The use of tablet disintegration measurement and modelling in the prediction of in-vitro dissolution performanceDavid WilsonGavin ReynoldsStephen WrenAndrea Moir

Contents

• Introduction- Dissolution – USP approach- Disintegration – USP approach

• Linking disintegration to dissolution- Experimental

• Modelling dissolution from disintegration• Predicting the affect of physical factors on dissolution

- Tablet porosity- API particle size

USP Dissolution

• The act of an API (or any other substance) will go into solution

• A variety of dissolution mediums available, designed to discriminate between in-vivo important factors- Tablet is placed inside a standard dissolution bath (USP II)- Paddle rotates at a specific speed (typically 50-75 RPM)- Concentration of drug in solution measured using HPLC,

UV-VIS or something similar- Only drug content in solution measured – the end result of

wetting, disintegration and dissolution

USP Disintegration

• The extent (rate?) at which a tablet breaks up into smaller pieces

• Standard test, defines disintegration as the time it takes for the last particle of a tablet to fall through a 2 mm square mesh grid (although other grids available)- Mechanically agitated basket- Average of 6 tablets used or time taken for the last tablet to disintegrate- Typically performed at 36 ºC in water although other mediums can be used

Can you use one test to understand the other?

• Can you attribute observed differences in dissolution profiles to measured differences in disintegration time?

• Can we pull apart drug substance phenomena (API particle size, solubility, etc) from formulation phenomena (tablet porosity, formulation components, etc)

• Can you define disintegration in a dissolution bath in the same way as it is measured in the disintegration test?

• What is the mechanism of “dissolution”? Fully wet – fully disintegrated –dissolving particles? Is this a constant for all tablets?

• Which is the limiting factor for dissolution rate?• What are the rates of these phenomena?• How does an “eroding” tablet disintegrate? – You can measure it in a

disintegration apparatus...• What exactly do people meaning by an “eroding” tablet and a

“disintegrating” tablet anyway? How do I conclude which I have and is it important?

Dissolution and Disintegration

• Both tests are a measure of:- Wetting – how quickly the tablet is exposed to the media- Disintegration – the speed and nature of particle release- Dissolution – the speed and nature of API dissolving

• However, they measure different ratios of these phenomena in a different way- Dissolution in the disintegration bath won’t be the same as in the

dissolution media!- Disintegration in the dissolution bath won’t be the same as in the

disintegration test!• Beyond a simple rank order it would be difficult to understand one

test with the other

Case study

• Tablet porosity can be easily manipulated with compression force

• High and low porosity tablets were manufactured as part of a study into the affects of process upon a newly formulated product

• Is compression force important for in-vitro drug release and if so why?

Tablet envelop porosity

0.0

5.0

10.0

15.0

20.0

25.0

003 core 009 core

Poro

sity

(%)

Standard USP disintegration time

0.00

2.00

4.00

6.00

8.00

10.00

12.00

003 core 009 core

Sample

Tim

e (m

inut

es)

Standard USP dissolution profile

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

Time (mins)

% D

isso

lved

core 003core 009

Measuring disintegration during dissolution

• Could observed differences in dissolution be attributed to measured differences in tablet disintegration?

• It was desired to measure the evolution of particle size distributions of entrained particles as a function of time- Measure particle release rate - Measure the size distribution of released particles as a

function of time- Analyse dissolution rate in conjunction with particle release

rate

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

0 10 20 30 40 50 60 7

Time (mins)

Num

ber o

f par

ticle

s en

trai

ned

High porosityLow porosity

y = 0.0214x + 70.897

y = -0.2246x + 89.494

50

55

60

65

70

75

80

85

90

95

100

0 10 20 30 40 50 60 70

D50 (microns)

Time (minutes)

A

B

Experimental Conclusions

• High and low porosities tablets had radically differing particle release rates

• Disintegration time difference is probably and under estimate of the difference between the formulations

• Low porosity tablets may “erode” where as high porosity tablets may “disintegrate”

• Dissolution rate is generally proportional to the number of particles entrained in solution

• Weight distributions produced are slightly different, i.e. the tablets disintegrate into differing things

• Drug particle evolution with time can be tracked

Process Modelling

Potential Disintegration Mechanisms

Insoluble mass

Number of particles

Time

• API particles

• Soluble excipient particles

• Insoluble excipient particles

• Mass balanceTablet

ε

D

0B

• Tablet ‘erosion’

• Particle generation

( ) ( )( ) ( )( ) ( )( )( )thtdtdtVt εεεεεπ−−+−=′ 0020

42

( )3,0

0

aa

taa l

tVxB

φ′

=( )

3,0

,0,

sa

tsese l

tVxB

φ′

=( )

3,0

,0,

ia

tieie l

tVxB

φ′

=

( ) ( ) ( )( ) ( )tmV

tVVxts am

ttaa 3,

0ρφρ −

−=

( )dlnDllB

tn a

aaaa ∂

+−=∂∂

,00δ

( )dln

DllBtn se

sesesese ,

,,,00,

, ∂+−=

∂

∂δ

( )ieieie llBtn

,,00,

, −=∂

∂δ

Modelling Result

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

% D

issol

ved

Time (min)

A (Simulation)B (Simulation)A (Experiment)B (Experiment)

( ) ( )[ ]εε 2

0,0min hdt =

A new parameter: “Time to Complete Disintigration” (TCD) has been defined as the time taken to completely “errode” the shortest dimension of the tablet

Simulated Effect of Change in TDT (porosity)

Fitting – Dissolution Data(Range of tablet compression force/porosity)

24

Experimental data shown by discrete points.

Fitting parameters:• Time to complete disintegration

Fitted Time to Complete Disintegration

25

0

1

2

3

4

5

6

0 5 10 15 20

Tim

e to

Com

plet

e Di

sinte

gatio

n (m

in)

Tablet Porosity (%)

Tablet porosity Vs Compression force

0

2

4

6

8

10

12

14

16

18

20

0 5 10 15 20 25

Tablet Porosity (%)

Compression Force (kN)

Experiment 16

• API particles

• Soluble excipient particles

• Insoluble excipient particles

• Mass balanceTablet

ε

D

0B

• Tablet ‘erosion’

• Particle generation

( ) ( )( ) ( )( ) ( )( )( )thtdtdtVt εεεεεπ−−+−=′ 0020

42

( )3,0

0

aa

taa l

tVxB

φ′

=( )

3,0

,0,

sa

tsese l

tVxB

φ′

=( )

3,0

,0,

ia

tieie l

tVxB

φ′

=

( ) ( ) ( )( ) ( )tmV

tVVxts am

ttaa 3,

0ρφρ −

−=

( )dlnDllB

tn a

aaaa ∂

+−=∂∂

,00δ

( )dln

DllBtn se

sesesese ,

,,,00,

, ∂+−=

∂

∂δ

( )ieieie llBtn

,,00,

, −=∂

∂δ

Simulated time to Q=80%Variation of tablet porosity and API size

28

Conclusions

From tablet disintegration measurements it is possible to understand in-vitro dissolution variance as a function of tablet physical properties

Subsequently the affect of altering tablet physical properties (via processing) on dissolution behaviour can be modelled

This model has been further developed to understand the interplay between tablet porosity, API particle size and dissolution performance

Extra Slides

Implications...

“Disintegration time” not important?

“Disintegration time” important?

Author | 00 Month Year34 Set area descriptor | Sub level 1

35 Author | 00 Month Year Set area descriptor | Sub level 1

Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com