湿法制粒过程粘合剂选择

Introduction
A wide variety of materials have been used as binders for pharmaceutical preparations, including cellulosic polymers.Over the last several years, newer granulation techniques have come to the fore.This, the second in a series of T echnical Data Sheets from Dow, is designed to meet the needs of the pharmaceutical formula-tor in addressing these techniques and the value that METHOCEL* and HPC (hydroxypropyl cellulose) products have as pharmaceutical binders.The data presented here examines the use of a high shear mixer-granulator, in which the binders were applied both from aqueous solutions and by adding the binders to the dry mix followed by granulation with water.
Throughout this series of granulation studies, it is deemed important to provide data not only on the performance of several different METHOCEL and HPC polymers, but to provide side-by-side comparison data for other commonly-used binders.Therefore, information is supplied for granulations prepared with two viscosity grades of povidone (polyvinylpyrrolidone, or PVP), acacia, and a pregelatinized starch. Granulation was performed in a Fuji vertical high shear mixer-granulator, model VG-25P;this model has a 25 L bowl.The charge in each granulation was 4 kg.Granulations were prepared at 3% and 6% binder by weight, with the exception of the pregelatinized starch, which was used only at 10%.The particle size distributions were performed on an
A TM Sonic Sifter.The apparent and tap densities were determined by standard techniques.The formulations were compressed using
0.5 inch diameter standard concave
tooling on an instrumented tablet
press at a series of total compression
forces.Weight and thickness variation
as well as tablet hardness and
friability were also measured by
standard techniques.Finally, tablet
dissolution was recorded using a
system that consisted of a Perkin-
Elmer 3B spectrophotometer, with a
programmable cell changer
containing six flow-through cells and
interfaced with a personal computer,
a multi-channel peristaltic pump, and
a Distek dissolution apparatus.
Applicable USP dissolution testing
conditions were followed, with the
exception that the release of the drug
was followed via continuous flow from
the dissolution apparatus through the
spectrophotometer.
Three model systems were studied.
Acetaminophen was used as an
example of a high-dose, low-solubility
drug;Vitamin C was examined as an
example of a high-dose, high-
solubility drug;and methazolamide
was investigated as an example of a
low-dose, low-solubility drug.While a
detailed discussion is contained
within the section dealing with each
model system, a few general com-
ments can be made here.Cellulosic
polymers such as METHOCEL
methylcellulose (MC) and
hydroxypropyl methylcellulose
(HPMC) and HPC have excellent
binding properties.In some cases,
they both outperform and are more
cost effective than other commonly
used binders.They are familiar
materials, being used in many other
pharmaceutical applications, and
are well known for their excellent
safety and toxicological properties.
Finally, METHOCEL and HPC
products have broad international
regulatory approval.
Model Formulation 1:
Acetaminophen
Composition and Preparation
The acetaminophen formulations
used in this study are given by the
following:
50% Acetaminophen
44.5% Lactose
3.0% Binder
2.0% Disintegrant
0.5% Lubricant
75% Acetaminophen
16.5% Lactose
6.0%Binder
2.0% Disintegrant
0.5% Lubricant
The acetaminophen used was
Mallinckrodt USP powder, having a
purity of 99.9%.The lactose was
Fast-Flo Lactose 316 from Foremost
Whey Products.Ac-Di-Sol crosslinked
sodium carboxymethylcellulose from
FMC was the chosen disintegrant.
Finally, the magnesium stearate
used as a lubricant was supplied
by Whittaker.
A wide variety of binders were
evaluated.As stated above, this was
done not only to determine how each
of the seven METHOCEL and HPC
binders performed in the formulation,
but also to compare their
performance with other commonly-
used granulation binders.The
METHOCEL materials chosen were
among the lowest viscosity products
available in each substitution type.
This was done in order to maximize
the solids loading while still giving a
solution of manageable viscosity in
those experiments where the binder
was placed in solution.It is
recognized that polymer molecular
weight (which is directly related to
1
Granulation with Dow Cellulosic Polymers
II.High Shear Granulation
* *T rademark of The Dow Chemical Company
solution viscosity) can be an important variable in the effectiveness of a binder.The effect of molecular weight will be addressed in subsequent studies.
The METHOCEL polymers used included:METHOCEL A15P L V (15 cps methylcellulose USP); METHOCEL E5P L V and E15P L V (5 and 15 cps hydroxypropyl methylcellulose, USP substitution type 2910);METHOCEL K3P L V
(3 cps hydroxypropyl methylcellulose, USP substitution type 2208);and METHOCEL F4P L V (HPMC USP substitution type 2906).The METHOCEL polymer is in many ways similar to the material identified as METHOCEL F4P L V in Part I, Fluid Bed Granulation.By the USP monographs, MC and HPMC viscosities are reported as those obtained from 2% aqueous solutions, measured in a Ubbelohde (capillary) viscometer at 20°C.
The HPC polymers utilized were the HPC-EF and HPC-LF grades.HPC-EF has a viscosity of 250-750 cps, measured as the viscosity of a 10% aqueous solution at 20°C with a Brookfield viscometer, using the #2 spindle at 30 rpm.The viscosity of HPC-LF is 75-150 cps, measured as a 5% aqueous solution at 20°C, again using the Brookfield viscometer, #2 spindle, and 30 rpm.The povidones used in this study
were USP grades of the K29-32 and
K90 types.
Acacia (gum arabic, spray dried
SDGA/1) was obtained from AEP
Colloids, Inc.The spray dried form is
white to very pale yellow and is in
compacted fragments or whole
spheres.One gram dissolves in 2 ml.
of water, forming a solution which
flows readily and is acidic to litmus.
A pregelatinized starch having a cold-
water soluble fraction of 10 to 20%
was included in the study.This type of
starch is a combination of
approximately 5% amylose, 15%
amylopectin, and 80% unmodified
corn starch, with at least 90% of the
particle weight less than U.S.sieve
size 100.
In all cases except the pregelatinized
starch and the acacia, the binder was
added both as an aqueous solution
and in the dry state (in which the
granulating liquid was simply water).
The powders were charged into the
granulator and premixed for 60
seconds at high chopper speed and
200 rpm main impeller setting to
delump and homogeneously mix the
contents.The binder solution or
simply water was added to the
granulation while the Fugi was
operated at high chopper speed and
200 main impeller speed until a
proper wet mass was achieved.The
resultant wet mass was passed
through a CoMil (Quadro, Inc.)
equipped with a square hole screen
(2A-3750037/63), impeller (2A-1606-
086L) operating at a speed of 2665
rpm.The milled material was placed
on trays and oven dried at 110°F to a
final moisture endpoint of 1-2%.The
moisture analysis was performed on
a Mettler Infrared Drying Unit LP16-M
(Mettler, Inc.).Upon drying, the
granulation was dry sized via the
same CoMil operating at the same
speed setting and equipped with a
round hole grater-type screen
(2A 079G031/23120) and impeller
(2A-1601-173).After dry sizing, the
granulation was placed in a V-blender,
where the lactose and disintegrant
were added and mixed for 10
minutes.Finally, the lubricant was
added, and following an additional 2
minutes of mixing, the final mixture
was compressed at 1000, 2000, and
3000 lbs.total compression force on
an instrumented rotary tablet press.
2High Shear Granulation:Acetaminophen Model
Properties of the Granulation
The complete granulations (including the disintegrant and lubricant) were characterized by a number of simple techniques.The apparent and tap densities of the granulations were determined using simple
weight/volume measurements and a Vanderkamp tap density tester (500taps).From the apparent and tap densities, one can calculate the so-called compressibility index (I) given by the equation
I =
1 –
x 100,
where v a is the apparent density and v t is the tapped density.I can be used as a rough indication of the flow
properties of a material, where I
values of less than 15% are indicative of good flow characteristics, while values above 25% are indicative of poor flow properties.The data for the acetaminophen granulations are presented in T able 1, in the case where the binder was applied from a solution, and in T able 2, where the binder was added in a dry state to the mixer-granulator followed by granulation with water.The densities are in units of g/cm 3.
In this acetaminophen model system, because of composition differences (3% binder/50% drug and 6% binder/75% drug), comparisons are made only between similar binder levels.
For the "solution" method, there were only small differences in the apparent densities between the binders except for the PVP (K90) binder, which
exhibited a little lower density at both the 3% and 6% levels.The values for I varied from 15-25% at the 3% level,and from 12-26% at the 6% level, the highest values in both cases
occurring with the PVP (K90).With the "dry" binder addition method, the densities at both binder
concentrations tended to be very similar to those obtained by the
solution method.The lowest densities and highest I values resulted from the use of PVP (K90) as a binder in this case as well.
3
High Shear Granulation:Acetaminophen Model T able 2
BINDERS DRY
T able 1
BINDERS IN SOLUTION
[ ]v a v t
4High Shear Granulation:Acetaminophen Model
5 High Shear Granulation:Acetaminophen Model
HPC-EF and -LF are depicted in
Figures 4 and 5, respectively.The
HPC-EF and HPC-LF showed fairly
similar particle size distributions.PVP
(K29-32) (Figure 6) and PVP (K90)
(Figure 7) also exhibited somewhat
similar PSD profiles.The K29-32
grade shows a slightly greater
amount of material retained on the 40
mesh.Figure 8 is a comparison of the cellulosic polymer, METHOCEL
A15P L V, and pregelatinized starch.
The METHOCEL product produced substantially more 20 and 40 mesh
granules than the pregelatinized
starch.Finally, Figure 9 shows the
PSD of acacia and METHOCEL
A15P L V at 6%.The acacia produced
a PSD that was comparable to the
cellulosic binders.This distribution
was very different from the extremely
fine granulation obtained when acacia
was used in fluid bed granulation.
6High Shear Granulation:Acetaminophen Model
Tablet Physical Properties
The hardness and friability of the 0.5inch tablets compressed at 2000 lbs.total compression force are given in T ables 3 and 4.For both
measurements, 20 tablets were used;the reported friabilities are those after 4 minutes in a Roche-type friabilator.Examining the data of T able 3, it is clear that good, hard tablets were produced, with the exception of those compressed from the acacia
granulations;acacia has again been shown to be a relatively poor binder for this formulation.In most cases, the tablets with 3% binder were harder than those with 6% binder;this is most likely due to the differences in the formulations and the inherent incompressiblity of acetaminophen.The exceptions to this observation were the METHOCEL E15P L V and PVP (K90) binders.At the 3% level,the hardest tablets were made from HPC-EF and -LF granulations, from the povidone granulations, and from the METHOCEL K3P L V granulation.Similarly, at the 6% level, the hardest tablets were those resulting from
granulations prepared with the PVPs,METHOCEL K3P L V , and HPC-LF .
Overall, very good friabilities were achieved by the solution addition
method.The binders giving the lowest friability tablets were 3% HPC-EF , 3%METHOCEL E5P L V , 3% HPC-LF ,and 3% METHOCEL F4P L V .(Note that these all were formulations
containing 50% acetaminophen.) The tablets with the highest friability were the 6% acacia and 10%
pregelatinized starch, which both capped.T ablets containing 6%
METHOCEL E15P L V , which had a friability of only 0.50%, were the most friable of those that did not cap.
7
High Shear Granulation:Acetaminophen Model T able 3
BINDERS IN SOLUTION
T able 4
BINDERS DRY
The dry binder addition method (see T able 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 L V, 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 L V.In terms of friability, the lowest losses were predominantly from tablets containing 3% binders, namely 3% METHOCEL A15P L V, 3% METHOCEL F4P L V ≈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 L V and A15P L V.
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 L V excluded), the dry binder addition method was statistically harder in 7 cases:3% METHOCEL
A15P L V, E15P L V, and F4P L V, 6% HPC-EF and -LF, 6% PVP (K29-32), and 3% PVP (K90).The solution binder addition method produced statistically harder tablets in 4 cases:
6% METHOCEL A15P L V and
E15P L V, 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 L V
(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 pression
force were 20.9 SCU and 0.37%,
while the hardness and friability at
3000 pression 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 L V (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 L V (dry) formula, to
1.39% RSD for the 6% METHOCEL
E15P L V (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
(T ype 2 apparatus at 50 rpm, 900 mL
of pH 5.8 phosphate buffer).The
time to reach 80% dissolved is
designated by t80%.A number of
these dissolutions are presented in
Figures 10-18.
8High Shear Granulation:Acetaminophen Model
9 High Shear Granulation:Acetaminophen Model
The METHOCEL products are
compared in Figures 10-13.Figure 10 (solution binder addition method, 3%
level) shows that the polymers all
have t80%of about 20 minutes with
the exception of METHOCEL
E15P L V, which had a t80%of
approximately 7 minutes longer, but
which still passed the USP criteria.
The dry binder addition method
(Figure 11) shows more
differentiation.METHOCEL E5P L V
clearly was the fastest with a
dissolution time of 15 minutes;
METHOCEL A15P L V and F4P L V
were next, with about the same time
as was observed with the solution
addition method.METHOCEL
E15P L V was just 2-3 minutes slower
than the solution method, with a t80%
right at the USP limit.(The
dissolution results for the
METHOCEL K3P L V product were anomolous and are not included
pending repetition of the granulation.) Increasing the binder content to 6%
resulted in the typical lengthening of
the time for dissolution.In Figure 12,
the curve for METHOCEL A15P L V is
virtually unchanged from the 3%
solution case.However, the remaining METHOCEL products are shifted to
longer times, with METHOCEL
F4P L V, E5P L V, and E15P L V all at
t80%≈35 minutes, and with
METHOCEL K3P L V at nearly 45
minutes.In the dry binder addition
case (Figure 13), slightly different
profiles were obtained.METHOCEL
A15P L V, E5P L V, and F4P L V form
one group with t80%≈25 minutes,
while METHOCEL E15P L V and
K3P L V both have t80% greater than
the USP limit, but with different
curve shapes.
10High Shear Granulation:Acetaminophen Model
The remaining figures in this section are comparisons of METHOCEL polymers with the HPC polymers, with the PVP products, and with acacia and pregelatinized starch. Figure 14 illustrates that using the dry addition method at 3% results in virtually no difference between the two viscosity grades of HPC, both having 80% drug dissolution in 25 minutes.If the same binders at the same level utilized the "solution" method, the HPC-LF gave the same release profile, while the HPC-EF gave a slightly longer (t80%of 31 minutes) profile.T urning to the 6% level, Figure 15 shows the results of the solution method, with the HPC-EF and HPC-LF curves indistinguishable and with the time for 80% release at the USP ing the dry addition method was not different in terms of the release profile for HPC-LF, but once again the EF grade had a slightly longer release with t80%≈
32 minutes.
Figures 16 and 17 compare two METHOCEL products with polyvinylpyrrolidone.The dry method at 3% (Fig.16) shows that METHOCEL E5P L V and PVP
(K29-32) are equivalent in dissolution behavior, with the K90 grade just slightly longer but well within the specified time period.The solution addition method gave results essentially the same.T urning to the 6% level (Fig.17), METHOCEL A15P L V and PVP (K29-32) are practically equivalent, with the K90 polymer again slightly longer, now just within the ing the dry method at the 6% binder level produced dissolution curves where the METHOCEL A15P L V was just slightly longer than the PVP (K90) and which was at the 30 minute stly, a comparison of acacia, a
pregelatinized starch, and
METHOCEL A15P L V is illustrated in
Figure 18.Here it appears that the
derivatized starch is also acting as a
disintegrant, giving the fastest drug
release of all the binders evaluated.
Acacia, despite giving quite soft and
very friable tablets, nevertheless gave
a somewhat unexpectedly long time
for drug dissolution.
Conclusions:Acetaminophen
Model Formulation
Granulations with acceptable
densities and particle size
distributions were obtained when 2
acetaminophen formulations having
3% and 6% binder levels were
prepared in a high shear mixer-
granulator.There were only minor
differences in these properties
between granulations prepared by
adding the binder as an aqueous
solution or by adding the binder in a
dry state to the active followed by
granulation with water.The cellulosic
polymers (METHOCEL and HPC
products) tended to give granulations
with a higher proportion of granules
of 20-60 mesh, whereas the PVP
binders produced somewhat more
material in the 80-140 mesh region.
With the given milling conditions,
about 10% fines (<140 mesh) were
produced.Both binder addition
methods and both binder levels
produced granulations that
compressed well, giving tablets of
good hardness and low friability (all ≤
0.50%).In 76% of the cases, the dry
binder addition method led to tablets
that were statistically either harder
than or equivalent to the solution
addition method.The binders that
consistently gave tablets of the
highest hardness and lowest friability
were the HPC products, the PVP
products, METHOCEL K3P L V, and
METHOCEL F4P L V.Acacia and
pregelatinized starch were not
particularly effective binders.In terms
of tablet dissolution, the differences
were again rather small between the
addition methods.The pregelatinized
starch gave a very rapid drug release,
but the tablet physicals were poor, as
noted above.Of the cellulosic
binders, METHOCEL E5P L V
produced tablets with the most rapid
drug release at the 3% level, while
METHOCEL A15P L V produced the
most rapid release at the 6% level.
The PVP (K29-32) polymer gave
good drug release, with t80%
essentially equivalent to the
performance of METHOCEL E5P L V
and A15P L V at the 3% and 6%
levels, respectively.Considering all
the factors, the binders
recommended for the formulation
containing 3% binder are
METHOCEL E5P L V (using the dry
binder addition method), PVP
(K29-32) grade, and the HPC
products.For the formulation
containing 6% binder, the
recommended polymers are
METHOCEL A15P L V and PVP
(K29-32) grade.It must certainly be
emphasized that these
recommendations apply only to the
particular formulations tested;factors
such as granulating conditions, milling
conditions, disintegrant type, and
disintegrant location could have major
effects on the overall performance of
the dosage form.
11
High Shear Granulation:Acetaminophen Model
Model Formulation 2:Vitamin C Composition and Preparation In this section of the study, the following formulations were used:
75% Vitamin
C
19.5% Lactose
3.0% Binder
2.0% Disintegrant
0.5% Lubricant
75% Vitamin
C
16.5% Lactose
6.0% Binder
2.0% Disintegrant
0.5% Lubricant
Note that these formulations are identical with those used in the earlier fluid bed study.The formulation at 6% binder is identical with the acetaminophen model presented in the previous section except for the active ingredient;this will facilitate comparisons on the effects of the drug on the relative performance of the various binders.Here, Roche fine powder was utilized;all of the remaining components were the same as described on page 1.
The same binders were evaluated as described on pages 1 and 2.The processing of the Vitamin C formulations was different from that used in the acetaminophen formulations.In this case, the active and the lactose (and the binder in those experiments where the binder was not placed in solution) were placed in the Fuji and mixed for 60 seconds at 200 rpm, chopper speed high.The granulating liquid was then added by means of the attached funnel, and mixing was continued at 200 rpm, chopper speed high until a proper wet mass was achieved.The resultant wet mass was discharged and wet milled in a CoMil (model
197S) using a square hole screen
(2A-3750037/63) and an impeller
(2A-1607-086L) at 2665 rpm.This
combination of screen and impeller
worked very well for wet milling for all
binders with the exception of PVP
(K90), which had very poor wet
milling properties.After tray drying at
110°F overnight to a moisture content
of < 1%, the granulations were then
dry milled with the CoMil using a
round hole grater-type screen
(2A-079G031/23120) and impeller
(2A-1601-173), again at 2665 rpm.
The disintegrant and lubricant were
added to the Vitamin C granulations
in a twin shelled blender and mixed
for 2 minutes.The complete mixtures
then were compressed at 1000,
2000, and 3000 lbs.total
compression force.
Properties of the Granulation
The apparent and tap densities and
the compressibility indices I of the
Vitamin C granulations were
determined using the procedures
described on page 3, and are given
in T ables 5 and 6.As in T ables 1 and
2, the apparent and tapped densities
are in g/cm3.
In this model system using the Fuji
VG-25P, the densities increased as
the binder level was increased from
3% to 6%.For the granulations
produced with the METHOCEL and
the HPC products, the increase was
small.However, the PVP binders
(especially the K29-32 grade) showed
a slightly greater increase in density
with an increase in binder
concentration.Once again, this
behavior can be understood by
examining the particle size
distributions that are presented in the
figures that paring the
results where the binder was
prehydrated with those where it was
not shows that in the large majority of
cases, higher densities were obtained
by the "dry" binder addition method;
there was no trend in the I values.
Finally, note that for the comparable
6% binder levels, the compressibility
indices for Vitamin C granulations are
smaller (i.e., indicative of better flow)
than those obtained for the
acetaminophen granulations.It was
observed during tablet compression
that the Vitamin C granulations had
very good flow behavior.
Particle size distributions (PSD),
determined as described on page 4,
are given in Figures 19-27.The
figures show results for both of the
binder addition methods.Figure 19
compares granule sizes with 3% and
6% METHOCEL A15P L V.Increasing
the amount of binder gives small
increases in the quantity of material
≤60 mesh, but a decrease in the
amount of 40 mesh material.The 6%
binder level (solution) gave the finest
overall PSD.Granulation with
METHOCEL E5P L V (Figure 20)
shows a PSD that is typical of
virtually all of the other binders
tested.Increasing the amount of
binder gave an increase in granules
on 20 mesh, little change at 40 mesh
and < 140 mesh, and small
decreases in all other fractions.The
amount of material 80-140 mesh is
quite small.For the most part, the
binder addition method had relatively
little effect on the PSD at both the 3%
and 6% levels.This general pattern
was true for METHOCEL E15P L V,
METHOCEL F4P L V, METHOCEL
K3P L V (Figure 21), HPC-EF, HPC-
LF (Figure 22), and PVP (K29-32).
In Figure 23, it is seen that the PVP
(K90) granulations of Vitamin C
followed a somewhat different pattern
than the other binders just described.
With this binder, there was less
material on the 40 mesh screen,
somewhat more material on 80 mesh,
12High Shear Granulation:Vitamin C Model。