1 advisory committee for pharmaceutical science may 3, 2005 factors impacting drug dissolution and...
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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
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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
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Oral Drug AbsorptionOral Drug Absorption
Gastric Emptying
Transit PermeationDissolution
Metabolism
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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
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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
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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
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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
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Disintegration Dissolution
…………..
…..…..
What Affects Dissolution?What Affects Dissolution?
Drug Substance Factors
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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
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Quantitative Estimation of Quantitative Estimation of AbsorptionAbsorption
Dose VolumeDose Volume
Dissolution TimeDissolution Time
Absorbable DoseAbsorbable Dose
S
0dose C
MV
sdiss DC
hrT
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siseffabs TACPD
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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.
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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
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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
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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
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Applications of Predictive Absorption Applications of Predictive Absorption Model in Drug DiscoveryModel in Drug Discovery
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Disintegration Dissolution
…………..
…..…..
What Affects Dissolution?What Affects Dissolution?
Dosage Form Factors
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Plasma Concentration Profile of a Drug from Plasma Concentration Profile of a Drug from an Oral Solutionan Oral Solution
0
2
4
6
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12
14
0 2 4 6 8 10 12
Pla
sma
Co
nc
time (hr)
Oral Solution Data Oral Solution Simulation
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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
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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
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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
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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
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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
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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
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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.
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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.”
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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?
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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
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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
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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?
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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.
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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
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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