1

Advisory Committee for Pharmaceutical Science May Advisory Committee for Pharmaceutical Science May 3, 20053, 2005

Advisory Committee for Pharmaceutical Science May Advisory Committee for Pharmaceutical Science May 3, 20053, 2005

Factors Impacting Drug Dissolution Factors Impacting Drug Dissolution and Absorptionand Absorption: :

Current State of ScienceCurrent State of Science

Lawrence X. Yu, Ph. D.Lawrence X. Yu, Ph. D.Director for ScienceDirector for Science

Office of Generic DrugsOffice of Generic DrugsFood and Drug AdministrationFood and Drug Administration

2

Presentation OutlinePresentation Outline

In VitroIn Vitro Dissolution Testing Dissolution Testing

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation

In VitroIn Vitro Dissolution Testing Dissolution Testing

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation

3

Oral Drug AbsorptionOral Drug Absorption

Gastric Emptying

Transit PermeationDissolution

Metabolism

4

What Does Dissolution Measure?What Does Dissolution Measure?

Solid drug particle stagnant layer (h) with aconcentration = Cs

bulk solution with aconcentration = Ct = Xd/VBulk Solvent

V

XC

h

DA

dt

dXDR

ds

5

Quality Control: Pharmaceutical Solid Quality Control: Pharmaceutical Solid PolymorphismPolymorphism

0

20

40

60

80

100

120

0 15 30 45 60

Time (min)

Pe

rce

nt

Dis

so

lve

d

Form II

Form I

6

In VivoIn Vivo Bioequivalence: IVIVC Bioequivalence: IVIVC

0

30

60

90

120

0 5 10 15 20 25

Time (hrs.)

% A

bso

rbed

RegularFastSlow

0

30

60

90

120

0 5 10 15 20 25 30

Time (hrs.)

% D

isso

lved

RegularFastSlow

Dissolution Profiles Fraction Absorption Profiles

rsq=0.97

0

20

40

60

80

100

120

0 20 40 60 80 100 120

% Dissolved

% A

bs

orb

ed

7

Presentation OutlinePresentation Outline

In VitroIn Vitro Dissolution Testing Dissolution Testing

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation

In VitroIn Vitro Dissolution Testing Dissolution Testing

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation

8

Disintegration Dissolution

…………..

…..…..

What Affects Dissolution?What Affects Dissolution?

Drug Substance Factors

9

In VivoIn Vivo and and In VitroIn Vitro Relationship: Relationship: Scientific IssuesScientific Issues

Limits to oral drug Limits to oral drug absorptionabsorption

Dissolution-limited Dissolution-limited

Solubility-limitedSolubility-limited

Permeability-limitedPermeability-limited

Limits to oral drug Limits to oral drug absorptionabsorption

Dissolution-limited Dissolution-limited

Solubility-limitedSolubility-limited

Permeability-limitedPermeability-limited

Gastric Emptying

Transit PermeationDissolution

Metabolism

SolubilitySolubility

Dissolution Permeation

Conc Solubility

10

Quantitative Estimation of Quantitative Estimation of AbsorptionAbsorption

Dose VolumeDose Volume

Dissolution TimeDissolution Time

Absorbable DoseAbsorbable Dose

S

0dose C

MV

sdiss DC

hrT

30

siseffabs TACPD

11

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption(Yu, Pharm. Res. 16:1884-1888 (1999))(Yu, Pharm. Res. 16:1884-1888 (1999))

Rate-limiting

Steps

Conditions Comments

Dissolution limiting

Tdiss > 199 min

Peff > 2 10-4 cm/sec

Dabs >> Dose

The absolute amount of absorbed drug increases with the increased dose.

Permeability limiting

Tdiss < 50 min

Peff < 2 10-4 cm/sec

Dabs >> Dose

The absolute amount of absorbed drug increases with the increased dose.

Solubility

limiting

Tdiss < 50 min

Peff > 2 10-4 cm/sec

Dabs < Dose

The absolute amount of absorbed drug does not increase with the increased dose.

12

CAT Model: Extent of Intestinal Drug CAT Model: Extent of Intestinal Drug Absorption (Permeability-limited)Absorption (Permeability-limited)

(Yu et al. Int. J. Pharm. 186:119-125 (1999))(Yu et al. Int. J. Pharm. 186:119-125 (1999))

Human Permeability (cm/hr)0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Fra

ctio

n o

f D

ose

Ab

sorb

ed

0.0

0.2

0.4

0.6

0.8

1.0

PredictedExperimental

13

Digoxin: Dissolution-limitedDigoxin: Dissolution-limited ( (Yu, Pharm. Res. 16:1884-1888 (1999))Yu, Pharm. Res. 16:1884-1888 (1999))

Particle Diameter (m)0 20 40 60 80 100

Fra

ctio

n o

f D

ose

Ab

sorb

ed

0.0

0.2

0.4

0.6

0.8

1.0

14

Griseofulvin: Solubility-limitedGriseofulvin: Solubility-limited((Yu, Pharm. Res. 16:1884-1888 (1999))Yu, Pharm. Res. 16:1884-1888 (1999))

Diameter of Particle (m)

0 10 20 30 40 50 60

Fra

ctio

n o

f D

ose

Ab

sorb

ed

0.0

0.2

0.4

0.6

0.8

1.0

Dose = 250 mgDose = 500 mgDose = 1000 mg

15

Applications of Predictive Absorption Applications of Predictive Absorption Model in Drug DiscoveryModel in Drug Discovery

16

Disintegration Dissolution

…………..

…..…..

What Affects Dissolution?What Affects Dissolution?

Dosage Form Factors

17

Plasma Concentration Profile of a Drug from Plasma Concentration Profile of a Drug from an Oral Solutionan Oral Solution

0

2

4

6

8

10

12

14

0 2 4 6 8 10 12

Pla

sma

Co

nc

time (hr)

Oral Solution Data Oral Solution Simulation

18

Dissolution Profile from a Drug from A Solid Oral Dosage Form

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

fra

ctio

n d

isso

lve

d

time (hr)

SlowMedium

Fast

19

0

1

2

3

4

5

6

7

8

9

0 2 4 6 8 10

Pla

sma

Co

nc

time (hr)

SlowMedium

Fast

Plasma Concentration Profile of a Drug from a Solid Oral Dosage Form

20

Dissolution Profile of a Drug with Different Protective Coating

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

fra

ctio

n d

isso

lve

d

time (hr)

SlowMedium

Fast

21

PK Profile of a Drug with Different Protective Coating

0

0.01

0.02

0.03

0.04

0.05

0 5 10 15 20

Pla

sma

Co

nc

time (hr)

MeasuredSlow

MediumFast

22

Presentation OutlinePresentation Outline

In VitroIn Vitro Dissolution Testing Dissolution Testing

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation

In VitroIn Vitro Dissolution Testing Dissolution Testing

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation

23

Dissolution and Limits to Oral Dissolution and Limits to Oral AbsorptionAbsorption

When dissolution is rapid and, therefore, not the When dissolution is rapid and, therefore, not the rate determining step, drug levels in rate determining step, drug levels in blood/plasma may not reflect dissolution blood/plasma may not reflect dissolution differences differences Dissolution-limited absorptionDissolution-limited absorption

IVIVC possible for IR/ER productsIVIVC possible for IR/ER products In vivo fraction absorption profile is not always possible; In vivo fraction absorption profile is not always possible;

Deconvolution-based IVIVC methods Deconvolution-based IVIVC methods

Solubility-limited absorptionSolubility-limited absorption Permeability-limited absorptionPermeability-limited absorption

Convolution-based IVIVC methods Convolution-based IVIVC methods

When dissolution is rapid and, therefore, not the When dissolution is rapid and, therefore, not the rate determining step, drug levels in rate determining step, drug levels in blood/plasma may not reflect dissolution blood/plasma may not reflect dissolution differences differences Dissolution-limited absorptionDissolution-limited absorption

IVIVC possible for IR/ER productsIVIVC possible for IR/ER products In vivo fraction absorption profile is not always possible; In vivo fraction absorption profile is not always possible;

Deconvolution-based IVIVC methods Deconvolution-based IVIVC methods

Solubility-limited absorptionSolubility-limited absorption Permeability-limited absorptionPermeability-limited absorption

Convolution-based IVIVC methods Convolution-based IVIVC methods

24

Dissolution Profile ComparisonDissolution Profile Comparison

}100])TR(n1

(1{[log502f 5.02tt

ff22= ‘Similarity’ Factor. Values are scaled between 0-100. = ‘Similarity’ Factor. Values are scaled between 0-100.

ff22 values greater than 50 (50-100) reflect a values greater than 50 (50-100) reflect a 10%10% or less, ‘overall’ or or less, ‘overall’ or

‘global’ difference between the two curves. ‘global’ difference between the two curves.

ff22= ‘Similarity’ Factor. Values are scaled between 0-100. = ‘Similarity’ Factor. Values are scaled between 0-100.

ff22 values greater than 50 (50-100) reflect a values greater than 50 (50-100) reflect a 10%10% or less, ‘overall’ or or less, ‘overall’ or

‘global’ difference between the two curves. ‘global’ difference between the two curves.

25

In Vitro and In VivoIn Vitro and In Vivo

Dissolution testing is “non-discriminating”Dissolution testing is “non-discriminating” Dissolution - limited absorptionDissolution - limited absorption OthersOthers

Dissolution testing is “over discriminating”Dissolution testing is “over discriminating” Solubility - limited absorptionSolubility - limited absorption Permeability - limited absorptionPermeability - limited absorption

Dissolution testing is “non-discriminating”Dissolution testing is “non-discriminating” Dissolution - limited absorptionDissolution - limited absorption OthersOthers

Dissolution testing is “over discriminating”Dissolution testing is “over discriminating” Solubility - limited absorptionSolubility - limited absorption Permeability - limited absorptionPermeability - limited absorption

“f2 values greater than 50 (50-100) ensure

sameness or equivalence of the two curves and, thus, of the performance of the test (post-change) and reference (pre-change) products.”

26

Role of Dissolution TestingRole of Dissolution Testing A quality control tool to monitor batch-to-batch A quality control tool to monitor batch-to-batch

consistency of the drug release from a productconsistency of the drug release from a product An in vitro surrogate for product performance An in vitro surrogate for product performance

that can guide formulation development and that can guide formulation development and ascertain the need for bioequivalence testsascertain the need for bioequivalence tests

Are these goals consistent?Are these goals consistent?

A quality control tool to monitor batch-to-batch A quality control tool to monitor batch-to-batch consistency of the drug release from a productconsistency of the drug release from a product

An in vitro surrogate for product performance An in vitro surrogate for product performance that can guide formulation development and that can guide formulation development and ascertain the need for bioequivalence testsascertain the need for bioequivalence tests

Are these goals consistent?Are these goals consistent?

27

Hydrodynamic ConditionsHydrodynamic Conditions Current Paddle Speeds Result in Re: Current Paddle Speeds Result in Re:

Re = 4688 (50 RPM) Re = 4688 (50 RPM) Re = 9375 (100 RPM)Re = 9375 (100 RPM)

Some evidence that current speeds are Some evidence that current speeds are correlated with in vivo dissolutioncorrelated with in vivo dissolution

Slower laminar flows would lead to much more Slower laminar flows would lead to much more reproducible hydrodynamics, but may not reproducible hydrodynamics, but may not correlate with in vivo hydrodynamics.correlate with in vivo hydrodynamics.

Current Paddle Speeds Result in Re: Current Paddle Speeds Result in Re: Re = 4688 (50 RPM) Re = 4688 (50 RPM) Re = 9375 (100 RPM)Re = 9375 (100 RPM)

Some evidence that current speeds are Some evidence that current speeds are correlated with in vivo dissolutioncorrelated with in vivo dissolution

Slower laminar flows would lead to much more Slower laminar flows would lead to much more reproducible hydrodynamics, but may not reproducible hydrodynamics, but may not correlate with in vivo hydrodynamics.correlate with in vivo hydrodynamics.

A. Scholz, E. Kostewicz, B. Abrahamsson and J. B. Dressman Can the USP paddle method be used to represent in-vivo hydrodynamics? Journal of Pharmacy and Pharmacology 55 (2003) 443-451

28

MediumMedium Product Specific MediumProduct Specific Medium

Allows full dissolution for all products in a finite time Allows full dissolution for all products in a finite time and dissolution volumeand dissolution volume

Universal/Biorelevant MediaUniversal/Biorelevant Media A true A true in vivoin vivo correlation should use the same media correlation should use the same media

for all products for all products

Product Specific MediumProduct Specific Medium Allows full dissolution for all products in a finite time Allows full dissolution for all products in a finite time

and dissolution volumeand dissolution volume

Universal/Biorelevant MediaUniversal/Biorelevant Media A true A true in vivoin vivo correlation should use the same media correlation should use the same media

for all products for all products

29

Role of DissolutionRole of Dissolution Should the roles be separated?Should the roles be separated? Is single point acceptance criterion relevant for Is single point acceptance criterion relevant for

either role?either role? Do the multiple roles impede the reduction of Do the multiple roles impede the reduction of

variability?variability?

Should the roles be separated?Should the roles be separated? Is single point acceptance criterion relevant for Is single point acceptance criterion relevant for

either role?either role? Do the multiple roles impede the reduction of Do the multiple roles impede the reduction of

variability?variability?

30

Dissolution for Quality ControlDissolution for Quality Control A product specific quality control testA product specific quality control test

The hydrodynamics and medium for this test are The hydrodynamics and medium for this test are chosen for reproducibility and detection of product chosen for reproducibility and detection of product changeschanges

The design of this test is not constrained by a desire The design of this test is not constrained by a desire to mimic in vivo conditions.to mimic in vivo conditions.

A product specific quality control testA product specific quality control test The hydrodynamics and medium for this test are The hydrodynamics and medium for this test are

chosen for reproducibility and detection of product chosen for reproducibility and detection of product changeschanges

The design of this test is not constrained by a desire The design of this test is not constrained by a desire to mimic in vivo conditions.to mimic in vivo conditions.

31

Dissolution for In Vivo PerformanceDissolution for In Vivo Performance

A biorelevant dissolution testA biorelevant dissolution test All products should undergo dissolution testing in the All products should undergo dissolution testing in the

same device and same media (corresponding to stomach same device and same media (corresponding to stomach and intestine under fed and fasted conditions) that gives and intestine under fed and fasted conditions) that gives the best possibility to correlate with in vivo dissolutionthe best possibility to correlate with in vivo dissolution

The biorelevant dissolution test is a one-time test to The biorelevant dissolution test is a one-time test to provide a baseline for product performanceprovide a baseline for product performance

Any biowaivers should rely on the biorelevant dissolution Any biowaivers should rely on the biorelevant dissolution testingtesting

Biorelevant dissolution testing as a quality control testBiorelevant dissolution testing as a quality control test

A biorelevant dissolution testA biorelevant dissolution test All products should undergo dissolution testing in the All products should undergo dissolution testing in the

same device and same media (corresponding to stomach same device and same media (corresponding to stomach and intestine under fed and fasted conditions) that gives and intestine under fed and fasted conditions) that gives the best possibility to correlate with in vivo dissolutionthe best possibility to correlate with in vivo dissolution

The biorelevant dissolution test is a one-time test to The biorelevant dissolution test is a one-time test to provide a baseline for product performanceprovide a baseline for product performance

Any biowaivers should rely on the biorelevant dissolution Any biowaivers should rely on the biorelevant dissolution testingtesting

Biorelevant dissolution testing as a quality control testBiorelevant dissolution testing as a quality control test

32

SummarySummary

In VitroIn Vitro Dissolution Testing Dissolution Testing-- Over discriminating/Non-discriminating dissolution Over discriminating/Non-discriminating dissolution

-- Not sufficient to assure bioequivalence/bioavailability Not sufficient to assure bioequivalence/bioavailability

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

-- Dissolution/Solubility/Permeability-limited absorption Dissolution/Solubility/Permeability-limited absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation Dissolution Profile ComparisonDissolution Profile Comparison Role of Dissolution TestingRole of Dissolution Testing

In VitroIn Vitro Dissolution Testing Dissolution Testing-- Over discriminating/Non-discriminating dissolution Over discriminating/Non-discriminating dissolution

-- Not sufficient to assure bioequivalence/bioavailability Not sufficient to assure bioequivalence/bioavailability

Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

-- Dissolution/Solubility/Permeability-limited absorption Dissolution/Solubility/Permeability-limited absorption

Challenges to Regulatory EvaluationChallenges to Regulatory Evaluation Dissolution Profile ComparisonDissolution Profile Comparison Role of Dissolution TestingRole of Dissolution Testing