldbe adifference inthe pKa (reactivitypotential)
valuesbetweenthe twoconstituentsof atleast3 pKa units.Thismeansthat bothacidic andbasic
components are likelytobe ionisedtoanextentwherebytheywillinteractwitheachother;atpKa
differencesbelow0,itismore likelythatcocrystalswillform.Because of all this,the pKa of drug and
saltformerneedtobe matchedto ensure compatibility.The mostcommonsaltusedwithbasic
drugsis the hydrochloride saltbecause of itslow pKa value andhighprevalence inphysiological
systems.However,the saltresultsinamassive pHreductionaroundthe dissolvingsolutewhich
couldbe dangerousinparenteral administration,the saltisalsosomewhatcorrosive in
manufacturing,prone toinstabilityduringstorage andleadstothe commonioneffectwhen
administeredperorally.
Saltsmay be assignedtoone of three classesbasedontheirusabilityinformulations;firstclasssalts
like hydrochloride andsodiumsaltsare physiologicallywell-accepted,toleratedandprevalent.
Secondclasssaltshave some commonapplicationsandhave nosignificanttoxicological or
tolerabilityissuestoconsider i.e.sulphonicaids,mesilates.Thirdclasssaltsare unnatural and
reservedonlyforspecial circumstances. Thoughthe classificationandsolubilityof asaltare
important,the structure shouldalsobe consideredasamorphousandotherless-regularorstable
formswill cause problemsandshouldbe avoidedovercrystallinestructures.
Many potential saltcandidatescanbe testedina large batchby usingmicro-plate wellscontaining
about0.5mg of drug dissolvedinsuitable solventstowhichavolume of dissolved counterionis
added.The solventshouldbe selectedcarefullyatthisstage,andit isalsopossible toexaminethe
effectof the solventinthe x directionwhilstexaminingthe effectof counterioninthe ydirectionin
some configurations.Afterasufficientamountof time haspassed,the wellsare observedforcrystal
formation;inthe wellswithoutcrystals,theymaybe storedatlowertemperaturestoencourage
precipitation.If thisdoesn’toccurthough,thenthe solutionmaybe heatedtoevaporate solventand
leave behindthe crystal,howevercase shouldbe takenwiththisstepasthe solidleftafter
evaporationmaysimplybe drugandunreactedsalt-former.
Whenthe potential salthasbeenidentified,XRPDcanbe usedona sample of 10 – 50mg to analyse
the polymorphicformof the salt.HSM (hot-stage microscopy) canalsobe usedto visuallyconfirm
meltingpointwhilstDSCcanprovide meltingpoint,enthalpyof fusionandtherefore the ideal
solubilityof the newsalt.

9. George Wild Science of Medicines
9
Salt Solubility
The solubilityof saltsishardto predictasthere are manyfactors that affecta salt’ssolubilityinvitro,
and the empirical methodsthatdoexistinbooksoftenrelyonmeltingpointvalueswhich,inorder
to calculate,allowthe solubilitytobe calculatedexperimentallyanyway,soyoumayas well doit
yourself.
For a basic salt,the solubilityisequal tothe concentrationof the unionisedportionof the drugat
highpH values(i.e.completelyunionised) andthe solubilityisequal tothe concentrationof the
ionisedportionatlowpHvalues(i.e.completelyionised).Thismeansbydefaultthatthere isa
regioninbetweenthesetwoextremeswhere the solubilityof the saltisgreatlydependentonthe
pH of the environment.Graphically,the solubilityplottedagainstpHissaidby Kramerand Flynnto
be the sumof twosolubilityprofiles;one where the solute isdissolvinginequilibriumwiththe solid
saltand one where the solute isdissolvinginequilibriumwiththe solidfree base. Byextension,the
interceptof these “two”profilesisthe pHmax; the pointat whichthe free base co-existswiththe
solidsalt.Therefore forabase;the saturatedsolute solutionisinequilibriumwiththe saltbelowthe
pHmax and isequilibriumwiththe free base abovethe pHmax. If the pKa of the basic saltisincreased
by 1, thenthisalsoincreasesthe pHmax by 1; an effectalsoseenwhenincreasingthe solubilityof the
free base by1 orderof magnitude.Oppositely,the pHmax isreducedby1 whenthe solubilityof the
saltis increasedby1.
For an acidicsalt,the solubilityisequal tothe concentrationof the unionisedportionatlow pH
values(where the drugiscompletelyunionised) andthe solubilityisequal tothe ionisedportionat
highpH values(where the drugiscompletelyionised).Intermsof the solubilityprofiles,foranacid;
the saturatedsolute solutionisinequilibriumwiththe free acidbelowthe pHmax and isin
equilibriumwiththe solidsaltabove the pHmax.The value forthe pHmax may be increasedby1 when
the solubilityof the saltisincreasedby1 order of magnitude,butthe pHmax decreasesby1 whenthe
solubilityof the free acidisincreasedby1 and whenthe pKa is increasedby1.
Loweringthe pH of a saturatedsolutionof basic saltto below the pHmax will cause free base to
convertto saltand vice versa,butthischange tothe systemwon’thappenunlesssufficient[H+
] is
presenttoconvertthe free acidto salt (andvice versa).The systemtherefore actsasa buffersystem
until sufficientacidoralkali isaddedtoconvert1 phase completelyintothe other. Knowingthe
pHmax is therefore importantinpreformulationasitdeterminesthe pHat whichthe equilibrium
shiftsfromfavouring the ionisedto the unionisedform, whichformsthe basisof improvingthe
solubilityof adrug throughsaltformation.
Saltsare able to increase the dissolutionrate of free acidsandbasesby providingasaturated
diffusionlayerinwhichthe pHismore optimal forthe dissolvingfree acidorbase;thisisthe pH of
the microenvironmentandissotermedthe pHmenv. Thisisdifferenttothe bulkpHwhendissolution
firstbeginsandso althoughwhenthe bulkpHof the solventissimilartothe pHmax, the dissolution
ratesof the acid or base and the correspondingsaltare notequal,asthe pH to whichthe free acidor
base is actuallyexposedismuchdifferentfromthatof the pHmax (hence dissolution).The Noyes-
Whitneyequationsaysthatbecause the solubilityof these acidicandbasicdrugs ispH-dependent,
thenthe dissolutionrate willalsoreflectthis,withthe valueof Cs changingaccordingto pH and
ionisation;the solubilityisthe rate-controlling-variable.
The saturatedboundarylayermaximisesthe difference inpHbetweenthe bulkandimmediate
surroundingsof the dissolvingparticletherefore thisgraduallydecreasesasdissolutioncontinues

10. George Wild Science of Medicines
10
and C getscloserto Cs.However,because the pHintowhichthe drug isdissolvingisactuallythatof
the pHmenv, thenthe dissolutionrate ismeasurednotwithrespecttothe solubilityinthe dissolution
medium,busasif the drug were ina solutionwithapHequivalenttothe pHmenv.
Saltformationtherefore canincrease solubility,butwithconsequencesforlogP asionisedspecies
do notpartitioninthe organic phase,thereforeadrug maywell have asolubilityinthe intestine of
299 (like ibuprofen),butthiscomeswithapoor logPvalue of 0.63, meaningabsorptionispoor.This
compromise issomethingthatmustbe consideredinchoosingasalt.
Hygroscopicity
Hygroscopicityisthe tendencytoabsorbor adsorbwaterfrom the immediate environment,whichis
exhibitedbymanysaltsof drugs.The presence of wateron or withinsolidshasthe potential toalter
physical form,structure,physicochemical propertiesandwill alsomediate manychemical reactions
(thusfacilitatingdegradation) andmaycause API-excipientreactionstooccur.If the substance is
amorphous(unlikely) thentakingupwatercausesincreased mobilityandplasticisation;inextremes
crystallisationoccursbuteitherwaythe resultismajorstructural change.
Saltshave a greaterpropensitythanfree acidsorbasesto absorb waterand some,like KOHand
MgCl2 to suchan extentthatthe salt thendissolvesinthe absorbedwater;theydeliquesce.This
feature of some saltscan be overcome bycorrect choice of packagingand advice onhow to store
the medication.TGA can be usedinpreformulationtoassesschanges inmassafterexposure to
humidity asitmonitors masschanges withrespecttotemperature,whilstDVA canmonitorchanges
inmass as a functionof humidityandhence canbe usedduringthe exposure tohumidity.
Physical Form
Many solidstates(physical forms) are possibleformostdrugsand soknowingall the different
polymorphspossiblewithadrugis importanttooptimise drugefficacy,thoughitisalsoimportantin
termsof marketexclusivityaspatentingof the several useful polymorphspreventscopycat
manufacturers.Differentphysical formshave differentphysicochemical propertiesandstabilities,
but the moststable isalwaysthe mainpolymorphtowhichall otherless-stable (metastable) forms
revertdue to thermodynamicequilibria.Thoughthere isthistendencytorevert,the moststable is
not alwaysthe bestchoice asit oftencomeswitha strongerintermolecularstructure,highermelting
point,poorersolubilityandreducedbioavailability.However,there are caseswhere metastable
formscan be usedandso the tendencytorevertand the time takenshouldbe lookedatsothat
viable metastable formsare notdisregardedinthe beginning.
Polymorphsare screenedlike saltsinamicro-plate with96wellscontainingvarioussolventsand
solventmixtures.Afteranappropriate lengthof time,theyare observedforcrystallisationwithan
optical device i.e.microscope andassayedusingXRPDandDSC.XRPDanalysisrevealsthe physical
structure of the crystal and so allowsvisual identificationof variouspolymorphs,witheach
diffractogrambeingspecificforspecificstructures;the differencesbetween2θvaluesbeingevident
fromvisual comparison.DSCprovidesdataonthe enthalpyof fusionandmeltingpointof crystals,
whichcan be usedto calculate ideal solubilityandtoobserve whichcrystal islikelytobe the stable
polymorphandwhichare the metastable forms.Metastable formswill produceaDSC thermogram
withseveral peaks whichrepresentthe transitionsbetweenlessandmore stable formsas
temperature increases.Metastableformsare characterisedbyanendotherm-exotherm-endotherm

11. George Wild Science of Medicines
11
appearance,where energyistakeninfromthe environmenttomeltthe first(lessstable) form,
forminga moltensupercooledsolidthatthensolidifiesbyformingbonds,causingenergytobe
released.Thisformwilllikelybe the moststable polymorphandwillshow one more endothermic
peakat a highertemperature whenthe solidmeltsforthe final time.
Amorphousmaterial maybe formedif derivedfromcomplexbiological structuresorif ithas a large
molecularweight,throughapplicationof localisedpressure (i.e.duringmilling) todisruptstructure
or by not allowingsufficienttime toforma regularstructure like byquench-coolingorprecipitation.
The resultisunstable andhas notlattice energymeaningthatitismore soluble thancrystalline
forms.Confirmationthatacompoundisamorphousisseenthrougha “halo”on an XRPD
diffractogram,where there are nodistinctpeaksbutabroad massive peakformedfrommany
spikes.
The combinationof data fromDSC and XRPDis verypowerful andallowsrapidassignmentof the
differentpolymorphicformsscreened.
Powder and Compaction Properties
Particle size andshape can be seenusinglightorscanningelectronmicroscopyandcan indicate the
likelinessof bulkpowderstofloweasilyandbe easilymanipulatedduringmanufacture.Flow
propertiescanbe determinedusingsmall quantitiesof the powderbyusingthe angle of repose,the
Carr’s index andHausnerratio;smalleranglesof repose andCarr’sindex valuesindicate betterflow
properties.
The angle of repose isa measure of the intraparticularcohesive andadhesive forcesof abulk
powder.If a powderispouredfromabove ontoa horizontal surface,thenaheapwill form.Asmore
powderisadded,the pull of gravityandangle of inclinationreachalevel where the forcesof
cohesionbetweenparticlesisovercomeandparticlesslide downward,creatinganew slope witha
newangle,whichwill be lessthanbefore.If enoughisadded,the angle of inclinationatwhichthe
intraparticularforcesare againovercome,will happenagain.Thisangle isthe angle of repose and
can be usedtoindicate pooror goodpowderflow.Highanglesof repose willindicatethata greater
pullingforce needstobe exertedonthe moleculesonthe outerof the heap before theyfall and
therefore greaterintraparticularforcesandpoorerflow properties.A powdermayhave more than
one angle of repose if itis particularlycohesive innature.Incaseslike this,the slopeangle will
increase largely,thensuddenlythe stackwill fall,trappingairwithinthe bulkandincreasingfluidity.
From thisthere maybe three anglesof repose;the maximum(θm) angle,the shallowestangle
formedoncollapse (θs) anda possible intermediate angle(θi) formedbycohesive particlesstacking
on a fluidbed.Those powderswithanglesabove 45°have undesirableflow properties,whilstthose
witha minimumclose to25° will have goodflow properties.
Determinationsof powderflow canbe basedonbulkdensitybehaviour,usingthe Hausnerratioand
Carr’s index,because the bulkdensitywill be dependentonparticle size andshape,packingand
consolidation.Measurementsof bulkdensitycanbe obtainedthroughusingamechanical tappingor
joltingvolumeterdevice,where aknownmassof powderisplacedina vessel andhasitsvolume
recorded,before beingtappeduntil the volume dropstoanunchanginglevel.The original (fluff)
densityisfoundasm/VO,where VO isthe original volume,whilstfinal (tapped) densityisfoundas
m/VF.

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The ratio of the twodensities,orindeedthe ratioof the volumesgivesthe Hausnerratiowhen
multipliedthroughby100. It wasshownthat the ratios were relatedtothe interparticulate friction
of the powderandso waspredictive of powderflow,withHausnerratiosof more than1.3 being
poor,and those lessthan1.18 beinggoodintermsof powderflow.
Hausner ratio=
final or tappeddensity (ρBmax)
original or fluff density(ρBmin)
× 100 Carr's index =
ρBmax- ρBmin
ρBmax
× 100
The Carr’s/compressibilityindex iscalculatedasabove fromthe informationthatthe percentage
compressibilityof apowderisa directmeasure of the potential powderarch/bridgestrengthand
stability.