Transcript Document

Evaluation of the Critical Process Parameters in Optimization of Formulation Composition Involving Wet Granulation
Feiqian Yu1, Yusheng Fang1, Lei Chen2, Jim Fang2
1. Product Development, TAI HENG Industry Co.,Ltd, No.18 Cao Xi Road(North), Shanghai, P.R.China
2. Product Development, Stason Pharmaceuticals Inc., 11 Morgan, Irvine, CA 92618, USA
INTRODUCTION
RESULTS
Factorial design approach has been approved to be effective
but also time consuming and expensive. Effort of trying to
increasing the efficiency of this approach was presented here
through the granulation study during product development
process of a high drug load (~84%) generic product. The
target is to find out a formulation/process which has
equivalent dissolution profile compared to that of RLD.
Fig 1 HPMC Level Evaluation Study Results
Fig 4 RLD and TH tablet dissolution profiles
RLD and TH tablets dissolution in Water
120
100
Release/%
80
METHODS
60
40
20
Wet granulation approach was chosen due to the physical
property of API and high drug load of this product. Since
this is a IR product, so the binder level in the formulation
is critical to the in-vitro dissolution profile. A 32 full
factorial design (See Table 1) was used to optimize the
binder (HPMC) amount in the formulation. In the
subsequent study, critical wet granulation process
parameters were evaluated through single factor DOE on
the optimized formulation to determine their impact on the
product dissolution profile.
Table 1 Variables in 32 full factorial design
T/min
0
0
RLD In Water
HPMC was added into the formulation through blending process only in Exp, 1, 2 and 3 (when
X1=-1). For all other experiments, HPMC was added into the formulation through different
concentration of granulation fluid (2% when X1=0 and 4% when X1=1).
Fig 2 Effect of Granulation Fluid Amount on Product Dissolution
Effect of different moisture level
Other Process Parameters
120
100
Low
(-1)(%)
Middle (0)
(%)
High
(1) (%)
X1: HPMC concentration in
the granulation fluid
0
2
4
X2: Total HPMC level in the
final formulation
1
Independent variable ,factor
Dependent variable ,response
Release/%
80
Levels used
60
40
20
0
0
20
Low level(0.3g/g)
2.5
40
60
Middle level（0.33g/g)
80
100
High level（0.37g/g）
T/min
Fig 3 Effect of Granulation Time on Product Dissolution
Y=In Vitro Dissolution Release
Effect of different Impeller/Chopper shearing time
Experiment
1
2
3
4
5
Other Process Parameters
X1=-1
X2=-1
-1
0
-1
1
1
0
1
-1
6
7
8
9
X1=1
X2=1
0
1
0
0
0
-1
100
80
Release/%
Design
60
40
20
0
Design
Moisture level：variable
Impeller speed：200rpm
Chopper speed：2000rpm
Impeller/Chopper shearing time：2min
Milling-sieve mesh：20#
Tablet thickness：3.4mm
4
120
Experiment
20
0
20
Shearing time(2min)
40
60
Shearing time(3min)
80
100
T/min
Shearing time(5min)
Moisture level：0.3g/g
Impeller speed：200rpm
Chopper speed：2000rpm
Impeller/Chopper shearing time：variable
Milling-sieve mesh：20#
Tablet thickness：3.4mm
Copyright®2009 Taiheng Industry Co.,Ltd
40
60
80
100
TH In Water
The results shown in figure 1 suggests that the
amount of HPMC in pre-blend is critical to the
dissolution profile of final product. If HPMC is
added
thought
granulation
fluid,
the
concentration of HPMC or amount of HPMC in
the final formulation does not affect the
dissolution profile. Thus water was chosen as
granulation fluid. The effect of the amount of
water used for granulation was also evaluated
and results are shown in figure 2. Similar study
was performed to evaluate the effect of
granulation time on product dissolution (figure
3). Based on all the studies listed above, an
optimized wet granulation process was designed
and product in-vitro dissolution profile was
equivalent to RLD (figure 4).
CONCLUSION
Selectively
choosing
formulation/process
parameters for factorial design will significantly
improve efficiency of product development
process. Critical parameters can be evaluated to
create enough design space for target product
while less critical parameters can be fixed at
reasonable level to simplify the situation.