Use and Limitations of In Vitro Dissolution Testing: Topic Introduction and Overview

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Use and Limitations of In VitroDissolution Testing:

Topic Introduction and OverviewLawrence X. Yu, Ph. D.

Deputy Director for Science and ChemistryOffice of Generic Drugs

Food and Drug AdministrationAdvisory Committee for Pharmaceutical Science

and Clinical Pharmacology

August 8, 2012


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In VitroDissolution Testing: Objectives

Assure batch to batch qualityGuide development of new formulationsProvide process control and qualityassurance

Ascertain the need for bioequivalence studies

Different strengthsPost-approval changesMulti-source products 2


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Dissolution Testing: Issues

Dissolution testing can be non-discriminating. Dissolution testing can be over discriminating. Products that dissolve about 70% in 45 minutes oftenhave no medically relevant bioequivalence problems. Dissolution testing (especially only a single pointcriterion) is often not sufficient to assure product

quality/ bioavailability. Demonstration of in vitro-in vivocorrelation (IVIVC) isnecessary.

IVIVCs are Product Specific.3


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Desired Future State ofIn VitroDissolution Testing

Sensitive enough to detect relevant productchanges so as to ensure the quality and

consistent performance of productsPredictive of in vivoperformance of drugproducts and thus reduce unnecessary human

studies, accelerate drug development, andhasten evaluation of post-approval changes

4


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Uses and Limitations ofIn VitroDissolution Testing

Use and Limitations of In VitroDissolution Lawrence YuTesting: Topic Introduction and Overview

Dissolution Testing: Evolving Dissolution Cindy BuhseApparatus

Dissolution Testing: Evolving Dissolution Arzu SelenMedia for Predicting In VivoPerformance

Oral Bioperformance & 21st Century Gregory AmidonDissolution Testing

Dissolution Testing and Quality-by-Design Lawrence Yu

Followed by:

Topic Wrap-up and Future Directions

Questions to the Committee/Committee Discussion 5


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Dissolution Testing:

Evolving Dissolution ApparatusAdvisory Committee for Pharmaceutical Science and

Clinical PharmacologyAugust 8, 2012Cindy Buhse, Ph.D., Director

Zongming Gao, Ph.D., ChemistDivision of Pharmaceutical Analysis

Center for Drug Evaluation and ResearchUS Food and Drug Administration


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Dissolution Testing Evolves from Disintegration Test

Stoll-Gershberg disintegration apparatus

ERSHBERG S, STOLL FD, 1946, Apparatus, for tablet disintegration, and for shaking-

out extractions, Journal of the American Pharmaceutical Association, 35(9), 284-7.

Convenient and sensitive chemical

analyses weren't available in 1950s.

Official disintegration tests were

adopted in 1945 by the British

Pharmacopoeia and in 1950 by the

USP.

However, disintegration was

recognized as an incomplete test as

evidenced by the 1950 USP-NF

statement that "disintegration does

not imply complete solution of the

tablet or even of its active

ingredient".

G2


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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 Basket Method

Searl and Pernarowski, 1967

Belachew Desta, An evaluation of the USP dissolution apparatus, 1972, Thesis of the University of British Columbia.

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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 Paddle Method

Levy-Hayes, 1960


4


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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 -- Reciprocating Cylinder Method

Vliet, 1959


5


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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 Flow-through Method

Lapidus and Lordi, 1966


6


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The First USP Dissolution Apparatus 1, Basket

USP Apparatus 1

A Basket

B 1000ml resin flask

C Cover

D High-torque stirring

motor

1970 - Dissolution test, apparatus 1

(basket), USP 18

1976 - Dissolution test, apparatus 2

(paddle), USP 19


7


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Early Dissolution Testing in a FDA Lab in 1970s

USP rotating-basket apparatusand a centering tool

USP paddle apparatus

Pharmaceutical Technology, April, 1978, Vol 2, 16-53 8


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FDAs Definition and Views on

Dissolution Testing in 1970s

In vitro dissolution testing as applied to solid-dosage drug forms

measures the amount of drug dissolved in a known volume of

liquid medium at a predetermined time, using a specified

apparatus designed to carefully control the parameters of

dissolution testing.

In vitro dissolution testing can help pinpoint formulations that

may present potential bioequivalence problem.

Once a formulation has been shown to be bioavailable,dissolution testing is of great value in assuring lot-to-lot

bioequivalence.

Don C. Cox, Carol C. Douglas, William B. Furman, Ross D. Kirchhoefer, James W. Myrick and Clyde E.

Wells, 1978, Guidelines for dissolution testing, Pharmaceutical Technology, Vol 2, No.4, 41-53 9


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FDAs Concerns and Standpointon Dissolution Testing in 1970s

Dissolution tests are critical and difficult to carry out properly. Care andattention must be given to those aspects that have been identified as crucial.

It is our hope that other scientists will share their findings and techniques so

that dissolution testing may be advanced to a reproducible and reliable

scientific procedure.

If labs can not be expected to agree on the results of a dissolution test, then

an IVIVC obtained by one lab can not be generalized as being valid in all

labs.

Differences between dissolution results obtained in industrial labs and thoseobtained in agency labs raise problems in the making of regulatory

decisions.

Don C. Cox, Carol C. Douglas, William B. Furman, Ross D. Kirchhoefer, James W. Myrick and Clyde

E. Wells, 1978, Guidelines for dissolution testing, Pharmaceutical Technology, Vol 2, No.4, 41-53 10


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USP Monographs for Dissolution TestingUSP Monographs for Dissolution Testing

Aristides Dokoumetzidis, Panos Macheras, 2006, Historical Perspectives: A century of dissolution research: From

Noyes and Whitney to the Biopharmaceutics Classification System, International Journal of Pharmaceutics, 321, 111 11


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FDAs Guidances for Dissolution Testing1978 FDA/DPA published a guideline for dissolution testing

1984 FDA/DPA published the Guidelines for dissolution testing: an addendum

1995 Guidance for Industry, SUPAC-IR: Immediate-Release Solid Oral Dosage Forms:

Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In

Vitro Dissolution Testing, and In Vivo Bioequivalence

1997 Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms

Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; InVitro Dissolution Testing and In Vivo Bioequivalence

1997 Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage

Forms

1997 Guidance for Industry, Extended Release Oral Dosage Forms: Development,Evaluation, and Application of In Vitro/In Vivo Correlations

2010 Guidance for Industry, The Use of Mechanical Calibration of Dissolution Apparatus 1

and 2 Current Good Manufacturing Practice (CGMP)

2011 Guidance for Industry, Q4B Evaluation and Recommendation of PharmacopoeialTexts for Use in the ICH Regions, Annex 7(R2) Dissolution Test General Chapter

12


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Current Official USP Dissolution Apparatuses

13

USP 6 (cylinder)

USP 1 (basket) USP 5 (paddle over disk)

Te perature, rotationspeed, dissolution medium

Primary use is for semi-solidtopical dosage forms but hasalso been used for drug

release and skin/membranepermeation for transdermalpatches.

Apparatus 5(Paddle overdisk)

Temperature, rotationspeed, dissolution medium

Transdermal system.Apparatus 6(Cylinder)


Immediate-release, extended-release, and delayed-releasedosage forms.

Apparatus 2(Paddle)


Test Parameters


Apparatus 1(Basket)

SamplesApparatus

mTemperature, rotationspeed, dissolution medium

Primary use is for semi-solidtopical dosage forms but hasalso been used for drug

release and skin/membranepermeation for transdermalpatches.

Apparatus 5(Paddle overdisk)


Transdermal system.Apparatus 6(Cylinder)



Apparatus 2(Paddle)


Test Parameters


Apparatus 1(Basket)

SamplesApparatus

Pictures copied from website, http://www.protechcro.com/images/01Dissolution.pdf, accessed July 2, 2012

USP 2 (paddle)


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Reciprocating Apparatus is typically used for

imitating the pH changes that occur in the body and is

suited for extended and sustained release dosageforms.

Te perature, dip rate,

dissolution medium

Transdermal system,

extended-release dosageforms (coated tablet)

Apparatus 7

Temperature, dip rate,dissolution medium.

Test Parameters

Immediate-release, extended-release, and delayed-release

dosage forms.

Apparatus 3

SamplesApparatus

mTemperature, dip rate,

dissolution medium

Transdermal system,

extended-release dosageforms (coated tablet)

Apparatus 7

Temperature, dip rate,dissolution medium.

Test Parameters

Immediate-release, extended-release, and delayed-release

dosage forms.

Apparatus 3

SamplesApparatus

USP 3 - reciprocating cylinderAngled

diskDisk cylinder

Pointed

rod

spring

holder

USP 7 - reciprocating holderPictures copied from website, http://www.protechcro.com/images/01Dissolution.pdf, accessed July 2, 2012

14
http://www.protechcro.com/images/01Dissolution.pdfhttp://www.protechcro.com/images/01Dissolution.pdf


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USP 4 flow through

Tablet cell12 mm

Cell forimplants

Tablet cell22.6 mm

Cell forsuppositories

and softgelatin capsules

Cell forpowders

and granulates

Temperature-Measuring Head

T st ParametersSamplesTemperature, flow rate,pulses per minute,dissolution medium

Immediate-release, extended-release, anddelayed-release dosage forms.

tablets, capsules, suppositories, powders, drugeluting stents, creams, gels, suspensions etc.

eTest ParametersSamplesTemperature, flow rate,pulses per minute,dissolution medium

Immediate-release, extended-release, anddelayed-release dosage forms.

tablets, capsules, suppositories, powders, drugeluting stents, creams, gels, suspensions etc.

Pictures copied from website, http://www.sotax.com/USP-4-Semi-automated-systems.127.0.html, accessed July 2, 2012 15
http://www.sotax.com/USP-4-Semi-automated-systems.127.0.htmlhttp://www.sotax.com/USP-4-Semi-automated-systems.127.0.html


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Does Current Dissolution Method Have AnyBiological Relevance?

Disintegration

Solids transfer

Dissolution

Changing pH

X

Food and drink

AbsorptionX

Clearance X

Picture copied from website,

http://www.google.com/images?q=digest+system&hl=en&gb

ju0gHx8oCYAg&start=20&sa=N,accessed July 30, 2012

v=2&tbm=isch&ei=uZQZUIT4O-

Picture copied from website,

http://www.protechcro.com/images/01Dissol

ution.pdf, accessed July 2, 2012
http://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.protechcro.com/images/01Dissolhttp://www.protechcro.com/images/01Dissolhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=N


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New Designs for Dissolution Testing

Garbacz, G. et al. Irregular absorption profiles observed from diclofenac extendedrelease tablets can be predicted using a

dissolution test apparatusthat mimics in vivo physical stresses.Eur. J. Pharm. Biopharm. 2008, 70 (2), 421428. 17


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Makoto KATAOKA et al. 2011,In VitroDissolution/Permeation System to Predict the Oral

Absorption of Poorly Water-Soluble Drugs: Effect of Food

and Dose Strength on It, Biol. Pharm. Bull. 34(3) 401407

M. Kobayashi et al.International Journal of Pharmaceutics 221 (2001) 8794

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Hanks Balanced Salts Solution (HBSS) at pH 6.8was used as the dissolution medium, in order to

accommodate the Caco-2 monolayer.

SGF and deionized water do not support Caco-2 cellviability.

The dissolution testing time is limited by Caco-2 cellsfor less than 2 hours.

Mark J. Ginski, Rajneesh Taneja, and James E. Polli, 1999, Predictionof Dissolution-Absorption Relationships from a Continuous

Dissolution/Caco-2 System,AAPS Pharmsci, 1 (3) article 3

L. Hughes et al. Dow Apparatus (FloVitro)

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Paul A. Dickinson, et al. An Investigation into the Utility of a Multi-compartmental, Dynamic, System of the Upper Gastrointestinal Tract

to Support Formulation Development and Establish Bioequivalence of Poorly Soluble Drugs. The AAPS Journal, Vol. 14, 196-205, 2012. 20


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New Designs for Dissolution TestingUV/vis UV/vis

DissolutionMedium

Waste

Cell 1 Cell 2

Z Gao,AAPS PharmSciTech, 10(4), 2009, 1401-1405.21


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USP4 as dissolution apparatus @ 4mL/min

150 mL SGF for 1 hour

Then, 500 SIF for 23 hours

BCS I, propranolol HCl

BCS II, phenazopyridine HClZ Gao,AAPS PharmSciTech, submitted, 2012.

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Advantage and Disadvantage of Newly DevelopedDissolution Method

CurrentUSP

Dissolution

Methods

X

X

X

Disintegration

Solids transfer

Dissolution

Changing pH

Food and drink

Absorption

Clearance

Standardized MethodX

NewlyDeveloped

Dissolution

Methods

23


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DissolutionTesting:EvolvingDissolutionMediaforPredictingInVivoPerformance

ArzuSelen,Ph.D.BiopharmaceuticsResearchLead

OfficeofNewDrugQualityAssessment/OPS/CDER/FDAAdvisoryCommitteeforPharmaceuticalScience

andClinicalPharmacologyAugust8,2012


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OutlineBackgroundDissolutiontesttorelevanceofdissolutionmedium

RecommendationsfromtheguidanceTypesandfunctionSomeexamples:productcharacterization,foodeffect,screenforalcoholdosedumpingNext

phase?

Integration

of

Quality

by

Design

(QbD)andBiopharmaceuticsandmechanisticvalue

Summary 2


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DissolutionRateLinkedwithClinicalOutcomeINARECENTstudyoffactorsaffectingtheabsorption

rate

and

gastrointestinal

irritant

effect

of

aspirin(1)itwasconcludedthat(a)absorptionratesandincidenceandseverityoflocalirritationareinterrelated,(b)bothofthesecharacteristicsareafunctionofthedissolutionrateofaspirininitsparticulardosageform,and(c)therearesignificantdifferencesininvitrodissolutionratesamongdifferentnationallydistributedbrandsofaspirintablets.GerhardLevy,ComparisonofDissolutionandAbsorptionRatesofDifferentCommercialAspirinTablets,J.Pharm.Sci.Vol.5,388392,1961

3


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FromtheBeginning2009

2006

199

198

1950s and 1960s

0s

7

Ref.1:WorkshopcosponsoredbyASCPT/DIA/APS/FDA,1987Ref.2: FromCommentaryonAAPSWorkshop,May2006,Arlington,VAC.Tong,S.S.DSouza,andT.Mirza,Pharm.Res.24(9),16031607,2007

Adissolutionmethod(andtheacceptancecriteria)shouldbedefinedtodeliverdesiredperformanceofaproductintheintendedinvivoenvironment.(Ref.2)

IVIVCisafutureobjectiveforERformulationsDissolution

testing

for

processcontrol,stability,minorformulationchangesandmanufacturingsitechanges.(Ref.1)

4


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OurIncreasingExpectationsinDrugDissolution/ReleaseTesting

ProvidebasiccriteriafordrugreleasefromtheproductFor

batch

to

batch

consistency/quality

(product

specification)AspotentialsurrogateforinvivoBEstudiesFor linkingtheproductanditsinvivoperformance(correlationsorrelationships:IVIVCorIVIVR) 5


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RecommendationsfromGuidanceforIndustryDissolutionTestingofImmediateReleaseSolidOralDosageForms(August1997)

Anaqueousmedium pHrange1.2to6.8(ionicstrengthofbuffersthesameasinUSP)Tosimulategastricfluid(SGF),adissolutionmediumofpH1.2(withoutenzymes)TheneedforenzymesinSGFandSIFshouldbeevaluatedonacasebycasebasisandshouldbejustified.Tosimulateintestinalfluid(SIF),adissolutionmediumofpH6.8shouldbeemployed(also,recommendedfortestingofERproducts).AhigherpHshouldbejustifiedonacasebycasebasisand,ingeneral,shouldnotexceedpH8.0.

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RecommendationsforDissolutionMedium(Continued)

Withgelatincapsuleproductsmediumcontainingenzymes(pepsinwithSGFandpancreatinwithSIF)maybeusedtodissolvepellicles.Useofwateraloneasadissolutionmediumisdiscouraged(watersourcemayaffecttestconditionssuchaspHandsurfacetension,andmaychangeduringthedissolutiontestduetotheinfluenceoftheactiveandinactiveingredients)Forwaterinsolubleorsparinglywatersolubledrugproducts,useofasurfactantsuchassodiumlaurylsulfateisrecommended(Shah1989,1995). Theneedforandtheamountofthesurfactantshouldbejustified.

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AShortListofDissolutionMediaStandardCompendial(inUSP):

SimulatedGastricFluid(withandwithoutpepsin)SimulatedIntestinalFluid(withandwithoutpancreatin)WaterTheirmodifications(mediawithsurfactants)AdditionalMedia(includingpatentedBiorelevantmedia)

FastedStateSimulatedGastricFluid(FaSSGF)FedStateSimulatedGastricFluid(FeSSGF)FastedStateSimulatedIntestinalFluid(FaSSIF)FedStateSimulatedIntestinalFluid(FeSSIF)BlankFastedandFed(GF)and(IF)Andothers(suchasEnsurePlusforforecastingfoodeffect)

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Composition ofFaSSGFand FeSSGF

Reference:Jantratidetal.,Europ.JofPharm.andBiopharm.69,776785,2008 9


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Last20 30years:Dissolution/releaseTesting

Linksdrugproducttoitsinvivoperformance

Qualitycontrol

tool

Andrecently:Can/shouldQbDmergethetwopaths?Does

it

help

if

single

and/or

multiple

media

are

used? 10


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Desired State for

Drug Release/Dissolution Method

Reliable,reproducible,wellcharacterizedmethod

InfluencedbyCriticalQualityAttributes

Hasinvivorelevance

Supportslinkingprocess,product

and

patient

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Desired State forDrug Release/Dissolution Media

Standardized,wellcharacterized,easytoprepareandstableduringtesting

FacilitatesAssessmentof CriticalQualityAttributes hasproductrelevance

Hasinvivorelevance

Supports

linkingprocess,productandpatient

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ConsiderationsforSelectionofDissolutionMedium

Consistentwithrouteofdrugadministrationandinvivoenvironment(Relevance)Physiologicalandconditionalsimilarity(suchasfed/fasted)Function(mechanisticunderstanding,exploratoryvs.predictive)Possiblealternates(suchassimplifiedmedia)Easeofpreparation(reliablemethod)Standardized(reproducibleandstableduringtesting) 13


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InVitroTestsforProductCharacterization(usingcompendialand/ornoncompendialmethods)

USPApparatusandcompendialmedia(and/ormodifications)Assessingsolubility,dispersionandconditionsleadingtoprecipitation

BilesaltsolubilityExploringinvivosolubilizingcapacityofgutlumenFormulationdispersion,dissolutionanddrugprecipitationFormulationdevelopmentTestingchangesinformulationandproductandenvironmentinteractions(foodeffect,alcoholdosedumping)

Invitrodigestion/lipolysistestsaspossiblepredictorsforfoodeffect(effectofthedigestionproducts) 14


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EffectofLikelyComponentsintheGutLumenonRateandExtentofDissolution

MeanDissolutionProfilesofRomazinTablets(Troglitazone)inVariousMedia

References:Nicolaides,Galia,Efthymiopoulos,Dressman,andReppas.Pharm.Res.16:18771883,1999andC.W.Pouton,Europ.J.ofPharm.Sci.29,278287,2006 15


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FurosemideSolubilityinSimulatedGastricMedia1:1milk:BlankFeSSGF

FaSSGF(FastedStateSimulatedGastricFluid,pH1.6)andFeSSGF(FedStateSimulatedGastricFluid,pH5),andcorrespondingblankbuffers(withoutsurfactant)

Reference:Fromthe2011AAPSposterpresentationofSarahGordon, AnetteMuellertzandothers16


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ExploringFoodEffectandPossibleUseofSimplifiedBiorelevantMediaKetoconazoleReleasefromNizoralTabletsinBiorelevantMediaandRespectiveBlankBuffers

Time (min)

%R

elease

Reference:T.ZoellerandS.Klein,Dissol.Technol. 813,November2007 17


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KetoconazoleReleasefromNizoralTabletsinSimplifiedBiorelevantDissolutionMedia(Continued)

Time (min.)

%R

elease

18


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SingleMediumvs.pHGradientMethodDiclofenacreleasefromdiclofenacsodiummodifiedreleasepellets

(E.Jantratid,V.DeMaio.E.Rondaetal.Eur.J.Pharm.Sci.37,434441,2009)

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Single Medium

900 mL pH 6.8Phosphate buffer

Biorelevant pH Gradient Method


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InvitroresultsfromthebiorelevantpHgradientmethodpredictfoodeffect

Plasmadiclofenacconcentrationsafterasingleoraldoseofmodifiedreleasediclofenacsodiumpellets(n=16healthyvolunteers,fastedandfedstates).

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InVitroReleaseofOpioidsfromOralProlongedreleasePreparationsinSimulatedGastricFluidandSimulatedGastricFluidwithEthanol

Hydrom

orphoneRe

leased(%) 40% ethanol

20%

15%

10%

5%

control

10 20 30 40 50 60

10203040

9080706050

100

00

Time(min)Reference:Waldenetal,DrugDev.AndIndust.Pharm.33:11011111,2007 21


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ScreeningforAlcoholEffectonDrugProductIntegrityCorrelationBetweenHydromorphoneCmaxandInVitroReleaseat30min.and60min.

PalladoneXLwasgivenwith240mLwaterandalsowith4%,20%and40%alcoholicbeverage

22

Reference: Lennernas,Molec.Pharma.6(5),14291440,2009


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IntegrationofQbDandBiopharmaceutics

23

June2009workshopofQbDandBiopharmaceuticsRockville,MDRef.:AAPSJ,12(3),465472,September2010

PatientBenefit

QTPPdrivenspecification

BiopharmaceuticsRiskAssessmentRoadMap

MechanisticUnderstanding(invivoandinvitro)


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Summary:TowardsDevelopinganInVitroTestMimickingInVivoConditions(Mechanistic/PredictiveMethods)

Dissolution/releasetestmethodshouldbewellcharacterized(sourcesofvariabilityandtheimpactofchangesshouldbeknown).Dissolutiontestmediashouldbephysiologicallymeaningful.Dissolution/releasetestconditions(e.g.agitation),durationandsamplecollectiontimesshouldbeconsistentwithitsintendedreleasepattern/environment,anduse(asinQualityTargetProductProfile). 24


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Oral Bioperformance

&21st Century Dissolution Testing

Gregory E. AmidonResearch Professor of Pharmaceutical Sciences

College of PharmacyUniversity of Michigan

1


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What is it that we cant do today, but if we

could, it would revolutionize our business?Joel Barker

Futurist

Comprehensive computational tools and

meaningful in vitro test methods that accuratelyreflect and predict oral bioperformance wouldrevolutionize oral formulation development.

2

Topics


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Topics

Where are we now?What opportunities are there? There are many!

GI physiology

Fluid volumeHydrodynamics

Buffer (bicarbonate)

Advanced dissolution methods

Two phase systems (simulating dissolution and absorption)

Two compartment systems (simulating stomach and intestine)

Computational Tools

Fluid Dynamics

Dissolution

Absorption Modeling

3

USP C di l T f O l Bi f


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USP Compendial Tests for Oral Bioperformance

1950: Disintegration Test1970: Dissolution Apparatus 1 (rotating basket)

1980: Dissolution Apparatus 2 (paddle)

. .

USPDisintegrationTest

USPDissolutionTest(basket)USPDissolutionTest(paddle)

4


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Dissolution Testing is what links the dosage form

to the proven efficacy (eg: typically the clinicallot used in the Phase 3 pivotal efficacy study)!

..

Dissolution testing is what links every lot of the

dosage form from every manufacturer to thelabeling (proven efficacy and safety)! This canbe 100s or 1000s of lots separated by years or

decades as well as continents from the pivotalefficacy lot.

5


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Some areas of success (1970-2012)

Dissolution Testing as an analytical measure of:

Product consistency

Product quality

Manufacturing process controlIVIVC, IVIVR, IVIVE

BCS

Intestinal media simulation

FaSSIF

FeSSIF

Physiologically relevant solubilityImproved understanding of GI environment

Application of computational tools

6


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Some weaknesses (1970-2012)

IVIVC, IVIVR, IVIVE

Application of oral physiology understanding to drug and

drug product testingDissolution Testing as in vivo simulation

Application of advanced computational tools

Application of comprehensive physicochemicalprinciples to oral absorption

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The price of less than ideal in vitro methods is:

Over-discriminatory in vitro test methodsResult is wasted resources and delays in the development of newproducts to meet unmet medical needsChasing down unimportant problems

Spending unnecessary development and analytical resources

Slowing development of innovative dosage forms for difficult

to deliver drugs

Conducting unnecessary clinical or animal testing

Under-discriminatory in vitro test methods Result in a lack of meaningful product quality control

Difficulty comparing innovator and generic products Product failure (eg: efficacy and/or safety) in patients!

8

A b tt di l ti t t!


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A better dissolution test!Rube Goldberg

More Accurate Oral Bioperformance Prediction would help:

Formulation finding/screening (early development)Define meaningful in vitro performance requirements such asdisintegration, dissolution, supersaturation extent and time,functional excipient impact (solubilizer, precipitation inhibitor) etc.

Optimize dosage form delivery rate

Enhance material and process understanding (Quality by Design)Facilitate meaningful in vitro testing of varying in vivo conditions

9

Topics
http://marynowsky.wordpress.com/2006/04/10/rube-goldberg/http://marynowsky.wordpress.com/2006/04/10/rube-goldberg/


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Topics

Where are we now?What opportunities are there (there are many)?

GI physiology






BCS Advances

Computational Tools

Fluid Dynamics

Dissolution

Absorption Modeling

10

What have we learned about human physiology that


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at a e e ea ed about u a p ys o ogy t atmight related to dissolution testing?

Key considerations include:

Fluid volumeIntestinal surface area

Buffer (bicarbonate)pH (average, range)Ionic strengthSurfactants (bile acids)

Carbonic anhydraseHydrodynamicsResidence timeStomach emptying rate

.

Intestinal ContentsBicarbonate (mEq L-1)Bile salts (mM)Lipids (mg/mL)Phospholipids (mM)Pepsin (mg/mL)LipasePotassium (mM)Sodium (mM)Chloride (mM)Calcium (mM)Buffer capacity (mmol L-1 pH-1)Osmolality (mOsm kg-1)Surface tension (mN m-1)ViscosityVolumeShearpH

11

Physiology: What volume of liquid is the dosage form exposed to?


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Physiology: What volume of liquid is the dosage form exposed to?

Average aqueous volume in the fasted small intestine is ~100 ml (Refs: multiple)Total volume in the small intestine

Fasted Mean

Range

Fed Mean

Range

86, 81, 11227, 109 36, 16522, 10572 ~ 100 mL34-46, 37-130, 45-319

47, 381, 59073, 5441

18-78, 343-491, 20-156

Evidence of liquid pockets Schiller et al. Aliment Pharmacol .Ther. 22:971-979 (2005).

Fasted Fed

Number of liquid

pockets

Mean 4 6

Individual(approx.)

2, 3, 4, 5, 8 2, 5, 6, 7, 11

Volume of liquidpocket (mL)

Median 12 4

Ref: D.M. Mudie, G.L. Amidon, and G.E. Amidon. Physiological Parameters for OralDelivery and In Vitro Testing. Mol Pharmaceutics. 7:1388-1405 (2010).

12


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Physiology is complex

13

Some physiological dissolution systems


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Some physiological dissolution systems

Artificial Dynamic GI System, TIM-1 (TNO)

Stress test apparatus

Dissolution/Permeation system (uses Caco-2 cells)

Two-compartment apparatus:

Artificial Stomach and Duodenum (ASD)

FloVitro Technology (Rohm and Haas)Two-phase dissolution apparatus

Simultaneous dissolution and partitioning in singlecompartment containing two phases (water:organic)

1-octanol

water

14

In vivo Intestinal Fluid Flow Rates


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In-vivo Intestinal Fluid Flow Rates

Time (s)Gutzeit A, Patak MA, Weymarn Cv, Graf N, Doert A, Willemse E, Binkert CA, Froehlich JM 2010. Feasibility of SmallBowel Flow Rate Measurement With MRI. Journal of Magnetic Resonance Imaging 32:345-351.

15

Hydrodynamics of dissolution apparatus: USP


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y y ppApparatus 2 - Velocity & Shear Profiles meters/s

Highest velocities occur at the tip ofthe paddle (~20 cm/sec)The lowest velocities are directlybeneath the centerline of the

impeller and around the shaft of theimpeller.

The Reynolds numbers (Re) vary depending onthe rotational speed and location(Re ~ 104).

The shear rates throughout the vessel are

heterogeneous.Maximum shear rates: 92s-1 at 50 RPMAverage shear rates: ~ 20s-1 at 50 RPM

Ref: Bai G, Wang Y, Armenante PM 2011. Velocity Profiles and Shear Strain Rate Variability in theUSP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds. International Journal ofPharmaceutics 403:1-14.

16

Fl Th h C ll


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Flow Through Cell

May allow for testing at more physiologically relevant Reynoldsnumber (5 300) and flow rates (0.1 0.6 cm/sec).Velocity Profiles in a 12mm Cell

Ref: Schematic of a flow through cell: Kakhi (2009). Mathematical Modeling of the Fluid Dynamics in the FlowThrough Cell. International Journal of Pharmaceutics. Vol 376, pg 25.

17

Impact of Fluid Shear on Particle Dissolution (h ):


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Impact of Fluid Shear on Particle Dissolution (happ):High Performance Computational Analysis

Hintz, Johnson (1989)

Predicted based on

Ref: (1) JJSheng, etal. JPharmSci.

97:4815-4829 (2008). human intestinal shear(2) Wang, Brasseur, Penn State University (unpublished) rates

18

Importance of physical chemistry and


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Importance of physical chemistry andphysiologic buffer (bicarbonate)

Drug Properties:

Solubility

pKa

Diffusion coefficient

Particle size

Physiological Properties:

pH

Buffer species and concentration

Fluid hydrodynamics

Intestinal motilityBulk concentration

Volume and temperature etc.

19

Bicarbonate Buffer Physiological


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Bicarbonate Buffer Physiological

Relevance Bicarbonate is secreted by the pancreas and

epithelial cells throughout the GI lumen.

GI Lumen

Blood Ref: Sly WS, Hu PY 1995.Human Carbonic Anhydrasesand Carbonic Anhydrase

Deficiencies. Annu RevBiochem 64:375 - 401

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Dissolution (37oC) of Ibuprofen in bicarbonate


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( ) pbuffer compared to phosphate buffer (rotating disk)

Bicarbonate buffer, pH=6.5

Phosphate buffer pH=6.5

Dissolution in 50 mM phosphatebuffer @ pH=7.2 (USP test)

is 0.7 mg/cm2/min

21

Topics


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op cs

Where are we now?

What opportunities are there (there are many)?

GI physiology






BCS Advances

Computational Tools

Fluid Dynamics

Dissolution

Absorption Modeling

22

Combining dissolution and


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Combining dissolution and

absorption (two phase model)

1-octanol

water

Ten + systems described in literature

Being used in industryOvercome difficulties in maintainingsink conditions for poorly-solubledrugs (BCS 2, 4), super-saturablesystems, and controlled-release

Circumvent analytical difficultiesassociated with lipid-based capsuleformulations

Simultaneously study impact offormulation changes (e.g.

surfactants) on dissolution andabsorption processes!

Can potentially be scaled to moreaccurately reflect in vivo conditions!

23

Two phase IVIVR: Nifedipine GITS tablets


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Two-phase IVIVR: Nifedipine GITS tablets

BCS IIc

Log P = 2 - 4

Sol. FaSSIF = 0.024mg/ml Two-phase

Single-phase

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Two phase physiologic dissolution model


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p p y gPm= 5 x 10

-4 cm/sec, particle radius = 50 m100 BCS Class II

90Sol=100g/mL Dose= 25 mg

80(Dose number = 1)

70 A/V = 2.360 Vw = 100 mL

50%

% in buffer - two phase40

% in 1-octanol% dissolved - two phase30 % in buffer (% dissolved) - single phase

% saturation in buffer - two phase20 % saturation in buffer - single phase

10

00 50 100 150 200 250 300 350

time, min

25



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p p y gPm= 2 x 10

-4 cm/sec, particle radius = 50 m

%

100908070605040302010

00 50 100 150 200 250 300 350

time, min

BCS Class IISol=100g/mL Dose= 25 mg(Dose number = 1)

A/V = 2.3Vw = 100 mL

% in buffer - two phase

% in 1-octanol% dissolved - two phase

% in buffer (% dissolved) - single phase

% saturation in buffer - two phase

% saturation in buffer - single phase

26



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Pm= 1 x 10-4 cm/sec, particle radius = 50 m

27

%

100908070605040302010

00 50 100 150 200 250 300 350

time, min


A/V = 2.3Vw = 100 mL








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p p y gPm=1x10

-4 cm/sec, particle radius = 5 m

%

100908070605040302010

00 20 40 60 80 100 120 140 160

time, min


A/V = 2.3Vw = 100 mL






28

Stomach and intestine: Two-compartment


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Sto ac a d test e o co pa t e tdissolution apparatus

Several publications inliterature describing

Artificial Stomach-Duodenum (ASD)

Used in pharmaceuticalindustry

Used to compare ASDperformance with in vivobioavailability values

Relative bioavailability estimationof carbamazepine crystal forms

CmaxAUC

SRCarino, DCSperry, MHawley. JPharmSci 95:116-125 (2006).

29

Impact of stomach pH on Oral Absorption ofA i A


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Anticancer Agents

Ref: N.R. Budha, A. Frymoyer, G.S. Smelick, J.Y. Jin, M.R. Yago, M.J. Dresser, S.N. Holden, L.Z. Benet, and J.A.Ware. Clinical Pharmacology & Therapeutics (2012).

30

Advantages & disadvantages of two-


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Advantages & disadvantages of two

compartment systemsAdvantages

Sequentially exposes drug to gastric followed by intestinalmedia Differing media properties in stomach and intestine (e.g. pH,

lipid & bile salt concentrations) can affect dissolution

Captures in vivogastric-emptying rates and flow rates

Can vary to simulate effect on dissolutionPotential to integrate peristaltic motion

Disadvantages

Does not contain separate phase/chamber for absorption Assumes dissolved drug proportional to drug in plasma

31

Topics


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p

Where are we now?

What opportunities are there (there are many)?

GI physiology






Computational Tools

Fluid Dynamics

Dissolution

Absorption Modeling

a particle path32

Exciting research is going on.


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c t g esea c s go g o

Motility and Absorption in the Small Intestine

Quantification of Small Bowel Water/Physiology

Coupling Biorelevant Dissolution Testing with PBPK Modeling

Modeling Hydrodynamics in the Intestine

Bicarbonate Buffer and Surface pH

In Vitro Dynamic Lipolysis Model

Precipitation Kinetics of Poorly Soluble Drugs under Supersaturated State and PrecipitationInhibitorsRotating Disk as a Dissolution ToolArtificial Stomach Duodenum (2 compartment dissolution)Miniscale Dissolution-membrane Partitioning System

Two Phase Dissolution SystemTwo Compartment Caco2 model /Mini-scale Dissolution

In vivo and computational biopharmaceutical aspects of precipitation and intestinal permeability

Dynamic Dissolution (TIM-1)

Methods for Estimation of Biorelevant Drug Solubility

Combining Experimental and Computational Approaches for Predicting Oral Bioperformance

33

Future Direction and Research Needs


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Enhanced Understanding In Vivo environment (human, animal)

HydrodynamicsVolumeGastric EmptyingFluid content, buffer

Development of Relevant In Vitro Methodologies

Likely not one-size-fits-allAddress/simulate dissolution and absorption kineticsPrecipitation assessment / inhibition

Modified / Delayed Release optimizationDevelopment of Advanced Computational Tools (In Vitro & InVivo)HydrodynamicsDissolutionAbsorptionMetabolism

Application of physicochemical principles to dissolution

34

Questions/discussion


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Questions/discussion

35


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Dissolution Testing and

Quality-by-Design

Lawrence X. Yu, Ph. D.Deputy Director for Science and ChemistryOffice of Generic Drugs

Food and Drug Administration

Advisory Committee for Pharmaceutical Scienceand Clinical Pharmacology

August 8, 2012 1


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Quality-by-Design

ICH Q8(R2)Pharmaceutical Quality-by-Design (QbD) is a

systematic approach to development that begins withpredefined objectives and emphasizes product and

process understanding and process control, based onsound science and quality risk management

Quality-by-Design Tools

Prior knowledgeRisk assessment

Design of experiments and data analysis

Process analytical technology (PAT) tools 2


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QbD: Linking Process/Product /PatientPatient

Product

Quality Target

Product Profile

Critical QualityAttributes

ProcessMaterial Attributes &Process Parameters

3


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Quality Target Product Profile (QTPP)

QTPP

A prospective summary of the qualitycharacteristics of a drug product that ideally

will be achieved to ensure the desired quality(performance)

Guide to establish product design strategyand keep product development effort

focused and efficient

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What Does QTPP Include?

Intended use in clinical setting

Route of administration, dosage form (deliverysystems), and container closure system

Quality attributes of drug productAppearance, Identity, Strength, Assay, Uniformity,Purity/Impurity, Stability, and others

Active pharmaceutical ingredient release ordelivery and attributes affecting pharmacokineticcharacteristics (safety and efficacy)

Dissolution, aerodynamic performance, etc. 5


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Dissolution and QbD

Dissolution can be used to help relate the

Product to the Patient in the QbD paradigm

Relate in vivoperformance of a drug to in vitromeasurements

Enable development of clinically relevantspecificationsUnderstand the impact of formulation andmanufacturing process variations

Clinically meaningful dissolution specificationsthat assure consistent therapeutic benefit can

aid manufacturing control strategy development 6


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Roles of Dissolution Testing

A quality control tool

Batch-to-batch consistencyProvide quality assurance

An in vitrosurrogate for productperformance

Formulation developmentBioequivalence studies7


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Dissolution for Quality Control A product specific quality control test

The hydrodynamics and medium for this testare chosen for reproducibility and detection of

product changes

The design of this test is not constrained by a

desire to mimic in vivoconditionsAcceptance criteria for consistency of batches

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Dissolution for In VivoPerformance A biorelevant dissolution testCorrelates with in vivodissolution

The hydrodynamics and medium for this test

are chosen to reflect in vivo

Biorelevant dissolution test is a one-time test

to provide a baseline for product performance

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Predictive Dissolution EnablesEfficient Product Development

It is unrealistic to conduct in vivobioequivalencestudies for every formulation and manufacturing

change during pharmaceutical development orfor every post-approval change

Predictive dissolution can streamline productdevelopment and lead to time and cost savingsduring product development while enhancing

the significance of in vitrotesting 10


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FDA IVIVC Guidance

IVIVC = in vitro-in vivo

correlation

Contents

Data/formulationrequirementsPredictability evaluationApplication in waivers of in

vivo bioequivalence studiesand dissolution specifications(pre- and post-approval)

11


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Oral Drug Absorption Process

Transit

PermeationDissolution

Metabolism

Gastric

Emptying

DisintegrationDissolution

12


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Limits to Oral Drug Absorption

Gastric emptying

DissolutionDS dissolution rate = D *S/h (Cs - Cl)

D - diffusion coefficientS - dissolution surface area : Drug substance

h - Aqueous boundary thickness

Cs - Solubility: Drug substance

Cl - Concentration in dissolution media

Permeability: Drug substance

13


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In Vitroand In VivoRelationship Limits to oral drug absorption

Dissolution-limited

dM D= S (CS - C )ldt hSolubility-limited

Permeability-limited

Dissolution Permeation

Concentration Solubility 14


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The CAT ModelSmall InteKttinal Tracts

15

Plasma

KaKa Ka

M0 Mexit

Liver

Dissolution


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Predicting Oral Absorption

0.2

0.4

0.6

0.8

1.0

PredictedExperimental

0.0

Human Permeability (cm/hr)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Fraction

ofDose

Absorbed

1.0

0 20 40 60 80 1000.0

Particle Diameter ( m)

Fraction

ofDose

Absorbed

0.8

0.6

0.4

0.2

1.0

Dose = 250 mg

Dose = 500 mgDose = 1000 mg

0 10 20 30 40 50 60

0.8

0.6

0.4

0.2

0.0

Diameter of Particle ( m)

Fraction

ofDoseAbsorbed

Permeability-limitedDissolution-limitedSolubility-limited

16


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Biopharmaceutics Classification SystemAmidon, et al., Pharm. Res., 1995

The Biopharmaceutics Classification System (BCS) is a

scientific framework for classifying drugs based on theiraqueous solubility and intestinal permeability.Biopharm. Class Solubility Permeability

I High High

II Low High

III High Low

IV Low Low

The understanding of drugs based on BCS can aid informulation and manufacturing development in a QbD

paradigm. 17


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BCS Class I and III DrugsRapid dissolution for BCS Class I drugsand very rapid dissolution for BCS ClassIII drugs ensure that in vivo dissolution isnot the rate limiting step. Bioequivalenceis assured provided no effect of excipient

on absorption and similar dissolutionprofiles

18

Transit Permeation

Metabolism

GastricEmptying


Dissolution


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BCS Class II and IV DrugsIVIVR possible for BCS Class II drugsand difficult for BCS Class IV drugs. Inreality, it is often not attempted todevelop in vitrodissolution that is

predictive of in vivo

19

Transit Permeation

Metabolism

GastricEmptying


Dissolution


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BCS Class I BCS Class I drugs formulated in an

immediate release dosage forms

No bioequivalence studies may be needed for

developing predictive dissolutionRapid dissolution may be used for formulation

development and establishment of design space

Rapid dissolution for BCS Class I drugs inimmediate release dosage forms may be used to

justify formulation and manufacturing changes

20


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BCS Class II BCS Class III drugs formulated in an

immediate release dosage forms

No bioequivalence studies may be neededVery rapid dissolution may be used forformulation development and establishment ofdesign space

Very rapid dissolution for BCS Class III drugsin immediate release dosage forms may beused to justify manufacturing changes

Excipient effect needs to be furtherinvestigated 21


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BCS Class II and IV BCS Class II and IV drugs formulated in

an immediate release dosage forms

Bioequivalence studies are most likelyneeded to develop predictive dissolution

Predictability of biorelevant dissolution should

be further explored and investigated

22


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Extended-release Dosage Forms

Extended-release Dosage Forms

Bioequivalence studies are likely needed toestablish IVIVC/IVIVR and develop predictive

dissolutionPredictive dissolution can then be used tosupport establishment of a design spaceIVIVC/IVIVR can be used to supportmanufacturing changes

23

Dissolution for a BCS Class I Drugs


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g

%

DR U

GRE

LE

ASE D

110

100

90 ANDA1

ANDA280ANDA3

ANDA470

ANDA5

ANDA660ANDA7

ANDA850ANDA9

74-21740UMAB-SLOW

UMAB-MEDIUM30UMAB-FAST

20

10

00 5 10 15 20 25 30 35

TIME IN MINUTES 24

In Vitrovs. In VivoDissolution


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IR suspension IR tablet

XR tablet XR capsule

25


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Future Directions

Application of the QbD approach has the

potential to bridge the gaps between in vitromeasurements and in vivoperformance

A science based approach incorporating studies both

in the laboratory and clinicUtilization of advanced dissolution methodologies forpredictive dissolution

Other approaches other than IVIVC/IVIVR arepossible that provide increased product andprocess understanding

26


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Conclusions

There are many tools related to dissolution

that can aid in implementation of QbD

Biorelevant dissolution methods, which mayutilized advanced apparatus and/or mediaPredictive dissolution modelingIVIVC or IVIVR studies

All of these tools can aid product qualityEnhanced product and process understanding

Cli i ll l t ifi ti

Documents

Use and Limitations of In Vitro Dissolution Testing: Topic Introduction and Overview