In-Vitro-In Vivo (IVIVC).pdf

An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.

1. IN-VITRO-IN VIVO
CORRELATION (IVIVC)
Submitted By: Rahul Pal, Prachi Pandey Submitted to: Dr. Tejpal Yadav
M. PHARM (PHARMACEUTICS), II
ND
SEM
Subject:“Advanced Biopharmaceutics & Pharmacokinetics”
Department of Pharmacy, NIMS Institute of Pharmacy, NIMS University Jaipur, Rajasthan India.

2. INTRODUCTION
IVIVCplays an critical role in
drug development and in
optimization of formulation
which is certainly a time
consuming and expensive
process.
In IVIVC, “C”denotes
“Correlation” whichmeans
“The degree of relationship”
between Two variables.
“ThetermIVIVC,couldalsobeemployedtoestablishdissolutionspecification
andtosupportand/orvalidatetheuseofdissolutionmethods.”

3. IVIVC: DEFINITION
USP(UnitedStatePharmacopoeia)Definition:“Theestablishmentofrationalrelationshipbetweena
biologicalpropertyoraparameterderivedfromabiologicalpropertyproducedbyadosagefromand
physicochemicalpropertyofsamedosageform”.
Conceptually,IVIVCdescribesarelationshipbetweenthein-vitrodissolution/releaseversusthein-vivo
absorption.
FDA(FoodandDrugAdministration)Definition:“Apredictivemathematicalmodeldescribing
relationshipbetweenin-vitropropertyofadosageformandin-vivoresponse.”

4. IN VITRO-IN VIVO CORRELATION
(IVIVC)
Itisdefinedas“Thepredictivemathematicalmodelthatdescribestherelationshipbetweeninvitroproperty
(suchasrate&extentofdissolution)ofadosageformandin-vivoresponse(suchasplasmadrug
concentrationoramountofdrugabsorbed)”.
-ThemainobjectivesofdevelopingandevaluatingIVIVCistousedissolutiontesttoserveasalternatefor
In-vivostudyinhumanbeings.
-Assuringthebioavailabilityofactiveingredientsfromadosageform.
-Supportandorvalidatestheuseofdissolutionmethodsandspecification.

5. APPROACHES
Therearemainlyoftwoapproaches:
Byestablishingarelationshipbetweenthein-vitrodissolutionandthein-vivobioavailability
parameters.
Byusingthedataobtainedfrompreviousbioavailabilitystudiestomodifythedissolutionmethodology
inordertoarriveatmeaningfulin-vitroinvivocorrelation

6. PARAMETERS FOR RELATED
CORRELATION
IN-VITRO
Dissolution rate.
Percentage (%) drug dissolved.
Percent drug dissolved.
IN-VIVO
Absorption rate (or absorption time)
Percent of drug absorbed.
Maximum plasma concentration, Cmax.
Serum drug concentration, Cp

7. LEVELS OF CORRELATION
IN IVIVC
Correlation
level
LEVEL B
LEVEL C
MULTIPLE C
LEVEL A

8. DIFFERENT LEVEL OF CORRELATION
Highestcategoryof
correlation.
Linearcorrelation.
Superimposablein-vitroand
in-vivoinputcurveorcanbe
madesuperimposableby
userofconstantoffsetvalue.
Mostinformativeanduseful
from a regulatory
perspective.
Usestheprincipleof
statisticalmomentanalysis.
The mean in-vitro
dissolutiontimeiscompared
eithertothemeanresidence
time(MRT)ortothemean
in-vivodissolutiontime.
Isnotapoint-to-point
correlation.
LevelBcorrelationarerarely
seenintheNDAs.
Level C correlation
representsasinglepoint
correlation.
Onedissolutiontimepoint
(t50%,t90%)iscomparedto
onemeanpharmacokinetics
parametersuchasAUC,
tmaxandCmax.
Weakestlevelofcorrelation
aspartialrelationship
betweenabsorptionand
dissolutionisestablished.
LEVEL A LEVEL B LEVEL C

9. MULTIPLE LEVEL C
MultipleLevelCcorrelationrelatesoneorseveralpharmacokineticsparametersofinterest(Cmax,AUC,
oranyothersuitableparameters)totheamountofdrugdissolvedatseveraltimepointsofthedissolution
profile.
ItscorrelationismoremeaningfulthanthatofthelevelCasseveraltimepointsareconsidered.

10. DISSOLUTION PROFILE COMPARISON
Definition:“Itisagraphicallyrepresentationintermsof(concentrationvs.time)ofcompletereleaseofAPI
fromadosagefrominaappropriateselecteddissolutionmedium”.
Objectives:
Developmentofbioequivalentproduct.
Todevelopin-vitro-in-vivo(IVIVC)correlationwhichcanhelptoreducethecosts,speed-upproduct
developmentandreducedtheneedofperformcostlybioavailabilityhumanvolunteerstudies.
Tostabilizefinaldissolutionspecificationforthepharmacological.
Foroptimizingthedosageformulabycomparingthedissolutionprofilesofvariousformulasofthesame
API.

11. IMPORTANCE OF DISSOLUTION
PROFILE COMPARISON
DissolutionprofileofanAPIreflectsitsreleasepatternundertheselectedconditionsets,i.e.either
sustainedreleaseorimmediatereleaseoftheformulatedformulas.
Foroptimizationthedosageformformulabycomparingthedissolutionprofileofvariousformulasof
thesameAPI.
FDAhasplacedmoreemphasisondissolutionprofilecomparisoninthefieldofpostapprovalchanges.
ByknowingthedissolutionprofileofparticularoftheBRAND
®
.

12. METHODS TO COMPARE DISSOLUTION
PROFILE

13. GRAPHICAL METHOD
Graphicalmethodisfirststepincomparingdissolutionprofileanditiseasytoimplementbutitisdifficult
tomakedefinitiveconclusionsfromtheit.
Inthismethod,plotgraphoftimevs.concentrationofsolute(drug)inthedissolutionmediumor
biologicalfluids.
Theshapeoftwocurvesiscomparedfromcomparisonofdissolutionpatternsandtheconcentrationof
drugateachpointiscomparedforextentofdissolution.
Iftwoormorecurvesareoverlappingthenthedissolutionprofileiscomparable.
Ifdifferenceissmallthenitisacceptablebuthigherdifferencesindicatethatthedissolutionprofileisnot
comparable.

14. DISTINGUISH BETWEEN
STUDENT
T-TEST AND ANOVA
Itisastatisticaltestusedtocomparethemeansof
twosamples.
Thecommontypesoft-test,areone-sample,
two-sampleandpairedt-test.
Theteststatisticalvalueift.
Ifthet-soreort-valueissmall,thegroupor
samplesaresimilar,whereasifthet-valueis
large,thegrouporsamplesaredifferent.
Itisastatisticalmethodthatcomparesthemeans
ofmorethantwosamples.
Ithavingtwotypessuchasone-wayandtwo-
wayANOVA.
TheteststatisticalvalueifF.
ThehighertheFvalue,thereexistsignificant
variationbetweensampleorgroupsmeans,anda
lowFvalueindicateslowvariability.
ANOVA TestStudent t-test

15. METHODS OF DEPENDENT
METHOD
Zero-order kineticsFirst-order kinetics
Korsmeyer-
Peppas Model
Higuchi ModelHixon-Crowell Model
Osmotic/
transdermal
system
Water-soluble
druginpolymer
matrix
Erodible matrix
formulation
Diffusionmatrix
formulation
Thevariousdependentmethodscanbeusedtocomparethedissolutionprofilebutselectingthemodel,
interpretationofmodelparametersandsettingsimilaritylimitisdifficult.

16. MODEL DEPENDENT METHODS:
ZERO ORDER KINETICS
ZeroorderAPIcontributesdrugreleasefromdosageformthatisindependentofamountofdrugindeliverysystem
(constantdrugrelease):
Qt = Q
o+ K
ot
Where,Qtistheamountofdrugdissolutionintimet,QoistheamountofdruginthesolutionandKoisthezeroorder
kineticsconstantexpressedinunitsofconcentration/time.
Plot:Thegraphplottedbetweencumulativeamountofdrugreleasedversustime.
Application:Transdermalsystem,aswellasmatrixtabletswithlowsolubilitydrugsincoatedforms,osmoticsystemsetc.
Thisreleaseisachievedbymaking:
Reservoirdiffusionsystems.
Osmoticallycontrolleddevices.

17. FIRST ORDER MODEL (WATER SOLUBLE
DRUGS IN MATRIX)
log C = log C
0–Kt/2.303
WhereC
oistheinitialconcentrationofdrug,Kisthefirstorderrateconstantandtisthetime.
Plot:logcumulativepercentageofdrugremainingvs.timewhichwouldyieldastraightlinewithaslope
of–K/2.303.
Application:Therelationdescribingthedrugdissolutionindosageformsuchasthosecontainingwater
solubledrugsinporousmatrix.

18. HIXON-CROWELLMODEL (ERODIBLE MATRIX
FORMULATION)
Itmodelusedtoevaluatethedrugreleasewiththechangesinthesurfaceareaandthediameterofthe
particles/tablets.Thismodelisalsoknownas“RootLaw”.
HixonandCrowelldescribingthis;
W
o
1/3
–W
t
1/3
= kt
Wherewoistheinitialamountofdrug,w
tistheremainingamountofdrugattimet.
Plot:Dataistobeplottedcuberootofdrugpercentageremaininginthematrixversustime.
Application:Appliedtodosageformssuchastablet,wherethedissolutionoccursinplanesthatare
paralleltothedrugsurfaceifthetabletdimensiondiminishproportionally.

19. HIGUCHI MODEL (DIFFUSION MATRIX
FORMULATION)
Thismethod/modelusedtostudythereleaseofwatersolubleandlowsolubledrugsincorporatedin
semisolidandsolidmatrix.
ThisisgivenbyHiguchi;
Q =
??????
??????
Where,Qistheamountofdrugreleasedintime‘t’perunitarea,kisHiguchiconstantandTis
timeinhr.
Plot:Thedataisobtainedistobeplottedascumulativepercentagedrugreleaseversussquare
rootoftime.
Application:Modifiedreleaseofdosageforms,transdermalsystemandmatrixtabletwithwater
solubledrugs.

20. KORSMEYER -PEPPAS MODEL
(SWELLABLE POLYMERIC DEVICES)
Thisisempiricalexpressionrelatesthefunctionsoftimefordiffusioncontrolledmechanism.
Itisgivenbytheequation;
Mt/Ma = Kt
n
WhereMt/Maisfunctionsofdrugreleased,tistimeandkistheconstantstructuralandgeomatical
characteristicsofthedosageform.
nisthereleasecomponentswhichisindicativeofdrugreleasemechanism.
Ifn=1,thereleaseiszeroorder.
N=0.5thereleaseisbestdescribedbytheFickiandiffusion.
0.6<n<1thenreleaseisthoughamnomalusdiffusionorcasetwodiffusion.
Thismodelaplotofpresentdrugreleaseversustimeisliner.

21. GRAPHICAL REPRESENTATION OF MODELS
Higuchi-Model Korsemeyar Peppas-Model Higuchi-Model

22. SIMILARITY FACTORS
f1 Factors
Itcalculatesthepercent(%)differences
betweenthetwocurvesateachpointandisa
measurementoftherelativeerrorbetweenthe
twocurves.
f2 Factors
Itislogarithmicreciprocalsquareroot
transformationofthesumoferrorandisa
measurementofthesimilarityinthepercent
(%)dissolutionbetweenthetwocurves.
Thevaluersoff1andf2aresensitivetothenumberofdissolutiontimepointused.