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FUNCTIONALITY IMPROVEMENT OF GEMFIBROZIL FORMULATIONS BY QbD APPROACH- A Research Article by Amit Mukharya & Shivang Chaudhary

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Die fill problem is encountered in production batches if the flow of the blend is not optimum. The flow of the blend is related to the particle level properties of API, grades of excipients utilized & characteristics of granules formed. The aim of this Research work was to formulate solid oral dosage form of Gemfibrozil, an anti-hyperlipoproteinemic agent. Gemfibrozil is a waxy, fluffy, crystalline, hydrophobic material having very high daily dose of 600 mg that creates lots of flow related issues, because more than 75% part of formulation involves only gemfibrozil API as such. In QbD approach; Product and process characteristics important for desired performance must be derived from combination of prior knowledge and experimental assessment during product development, which is required to achieve objectives of Quality by Design (QbD). Thus, from prior knowledge of API characteristics and experimental data, a multivariate response surface model linking product and process measurements and desired attribute(angle of repose within the desired range of 28.0◦-32.0◦) was constructed & flow was optimized. To conclude, flow of waxy gemfibrozil blend was mainly improved by addition & optimization of intra & extragranular role of colloidal silicone dioxide, selecting microcrystalline cellulose of sufficient higher particle size and by producing granules of sufficient strength with optimized binder level & optimized parameters of high- shear wet granulation process. In addition, Since the major portion of the tablet was gemfibrozil, the role of particle characteristics of API itself & particle characteristics of granules was also investigated.
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Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.
International Journal of Contemporary Research and Review
Functionality Improvement of Gemfibrozil Formulations by QbD Approach

Mukharya A1*, Mulay A1, Chaudhary S1, Mansuri N1, Misra AK1
1Formulation Development Department, Cadila Pharmaceuticals Limited, 1389, Trasad Road, Dholka, Ahmedabad, India.


Abstract
Die fill problem is encountered in production batches if the flow of the blend is not optimum. The flow of the blend is related to
the characteristics of granules. The aim of this study was to formulate solid dosage form of gemfibrozil. Gemfibrozil is a waxy,
crystalline, hydrophobic material that results in prolongation of disintegration time during storage in stability studies. Because of
the fluffy nature of API flow problem was also encountered. Product and process characteristics important to desired performance
must be derived from combination of prior knowledge and experimental assessment during product development, which is re-
quired to achieve objectives of Quality by Design (QbD). From prior knowledge and experimental data, a multivariate model link-
ing product and process measurements and desired attributes was constructed. Flow of gemfibrozil blend was improved by addi-
tion of colloidal silicone dioxide, selecting microcrystalline cellulose of higher particle size and by producing granules of suffi-
cient strength. Since the major portion of the tablet was gemfibrozil, the role of particle characteristics was also investigated.

Key words: Gemfibrozil; Quality by design; Hydrophobicity; Disintegration time; Die fill problem.


Introduction

The flow properties of powders are im-
* Ejection cam, where the tablet is and prolongation of disintegration time
portant in manufacturing operations of
ejected from the die
on stability conditions (400C 20C &
solid dosage forms. Flow properties af-

75% 5%RH).
fect mixing, granulation, drying, milling
Single station presses are mostly used in
Good pharmaceutical quality represents
and compaction [1], [2]. Powder flow is
research and development; while rotary
an acceptably low risk of failing to
determined by a combination of (i) presses are used for high volume pro-
achieve desired clinical attributes. Quali-
powder characteristics, such as particle
duction (i.e. hundreds of thousands of
ty by Design (QbD) means that product
size, size distribution, shape, packing, tablets per hour). Die fill on rotary and process performance characteristics
density and surface properties and (ii)
presses is more complex. Gemfibrozil
are significantly designed to meet specif-
operating conditions, such as moisture,
{5-(2, 5-dimethylphenoxy)-2, 2-
ic objectives, not merely empirically
temperature, static charge and aeration.
dimethylpentanoicacid}is an antihyper-
derived from performance of test
The final properties of the tablets depend
lipo- proteinemic agent. It belongs to a
batches.
on the choice of ingredients used in the
group of drugs known as fibrates[5].
The aim of the present research work
powder formulation, the details of the
Gemfibrozil increases the activity of was to achieve the desired disintegration
mixing, agglomeration processes and extrahepatic lipoprotein lipase (LL), time of tablets and to overcome die fill
selection of process parameters applied
thereby increasing lipoprotein triglyce-
problem during compression so that
on the tabletting equipment. On com-
ride lipolysis. The typical daily dose of
gemfibrozil tablets can be manufactured
mercial scale, tablets are mass produced
gemfibrozil (API) is high, two capsules
on commercial scale.
using high speed rotary presses. The of 300 mg or a single compressed tablet

central part of a rotary press is the turret
of 600 mg [6].
Materials and Methods
(or die table) which is equipped with a
Gemfibrozil is a crystalline active phar-
Materials
number of tool stations consisting of maceutical ingredient (API) with melt-
Gemfibrozil USP was purchased from
upper punch-die-lower punch assem-
ing point in the range of 61C to 63C. It
Symed Labs Limited, Hyderabad, India.
blies. As the die table rotates each sta-
has very poor solubility in water. This is
Colloidal Silicon Dioxide (SiO2) USNF
tion passes successively through the fol-
particularly true in highly acidic medium

lowing mechanisms [3], [4]
*Corresponding Author: Amit Mukharya
:
(such as is encountered in the stomach)
Formulation Development Department, Cadila
* Feed frame, where the powder is intro-
since its apparent pKa is 4.7[7]. During
Pharmaceuticals Limited,
duced into the die
formulation development of gemfibrozil
Email Id: amit.mukharya@cadilapharma.co.in
* Compression rollers, where the powder
tablets two problems were noticed, first
International Journal of Contemporary
is compressed into a tablet
was the die fill issue during compression
Research and Review

1
December, 2010|Volume 01|Issue 07|


Available Online at www.ijcrrmds.info.
Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.
(Cabot Sanmar Limited, India), Klucel
tle stirring (to avoid foaming). In rapid
spray gun, keeping bed temperature not
LF (HPC- LF USP) was supplied by mixer granulator (Rimek, India) gemfi-
more than 400C. Core tablets were
Aqualon Hercules, USA. Pregelatinized
brozil, colloidal silicon dioxide, pregela-
coated till 2.0% - 3.0% of weight gain
Starch USP (Starch 1500) from Color-
tinized starch 1500, croscarmellose so-
(877.0 mg - 886.0 mg) was achieved.
con Asia Pvt. Ltd., India. Microcrystal-
dium and microcrystalline cellulose PH-

line Cellulose USPNF (Avicel PH 101)
101 were mixed for 10 minutes at 75
Selection and optimization of factors
from FMC Biopolymer, India. Croscar-
RPM speed of impeller. This mixture affecting flow property of gemfibrozil
mellose Sodium USP from Prachin was granulated with binder solution. The
by QbD approach
Chemicals, India. Polysorbate 80 NF granules were dried in fluidized bed Quality by design (QbD) refers to the
was supplied by Croda Chemicals, India.
dryer (Retsch, Germany) at 400C not
achievement of certain predictable quali-
Microcrystalline Cellulose USPNF more than 1.0 % w/w loss on drying ty with desired and predetermined speci-
(Avicel PH 200) from FMC Biopolymer,
(LOD) was achieved, when checked in
fications. A very useful component of
India. Calcium Stearate USNF from halogen moisture balance (Sartorius AG,
the QbD is the understanding of factors
Komal Pharmaceuticals, India. Opadry Germany) at 500C for 5 minutes. The
and their interaction effects by a desired
White IH from Colorcon Asia Pvt. Ltd.,
dried granules were mixed with extra-
set of experiments.
India.
granular part (croscarmellose sodium,
In present investigation, independent

colloidal silicon dioxide, microcrystal-
significant factors [intragranular SiO2
Experimental Methods
line cellulose PH-200 and calcium stea-
(A) & extragranular SiO2 (B)] affecting
Preparation of core tablets
rate) in double cone blender (Rimek, dependent factor (angle of repose) were
Gemfibrozil tablets were prepared by
India) at 10 RPM for 10 minutes. The
first extracted out by means of ANOVA
wet granulation method. Briefly, API
blend was ready to be compressed. Fi-
and then extracted factors were opti-
and Hydroxy propyl cellulose (HPC)-LF
nally, tablets were compressed using mized by 32 Full factorial experimental
were sifted separately using 20# sieve,
19.3 mm x 9.5 mm ellipsoidal punches
design. Mathematical modeling and Re-
while colloidal silicon dioxide, pregela-
within the hardness range of 80 N to 120
sponse Surface Methodology (RSM)
tinized starch 1500, croscarmellose so-
N. The average weight of the com-
were performed by employing Design-
dium and microcrystalline cellulose PH-
pressed tablets was 860 mg.
Expert(R) software (Version 8.0.0.2, Stat-
101 & PH-200 were passed separately
Film coating
Ease Inc., Minneapolis, MN). Table I
through 40# and calcium stearate
Coating solution was prepared by dis-
summarizes the independent and depen-
through 100#. The binder solution was
persing 10 gm of Opadry(R) white in to
dent variables along with their coded and
prepared by addition of HPC-LF into
90 gm of purified water under stirring
actual levels.
purified water with gentle stirring to for 45 minutes to form homogeneous Total 9 experimental testing runs were
form homogeneous viscous solution. dispersion. Tablets were coated in Gans-
carried out as enlisted in Table II (from
Polysorbate 80 was added to it with gen-
coater (Gansons, Ltd. India) using single
formulation A to I).



Table I. Independent and dependent variables along with their coded and actual values


Factors (Indepen-
Levels used
Response ( Dependent variable)

dent variables)




-1
0
+1


A
Intragranular SiO2
8
10
12
Angle of repose

B
Extragranular SiO
17
15
13
2


Statistical analysis of the data and
sponse surface graphs were constructed
calculated from predicted equation of
validation of the model
using the same software.
Angle of repose (AR) were:
RSM computation for the current opti-
A numerical optimization technique us-
A= intragranular SiO2 of 8.0 mg
mization study was performed employ-
ing the desirability approach was em-
B = extragranular SiO2 of 17.0 mg
ing Design Expert software. Polynomial
ployed to develop a new formulation
A final formulation "I" corresponding to
models including interaction (A*B) and
with the desired responses. In this study
the predicted amount of Extragranular
quadratic terms (A2 or B2) were generat-
optimization was performed with con-
SiO2 and Intragranular SiO2 was carried
ed for the response variable using Mul-
straints for Angle of Repose (AR), (28.0
out to determine the validity of the mod-
tiple Linear Regression Analysis

< AR < 32.0 ) set as goals to locate the
el generated. Subsequently, the resultant
(MLRA) approach. Statistical validity of
optimum settings of the independent actual experimental data of the response
the polynomials (A and B) was estab-
variables in the new formulation. The properties were quantitatively compared
lished on the basis of ANOVA provision
optimal parameters to achieve predicted
with those of the predicted valus.
in the Design Expert software. 3-D re-
flow property (angle of repose=30) as

2
December, 2010|Volume 01|Issue 07|


Available Online at www.ijcrrmds.info.
Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.



Tablet Formulations (mg/tab)
Ingredients

Category
A
B
C
D
E
F
G
H
I
Intragranular



Gemfibrozil
API
603.19*
API Charac-
teristics
Crystal-
Crystal-
Anti-
Agglomerate (Fluffy)
Agglomerate (Fluffy)
(Appear-
line
line
lipidic
ance/
agent
Bulk density
0.28
0.45
0.45
0.28
0.28
0.28
0.28
in g/ml)
Anticak-
Colloidal
ing agent/
silicon dio-
12
10.0
10.0
10.0
8
8
8
Disinte-
xide
grant
Hydroxy-
propyl cellu-
Binder
16
16
8
16
lose
Cros carmel-
Disinte-
35
35
12
NA
24
lose sodium
grant
Pregelati-
Disinte-
nized
grant/
N.A.
136.95
93.81
65.81
43
43
21
starch1500
Binder
MCC 101
Diluent
132.81
121.81
130.8
NA
NA
25
NA
20
Polysorbate
Surfactant
6
80
Methyl para-
Preserva-
0.77
ben
tive
Propyl para-
Preserva-
0.086
ben
tive
Purified wa-
Vehicle
q.s.
ter
Extragranular

Pregelati-
Disinte-
nized
grant/
NA
NA
25
NA
starch1500
Binder
Cros carmel-
Disinte-
10
15
5
NA
15
lose sodium
grant
Colloidal
silicon dio-
Glident
13
13
13
15
15
15
17
17
17
xide
Microcrys-
Disinte-
talline cellu-
38.0
29.0
38.0
65.0
NA
105.81
105.81
grant
lose 200
Calcium
Lubricant
6.0
10
Stearate
Microcrys-
Diluent/
talline cellu-
Disinte-
NA
59
59
106.81
NA
lose 112
grant
Total weight

860
Coating

Opadray

17.2
white
Total weight

880
*Based on potency calculation



3
December, 2010|Volume 01|Issue 07|


Available Online at www.ijcrrmds.info.
Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.
Evaluation of tablet characteristics
observed to be between 250 to 300, Good
as a super disintegrant in formulation
100 tablets from each batch were col-
between 310 to 350, Fair (360 - 400)1 [8].
"E", and the blend was compressed.
lected and their weight variation, Hard-
Flow property of Formulation "A", "B"
Formulation "E" tablets passed the phys-
ness, Drug content uniformity, Disinte-
and "C" was very poor and not suitable
ical parameter limits when compressed
gration time and Friability were studied
for further processing. Formulation "D"
at 5 rpm turret speed, but when the same
using the USP 31 methods [8].
(Table II) was prepared without using
tablets were compressed at 15 rpm,

disintegrant. Formulation "D" showed weight variation problem was observed.
Results and Discussion
initial disintegration time (DT) as 8 mi-
There was a die fill problem due to poor
Table II. Composition of the nine dif-
nutes that prolonged to 20 minutes after
flow of granules (angle of repose 400),
ferent formulations of gemfibrozil tab-
1 month stability studies at 40C /75 %
slight sticking was also observed (Table
lets
RH. To overcome the DT related prob-
III).
As per USP 31, the flow of blend is con-
lem, croscarmellose sodium was added

sidered as excellent if angle of repose is

Table III. Physical parameters of different tablet formulations of gemfibrozil
Batch number
E
F
G
H
I
Hardness (N)
90-120
DT (min)
3
4
4
4
3
Friability (%)
0.5
0.3
0.6
0.1
0.12
Granules analysis
Bulk density
0.45
0.4
0.4
0.41
0.42
Taped density
0.58
0.5
0.5
0.49
0.51
C.I
22.41
20
20
16.32
17.64
H.R.
1.3
1.25
1.25
1.19
1.2
Angle of repose
39
38
36
35
30
Die fill problem
Yes
Yes
Yes
Yes
No
PSD(% retained)
20#
13
5
6
2
16
40#
23
28
25
19
26
60#
8
17
11
19
18
80#
5
6
5
13
12
Below 80#
50
43
47
48
32

In formulation "F" microcrystalline cel-
rpm due to poor flow of granules (angle
half from 5% to 2.5% for tablets. In this
lulose 101 (particle size~ 100 m) was
of repose was 360).
case the tablets were compressed at 15
added intragranularly that resulted in
In formulation "H" MCC200 (because of
rpm to 20 rpm and all the tablet parame-
formation of better granules. The propor-
its larger granules size -180 m, hence
ters such as hardness, compressibility
tion of colloidal silicon dioxide was also
better flow) was used extragranularly
and sieve analysis data were found satis-
modified to provide better flow by re-
and major portion of aerosil was added
factory. The angle of repose was 300
ducing intergranular friction. As com-
extragranularly. In this case also die fill
which is classified as excellent flow.
pared to granules of formulation `E', problem was observed at 15rpm due to

granules of formulation `F' exhibited poor flow of granules (angle of repose
Evaluation of factors affecting flow
more or less similar flow characteristics
was 420).
property of Gemfibrozil by RSM
(angle of repose = 380).
The above mentioned formulations indi-
From Response Surface graph, It was
In formulation "G" microcrystalline
cated that due to waxy nature of the illustrated that as the amount of extra-
cellulose (MCC) was removed from in-
gemfibrozil, the formed granules were
granular colloidal Silicone dioxide in-
tra-granular portion and was added to soft and hence created air pockets during
creases and intra-granular silicone dio-
extra-granular portion as MCC 112 (be-
its movement from hopper to turret and
xide angle of repose of blend decreases,
cause of its larger granules size- 100 m,
further to die cavity. To improve the so ultimately flow property of blend
hence better flow) while the amount of
strength of granules the proportion of increases. From Response Surface Mod-
pregelatinized starch1500 was reduced binder was increased in the formulation
el (RSM) predicted angle of repose :
from 7.55% to 5%. During compression
"I". Additionally, MCC101 was added
Predicted AR (Angle of repose) =
problem of die fill was observed at 15
intragranularly while the amount of pre-
+34.14+1.35-3.17B.....equation (1)
gelatinized starch 1500 was reduced to

4
December, 2010|Volume 01|Issue 07|


Available Online at www.ijcrrmds.info.
Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.
Where A= intragranular amount of
factor represent the effect of that particu-
Positive sign in front of the terms indi-
SiO2
lar factor while the coefficients with cates synergistic effect while negative
B= extragranular amount of SiO2
more than one factor and those with sec-
sign indicates antagonistic effect of the
The equation (1) represents the quantita-
ond order terms represent the interaction
factors.
tive effect of factors (A & B) upon the
between those factors and the quadratic
response (DR). Coefficients with one nature of the phenomena, respectively.



































Figure 1. Response surface model of Gemfibrozil formulation

When final formulation "I" correspond-
angle of repose was found to be 29.8,
compared with those of the predicted
ing to the predicted amount of extragra-
which was within the desired range of
values, then they also matched with the
nular SiO2 (17mg) and intra-granular
28.0-32.0. Subsequently, when other predicted values of angle of repose,
SiO2 (8 mg) was carried out to determine
resultant actual experimental data of the
which suggested that model was vali-
the validity of the model generated, the
response properties were quantitatively
dated.

Crystallographic study of Gemfibrozil API in different formulations

Table IV. XRD data of gemfibrozil API
S.N.
2 Theta
d spacings
Peak Height
B.N.
209
709
209
709
209
709
1
11.5430 11.5494 7.66636 7.66208 19465 30028
2
24.2084 12.7279 3.67655 6.95519 16305 25357
3
11.8967 11.9171 7.43920 7.42650 12675 18969
4
18.2717 13.8596 4.85551 6.38971
9979
15458
5
13.8370 16.6643 6.40009 5.32006
8429
15275
6
17.3850 24.2101 5.10111 3.67629
7046
14661


5
December, 2010|Volume 01|Issue 07|


Available Online at www.ijcrrmds.info.
Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.
Gemfibrozil is a waxy material, belongs
longing to different batch numbers. The
formulation "F" silicone dioxide was
to BCS class II. It offers dissolution re-
crystals are abundant and platy (tessel-
added to reduce interparticlulate friction
lated problem and process related prob-
late) in nature. Generally two types of
and static charge development between
lem such as die filling problem during
particles are observed in pharmaceutical
gemfibrozil particles. In formulation "G"
compression that results in weight varia-
formulations. The first group is tessellate
MCC 112 (bigger particle size~ 100 m)
tion during compression. Fig. g 209 and
and another one that cannot tessellate. In
while in "H" MCC 200 (particle size ~
g 709 show microscopic plates of gem-
principle, tessellate particles could com-
180 m) was used along with some pro-
fibrozil API. In API batch of g 209 al-
pletely fill the die (such as monosized
portional changes in silicone dioxide. To
though API looks crystalline in nature
rectangular and hexagonal particles). It
some extent die fill problem was re-
but the crystals are very small and of
is found that the former generally has a
solved but granules were not strong
irregular shape. Some agglomerates lower flowability than the latter (9, 10).
enough to bear the compression force,
were also observed. In Fig. g 709 API
As shown in Table II, in formulation hence amount of binder was increased
gemfibrozil is depicted in Figure II. It is
"D" and "E" g 709 API was used while
along with some formulation changes. In
crystalline in nature. From the XRD in F, G, H and I g 209 API. Formulation
the final blend of formulation "I" the
study (Table IV) it is evident that there
F, G, H and I showed better flow proper-
granules were free flowing, hence die fill
are significant differences in APIs be-
ties as compared to "D" and "E". In problem was overcome.




















Figure II. Photomicrographs of Gemfibrozil API (g 209 & g 709) and its blend at magnification 20X.



Conclusions
investigated. Generally it is difficult to
a material with low bulk density and low
The flow related problems during com-
compress the fluffy material because of
melting point. In present study, the flow
pression at commercial scale have been
its low bulk density. Gemfibrozil is also
related issue during compression was

6
December, 2010|Volume 01|Issue 07|


Available Online at www.ijcrrmds.info.
Research Mukharya A et al.: Functionality Improvement of Gemfibrozil Formulations by QbD Approach
ISSN 0976 - 4852
(c) 2010, IJCRR, All Rights Reserved.
resolved by formulation development.
F&D, for his prompt help whenever re-
flow of powder into a confined
Concerning statistical analysis related to
quired.
space, Mechanics of Materials. 2006;
QbD approach, it was shown that 32 full

38: 304-324.
factorial experimental design and opti-
References
5. http://en.wikipedia.org/wiki/Gemfibr
mization technique can be successfully
1. Schneider LCR, Sinka IC, Cocks
ozil; access date April 28, 2010.
in the development of proper formula-
ACF, Characterisation of the flow 6. http://www.rxlist.com/script/main/src
tion of gemfibrozil without creating die
behaviour of pharmaceutical powd-
hcont_rxlist.asp?src=gemfibrozil;
fill problem and having sufficient gra-
ers using a model die-shoe filling
access date May 17, 2010.
nule strength. The microscopic characte-
system, Powder Technol. 2007;
7. Huanga Q, Wanga J, Chena G, Shena
ristics are also important factor in this
173: 59-71.
Z, Chena J, Yunb J, Micronization
study because the API was approx 70 %
2. Sinka IC, Schneider LCR., Cocks
of gemfibrozil by reactive precipita-
of the total tablet weight. In future the
ACF, Measurement of the flow prop-
tion process, Int. J. Pharm. 2008;
drugs having similar such characteristics
erties of powders with special refer-
360: 58-64.
(drug content more than 70 %, fluffy-
ence to die fill, Int. J. Pharm. 2004;
8. United States Pharmacopeia 31 NF
low bulk density, low melting point) can
280: 27-38.
26, Vol. I, 639-640.
be manufacture successfully on com-
3. Sinka IC, Motazedian F, Cocks
9. Wu CY, Cocks ACF, Flow beha-
mercial scale by this approach.
ACF., Pitt KG, The effect of
viour of powders during die filling,

processing parameters on pharma-
Powder Metallurgy. 2004; 47: 127-
Acknowledgement
ceutical tablet properties, Powder
136.
Authors are thankful to Mr. Jayant Pa-
Technol. 2009; 189: 276-284.
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Pharm. 2002; 244: 45-57.




7
December, 2010|Volume 01|Issue 07|


Document Outline

  • Selection and optimization of factors affecting flow property of gemfibrozil by QbD approach
  • Quality by design (QbD) refers to the achievement of certain predictable quality with desired and predetermined specifications. A very useful component of the QbD is the understanding of factors and their interaction effects by a desired set of experi...
  • From Response Surface graph, It was illustrated that as the amount of extragranular colloidal Silicone dioxide increases and intra-granular silicone dioxide angle of repose of blend decreases, so ultimately flow property of blend increases. From Res...

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