Granulation with Dow Cellulosic Polymers II. High Shear Granulation

The dry binder addition method (see
Table 4) also produced tablets with
excellent hardness overall. The
results were somewhat mixed
concerning which binder level gave
the harder tablets (in 5 of the 9
cases, the tablets at 3% binder were
harder). At the 3% binder
concentration, the hardest tablets
were made with the PVP (K90),
METHOCEL F4P LV, HPC-LF, and
PVP (K29-32) materials. Note that
these are essentially the same
binders and essentially the same
hardness values that were obtained
by the solution addition method. This
was a somewhat surprising result,
since it is generally considered that
binders are more effective when they
are placed in solution prior to the
granulation operation. Similarly, at the
6% level, the best binders were PVP
(K29-32), PVP (K90) ≈ HPC-LF, HPC-
EF, and METHOCEL K3P LV. In
terms of friability, the lowest losses
were predominantly from tablets
containing 3% binders, namely 3%
METHOCEL A15P LV, 3%
METHOCEL F4P LV ≈ 3% and 6%
HPC-EF, and 3% PVP (K90). The
highest friabilities, which were still
less than 0.50%, resulted from the
use of 6% METHOCEL E15P LV
and A15P LV.
The statistical significance of
differences in the two binder addition
methods was examined. Due to the
differences in the formulations, only
comparisons between 3%
solution/3% dry and 6% solution/6%
dry were made. Of the 17 sets of data
(results of the 3% METHOCEL
K3P LV excluded), the dry binder
addition method was statistically
harder in 7 cases: 3% METHOCEL
A15P LV, E15P LV, and F4P LV, 6%
HPC-EF and -LF, 6% PVP (K29-32),
and 3% PVP (K90). The solution
binder addition method produced
8 High Shear Granulation: Acetaminophen Model
statistically harder tablets in 4 cases:
6% METHOCEL A15P LV and
E15P LV, and 3% HPC-EF and -LF.
The remaining 6 cases showed no
statistically significant difference in
hardness between the binder addition
methods.
As mentioned on page 3, the
formulations were compressed at
1000, 2000, and 3000 lbs. total
compression force. For both binder
addition methods, tablet hardness
increased with force with very few
exceptions, those being 6% acacia
(hardness was essentially constant),
10% pregelatinized starch (tablets
compressed at 3000 lbs. were about
5 SCU softer than those compressed
at 2000 lbs.), and the 3% K3P LV
(solution) and 3% PVP (K29-32) (dry)
tablets (which had slightly softer
tablets produced at 3000 lbs.
compression compared to 2000 lbs.
compression). The friabilities were
measured at 2, 4, and 6 minutes at
each force. At a given force, the
percent weight loss naturally
increased with time. At a given time
(e.g., 4 minutes), there was the
expected decrease in friability as the
compression force, and thereby the
tablet hardness increased. There was
a proportionally smaller decrease in
friability between 2000 lbs. and 3000
lbs. than there was between 1000 lbs.
and 2000 lbs. There were a few
cases in which the friability of tablets
compressed at 3000 lbs. was greater
than those compressed at 2000 lbs.
despite the fact that the one
compressed at the higher force had a
higher hardness. One example of this
behavior is 3% PVP (K29-32)
(solution), where the hardness and
friability at 2000 lbs. compression
force were 20.9 SCU and 0.37%,
while the hardness and friability at
3000 lbs. compression force were
21.9 SCU and 0.75%, respectively.
The weight and thickness variation of
the tablets for each formulation and
binder addition method were also
measured (n = 20). The thickness
variation in all cases was excellent,
varying from a low of 0.12% relative
standard deviation (RSD, equal to the
standard deviation/mean x 100) for
the 6% METHOCEL F4P LV (solution
method) formulation, to 0.84% RSD
for the 3% HPC-EF (solution)
formula; the range of thickness
variation for the dry addition method
was 0.18–0.67% RSD. Similarly, the
weight variation was very good for the
majority of the formulations, varying
from 0.47% RSD for the 3%
METHOCEL F4P LV (dry) formula, to
1.39% RSD for the 6% METHOCEL
E15P LV (solution) case. The binders
that performed well in one of the
binder addition methods tended to
perform well in the other addition
method as well.
Tablet Dissolution Properties
The in vitro dissolution properties
varied both as a function of the
nature of the binder and the amount
of binder in the formulation, but
relatively little as a function of the
binder addition method. The USP
dissolution conditions for
acetaminophen tablets were used
(Type 2 apparatus at 50 rpm, 900 mL
of pH 5.8 phosphate buffer). The
time to reach 80% dissolved is
designated by t 80% . A number of
these dissolutions are presented in
Figures 10-18.