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AND PHARMACOKINETICS BIOPHARMACEUTICS
Acqte PharmacologicResponse by pharmacokinetic methodsis dif. - Wtt"n bioavailabilitymeasurement pharmacologic an acute effect such or nonreproducible, fibulq-lnaccurate as changein ECG or EEG readings,pupil diameter,etc. is relatedto the time cburseof a given drug. Bioavailabilitycan then be determinedby constructionof pharmacologiceffect-timecurve as well as dose-respgnse graphs. The method requiresmeasurementof responsesfor at least 3 biological half-lives of the drug in order to obtaifr-a lobd estimateof' AUC. A disadvantageof this method is that the pharmacologicresponse tends to be more variable and accuratecorrelationbetweenmeqsured responseand drug availablefrom the formulationis difficult. Moreover, the observedresponsemay be due to an activemetabolitewhoseconcentration is not proportionalto the concentrationof parentdrug responsible for the pharmacologiceffect. Therapeutic Response Theoreticallythe most definite,tliis methodis basedon observingthe clinical respohseto p drug formulali\n given to patientssuffering from diseasefor which it 1isintendedto bd used. A major drawbackof this methodis that quantitationof observedresponseis too improperto allow for reasonableassessrpurt of relative bioavailabilitybetweentwo dosage forms of the samedrug.
BIOAVAILABILITY ANDBIoEeurvALENcE
291
Despiteattemptsto standardizethe test performance,the in vitro dissolution techniqueis still by no meansa perfect approach. The efforts are mainly aimed at mimicking the environmentoffered by the biological system. There are severalfactorsthat must be consideredin the design of a dissolutiontest. They are: l. Factorsrelating to the dissolutionapparatzssuchas-the design, the size of the container(severalmL to severalliters), the shapeof the container(round bottomedor flat), natureof,agitation(stining, rotatingor oscillating methods),speed of agitation, performanceprecision of the apparafts,etc. 2. Factors relating to the dissolution fluid such as----composition (water, 0.lN HCl, phosphatebuffer, simulatedgastric fluid, simulated intestinalfluid, etc.), viscosity,volume (generallylargerthan that needed to completelydissolvethe drug undertest), temperature(generally37oC) and maintenanceof sink (drug concentrationin solutionmaintainedconstantat a low level) or nonsink conditions(gradualincreasein the drug concentrationin the dissolutionmedium). 3. Processparameterssuch as method of introductionof dosage form, samplingtechniques,changingthe dissolutionfluid, etc. The dissolutionapparatushasevolvedgraduallyand considerablyfrom a simplebeakertype to a highly versatileand fully automatedinstrument. The devicescan be classifiedin a numberof ways. Basedon the absence or presenceof sink conditions,thereare rwo principaltypesof dissolution apparatus:
Drug Ilissolution Rate and Bioavailability The physicochemicalproperty of most drugs that has greatestinfluence on their absorptionch_aracteristics from the GIT is dissolutionrate. The best way of assessingtherapeuticefficacy of drugs with a slow dissolutionrate is rn vpo determinationof bioavailabilitywhich is usually done whenevera new formulation is to be introducedinto the market. However, monitoring batch-to-batchconsistencythrough use of such in vrvo testsis extremelycostly,tediousand time consuming'besides exposing the healthysubjectsto hazardsof drugs. It would thereforebe always desirableto substitutethe in vivo bioavailabilitytestswith inexpensivein vitro methods. The simple in vitro disintegrationtest is unreliable. The best ai'ailable tool .todry which can at least quantitativelyassureabout - the biologic availability of a *ug from its formulation r rrs in vitro dissolution [est.
A third type called as dialysis systems are used for very poorly aqueoussoluble drugs for which maintenanceof sink conditionswould otherwiserequire large volume of dissolutionfluid. Only the official methodswill be discussedherebriefly.
' In Vitro Dru€ DissolutionTesting Midels For dii'tinvttto teistto be useful,it must predictthe in vivo behaviorto such an extent.that in vivo bioavailability test need not be performed.
' Rotating BasketApparatus(Apparatus1) It is basicallya closed-comparfrnent, beakertype apparatuscomprising of a eylindrical glass vesselwith hemisphericalbottom of one liter capac-
l. Closed-compartment apparatus : It is basicallya limited-volume apparatusoperatingunder nonsinkconditions. The dissolutionfluid is restrainedto the size of the container,e.g. beakertype apparatus. 2. Open-compartmentapparatus: It is the one in which the dosage form is containedin a columnwhich is broughtin continuouscontact with fresh,flowing dissolutionmedium(perfectsink condition).
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