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12/18/2009

1

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

© PHAST GmbH, www.ph ast.de 2

• Setting specifications for disintegration testing



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2

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…


• 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


• 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


Biopharmaceutics

Classification Scheme (BCS)

• solubility of drug

substance under

• permeability of drug

substance in an


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


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


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:


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


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


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


Has a relationship been

determined betweendisintegration and dissolution?



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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


• • dissolution of API particl es

Dissolution - a composite

process

rug mo ecu es

release


• • • •

⌫

•••

• ••• •• •• •

••

⌫ ⌫⌫ ⌫⌫

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%


e ng

Disintegration

Deaggregation

Time

%

0%

USP: fundamentals of dissolution, 2009



A Case Report for a BCS Class I Drug




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• 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


– 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


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


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


• 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


• 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


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


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


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


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


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


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


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

-


, .

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


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


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)


For all immediate release dosage strengths of thatM containing product, the spec’s fordis integration time were set: NMT 5 min



12/18/2009

Thank you


. .

tablets disintegration

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