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VALLABHPRAKASHAN

BIOPHARMACEUTICS
Acqte PharmacologicResponse
. - Wtt"n bioavailabilitymeasurementby pharmacokinetic methodsis dif-
fibulq-lnaccurate or nonreproducible,an acute pharmacologic effect such
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 activemetabolitewhoseconcen-
tration 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.
Drug Ilissolution Rate and Bioavailability
The physicochemicalproperty of most drugs that has greatestinflu-
ence on their absorptionch_aracteristicsfrom 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 expos-
ing 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.
' 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.
 290 AND PHARMACOKINETICS
BIOAVAILABILITY
ANDBIoEeurvALENcE 291
Despiteattemptsto standardizethe test performance,the in vitro dissolu-
tion 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 solutionmaintainedcon-
stantat 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:
l. Closed-compartment apparatus : It is basicallya limited-vol-
ume 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 dos-
age form is containedin a columnwhich is broughtin continuouscontact
with fresh,flowing dissolutionmedium(perfectsink condition).
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.
' Rotating BasketApparatus(Apparatus1)
It is basicallya closed-comparfrnent,beakertype apparatuscomprising
of a eylindrical glass vesselwith hemisphericalbottom of one liter capac-
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