ivivc-01

http://www.locumusa.com International Journal of Generic Drugs e-* [email protected]

http://www.locumusa.com International Journal of Generic Drugs e-* [email protected] 0793 758X US/ Canada ISSN 0793 7776 Euro ISSN 0793 7849 Pacific Rim

In-Vitro-In-Vivo Correlation Definitionsand

Regulatory Guidance

Nattee Sirisuth and Natalie D. Eddington1,2*

1Pharmacokinetics Biopharmaceutics Laboratory

2Department of Pharmaceutical Sciences Schoolof Pharmacy, University of Maryland atBaltimore 100 Penn Street, AHB Baltimore, MD21201-6808 (410) (Fax) 706-6710 (410) 706-6580 [email protected]

ABSTRACTThe purpose of this report is to presentdefinitions of the various levels of invitro in vivo correlations (IVIVCs) and toprovide a regulatory perspective on itsutility in product development andoptimization.

The importance of a representativedissolution testing method thataccurately describes the in vivo releaserate is discussed in the context ofdeveloping a predictive IVIVC.

The role of the dissolution testingmethod in IVIVC development andvalidation is to serve as a surrogatemeasure of the rate and extent of oralabsorption.In addition, the BiopharmaceuticalClassification System provides ascience-based guidance on solubilityand permeability drug issues, which areindicators of predictive IVIVCs.A valid IVIVC will allow for dissolutiontesting for subsequent formulationchanges which take place as a functionof product optimization without the needfor additional bioavailability /bioequivalency studies.

INTRODUCTIONFormulation development andoptimization is an ongoing process inthe design, manufacturer and marketingof any therapeutic agent.

Depending on the design and deliverygoals of a particular dosage form, thisprocess of formulation development andoptimization may require a significantamount of time as well as financialinvestment.

Formulation optimization may requirealtering formulation composition,manufacturing, equipment and batchsizes. In the past when these types ofchanges are applied to a formulation,bioavailability studies would also haveto be performed in many instances toensure that the “new” formulationdisplayed statistically similar in-vivobehavior as the “old” formulation.Of course this requirement delayed themarketing of the new formulation andadded time and cost to the process offormulation optimization.Recently a regulatory guidance wasdeveloped to minimize the need foradditional bioavailability studies as partof the formulation design.This guidance referred to as the, InVitro/In Vivo Correlation Guidance wasdeveloped by the Food and DrugAdministration and was based onscientifically sound research.(1)



It states that the main objective ofdeveloping and evaluating an IVIVC isto enable the dissolution test to serve asa surrogate for in vivo bioavailabilitystudies (Figure 1).This may reduce the number ofbioequivalence studies required forapproval as well as during scale-up andpost-approval changes. (2)Definition of In Vitro-In-VivoCorrelationsAn In-vitro in-vivo correlation (IVIVC)has been defined by the Food and DrugAdministration (FDA) as “a predictivemathematical model describing therelationship between an in-vitro propertyof a dosage form and an in-vivoresponse”.1

Generally, the in-vitro property is therate or extent of drug dissolution orrelease while the in-vivo response is theplasma drug concentration or amount ofdrug absorbed.

The United States Pharmacopoeia(USP) also defines IVIVC as “theestablishment of a relationship betweena biological property, or a parameterderived from a biological propertyproduced from a dosage form, and aphysicochemical property of the samedosage form”.(3)

Typically, the parameter derived fromthe biological property is AUC or Cmax,while the physicochemical property isthe in vitro dissolution profile.

A linear relationship with slope of unity,if possible, is preferred, as thedissolution profile is a representative ofthe absorption profile.(1,3)Figure 2 presents a linear correlationbetween Cmax and the percentdissolved in 15 minutes for animmediate release dosage form.

Since, IVIVCs are basicallymathematical relationships, non-linear

correlations may also be appropriate.IVIVC plays an important role in productdevelopment in that it:-

first, serves as a surrogate of in vivoand assists in supporting biowaivers;

second, supports and / or validatesthe use of dissolution methods andspecifications; and

Thirdly, assists in quality controlduring manufacturing and selectingappropriate formulations (1,4).

The first and main role of establishingIVIVC is to use dissolution test as asurrogate for human studies.

The benefit of this is to minimize thenumber of bioequivalence studiesperformed during the initial approvalprocess and during the scaling-up andpost-approval changes (1).

Additional advantages of an IVIVC is toassist in validating or setting dissolutionspecifications. This is because theIVIVC includes in-vivo relevance to in-vitro dissolution specification. In otherwords, dissolution specifications are setbased on the performance of thebiobatch in-vivo.

The general dissolution time pointspecification is ± 10% deviation from themean dissolution profile obtained fromthe biobatch (1).Bioequivalency between formulationswould be expected if the formulation(s)fall within the upper and lower limits ofthe specification.

Dissolution specification setting basedon an IVIVC can also be used as aquality control for product performance.However, this quality control maysometimes be more rigorous than theusual control standard since it dependson the product bioavailability.

The use of IVIVC, however, is limited toa certain drug product. It can be usedonly on that particular formulation.



The IVIVC cannot be used across theproducts, especially drug product withdifferent release mechanisms (1,5).

This premise has been recentlyinvestigated in our laboratory. In thiswork, two major types of oral extendedrelease dosage forms were compared:

coated pellets filled in a gelatincapsule and

a hydrophilic matrix tablet.

The tablet formulation wasmanufactured under separateinvestigations using fluid bedgranulation.

The active compound, metoprololtartrate, was blended with the releaserate-controlling polymer (hydroxypropylmethylcellulose) and with otherexcipients, such as a filler (lactose anddicalcium phosphate), a binder(hydroxypropylmethylcellulose) and alubricant (magnesium stearate).

The granules were then compressedinto a tablet. A correlation developedwith the hydroxypropyl methylcellulosesystem and was applied to predictingthe in vivo behavior of the multi-particulate gelatin capsule.

The IVIVC was predictive of the extentof absorption. Prediction errorsassociated with AUC were found to beless than 10 percent.

However, the IVIVC was unable toaccurately estimate the rate of drugabsorption, Cmax. Prediction errorswere found to be greater than 20 %.

These results support the contentionthat IVIVCs are product specific. IVIVCis usually developed when drugdissolution is a rate-limiting step for thein vivo absorption.The absorption and consequently thebioavailability of an oral solid dosage

form depends on two main processes,drug dissolution and permeation.

Drug dissolution is the process in whichthe drug is released and available insolution and ready to be absorbed.

Physicochemical properties of a drugsuch as solubility as well as thegastrointestinal environment are thecrucial parameters affecting dissolution.

Drug permeability is the secondprocess beginning after the solid drug isconverted into a solution form.Permeability is the ability of the drug topenetrate across a membrane into thesystemic circulation.

The extent of permeation and ultimatelyabsorption also depends upon thephysicochemical properties of the drugand blood perfusion (6).

The complete penetration of a highlypermeable drug occurs in a short time.Thus, the only factor governing drugabsorption is drug release and/ordissolution from the dosage form.In-vitro drug dissolution then can beused as a surrogate for the in-vivoabsorption.

On the contrary side, the dissolutionrate of immediate release drug productsis relatively very rapid. The rate ofabsorption then is likely to be a functionof the gastric emptying rate or theintestinal permeability. In this case, theIVIVC may not be obtained (5).In Vitro - In Vivo CorrelationsExamplesPrevious IVIVC studies have beenreported for various drugs (7-18). Thestudies were conducted both in animal,such as rat, rabbit, and dog and human.

Most of the studies focused on thedevelopment of a level B and level Ccorrelations. The level B is a correlationin which it compares the mean in-vivo



dissolution to the mean in-vitrodissolution as outlined in Figure 3.

Whereas the level C correlationdescribes a relationship between theamount of drug dissolved at one timepoint and one pharmacokineticparameter.

The level C is also considered thelowest level of correlation. Figure 4displays a typical level C correlationbetween Cmax and percent dissolved at15 minutes.

Level B and C IVIVCs have beendeveloped for several purposes informulation development, for example,for selecting the appropriate excipientsand optimizing manufacturingprocesses, for quality control purposes,and for characterizing the releasepatterns of a newly formulatedimmediate release (IR) and modifiedrelease (MR) products relative to thereference (7-18).However, current IVIVC studies havefocused on the development andvalidation of a level A correlation.

It is a point-to-point relationshipbetween drug release in-vitro and in-vivo. Although, a concern of non-linearcorrelation has been addressed, noformal guidance on the non-linear IVIVChas been established (1).

In summary, the IVIVC is established toenable the dissolution test to be used asa surrogate for bioequivalency.

A validated IVIVC is of significantbenefit for pharmaceuticalmanufacturers due to minimizing thetime and cost invested in additionalbioavailability studies.

In addition, IVIVC is normally expectedfor highly permeable drugs or drugsunder dissolution rate-limiting

conditions. This statement is further

supported by the regulatoryBiopharmaceutical Drug Classification(BCS), which anticipates the successfulIVIVC for highly permeable drugs (4).Biopharmaceutics ClassificationSystem (BCS)Biopharmaceutics Classification System(BCS) is a fundamental guideline fordetermining the conditions under whichin-vitro in-vivo correlations are expected(4).

It is also used as a tool for developingthe in-vitro dissolution specification (5,19).

The classification is associated withdrug dissolution and absorption model,which identifies the key parameterscontrolling drug absorption as a set ofdimensionless numbers: the Absorptionnumber, the Dissolution number andthe Dose number (4, 5, 19).

The Absorption number is the ratio ofthe mean residence time to theabsorption time.

The Dissolution number is a ratio ofmean residence time to meandissolution time.

The Dose number is the mass dividedby an uptake volume of 250 ml and thedrug’s solubility.

The mean residence time here is theaverage of the residence time in thestomach, small intestine and the colon.

The fraction of dose absorbed thencan be predicted based on these threeparameters. For example, Absorptionnumber 10 means that the permeationacross the intestinal membrane is 10times faster than the transit through thesmall intestine indicating 100% drugabsorbed.

In the BCS, a drug is classified in one offour classes based solely on its



solubility and intestinal permeability(19):

Class IHIGH solubility / High permeability,

Class IILOW solubility / High permeability,

Class IIIHIGH solubility / LOW permeability

Class IVLOW solubility / LOW permeability.

Class I drugs such as metoprolol exhibita high Absorption number and a highDissolution number.The rate-limiting step to drug absorptionis drug dissolution or gastric emptyingrate if dissolution is very rapid.

Class II drugs such as phenytoin have ahigh Absorption number but a lowDissolution number. In-vivo drugdissolution is then a rate-limiting step forabsorption (except at very high Dosenumber).

The absorption for Class II drugs isusually slower than Class I and occursover a longer period of time. IVIVC isusually expected for Class I and Class IIdrugs.

For Class III drugs, permeability is therate-controlling drug absorption.Furthermore, Class III drugs exhibit ahigh variability of rate and extent of drugabsorbed. Since the dissolution is rapid,the variation is due to alteration of GIphysiological properties and membranepermeation rather than dosage formfactors.

Class IV drugs are low solubility andlow permeability drugs. Drugs that fall inthis class exhibit a lot of problems foreffective oral administration. Drugexample for class III and IV is cimetidineand chlorothiazide, respectively.

In general, a high soluble drug ischaracterized based on the largestdosage strength soluble in 250 ml orless of water over a pH range of 1-8.

In addition, if the extent of drugabsorption is greater than 90% giventhat the drug is stable in thegastrointestinal environment, it will beconsidered as a high permeable drug(5).

Table 1 and 2 illustrate the BCS and theexpected IVIVC for immediate andextended release formulations (4).

In vitro dissolutionThe purpose of the in-vitro dissolutionstudies in the early stage of drugdevelopment is to select the optimumformulation, evaluate the activeingredient and excipient, and assessany minor changes for drug products.

However, for the IVIVC perspective,dissolution is proposed to be asurrogate of drug bioavailability. Thus, amore rigorous dissolution standard maybe necessary for the in-vivo waiver (5).

Generally, a dissolution methodology,which is able to discriminate betweenthe study formulations and which bestreflects the in vivo behavior would beselected.

Four basic types of dissolutionapparatus, i.e.[1] rotating basket,[2] paddle method,[3] reciprocating cylinder,[4] flow through cell,are specified by the USP andrecommended in the FDA guidanceespecially, for modified release dosageform (20).

Other dissolution methodologies maybe used, however, the first four arepreferred, especially the basket andpaddle. It is also recommended to start



with the basket or paddle method priorto using the others (5).

The in vitro dissolution release of aformulation can be modified to facilitatethe correlation development. Changingdissolution testing conditions such asthe stirring speed, choice of apparatus,pH of the medium, and temperature mayalter the dissolution profile.

As previously described, appropriatedissolution testing conditions should beselected so that the formulation behavesin the same manner as the in vivodissolution.

The appropriate dissolution testingconditions should also discriminatebetween different formulations thatpossess different release patterns.

A common dissolution medium is water,simulated gastric fluid (pH 1.2), orintestinal fluid (pH 6.8 or 7.4) withoutenzyme, and buffers with a pH range of4.5 to 7.5 (20).

For sparingly water-soluble drugs, useof surfactants in the dissolution mediumis recommended (6).A simple aqueous dissolution media isalso recommended for BCS Class I drugas this type of drug exhibits lack ofinfluence of dissolution mediumproperties (21).

Water and simulated gastric fluid thenare the default mediums for most of theClass I drugs. A typical medium volumeis 500 to 1000 ml.

The normal test duration for immediaterelease is 15 to 60 minutes with a singletime point. For example, BCS class Irecommend 15 minutes.

Additionally, two time points may berequired for the BCS class II at 15minutes and the other time at which 85%of the drug is dissolved (6). In contrast,in vitro dissolution tests for a modified

release dosage form require at leastthree time points to characterize thedrug release.

The first sampling time (1-2 hours or 20-30% drug release) is chosen to checkdose-dumping potential. Theintermediate time point has to be around50% drug release in order to define thein vitro release profile.

The last time point is to defineessentially complete drug release (2,20). The dissolution limit should be atleast 80% drug release. Furtherjustification as well as 24-hours testduration are required if the percent drugrelease is less than 80 (20).

Once the discriminatory system isestablished, dissolution testingconditions should be fixed for allformulations tested for development ofthe correlation (1).A dissolution profile of percentage orfraction of drug dissolved versus timethen can be determined.

The similarity of the dissolution profilesin particular dissolution testingconditions is evaluated using thesimilarity factor (f2 metric) defined byequation 1 (22,23).

f2 = 50 log{[1 + 1n Wt Rt - Tt)2

t=1

n

(∑ ]-0.5 x100 } [1]

Where Rt and Tt are the cumulativepercentage dissolved at time point t forreference and test products,respectively, and n is the number of poolpoints.

The f2 equation is a logarithmictransformation of the sum of squares ofthe difference between test andreference profiles (22).The results are values between 0 and100. The value of f2 is 100 when the testand reference profiles are identical andapproaches zero as the dissimilarityincreases.



An average difference of 10% at all timepoints results in the f2 value of 50. The f2value between 50 and 100, therefore,suggests the similarity between twodissolution profiles (23).

This equation is only applicable incomparing profiles in which the averagedifference between R and T is less than100. If this average difference is greaterthan 100, the equation will yield anegative number (22).

Normalization of the data is required tocompare values in which the differenceis not between 1 and 100.In vivo absorptionThe FDA requires in vivo bioavailabilitystudies to be conducted for a New DrugApplication (NDA). Bioavailabilitystudies are normally performed in younghealthy male adult volunteers undersome restrictive conditions such asfasting, non-smoking, and no intake ofother medications.

The drug is usually given in a crossoverfashion with a washout period of at leastfive half-lives.

The bioavailability study can beassessed via plasma or urine data usingthe following parameters: (I) area underthe plasma time curve (AUC), or thecumulative amount of drug excreted inurine (Du∞), (II) maximum concentration(Cmax), or rate of drug excretion in urine(dDu/dt), and (III) a time of maximumconcentration (Tmax).

Despite the knowledge of theseparameters, cumulative amountabsorbed or the in vivo absorption rateis required as the in vivo data for theIVIVC development.

Several approaches can be employedfor determining the in vivo absorption.Wagner-Nelson, Loo-Riegelman, andnumerical deconvolution are such

methods (23, 24). Wagner Nelson andLoo-Riegelman are both model-dependent methods in which the formeris used for a one-compartment modeland the latter is for multi-compartmentsystem.

The Wagner Nelson method is lesscomplicated than the Loo-Riegelman asthere is no requirement for intravenousdata (24).

However, misinterpretation on theterminal phase of the plasma profile maybe possible in the occurrence of a flip-flop phenomenon in which the rate ofabsorption is slower than the rate ofelimination

Deconvolution is a numerical methodused to estimate the time course of druginput using a mathematical model basedon the convolution integral (1).

For example, the absorption rate timecourse (rabs) that resulted in plasmaconcentration (c(t)) may be estimated bysolving the convolution integral equationfor rabs.c(t) = ∫0

t cδ(t-u) r abs(u) du [2]

The function cδ represents theconcentration time course that wouldresult from the instantaneous absorptionof a unit amount of drug and it istypically estimated from intravenousinjection bolus data or reference oralsolution data. c(t) is the plasmaconcentration vs. time level of theextended release formulation.rabs is drug input rate of the oral soliddosage form andu is variable of integration.

Deconvolution is a model independentmethod which can be employed foreither one- or multiple-compartmentmodels.

The key to developing an IVIVC isidentifying a dissolution testing method



that is descriptive of the in vivoabsorption of the test compound.

In vitro testing has several purposes. Itserves an important tool forcharacterizing the biopharmaceuticalquality of a product at different stages offormulation development.

In early drug development, in vitrodissolution properties are decisive forchoosing between different alternativedosage forms for further development ofthe respective drug product.

Also, in vitro dissolution data can behelpful in the evaluation andinterpretation of possible risks,especially in the case of extendedrelease dosage forms, e.g. dosedumping, food effects and drug -druginteraction. In addition, in vitrodissolution data has great importancewhen assessing minor changes inproduction site or manufacturingprocess and respective decision on thenecessity of bioavailability studies.

None of these purposes can be fulfilledby in vitro dissolution testing withoutsufficient knowledge of its in vivorelevance, that is by studying in vitro-invivo correlations.

If a correlation can be established withan individual drug, an in vitro dissolutiontest may serve not only as a guide toformulation development or as a qualitycontrol test, which indicates uniformity ofmanufacture or stability, but also as areliable predictor of drug absorption.

In summary, this report outlined theregulatory requirements for thedevelopment and validation of an IVIVC.It focuses on the role of theBiopharmaceutical Classification systemas an indicator of developing apredictive IVIVC and also examined theimportance of drug dissolution andpermeability on IVIVC validity.

Table 1.

Table 2.

Biopharmaceutics DrugClassification and Expected IVIVC

for Immediate Release DrugProducts.4

Class S P IVIVC

I High High Correlation (if dissolutionis rate limiting step)

II Low High IVIVC expected

III High Low Little or no IVIVC

IV Low Low Little or no IVIVC

S = Solubility P = Permeability

Biopharmaceutics Drug Classificationfor Extended Release Drug Products.4

Class S P IVIVC

IA High & SiteIndependent

High & SiteIndependent

IVIVCLevel Aexpected

IB High & SiteIndependent

Dependent on

site & Narrow

Absorption Window

IVIVCLevel Cexpected

IIa Low & SiteIndependent

High & SiteIndependent

IVIVCLevel Aexpected

IIb Low & SiteIndependent

Dependent on

site & Narrow

Absorption Window

Little or

no IVIVC

Va:Acidic

Variable Variable Little or

no IVIVC

Vb:basic

Variable Variable IVIVC

Level A expected

S = Solubility P = Permeability



Time (hr)

0 2 4 6 8 10 12

FR

A

0.0

0.2

0.4

0.6

0.8

1.0

1.2

SlowModerataeFast

Time (hr)

0 5 10 15 20 25

Met

op

rolo

l (n

g/m

l)

0

20

40

60

80

Figure 1.Representative mean fraction of drug dissolved convolved to provide plasma drug

concentration vs. time profile.

15

17

19

21

23

1 1.2 1.4 1.6F R D a t 3 0 m in

Cm

ax

Figure 2Level C In Vitro In Vivo Correlation between Cmax and percent

dissolved at 15 minutes.

15

20

25

30

1 1.2 1.4 1.6 1.8M D T (h r)

MR

T (

hr)

Figure 3Level B In Vitro In Vivo Correlation between Mean Dissolution Time

(MDT) and Mean Absorption Time (MAT).



Subsequent topics in this series willinclude:

(1) Systematic method for thedevelopment and validation of an IVIVCwith relevant examples,

(2) Development of an IVIVC for a ClassI agent metoprolol tartrate using twoformulations,

(3) The role of stereoisomerisms in IVIVCdevelopment,

(4) The application of IVIVC forimmediate release products, a Class Iand III drug example,

(5) The role of mathematical modeling inIVIVC development, Case Report Using aNon-linear relationship between FRA andFRD, and

(6) The role of pharmacokinetic variabilityin individual IVIVC in productdevelopment.…LITERATURE CITED1. U.S. Department of Health and HumanServices. (September 1997). Guidance forindustrial. Extended release oral dosageforms: Development, evaluation andapplication of In Vitro/In Vivo correlations.Food and Drug Administration, Center forDrug Evaluation and Research (CDER).Rockville, MD.2. The United Stated Pharmacopeia. (23thed.). (1995). In Vitro and In Vivo Evaluationof Dosage form < 1088>. 1824-1929.Rockville, MD.3. Leeson, L. J. (1995). In vitro/ In vivocorrelations. Drug Information Journal. 29,903-915.4. Young, D., Devane, J. G., and Butler, J.(Eds.). (1997). In Vitro-In Vivo Correlations.New York: Plenum press.5. Amidon, G. L., Robinson, J. R., andWilliams, R. L. (Eds.). (1997). ScientificFoundations for Regulating Drug ProductQuality. American Association ofPharmaceutical Scientists. Alexandria,Virginia: AAPS Press.6. Shargel, L., and Yu, A. B. C. (1993).Applied Biopharmaceutics and

Pharmacokinetics. East Norwark,Connecticut: Appleton & Lange.7. Chattaraj, S. C., and Das, S. K. (1990).Effect of formulation variables on thepreparation and in vitro-in vivo evaluation ofcimetidine release from ethyl cellulosemicropellets. Drug Development andIndustrial Pharmacy. 16(2), 283-292.8. Lin, S., Kao, Y., and Chang, H. (1990).Preliminary evaluation of the correlationbetween in vitro release and in vivobioavailability of two aminophylline slow-release tablets. Journal of PharmaceuticalSciences. 79(4), 326-330.9. Hussein, Z., and Friedman, M. (1990).Release and absorption characteristics ofnovel theophylline sustained-releaseformulations: In vitro-in vivo correlation.Pharmaceutical Research. 7(11), 1167-1171.10. Ebel, J. P., Jay, M., and Beihn, R. M.(1990). An in vitro/in vivo correlation fordisintegration and onset of drug release fromenteric-coated pellets. PharmaceuticalResearch. 10(2), 233-238.11. Bhagavan, H. N., and Wolkoff, B. I.(1993). Correlation between thedisintegration time and the bioavailability ofvitamin C tablets. Pharmaceutical Research.10(2), 239-242.12. Drewe, J., and Guitard, P. (1993). Invitro-in vivo correlation for modified-releaseformulations. Journal of PharmaceuticalSciences. 82(2), 132-137.13. Ammar, H. O., and Khalil, R. M. (1993).Discrepancy among dissolution rates ofcommercial tablets as a function ofdissolution method. Part 3: In vitro/in vivocorrelation of paracetamol tablets.Pharmazie. 48(Feb), 136-139.14. Brock, M. H., Dansereau, R. J., and Patel, V.S. (1994). Use of in vitro and in vivo data in thedesign, development, and quality control ofsustained-release decongestant dosage form.Pharmacotherapy. 14, 430-437.15. Hayashi, T, Ogura, T., and Takagishi, Y.(1995). New evaluation method for in vitro/in vivocorrelation of enteric-coated multiple unit dosageforms. Pharmaceutical Research. 12 (9), 1333-1337.16. Qui, Y., Cheskin, H., Briskin, J., and Engh, K.(1997). Sustained-release hydrophilic matrixtablets of zileuton: formulation and in vitro/in vivo



studies. Journal of Controlled release. 45, 249-256.17. Jung, H., Milan, R. C., Girard, M. E., Leon, F.,and Montoya, M. A. (1997). Bioequivalence studyof carbamazepine tablets: in vitro/in vivocorrelation. International Journal ofPharmaceutics. 152, 37-44.18. Abuzarur-aloul, R., Gjellan, K., Sjound, M.,and Graffner, C. (1998). Critical dissolution testsof oral systems based on statistically designedexperiments. III. In vitro/in vivo correlation formultiple-unit capsules of paracetamol based onPLS modeling. Drug Development and IndustrialPharmacy. 24, 371-383.19. Amidon, G. L., Lennernas, H., Shah, V. P.,and Crison, J. R. (1995). A theoretical basis for abiopharmaceutic drug classification: Thecorrelation of in vitro drug product dissolution andin vivo bioavailabilty. Pharmaceutical Research.12(3), 413-419.20. Sievert, B., and Siewert, M. (1998).Dissolution tests for ER products. DissolutionTechnologies. 5(4).21. Galia, E., Nicolaides, E., Horter, D.,Lobenberg, R., Reppas, C., and Dressman, B.(1998). Evaluation of various dissolution media forpredicting in vivo performance of class I and classII drugs. Pharmaceutical Research. 15(5), 698-705.22. Moore, J. W., and Flanner, H. H. (1996).Mathematical comparison of dissolution profiles.Pharmaceutical Technology. June, 64-74.23. U.S. Department of Health and Human Services.(November 1995). Guidance for industry: Immediaterelease solid oral dosage forms scale-up andpostapproval changes: chemistry, manufacturing, andcontrols, in vitro dissolution testing, and in vivobioequivalence documentation. Center for drugEvaluation and Research, Food and DrugAdministration. Rockville, MD.Abdou, H. M. (1989). Dissolution, Bioavailabilityand Bioequivalence. Easton, Pennsylvania: MackPrinting.

4Please send editorial correspondence andreprint requests to:Natalie D. Eddington, Ph.D. PharmacokineticsBiopharmaceutics Laboratory Department ofPharmaceutical Sciences School of Pharmacy,University of Maryland at Baltimore 100 PennStreet, AHB Baltimore, MD 21201-6808Tel (410) 706-6710 Fax: (410)[email protected]

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