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Dosage Form Design
- 1. George Wild Scienceof Medicines 1 The Design of Dosage Forms On a basiclevel,amedicine will containnotonlythe active pharmaceutical ingredient(the drug) but a host of otheradditives(excipients) thatwillmodifythe physical and/orchemical behavioursof the dosage form.Excipientsare carefullyselectedin preformulationtoachieve the bestpossible medicine andwill usuallybe presenttorectifyproblemsthatone of the otherconstituentscauses (oftenthisisthe drug).Withthisinmind,itcan be possible tohave apure or nearlypure drugina medicine, asexcipientsdon’ttendtobe addedunlesstheyare actuallyneeded,forpharmacological as well aseconomicreasons. A dosage formshouldseektoprovide auniform, repeatable andsafe dose of drugtoeach patientto achieve aneffectwhichhastherapeuticbenefittothe patient.Thisrequiresthe medicine tobe appealingtothe patient(i.e.notdisgustingflavoursfororal preparations)andforthe response withinthe patienttobe unifiedacrosspopulations.The latterisnotreallywidelyachieved due to patientvariationingenetics,metabolicactivityanddisease/illnesspresence orseverity.Excipients such as viscositymodifiers,organolepticmodifiers,preservatives,stabilisersandsolventsare usedto achieve this. Route of Administration Dosage FormsAvailable Oral Solution,suspension,syrup,linctus, elixir,gel,powder,tablet,granule, capsule Topical Solution,lotion,suspension,cream, gel,ointment,foam, transdermal patch Rectal Suppository,cream, powder,solution, ointment Respiratory Aerosol (solution,suspension, emulsion,powder),spray,inhalation Eye Solution,ointment Nasal Inhalation,solution Ear Suspension,solution,cream, ointment The dosage form will reflectthe solubilityof the drug,the clinical indicationforwhichitisused,the desiredbioavailability,particle size andotherpharmacokineticproperties.Multiple dosageformsfor the same drug are common,whichreflectsboththe differentindicationsforwhichadrugis prescribedandthe differentcharacteristicsthe drugpossesseswithmodification.Dosage formsfor medicinal productsarisingfrombiotechnologywillneedtoconsiderthe macromolecularnature of the product as well assome specificbiological andchemical properties.Assuch,biotechnological productsare formulatedprincipallyforuse viaparenteral andrespiratorydelivery,whichlimitsthe choice of excipientsfurther. Dosage formsshouldtherefore take intoaccount;the biopharmaceutical propertiesorabsorption, distribution,metabolismandelimination;the physical andchemical propertiesof the drugproduct; and the therapeuticconsiderationssurroundingclinical indication,patientattitudesandadherence issues.
- 2. George Wild Scienceof Medicines 2 Biopharmaceutical Aspects of Design The biopharmaceutical factors of dosage formdesignwill considerthe physical,chemical and biological aspectsof the drug,whichhave implicationsforthe absorptionof the drugacross biological membranes,it’sdistributionwithinthe body,the extentandrate at whichthe drug is metabolised,andthe rate of eliminationfromthe body(inurine,faeces,sweatandthroughthe lungs) eitherinmetabolisedorunchangedform. In orderfor a drug to be absorbedbythe bodyit mustfirstbe insolution,whichnecessitatesa degree of aqueoussolubilityfromthe drug.Once inthe body,the drug will be takenupbyeither passive diffusionorcarrier-mediatedtransport.The rate of diffusioninthe bodyisinfluencedbythe degree of ionisationof the drug(as nearlyall drugsare weakacids or bases) andthe lipophilicityof the drug. Dependingonthe route of administration,the drugwill eitherbe presentatitstargetsite or needtotravel there inthe circulatorysystem, commonlythe latterwillhappenregardlessof the route of administration.Giventhenthatthere are variousroutesof administrationandvarious dosage forms,there are differencesbetweenthe onsetsof actionthatdependonthese twofactors. Intravenousinjectionsare byfar the quickestactingroute of administrationbecausethe drugis injecteddirectlyintothe bloodstream(givingit100% bioavailabilitytoo).Intramuscular,buccal, subcutaneous,rectal andrespiratoryroutesof administrationare alsofast-actingdue tothe fact that the drug bypassesfirst-passmetabolisminthe liveranddoesnothave topass throughthe gastric systemorthe skin. Thoughsome drugs maybe betterthanothersat beingabsorbedordistributedinthe body,all drugs are essentiallyforeignbodiesandwill begintobe distributed,metabolisedandeliminatedassoonas theyenterthe body. Time of Onsetof Action Dosage Forms Seconds Intravenousinjections Minutes Intramuscularandsubcutaneous injections,buccal tablets,aerosols, gases Minutesto hours Short-termdepot, solutions, suspensions,powders,granules, capsules,tablets,modified-release tablets Several hours Enteric-coatedformulations Days to weeks Depotinjections,implants Varies Topical preparations The most commonroute of administrationisthe oral route,primarilybecause itissimple,reliable, safe and providesalarge surface areaoverwhicha drugmay be absorbed(throughthe various epitheliaandmucosainthe GI tract).However,manydrugs suchas proteins are notsuitable tobe usedorallydue tothe enzymesandacidspresentinthe stomach(thisislessonan issue forthe small numberof drugs that maybe takenorallyfora local effectinthe mouth).The low pH of the stomach can alsopose problemsforbioavailabilityanddrugactionbecause of the effectithason degree of ionisationandlipophilicity.Othersubstancespresentinthe stomachsuchas foodwill ofteninteract
- 3. George Wild Scienceof Medicines 3 withdrug molecules,whichcanrenderthemtherapeuticallyinactive,reduce effectivenessorcould evencause unwanted adverse effects. The gastric emptyingtime isanotherfactorthatwill affectthatrate and extenttowhicha drug is absorbedinthe GI tract. If gastric emptyingisslow,thendrugsthatare inactivatedormodifiedby the gastric juiceswill undergodetrimental change,anddrugsthatare absorbedinthe intestine have a delayedonsetof action. Tabletsare the mostcommonoral dosage formand consistof a knownquantityof the drug compactedwithotheradditivessuchasdisintegrantsthatwill improvedissolutionand absorptioninthe GI tract. Oftenthe tabletsare coatedwitha filmthatwill improve organolepticpropertiesof the medicine,improve stability,protectitfromenvironmental damage (suchas from pH or moisture) ormodifyitsreleaseinthe GItract. Capsules will containthe druginpowderedform, aswell asappropriate fillermaterialsthat can increase dissolutioninthe gut.Theymayinsteadcontainmicroemulsionsorsemi-solid fillings,butwill alwayscome inahard/softgelatine orpolymericshell thatrupturesor dissolvesinthe stomach. Suspensionscontainfinelydividedparticlessuspendedinanappropriate (oftenoilyvehicle). Thisdosage formis useful foruse whenusingthe drugintabletor capsule formisin appropriate,andforpatientswhohave difficultyswallowing.The large surface area presentedbythe finelydividedparticlesinasuspension improvesthe onsetof actionand drug dissolutionandabsorption. Rectallyadministereddrugsare insolution,suppositoryoremulsionformandare sued advantageouslyoversome otherroutesof administrationdue tothe factthat the drug may pass directlyintosystemiccirculationwithoutgoingthroughhepatoentericmetabolism,whichisuseful for drugsthat are inactivatedthroughthispathway. Thisroute mayalsobe usedincaseswhere oral administrationisprecluded(i.e.unconsciouspatient,vomitingpatient),butisdisadvantageousinas much as itis inconvenientandthe absorptionisoftenirregularanddifficulttopredict.With suppositories,the base orcarriermassivelyinfluencesthe degreeandrate of drug release. Parenteral routesof administrationinvolve the use of ahollow needle todeliversolutionor suspensionof drug,atvariousdepthsandlocationsof the body.Intravenousinjectionsare the most commonlyusedparenteral administrationandwillinvolveinjectingtinyorlarge volumesof the drug directlyintoavein,whichcanbe painful andinconvenient.Despite this,IV injectionsare the best wayof administeringadrugfast (i.e.inemergency) whilstavoidingfirst-passmetabolism, and produce predictable bloodplasmaconcentrationlevels.The preparationsare sterile andoften include “waterforinjections”asthe solvent,perhapswithavasoconstrictorlikeadrenalinewhena local and notsystemiceffectisrequired.Intramuscularandsubcutaneousinjectionsinvolve injecting a volume of drugeitherdeepintoskeletal muscleorjustunderthe skinrespectively,producinga slow reservoirof drugintothe body;the “depot” effect. Topical deliveryinvolvesapplyingthe drugpercutaneously,whichisseldomusedforsystemic circulationdue tobeingerraticandpoor, more oftenforlocal effect.Transdermal patchesfor analgesiaandsmokingcessationexist,butmore commonlytopical applicationswillhave an antiseptic,antifugal oranti-inflammatoryfunctionalongwithskinemollientsforprotective effects.
- 4. George Wild Scienceof Medicines 4 Topical formulationslike ointments,pastesandcreamsinvolve the drugbeingcarriedinasemi-solid base whichcan be hydrophobicorhydrophilicincharacter.Ointmentsare hydrophobicbecauseof theiroilynature,creamsare semi-solidemulsionsandpastesare harderthanointmentsbecause of a greatersolidmass.Ophthalmicpreparationsare alwayssterile,nasal dosage formsare always solutionsof suspensionsandearformulationsare usuallyviscous toprolongthe contactwiththe affectedareas. Respiratoryadministrationprovidesanexcellentsurface forabsorption throughthe alveolar epithelium,butthismeansthatparticle size playsanimportantrole inthe extenttowhicha drugis absorbed.Drugparticleswithadiameterof 0.5 – 1 micronreach the alveolarsacs,anysmallerthan thisand theyare exhaled;anylargerandtheyare depositedonthe bronchial airways.Thisroute of administrationisuseful forthe directtreatmentof asthmaandothersuchillnesses,viapowdered aerosolsormetereddose aerosolswithaliquefiedinertpropellant. Asaroute,thisisalso being increasinglyrecognisedasa route of administeringbiotechnological therapeuticagentsfortargeted delivery,likeproteinsandpeptides. Drug Factors and Dosage Form Design Many physical andchemical drugfactors require careful considerationbefore adrugwithproven therapeuticbenefitbecomesalicensedmedicine foruse inthe publicdomain.These factorsinclude; polymorphictendencies,aqueoussolubility,particle size,drug-excipientinteractionsandsolid-state stability,whichcanall have huge differencesonthe physiological effectsof the druginthe body. Properties Processingstresses Manufacturingprocedures Particle size (surface area) Particle surface chemistry Solubility Dissolution Partitioncoefficient Ionizationconstant Crystal properties Polymorphism Stability Organolepticnature Molecularweight Pressure Mechanical Radiation Exposure toliquids Exposure togassesand vapours Temperature Precipitation Filtration Emulsification Milling Drying Mixing Granulation Compaction Autoclaving Crystallisation Handling Storage Transport The size of particlesisanaspectof preformulationstudiesthatisof massive importance,formany reasons.Itis widelyrecognisedthatparticlesof asmallersize representalargerspecificsurface (surface areaof drugparticles) thanlargerparticles,whichisseentoaidinthe dissolutionand therefore solubilityof manydrugs.Fordrugslike griseofulvinandtolbutamideinwhichabsorption involvesadissolutionrate-limitingstep,itisknownthatthe bioavailabilityof the drugmaybe increased throughdecreasingthe particle size toincrease the specificsurface.Thisisbecause a largersurface area resultsinfasterdissolutionof the drugandso will increase the rate of passive diffusion.Nowadaysdue tothe fact that manynew drugsemerge withincrediblypooraqueous
- 5. George Wild Scienceof Medicines 5 solubility,more novel methodsof improvingthispropertyare beingadopted,suchas;complexation witha hydrophilicpolymer,co-precipitationwithadjuvantchemicalsandco-crystal formation.It shouldbe notedthough,thatratesof dissolutioncanbe affectednegativelywhenexcipientsare incorrectlyselected,despitethe factthatdrug particlesof a smallersize are used.Fine powderscan actuallyincrease airabsorptionandagglomerationcomplications.Suspensions,inhalationaerosols and topical formulationscanalsobe affectedwhenexcipientsare correctlyselectedbutthe particle size iswrong,i.e.suspensionflowpropertiescanbe modified,topical preparationscanbe abrasive and grittyand inhalationaerosolscanhave theiruptake acrossalveolar/bronchi mucosaimpaired. Solubilityitself isanobviousfactortoconsiderinpreformulationthatcanand isoftenimproved throughmodifyingthe saltorchemical derivatives,complexingwithanothercompound,micronizing or usingsoliddispersiontechniques.Mostdrugsare acidicor basicand sothe extenttowhichthey ionise willbe dependentuponthe pHat variouslocationsalongthe GI tract, whichinturn affects theirsolubilityatthese sites. The rate at whicha drugenterssolutionistermedasthe dissolutionrate andisoftenanimportant stepthat mustbe overcome foranyand all drugsthat are not alreadyadministeredinsolutioni.e. intravenoussolutionororal aqueoussolution.The rate itself isdeterminedbyanumberof factors and can be illustratedthroughthe Noyes-Whitneyequation(below),wherekrepresentsthe intrinsic dissolutionrate constant,A representsthe specificsurface,dm/dtrepresentsthe differenceinmass dividedbythe difference in time andCS – C is the solubilityminusthe concentrationattime =t. dm dt =kA(CS-C) So,whena drug dissolvesparticleswill leave the bulkandenteradiffusionlayerarounditwhere the concentrationisquite high.Fromhere,particleswilldiffuse outintosolutionandbe absorbed throughvariousabsorbingmucosa,beingreplacedconstantlybyparticlesleavingthe bulk.If the rate of dissolutionisquick,thenitfollowsthatthe rate-limitingstepof absorptionwill be dependent on the abilityof the drugto meetwithandcross the variousbiological membranesatthe site of action. Drugs withintrinsicdissolutionrates(k) of below 0.1mg-1 cm-2 are expectedtoshow absorptionthat isdissolutionrate-limited,because the valueof kischaracteristicand indeedindicative of manysolid compounds,whenA andotherexperimental variablesare keptconstant. Thismeansthatdissolution rate data,whenviewedinconjunctionwithpKadata,solubilitydataandpartitioncoefficientresults can provide agood indicationof the invivoabsorptioncharacteristicsof the drug.However,invitro testsare neededinassociationwiththesepredictionstoaccuratelyassessthe clinical implicationsof the drug’sbehaviour. The partitioncoefficientof drugsrepresentthe extenttowhicha drug will partitionacross absorbable andunabsorbable fractions,whichisdependentuponlipophilicnature,hydrophilic nature,degree of ionisationandparticle size.Whereasthe dissolutionrate isoftenthe limitingstep indrugs that exhibitpooraqueoussolubility,foraqueousdrugsandthose withbettersolubilitiesit will be the rate of absorptionthatdeterminesthe overallrate.Inthe firstinstance,physicochemical
- 6. George Wild Scienceof Medicines 6 propertiesof the drugmay be modified,butthisislessapplicable whenitcomestomodifyingthe absorption,whichismore dependentupon ioniccharacter;inthese instances,itwillbe molecular modificationsthatare usedto improve the rate of absorption.Mostdrugs withsmall molecular weightsare acidicor basicin nature and sowill be ioniseddependentuponpHinthe various environmentsinthe GItract. Membranesinthe bodyare hydrophobicinnature andare more permeable tolipophilicmoleculesthanhydrophilicones.Thisisbecause those moleculesthatare lipophilicare unionisedandsodonot attract many watermolecule,causing asize increase.They may therefore approachthe biological membranesandpassthroughwithoutbecomingboundor repelledbythe variouschargesthatfeature onthe outside of the membrane.Onthe otherhand, ionisedspecieswill eitherinteractwiththe membrane orbe toolarge to passthrough,resultingin poor absorptionacrossthe membrane.Therefore,the overrulingfactorsaffectingabsorptionare; the pH at the site of absorptionandthe lipophilicityof the unionisedspecies. Usingthese ideasand the Henderson-Hasselbalchequationondrugionisation fractions,we can buildthe pH partitionhypothesis thatfocussesonlipophiliccharacteraffectingabsorption.There are flawsinthishypothesishowever,asthere are drugswithlow pH partitioncoefficientsand/or whichare ionisedoverthe entire bodilypHrange thatstill exhibitgoodbioavailability;there MUST therefore be otherfactorsinvolvedthatare notaccountedfor inthistheory. The crystal propertiesof adrug mustalsobe considered, because inrealitymostdrugswill be handledintheircrystalline formatsome pointduringtheirmanufacture.Crystalscanbe amorphous, crystalline,anhydrous,hydrated(tovariousdegrees)orsolvatedif the solventisnotwater,andwill exhibitdifferentcharacteristicswithregardtohardness,shape andsize.Some drugsmayalso presentthemselvesinmore thanone crystal form, dependinguponsolventof crystallisation, temperature of crystallisationandrate of cooling;these are saidtoexhibitpolymorphicactivity. These differentpolymorphswill likelyhave differentphysicalpropertiessuchasrate of dissolution, stabilityandmeltingpoint,whichwill undoubtedlyhave knock-oneffectsforthe therapeuticeffect of the drug.It is notuncommon that lessstable (metastable) formsof adrug will revertnaturally back to the more stable polymorphovertime orunderspecificconditions,whichcaneitherbe of benefitorharm.Thisis because the more stable polymorphwilllikelyhave ahighermeltingpoint due to a strongerand more stable lattice arrangement,whichmaycause the drug to precipitate fromsolutionorsuspensionasreversionoccurs,whichhasobviousimplicationsforpatient adherence anddrugsolubility. Thistransitionbetweendifferentchemical formscanoccur inthe body,as withinsulinthe presence of an acetate bufferandzinc.Here,aninsoluble complex formsof eitheramorphousorcrystalline nature dependinguponpH.The amorphousformcontainsparticlesof 2micronsin size,whichare quicklyabsorbedwithashortdurationof action,whereasthe crystallineformexhibitslargercrystals 10 – 40 micronsinsize that take longertoabsorb and therefore have alongerdurationof action. These changesmayalsooccur duringmilling(i.e.digoxinandspironolactone),granulationanddrying and othercompactionprocesses.Changesthatoccurduringthe lifetime of the medicine,suchasin suspensions,maybe counteredbythe presence of additivesandsurface-active agents(surfactants).
- 7. George Wild Scienceof Medicines 7 Chemical stabilityisperhapsone of the fundamental aspectsof medicinesbehaviourthatmustbe consideredwhendesigningadosage form.Stabilitytestingprogrammesare usedtoassessdrug- drug and drug-additive interactionsaswell astendencies toundergohydrolytic,oxidative,thermal and light-relateddegradations.Esterslikeaspirincommonlyundergohydrolyticbreakdownif exposedtomoisture orwaterandthe correct conditionsandvitaminslikeascorbicacidwill undergo oxidative decomposition,whichmustbe consideredindevelopingadrugthat ischemicallystable and therapeuticallyactive overthe maximumpossible range of conditions.Drugsensitivityto breakdowncanbe classifiedaccordingtofourcategories: - ONE: stable acrossall conditions,i.e.kaolin - TWO: stable if handledcorrectly,i.e.aspirin - THREE: moderatelystable,withspecial handling,i.e.vitamins - FOUR: veryunstable,i.e.manyantibioticsinsolution The mechanismsbywhichsome drugmoleculesbreakdownare oftencomplex tounderstand,but thenan intricate understandingisnotactuallyrequiredinthe formulationof manydosage forms; the problemscanbe overcome withthe simpleadditionof additivesand/orthe correctselectionof packaging.Forexample,drugsthatare susceptible tohydrolyticbreakdownmayhave adesiccant addedto them,be formulatedwithminimal moistureexposure (tolow moisture specifications) and be packagedin moisture-freepacking. Otherdrugsthatsufferfromoxidative decompositioncanbe formulatedwithantioxidants,andthose sensitive tolightcanbe placedamberglassbottlesor appropriate tabletpackaging. Comparedtothe costsof developingandmodifyingthe physical, chemical andmolecularpropertiesof the compound,packagingismuch, MUCH more economical. Drugs insolutionshouldhave stabilitiesandeffectsthatare well understoodforthe pHrange 1 – 8 (i.e.the bodilypHrange),asstabilitycanoftenbe improvedsimplythroughthe additionof abuffer to the solution.Preservativesmayalsobe neededforthose liquiddosage formsthatare particularly susceptibletomicrobial contamination,suchasoral preparationsthatcontainsweetenersand sugars. It’salso importanttorememberthatstabilitymustbe consideredintermsof drug-druganddrug- additive interaction,suchasbetweencolourants,flavours,flavourenhancers,preservatives, viscositymodifiers,solvents,co-solvents,differentAPIs,emulsifiers,stabilisers,buffersandmore. Nowadays,these interactionscanbe identifiedthroughmicrocalorimetryandDSC(differential scanningcalorimetry). Organolepticpropertiesmustalsobe consideredforpreparationsoftenadministeredorally,asit requiredthatdrugsubstancesare acceptable tothe patient,asto increase the adherence.Flavours are commonlyaddedtoovercome drugsthatare unpalatable,butthe drugmayalsobe placedina capsule,microencapsulated,coatedorplacedinsuspensiondependingonvariousphysical and chemical factorssuchas solubilityandpHeffects.The taste budsof the tongue respondquicklyto bitterandsour tastes,whichcan be overcome throughthe additionof acitrus flavouring,butwater- insolublederivativesof the drug(like amitriptyline palmoate) mayalsobe usedwhichhave little or no taste.It isvital that the presence of flavoursormodificationof themmustnotinterferewiththe bioavailability(andotherfactors) of the drug.
- 8. George Wild Scienceof Medicines 8 The target populationissomethingthatmustbe thoughtof whenchoosinga flavouringaswell,as paediatricmedicationsare likelytobe betteracceptedwhentheyare sweettastingandare flavouredtomatchthe psychological connotationsof specificcolourings(i.e.lemontaste –yellow colour).Diabeticpopulationswill notbe able totake medicineswhichhave ahighsucrose content and so these preparationswill needtohave asweetenerlike sorbitol thatisnotbrokendowninto glucose inthe body.Colourshelpstandardisecoloursof medicinesandcanbe natural like carotenoids,syntheticlikeamaranth,aqueouslike amaranth,oil solublelike SudanIV,orinsoluble in bothvehicles,like aluminiumlakes.Lakesare generallyaluminiumorcalciumcomplexesthatare useful intabletcoatingsandtabletsbecause of theirimprovedlightstability. Havingdiscussedsome of the drugfactors thatneedto be considered,it’salsoimportantto rememberthatmattersof practicalityconcerningflowability,compactability,hygroscopicityand othersuch elementsneedtobe consideredtoavoidlater,costlycomplicationsinformulation.Those drugsthat are otherwise infallible buthave ahygroscopicnature canbe manufacturedin environmentswithlowmoisture,thosewithpoorflow qualitiescanhave flow agentslike fumed silicaadded,andthose thathave poor compactionpropertiescanbe identifiedreasonablyearlyon (before large-scale manufacture)ininstrumentedtabletingmachines,duringpreformulation. Therapeutic Considerations and Dosage Form Design It’sall well andgoodif a drug physicallyworksandcanbe used,butit’salsonecessaryto consider whathappensto a drug and itsuse indifferentscenarios.Dependingonthe patient’scondition,age, weight,swallowingabilities,it maynotbe practical or evenpossibletoadministerone druginjust one dosage form.Thisnecessitatesthe preparationof severaldifferentdosage formstomeetthe needsof the clinicianaswell asforthe needsof certainsituations.It’salsotrue that differentdosage formshave theirownadvantagesoverothers;some provide systemicbenefit,othersprovidelocal effects,some drugsare requiredforimmediate effect,otherscanhave delayedorprolongedeffects dependingonthe conditions.Thisversatilityhelpsformulationscientiststoproduce arange of productsthat can be usedina varietyof importantclinical scenarios. For example,asthmasuffererssufferingfromanasthmaattack will needemergency(immediate) relief of the symptomsandsoinhalationaerosolshave beenformulatedtoprovide animmediate hit of the drug to the affectedarea.Patientsrequiringimmediatereliefof anginapectoriswilltake sublingual nitroglycerinsothatthe drugis rapidlyabsorbedintothe bloodstreamtorelieve the patientof the painful andpotentiallydangerouseffectsof the condition. The age of the patientisconsideredimportantbecause childrengenerallyshow betteradherence withliquiddosage forms,due todifficultyswallowingsoliddosage forms, whereasolderpatientswill prefersoliddosage formsbecause they’re generallymore practical.Liquiddosage formsbeing administeredtochildrenalsocarriesthe advantage thatthe liquidcanbe dilutedtovaryingdegrees to suitthe weightof the patienttowhichthe drug is tobe administered. Targeteddrug deliverythroughthe use of liposomesandnanoparticlesisalsoacontentiousareaof formulationsciencebecause of the benefitsof deliveringthe drugmainlytothe site where it was originallyintended.Thishasparticularbenefitstopatientsreceivingdrugswithwidely-feltharmful
- 9. George Wild Scienceof Medicines 9 effects,suchaspatientswithcancerreceivingcytotoxicchemotherapy. Alternative preparation methodslike supercritical fluidprocessingwithCO2 asa solventand crystal engineeringtoprovide specificcrystal propertiescanalsobe utilised.Withthe adventof gene therapy,formulation scientistswillneedtouse these existingmethodsanddevelopmore novel approachestodrug deliveryinordertodeliverlabile macromoleculestospecificphysiologicaltargets.Computational pharmaceuticsisan emergingareaof thisfieldthatfocussesonthe use of in-silicoproceduresto predictdrugproperties,experimental design,AI,neuralcomputingandoptimisationtoolsto facilitate fasterandrational formulationdesign.