Some of the factors to consider when compounding pharmaceutical solutions.

1. George Wild Science of Medicines
1
Pharmaceutical Solutions
A solutionisahomogenous,molecularmixture of atleasttwocomponentsinthe same phase,
presentinan opticallyclearstate.Aqueoussolventsare basedondifferentkindsof water,whichare
appropriate underdifferentcircumstancesanddifferentroutesof administration.Waterisperhaps
the most commonsolventbecause itischeap,well toleratedandnon-toxic,butisnotalwayssafe in
all forms.Tap (potable) waterisusedinsome extemporaneouspreparationsforexternalandoral
use,butonlyafterbeingboiledfirst,tokill anybacteria/virusesfirst.There are varyinggradationsof
purifiedwater,butthe mostpure andsterile issterilewaterforinjections.Waterforinjectionsis
purifiedwaterwhichhasbeenfurtherpurifiedtoremove pyrogensfromthe solventandisusedin
intravenousandsome intramuscularinjections.Cosolvents maybe addedtoany solutiontoimprove
solubilityandstabilityof acertaindissolvingsolute,examplesof whichincludeethanol,polyethylene
glycol andglycerol.Non-aqueous(organic) solventscanbe usedinlessroutesof administration,
such as intramuscularandtopical due totheirunpalatability,toxicity,irritancyandimmiscibilitywith
physiological fluids.Theymaybe usedascosolventsinaqueoussolutions,cosolventsinorganic
solutionsorontheirownas a solvent.
The drug is justthe ingredientinapreparationwiththe desiredtherapeuticeffectforthe intended
conditionandsomay be a molecule,ion,antibodyorotherbiological molecule.Nomatterwhat
formthe drugis in,itwill alwaysbe presentinaconcentrationlessthanthe CS of the drugto avoid
precipitationwithinthe bodyandduringstorage andtransport.All the otheringredientsare
excipientsandare presenttoimprove stability,bioavailabilityandotherproperties,whilstalsonot
interactingwithotheringredientsandavoidingbeingtoxic,irritantornon-sensitising.
Solvent Use(s)
Water Purified water:for preparationof medicinesthatdon’tneedtobe sterile
or apyrogenic,i.e.extemporaneousoral andtopical forms.
Highly purified:waterfor medicineswhere highbiological qualityis
needed,exceptwherewaterforinjectionsisappropriate.
Water forinjections: for parenteral administration.
Sterilised water forinjections: forparenteral administration,where water
isheat sterilisedandsuitablypackaged.
Alcohols Ethanol:mostcommonorganic solvent,andascosolventinoral,topical
and parenteral preparations.
Propyleneglycol:dihydriccosolventinoral,otic,topical andp/enteral.
Glycerol: trihydriccosolventwithwaterinoral andparenteral preps.
Polyethyleneglycol(PEGs): low molecularweightwith
HOCH2(CH2CH2O)nCH2OH,usedinp/enteral ascosolventorsolvent.
Fixedvegetable oil Expressedfromfruitorseedsandare usuallytriglyceridesof fattyacids
that are non-volatile.Examplesinclude; castoroil,cornoil,arachisoil,
almondoil andpoppyseedoil.TheyhadbeenusedforIMinjectionsbut
are beingreplacedwithsyntheticethersbecauseof theirreduced
irritancyand possibilityof allergicreactions.
Esters Vehicle forsome IMinjections,examplesinclude ethyloleate/ethanoate.
Dimethyl sulfoxide Carrierfor idoxuridine fortopical skinapplication.
Glycofurol Cosolventinparenteral solutionsforintramuscularorintravenous.
Ethyl ether Cosolventwithethanol incollodions.

2. George Wild Science of Medicines
2
Solutionsmusthave some commonconsiderationslikepatientacceptabilityandstability,butthere
are differentformsanddifferentroutesbywhichtheycanbe administeredandsothere are also
individualconsiderationsi.e.oral solutionsandpalatability,parenteralsolutionsandisotonicityand
physiological pH.There are manydifferenttypesof oral solutionavailablewhichare all slightly
differenttoaccommodate differentconsiderations;aromaticoilsare saturatedsolutionsof volatile
oil or aromaticsubstance;elixirsare sometimessolutionswithalcohol cosolvents;spiritsare
alcoholic/hydro-alcoholicsolutionsorvolatilesubstances;syrupsare solutionssaturatedwithsugars
like sucrose ordiabeticalternativeslike mannitol orsorbitol;tincturesare concentrationvariable,
alcoholic/hydro-alcoholicsolutionspreparedfromvegetable materials.
Route Requirementsof solution
Oral May have a local GI tract effectora systemiceffect,butpalatabilityisalwaysan
issue asthe medicine must passthe taste buds;thereforeflavouringagents,
colouringsandsweetenersmaybe added.The pHshouldbe 7 but 2 – 9 is
tolerated.The dose isusuallyin5ml measuresforconveniencebutviscositymay
vary because of excipientchoice,withsolutionsbeingmore viscousthanwater.
Oral cavity Examplesincludemouthwashesandgargles,whichare notswallowedandexert
a local effectinthe mouth.The solutionshouldbe aq,palatable andpHneutral.
Topical Vehiclesmaybe aqueousornot,butshould adhere toskinwithoutbeingtacky
and hard to getoff.Preparationsmustbe acceptable i.e.smooth,easytoapply,
easytransferfromcontainer.Examplesare;lotionswhichare intendedfor
applicationwithoutfriction;linimentswhichare alcoholicoroilyandrubbedinto
the skin;collodionswhichare polymersinvolatile organicsolventsystemsthat
evaporate toleave apolymerfilm;paints/tincturesare concentratedaqor
alcoholicantimicrobial solutions.
Rectal Aqueousoroilysolutionsforlocal or systemiceffecteitherbymicro(1 -20mL) or
macro (50mL +) enemas,withthe latterwarmedtobodytempbeforehand.
Vaginal Aqueoussolutionsforlocal ordiagnosticeffect,withpossiblepHmodifications.
Nasal Preparationslike dropsandspraysare aqueousforlocal (i.e.decongestant) or
systemiceffect.The pHissimilartothe nose (5.5 – 6.5), withnasal isotonicity
and viscosity.Flavouringsmaybe addedasa small proportionmaybe
swallowed.Preservativesincludedinmulti-dose preparations.
Otic Appliedtoouterearforlocal effecti.e.earwax removal,anti-infective,anti-
inflammatory,analgesicandsodo not needtobe isotonic.Theymaybe aqueous
or not but shouldbe viscousforbetterresidence timeandsonon-aqueous
solutionsare often usedlikeglycerolorpropyleneglycol,whichalsoallow ear
wax to solubilise inthem.
Ocular May be dropsto treat local disorderslike infection,orintraocularconditionslike
glaucoma,or may be eye lotionsusedtowashor rinse the eye.Mostare
aqueousandpH neutral because the eye toavoiddiscomfortandirritation,
thoughslightlyalkalinepHvaluesreduce lacrimationandthe eye canactually
tolerate pH3.5 - 9. Antimicrobial agentsmustbe presentasthe eye issensitive
to contamination,especiallyinmulti-dosepreparations.The medicineshouldbe
isotonictominimise discomfortbutinsmall dosestearscause dilution;however
inlarge doses,isotonicityisimportant.Increasedviscosityiscommonfor
improvedresidence timeinthe eye.
Pulmonary Solutionsare inhaledbypMDIs(pressurisedmetered-doseinhalers)or
nebulisers,mostcommonlyaqueous.Inhalerscontaindrugandexcipientin
liquefiedpropellantlike trifluouromonofluoroethane whereasnebuliserscontain
largervolumeswithpH3 – 8.5 that are isotonicforlocal or systemiceffect.

3. George Wild Science of Medicines
3
Parenteral routesare those thatinvolve injectionof the medicine viaahollow needleandinclude;
intravenous,intramuscular,intradermal,subcutaneous,intrathecal,intra-arterial andmore.The
solutionmustbe sterile andapyrogenic,withintravenousinjectionsalsoneedingtobe aqueous.
Preservativeslike benzyl alcoholmaybe neededformulti-dose preparations,butthe pHmust lie
within3 – 9 to avoidpain,phlebitis(veinwall-inflammation) andtissuenecrosis,ideallyatpH 7.4
(physiological pH).The isotonicityof parenteral solutionsshouldbe thatof the bodilyfluidswhen
large dosesare administeredlike ininfusionsandotherIV preparations,butislessimportantwhen
small dosesare administeredasthe solutionquicklybecomesdilute.
The advantagesof solutionsoverotherdosage formsincludethe factthatthe drugis alreadyina
formin whichitis acceptedinthe bodyand so isreadyfor absorption,makingitparticularlyuseful
incases like emergencieswhererapidactionisneeded.Solutionscanalsobe measuredoutto
provide uniformdoseswhichisinitself abenefit,butisalsouseful forcertainpatientpopulations
like the elderlyandchildrenforwhomadherence maybe an issue.The manufacture of solutionsis
alsorelativelyeasy.
Disadvantagesincludethe factthatalthoughthe manufacture of solutionsmaybe easierthansome,
the transport andpackagingof solutionsismore costlyandrisky.Impracticalityisalsoimportantto
considerasfor a patient,the dailydose inliquidformisprobablymuchlargerandmuchmore
impractical thancarryingaround a tabletforexample,whilstmattersof insolubilityandinstability
are impractical forpharmaceutical scientists.
Solution Stability
A solutionmustremainstable throughoutitsshelflifesothata uniform, safe andtherapeutically
effectivedose of the drugisconsistentlyadministered.Thismeansthatthe pharmaceutical
preparationmusthave the same physical,chemical,microbiological andtoxicological propertiesasit
had at manufacture,whilstalsohavingthe same taste,odour,viscosityandoptical appearance.It
mustalso be free fromcontamination(if sterile) orhave the intendedantimicrobial resistance asit
didwhenmanufactured.All of these elementsof stabilitymaybe decreasedundercertain
temperature,pH,catalystandUV lightconditionswherereactionssuchashydrolysis,oxidation,
photolysis,epimerisation,dehydrationanddecarboxylationmayoccur. Anyof these stability
decreasingagentsmayreduce APIconcentration,leadingtoreducedefficacy,butmayalsoleadto
the formationof toxicby-productsthatcause the medicine tobecome counter-therapeuticand
potentiallyfatal.
Oxidative photolysis maybe preventedbypackagingthe solutioninanamberbottle topreventthe
UV catalysisfromoccurring,whereasregularphotolysismaynecessitatethe inclusionof an
antioxidantasanexcipient,orthe purgingof oxygenfromthe bottle andthe use of a nitrogen
headspace. Itmayevenbe necessarytoinclude chelatingagentstocause chelationof heavymetal
ionsthat maybe presentthatwill otherwise catalysethe oxidation. Preservativesare oftenuse to
provide antimicrobial growth-resistance inmulti-dose preparationsbutthe excipientsmust always
functionwithinthe pHrange of the solution,notinteractwiththe otheringredientsorbe toxic,or
decrease inconcentration oreffectiveness andsomustbe chosencarefully.

4. George Wild Science of Medicines
4
Enhancing Solubility
Many methodsmaybe usedto improve the solubilityof adrugbut the nature of the solubility
modifierwill dependonthe route of administrationandthe drugmolecule assome modifiersmay
not be suitable forall routesof administration. Modifyingthe pHof the medicine bysaltformation,
or acidic/basic/bufferexcipientsmaybe requiredwhere the drugisa weakacidor base.Thisutilises
the equilibriathatexistwithweakacidsandbasesbyshiftingthe positionof equilibriumtothe
ionisedspeciesbecausethisisthe fractionof the drugthat is mostsoluble inwater.However,
increasingsolubilitywill oftenhave detrimental effectsonlogPandlogDvalues,thusdecreasingthe
rate andpossiblyextentof absorption,dependingonhow the solubilityis increased.The pHshould
alsoconsiderstabilityof all excipientsasthe optimumpHforsolubilitymaynotbe the same as the
pH for stability,thus;the chosenpHwill reflectthe bioavailability,solubility,stability,excipient
functionandphysiological acceptability,withthe latterbeingrelevantintermsof the tolerance of
specificroutesof administrationtocertainpHranges.
Cosolventsmaybe usedtoincrease solubilitywherethe drugisnotan electrolyte andsocannot
formsaltsor be affectedbypH as much.Loweringthe dielectricconstantof the dissolutionmedium
by addingorganic(non-polar) liquidsallowsnon-polarmoleculestobecome more solublebyseveral
ordersof magnitude.A linearincrease innon-polarsolventprovidesanexponential increase in
solubility,butmanyorganicliquidsare toxicandeventhe commononeslike glycerol andPEGscan
be toxicdependingonconcentrationandroute of administration.
Complexationwithcyclodextrinscanbe usedtoessentiallyremove the drug fromthe aqueous
solventbyprovidingahydrophobicmicroenvironmentwhichthe non-polarmolecule mayoccupy.
Alpha,betaandgamma cyclodextrinsare the mostcommonwith6, 7 and 8 memberednon-
reducing,D-glucopyranosylsubunitsrespectively,linkedby α (1-4) glycosidicbonds. The hydrophilic
outerallowsthe structure tobe soluble inwaterwhilststill possessingahydrophobicinnerregion
withwhichpoorly-soluble moleculesmaycomplex orself-associate.
Solubilisationmayalsobe appropriate,wherebysurfactantssuchasmicellesare usedtoencapsulate
varyingdegreesof poorly-soluble drugstovaryingextentswithinthe structure,upuntil the MAC
(maximumadditive concentration) isreached.The concentrationatwhichmicelleswill form(CMC)
frommonomersisalsoimportantto determinethe amountthatwill ultimatelybe needed,as
concentrationsbelow thisvalue will be ineffective andconcentrationsabove thisvaluemay
decrease absorptionandincrease toxicity.
Anyand all of these methodsof solubilityenhancementmaybe usedincombinationtoachieve the
bestpossible resultsinagivenscenario,withthe targetdrugconcentrationinpharmaceutical
solutionbeingthe endpoint.