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

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
Effect of HPMC contribution from preblend with water as granulation fluid
15 0
E x p. 1 (1%)

Fig 4 RLD and TH tablet dissolution profiles
RLD and TH tablets dissolution in Water
120 100 E x p. 8, 2. 5% HP M C

Erffect of HPMC on Dissolution Profile if Added T hrough Granulation Fluid
150 100 50
E x p. 7, 4% HP M C t hr ough 2% s ol ut i on E x p. 4, 2. 5% HP M C t hr ough 4% s ol ut i on R el ease/ %

80 60 40 20 T/ i m n 0 0 20 40 60 80 100

10 0 50 0 0 50 T i m e ( m i n u t e s) 10 0

E x p. 2 (2.5%) E x p. 3 (4%)

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
Levels used Independent variable ,factor X1: HPMC concentration in the granulation fluid X2: Total HPMC level in the final formulation Dependent variable ,response Experiment Design 1 X1=-1 X2=-1 6 X1=1 X2=1 Low (-1)(%) 0 1 Middle (0) (%) 2 2.5 High (1) (%) 4 4

0 0 50 T i m e ( m i n u t e s) 100

t hr ough 2% s ol ut i on E x p. 6, 4% HP M C t hr ough 4% s ol ut i on

RLD In Water

TH 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
120 100 80 R el ease/ % 60 40 20 0 0 20 Low level(0.3g/g) 40 60 80 100 Middle level 0.33g/g) High level 0.37g/g i T/ n m

Other Process Parameters
Moisture level variable Impeller speed 200rpm Chopper speed 2000rpm Impeller/Chopper shearing time Milling-sieve mesh 20# Tablet thickness 3.4mm


Fig 3 Effect of Granulation Time on Product Dissolution
Y=In Vitro Dissolution Release

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).

Effect of different Impeller/Chopper shearing time

Other Process Parameters
Moisture level 0.3g/g Impeller speed 200rpm Chopper speed 2000rpm Impeller/Chopper shearing time variable Milling-sieve mesh 20# Tablet thickness 3.4mm

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.

2 -1

3 -1 1 8

4 1

R el ease/ %

100 80 60 40 20 0 0 20 40 60 80 100

1 -1

Experiment Design








Shearing time(2min)

Shearing time(3min)

T/ i m n Shearing time(5min)

Copyright®2009 Taiheng Industry Co.,Ltd

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