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12/18/2009
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Establishing a Relationship betweenDisintegration and Dissolution
AAPS: DISSOLUTION WORKSHOPRhodes University, Grahamstown
December 09-10, 2009
Dr. Johannes Krämer
Relationship between
Disintegration and Dissolution....
• The scientific rationale
• The chance to waive dissolution testing: ICH Q6A
• Methods of establishing a relationship
• Results for specimen under investigation
• Extension to complete product line
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• Setting specifications for disintegration testing
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Risk evaluation mandatory
prior to start
• Vital medical indication (e.g. antiepileptic drug)
• Narrow therapeutic index (e.g. Annex to SUPAC IR)
• Extended BCS
– stability in the GI tract
– enterohepatic cycle
– absorption window…
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• Dosage form evaluation – excipients
• ….
Goals of Dissolution Testing
• prediction of changes of bioavailability, the
surrogate-parameter of therapeutic efficacy
• evaluation of robustness as a parameter of drug
product- related safety
critical manufacturing variables
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• in QC (quality control) to prove uniformity ofproduct quality w ithin the technological range
of manufacturing p rocesses
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Prediction of B ioperformance
based on BCS
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Biopharmaceutics
Classification Scheme (BCS)
• solubility of drug
substance under
• permeability of drug
substance in an
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physiolog ical pH-
conditions
isolated segment of
human jejunum at pH
6.5
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BCS - a base to establish specifications
for in vitro dissolution testing
definition of solubility
"high solubility" if dose/solubility volume < 250 ml
highest unit dose of drug is dissolved in buffer solutions atwithin physiolog ical range (pH 1.2 – 8.0) at 37°C. Thequotient of highest unit dose and lowest concentrationobtained in buffer solutions is determined
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e.g.: drug substance x has it’ s lowest solubility at pH 1.2 with1.5 mg/mL.
Tablets are available in dosage strengths 200 and 300 mg.300 mg / 1.5 mg/mL = 200 mL -> high solubili ty drug
Biopharmaceutics Drug
Classification Scheme (BCS) cont’d
solubilit ermeabilit
case 1 high high
case 2 low high
case 3 high low
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case 4 low low
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Dissolution Spec’s …
An IR product is considered rapidly dissolving if
85% of the labeled amount dissolves
within 30 min
Apparatus <1> @ 100/150 or Apparatus <2> @ 50/75 rpm
in 900 mL in each of the follow ing media:
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1) 0.1N HCl or SGF without enzymes and
2) buffer pH 4.5 and
3) buf fer pH 6.8 or SIF without enzymes
Using ICH Q 6A Guideline …
Decision Tree # 7:
1. What type of drug release acceptance criteria are
appropriate?
NOIs the dosage
form designed to producemodified release?
Is drug solubilityat 37 0.5 C high throughout
the physiological pH range?(Dose/solubili ty 250 mL
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p . - .
General single-point dissolution
acceptance criteria with a
lower limit are acceptable YES
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General single-point dissolutionNO
Using ICH Guideline …
lower limit are acceptable
s osage orm
dissolving rapidly?(Dissolution >80%/15min
at pH 1.2, 4.0, and 6.8)
YES General single-point dissolutionacce tance criteria with a
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Has a relationship been
determined between
disintegration and dissolution?
lower limit are acceptable
General d isintegration
acceptance criteria with an
upper time limit are acceptable
Relationship between disintegration
and dissolution
• disintegration in QC is defined as time of completeness of a
kinetic process
• dissolution in QC is amount of completeness at a specifiedtime
• no analogous parameters for a correlation available
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Has a relationship been
determined betweendisintegration and dissolution?
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Relationship between
disintegration and dissolution
prerequisite for dissolution for IR dosage forms
dissolution a composite process
• dissolving from the surface of tablet
• disintegration a surface enlarging process
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• • dissolution of API particl es
Dissolution - a composite
process
rug mo ecu es
release
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• • • •
⌫
•••
• ••• •• •• •
••
⌫ ⌫⌫ ⌫⌫
USP: fundamentals of dissolution, 2009
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Sigmoid Dissolution Curve of
Solid Dosage Forms
Mechanical Lag
+
Occlusion,
instability…
D r u g D i s s o l v e d
100%
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e ng
Disintegration
Deaggregation
Time
%
0%
USP: fundamentals of dissolution, 2009
Relationship between
disintegration and dissolution
A Case Report for a BCS Class I Drug
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Relationship between
disintegration and dissolution
• prove that disintegration is the prerequisite for dissolution
• defining comparable parameters
– i.e. amount dissolved at the time of complete disintegration in
the dissolution apparatus
• comparing analogous parameters fo r
– freshly manufactured batches
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– for samples after accelerated stability treatment – extension to historical data of batches successfully released
• proof of assumpt ion: amount dissolved at the time of
complete disintegration in the disintegration apparatus is
comparable to process analyzed for the dissolution
apparatus
M containing IR products
under investigation
tablet shapespecial*1 special* special* special*1 special*1
*1 *2
*2
C-exci ient/m 1.0 5.0
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per tablet
tablet mass / mg 174 174 174 174 174 174
*1 investigated with dissolution method 1 to 3
*2 investigated with dissolution method 1 only
= round tablet
special = anisodiametric
= round tablet with cross-standing braking notches
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Methods: Dissolution n=12
apparatus <2> <2> <2>
medium pH 1.2 pH 4.5 pH 6.8
medium degassed degassed degassed
volume 500/900 mL 500/900 mL 500/900 mL
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agitation 100 rpm 100 rpm 100 rpm
temperature 37°C 37°C 37°C
sampling
at 5, 10, 15, 20, 25, 30, and 45 min
at the time of complete disintegration
Methods: Disintegration
• with n=12
• use of water
sampling• at the time of complete disintegration
• at a zone validated prior to testing
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• pooled sampling for n=6
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Methods: chemical analysis,
data evaluation
• derivative spectroscopy
data evaluation
• disintegration time
– with regard to dossier / compendial requirements
– usin Statistical Moment Theor
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• dissolution profiles
– with regard to ICH spec’s
– using the Statistical Moment Theory
Statistical Moment Theory:
Mean Times
MDT tM(t)dt / M(t)dtvitro
0 0
=⎡
⎣
⎢⎤
⎦
⎥⎡
⎣
⎢⎤
⎦
⎥
∞ ∞
∫ ∫
M = drug released
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vitro = ean sso u on me n v ro
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Additivity of Mean Times
Mean Times: data reduction taking into account cur tosy and skewness of
distributions.
•The processes are overlapping and therefore, distribut ions do also overlap.
• According to the theory of stat is tical moments the statist ical moments are
adding up
MDT pH 1.2 = MDgT_Dissol1.2 + MDislnT 1.2
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MDT pH 1.2 the mean disso lution time in disso lution apparatus @ pH 1.2
MDgT_Dissol1.2 the mean disin tegration time in dissolution apparatus @
pH 1.2
MDislnT 1.2 the mean terminal dissolution t ime after disin tegration in the
dissolution appartus @ pH 1.2
Results: Solubility
pH 1.2 125 103.1
pH 1.2 250 97.2
pH 4.0 125 106.3
pH 4.0 250 97.0
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pH 6.8 125 100.5
pH 6.8 250 104.3
highest dose is soluble in NMT 250 mL
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Establishing a relationship:
Results BCS
• data prove good solubi lity
Permeability:
• data prove good permeability
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therefore, substance M is a BCS class I compound
Results: Dissolution kinetics
product name/ geometry
pH 5 10 15 20 25 30 45
M / 1.2 102.8 103.1 103.3 102.6 102.4 102.9 102.6
4.5 86.5 90.9 94.3 96.7 96.5 96.8 99.4
6.8 92.3 96.7 98.3 100.2 101.1 100.4 101.9
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1.2 102.8 103.1 103.3 102.6 102.4 102.9 102.6
4.5 86.5 90.9 94.3 96.7 96.5 96.8 99.4
dissolution >> 80% in 30 min and in 15 min
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Results: amount dissolved at
time of disintegration at pH 1.2
index
disintegrationtime dissolution
apparatus [s]
amountdissolved [%]
tabletspro uc name
geometry
M 1.25 / 1 60.0 64.8
2 65.0 89.2
3 60.0 87.5
4 60.0 78.9
5 60.0 91.7
6 60.0 79.0
7 55.0 86.2
in the
dissolution
apparatus
at pH 1.2
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8 55.0 87.8
9 55.0 91.5
10 60.0 98.3
11 65.0 85.7
12 65.0 89.6
Amount dissolved app.<2>pH 1.2, 4.5, and 6.8 vs. disintegrationtime in water (mean, n=12)
40
60
80
100
120
d i s s o l v e d A P I [ % ]
pH 6.8
pH 4.5
pH 1.2
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0
20
0 50 100 150 200 250
Disintegration time [s]
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Findings
• - _ .
6.8.
• This identifies the disintegration method as more variable.
• From the MDgT_Dissol at pH 4.5 and 6.8 it can be
concluded that the disintegration process is the most
-
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, .
6.8 are much less variable.
Summary
Conclusions:• Disintegration is the prerequisite for dissolution
• At the time of complete dis integrat ion a rather constantamount of drug is being dissolved
• This is valid for the dissoluti on apparatus and thedisintegration apparatus
• The sub-processes are overlapping, w ith the help ofstatistical moment theory the sub-processes can be clearly
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escr e
• Disintegration is the most variable sub-process
The relationship of disin tegration and dissolution isa cause and effect relation
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ICH Q6A decision tree #7
criteria are met
No modified release dosage form
Solubility is h igh throughout the physiological range pH 1.2 to 6.8
Dissolution i s rapid and complete. Under all experimentalconditi ons > 80 % in 15 min
No analogous data result form di ssolution and disintegration
No linear stochastical relationship is feasible
A relat ionship of dis in tegrat ion as the rate limiting step fordissolution was described
The f indin s for the dissolution tes ter wereconf irmed for the
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disintegration tester (data not shown) Disintegration was found to be the more variable process
The data generated for actual production lots represent theproperties of the drug p roduct (historical data)
As a consequence:
The dissolution test may be waived for batch release testing for allformulations included in the study
Finally: Setting Specifications
Dissolution testing as a biopharmaceutically
• Disintegration is prerequisite for dissolut ion recommended
for batch release testing
• Comparison of the disintegration results together with thedissolution results for the disintegration apparatus allowstightening of spec’s to 5 min (Ph,Eur. / USP: 15 min)
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For all immediate release dosage strengths of thatM containing product, the spec’s fordis integration time were set: NMT 5 min
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Thank you
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. .