Download read the full Application Note (M-2-122B)

as presented by Mark Menning
Amgen Inc.
at Lasentec® Users’ Forum 2001 - Barcelona
This study examined the feasibility of using a Lasentec® D600L (FBRM®
technology) to monitor formulation development processes in which the
in-process particle dynamics are not well characterized or understood. The
goal was to understand the effect of granulation and tableting on granule
and tablet dissolution.
Figure 1 shows the FBRM® mean square weight statistic of two different
tablet disintegrations. Tablet 1, with slow dissolution, has a larger mean
particle size than Tablet 2. As expected, disintegration and breakdown of
primary particles is seen. While these trends show roughly similar amounts
of the coarse particle population in both tablets, Tablet 2 is weighted
toward the finer end, leading to the suspicion that there may be
dependence on mean particle size with dissolution rate.
Counts per measurement (0-14)
Application Notes
Understanding the effect of granulation
and tableting on dissolution
Tablet
Tablet
Tablet
Tablet
1
1
2
2
t=0
25 min; 200 rpm
t=0
25 min; 200 rpm
®
Figure 1: FBRM data shows
disintegration and breakdown of
primary particles
Square weight, microns (0-1000)
Counts per measurement (0-18)
Application Notes
In Figure 2, significant disintegration is not really seen. It is important to note
that this process is agitating at 200 rpm, far faster than the dissolution test
which agitated at 50-75 rpm. The initial and final distributions are pretty
much the same for each granule type. It seems clear that the drug release is
primarily by diffusion. Diffusional release will have a dependence on particle
size.
Granulation
Granulation
Granulation
Granulation
1
1
2
2
t=0
30 min; 200 rpm
t=0
30 min; 200 rpm
Figure 2: Significant
disintegration is not seen - even
at high agitation rates
Square weight, microns (0-1000)
Mean square weight, microns (100-240)
In Figure 3, it looks as if agglomeration is occurring during tableting. In fact,
this was found to be plastic deformation, which may have then sintered into
larger particles. Fragmentation was believed to be occurring during tableting
and more fines were expected in the tablet’s distribution. But it turns out the
opposite is true. Again, it appears the primary release mechanism is by
diffusion, not disintegration.
Granulation 1: Mean Sqr Wt (0-1030)
Granulation 2: Mean Sqr Wt (0-1030)
Tablet 1: Mean Sqr Wt
Tablet 2: Mean Sqr Wt
Figure 3: FBRM®
proves that drug
release is by
diffusion, not
disintegration
Time, minutes (0-35)
By showing both drug release rate dependence on granule size and increase
in granule size after tableting, FBRM® proved to be a valuable tool for
characterizing solid dosage formulation in the development lab.
Mettler-Toledo AutoChem, Inc.
7075 Samuel Morse Drive
Columbia, MD 21046 USA
Tel: +1 410 910 8500
Fax: +1 410 910 8600
Email: [email protected]
M-2-122B Rev F (03/2006) Printed in USA
www.mt.com/lasentec
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