Achieving Optimum Levels of Discrimination in Dissolution Testing

PHAST GmbH 2005
Achieving optimum levels of discrimination in

dissolution testing
AAPS: DISSOLUTION WORKSHOP
Rhodes University, Grahamstown
December 09-10, 2009
Dr. Johannes Krmer
Achieving optimum levels of

discrimination in dissolution
testing.but how?
Goals of dissolution testing
Bioperformance of drugs
Biorelevant dissolution testing
Rank order for predictive power of dissolution testing
the BCS
a look at GI physiology
dosage form properties
Discriminative power
apparatus
media
patient vs. manufacturer risk

a qualitative issue
the attempt for a quantitative approach
PHAST GmbH, www.phast.de
office@phast.de
PHAST GmbH 2005

early phase
dissolution testing
g
to evaluate the in vitro performance of drug products
products for systemic and/or local administration and action
in early development: to model in vivo findings with the goal to identify
the best delivery concept
results always relative
Dissolution methodology
determining drug release
in closed systems
in open systems
with apparatus
and dissolution media that act
as
solvents
carriers of mechanical energy
absorbers of dissolved drug
nott (yet)
( t) tto model
d l GI-transit
GI t
it off
dosage forms
disintegrated particles
solutions alone or with
chyme
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GI transfer model
predictive?
Disintegration in SGFsp pH 2.0

Transfer to FeSSIF or FaSSIF (immediate or with transfer rate)
Monitor dissolution & precipitation

later phase
dissolution testing
in product lifecycle:
to predict differences in bioperformances
to ascertain constant quality
within a meaningful range
optimum: to evaluate the impact of critical quality parameters on the

in vivo performance of drugs
prerequisite
standardized equipment and reagents for
precise testing to measure quality differences
link to relevant in vivo parameters
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Concept of mapping
Critical manufacturing variables

critical formulation variables
critical processing variables
variables:
those materials and methods
used in the manufacturing
process that can significantly
affect drug release from the
product
to develop product
specifications with
bioavailability implications

testing.but how?
the BCS
dosage
g form p
properties
p
apparatus
media

a qualitative issue
office@phast.de
PHAST GmbH 2005
For locallyy and systemically

y
y acting
g drugs
g
Delivery of drug substance
at given pattern
prompt
immediate
modified
complete dose for orals

at given rate for implants and transdermals
i.e. in vivo drug release
not per se accessible

9
In vivo-dissolution vs.
BA as the surrogate parameter
drug
product
kr
stomach
small Int.
ka
feces /
urine
ka
blood
residual content
in dosage form
kr not directly
accessible
office@phast.de
ke
feces/urine
Classical BA
kr derived from
composite [kr, ka]
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Apparent in vivo dissolution
system function
time [h]
response function
time [h]
deconvoluted fct.
11
for systemically acting oral drugs

the surrogate parameter of therapeutic efficacy is the
bioavailability of the drug product
Bioavailability the rate and extent to which the active
ingredient or active moiety is absorbed from a drug
product and becomes available at the site of action
(product quality criterion!)
bioavailability in vivo dissolution
office@phast.de
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Lbenberg (AAPS, April 2007)
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testing.but how?
the BCS
dosage
g form p
properties
p
apparatus
media

a qualitative issue
office@phast.de
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In vitro in vivo
relationship?
in vitro
in vivo
15
Full GI tract simulation
TNO TIM-1
TIM 1 model
simulation takes into account:
dynamic conditions (sequential
passage)
mechanical stress (peristaltic
movement)
body temperature
body pH
concentration electrolytes
enzymes
concentration of bile salts
removal of water / solubilized molecules
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PHAST GmbH 2005
Standardized equipment
wanted
FIP Position
Paper<1-4>
on Qualification of Paddle and Basket Dissolution Apparatus
USP
Cynthia K. Brown[1], Lucinda Buhse[2], Horst-Dieter Friedel[3], Susanne Keitel[4], Johannes Kraemer[5], J.
harmonized via ICH Q4B
Michael Morris[6], Mary Stickelmeyer[7], Chikako Yomota[8] and Vinod P. Shah[9]
Special
more Interest
or lessGroup,
standardized
Members of FIP
Dissolution / Drug Release
Paddle/Basket
Dissolution Apparatus
Qualification
qualification
procedures
for GMP available
[1] Eli Lilly and Company
[2] Food and Drug Administration
[3] Bayer Schering Pharma AG, Germany
[4] European Directorate for the Quality of Medicines and Healthcare, France
[5] PHAST,
PHAST G
Germany
[6] Irish Medicines Board, Ireland
[7] Eli Lilly and Company, Indianapolis, IN, USA
[8] National Institute of Health Sciences, Japan
Any preference with regard to biorelevance?
[9] FIP Scientific Secretary, The Hague, Netherlands
17
19
35.8
Dissolution methodology:
closed systems
42
74.5
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Compendial apparatus-Basket
(apparatus <1>)
adopted
p
in 1970 by
y the USP
Shaft
standard basket
40 mesh stainless steel
e.g. 900 mL at 37 C
e.g. 100 rpm
Basket
Vessel
19
Compendial apparatus-Paddle
(apparatus <2>)
Adopted in 1975 by USP
Standard paddle
shaft & paddle made of inert material
(coated)/stainless steel (uncoated)
e.g. 900 mL at 37 C
e.g. 50 rpm
sinkers optional for floating
dosage forms
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Shaft
Paddle
20
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Compendial apparatusreciprocating cylinder

(apparatus <3>)
Apparatus developed by Beckett &
co-workers
Adopted by the USP in 1991
evaporation cap
e.g. 200 mL volume

e.g. 5-30 dips/min
upper mesh screen

inner cylinder
differences to <1,2>
pH profiling
dosage form
lower mesh screen
outer cylinder
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Dissolution methodology:
open systems
office@phast.de
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Flow-through cell
apparatus <4>
Laminar flow
linear flow
dampened pump pulsation
Turbulent flow
flow
fl
characteristics
h
t i ti
less predictable
glass beads
no beads
Laminar
flow
Turbulent
flow
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Any type of dissolution

apparatus preferred?
C
Cumulative
l ti dissolution
di
l ti profile
fil
Diff
Differential
i l dissolution
di
l i profile
fil
no!
office@phast.de
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In vitro modeling of food effects?

standard breakfast
mixer
dissolution test
25
Biorelevant media by
Jenny Dressman
Biorelevant Media:
stomach
FaSSGF (250 mL): Fasted State Simulated Gastric Fluid
pH 2.0, 0.01 N HCl, 0.1 mg/ml pepsin, 80 M Na-taurocholate, 20 M lecithin, 34 mM
NaCl.
small intestine
FeSSIF (900 mL): Fed State Simulated Intestinal Fluid
pH 5.0, 15 mM NaTC, 3.75 mM Lecithin, 670 mosmol/kg.
FaSSIF (500 mL): Fasted State Simulated Intestinal Fluid

pH 6.5, 3 mM NaTC, 0.75 mM Lecithin, 270 mosmol/kg.
food / co-medication
Milk
Bio-relevant medium + mixed food
Bio-relevant medium + co-medication
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PHAST GmbH 2005
Biorelevant media in QC
yes
y
but as qualified reagents
with regard to
pH
osmolality
ional composition
volume
temperature
surfactants
27

testing.but how?
apparatus
media
the BCS
dosage
g form p
properties
p

a qualitative issue
office@phast.de
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High Solubility / High Permeability Drug
a high solubility drug is one that dissolves in < 250 ml water at its
highest dose strength
a high permeability drug is a drug with Fraction Absorbed > 90%

((FDA))
(metoprolol taken as reference permeability drug)
29
Biopharmaceutical Classification
High
Permeability
Class 1
Class 2
High Solubility
High Permeability
Rapid Dissolution
Low Solubility
High Permeability
Class 3
Class 4
High Solubility
S
Low Permeability
Low Solubility
S
Low Permeability
office@phast.de
Low Solubility
Low
Permeability
High Solubility
Amidon et al., Pharm Res 12: 413-420, 1995
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Correlation of in-vitro- and

in-vivo-data
NF XIV (1975) 941: ...in many cases it is

possible to correlate dissolution rates with
biological availability of the active
ingredient.
31
Relationship between BCS

and IVIVC for IR dosage forms
Class
Absorption rate
control
when
IVIVC expected
predicting in vivo
p
performance
from
diss. data
Gastric emptying
Diss.rate < gastric emptying
Yes
II
Dissolution
In vitro diss.rate similar to

in vivo diss.rate
Yes
III
Permeability
absorption is rate
determining and limited or
no correlation
No
IV
Case by case
Limited or no IVIVC
correlation
No
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Gastrointestinal transit
stomach
continues grinding of food antral mill
PYLORUS
1. Propulsion
2. GRINDING
3. Retropulsion
emptying controlled by
pylorus
exclusion size 5-7 mm

large particles only with
p wave
housekeeper
small particles (2mm)
together with grinded
chyme
33
Gastric transit
MMC iin th
the fasted
f t d state
t t (interdigestive)
(i t di
ti )
phase I: 40 - 60 min, no to small activity
phase II: 30 - 45 min some occasional activity
phase III: 5 - 15 strong contractions, housekeeper wave
phase IV: leads to next cycle
MMC in the fed state (postprandial)

one phase with constant peristaltic activity
strong antral activities
pylorus is generally closed but opens to release chyme
office@phast.de
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Impact of drug product

properties
MR dosage forms designed to be robust against

physiological variables
gastrointestinal transit highly relevant
multiparticulates
monoparticulates (size matters)
BCS predictability
di t bilit greater
t for
f IR than
th for
f MR
FASSIF/FESSIF and others of greater significance
for IR
35

testing.but how?
apparatus
media
the BCS
dosage form properties

a qualitative issue
office@phast.de
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Discriminatory power
BA-study
i.e. detection of biorelevant differences
theophylline ER
[mg/ml]
Charge C
Charge A
vivo
Charge B
Zeit [h]
bio study
Zeit [h]
in vivo-dissolution
37
IVIVC: the Swiss Army

Knife in biopharmacy?
IVIVC is a stochastical
relationship!
An existing correlation
includes the proof of
the discriminatory power
but in the correct order
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Disriminatory Power Cont'd

in vitro
pH 6.8
150 rpm
p
[%]
Verification of
rank order
Charge C
Charge A
in vitro
pH 4.5
100 rpm
[%]
Charge B
Charge C
Charge A
Charge B
vivo
Zeit [h]
in vivodissolution
Zeit [h]
39
Discriminatory power a bioequivalence aproach
upper side batch

target profile
lower side batch
bio-study, n=18
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relative bioavailabilities
40
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Relation of in vivo and

in vitro performance
upper side batch

target profile
lower side batch
upper side batch

target profile
lower side batch
bio-study
in vitro study
upper side batch

target
lower side batch?
41
Discriminatory power
a bioequivalence approach, contd
from homomorphic profiles

office@phast.de
to best fitting "side batch"

within the bioequivalence range
42
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PHAST GmbH 2005
Summary
10
9
8
7
vivo [h]
manufacturer risk
shared risk
patient risk
4
3
2
1
0
0
10
vitro [h]
43
Thank
you
office@phast.de
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