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231
dependent
variables
Units
Response
R1
R2
R3
R4
D1
D6
D12
T50
%
%
%
hours
FORMULATION
Dalfampridine matrix tablets were prepared
employing Eudragit RSPO, Eudragit RLPO,
HPMCK100M as matrix former polymers by
direct
compression
technique
using
microcrystalline cellulose (avicel pH 102) as
diluents. All the ingredients were passed through
the sieve no 40 separately and shifted in plastic
bag to attain uniformity.The powder blend was
lubricated with 1% w/w magnesium Stearate
which was previously passed through the sieve no
60. Lubricated blend was then compressed into
tablets of weigh 250 mg using B tooling in a rotary
tablet press [4].
EVALUATION
Precompression parameters:
Angle of Repose, Bulk Density and Tapped
Density, Carrs Compressibility Index (%) &
Hausners Ratio (USP) was calculated by official
standard procedures.
Friability test:
Friability is the loss of weight of tablet in the
container/package, due to removal of fine particles
from the surface. This in-process quality control
test is performed to ensure the ability of tablets to
withstand the shocks during processing, handling,
transportation, and shipment. Roche friabilator
was used to measure the friability of the tablets. It
was rotated at a rate of 25 rpm. Five tablets were
weighed collectively and placed in the chamber of
the friabilator. In the friabilator, the tablets were
exposed to rolling, resulting from free fall of
tablets within the chamber of the friabilator. After
100 rotations (i.e. in 4 minutes), the tablets were
taken out from the friabilator and intact tablets
were again weighed collectively. Permitted
friability limit is 1.0%.
232
Sample preparation:
During the analysis, the 2 ml of blood samples
were centrifuged at 6000rpm at 15 minute to
separate the plasma. 0.5ml of plasma was pipetted
into 2.0 ml centrifuge tube with this 0.5 ml of
precipitating agent (10% Perchloric acid) was
added. The superannuated solution was vortexes
for 5 minutes and centrifuged at 5000 rpm for
7mins and used for the analysis [6].
Analysis of drug concentration in plasma:
Instrumentation:
Isocratic
chromatographic
separation
was
performed on a Shimadzu liquid chromatographic
system equipped with a LC-20AD solvent delivery
system (pump), SPD-20A photo diode array
detector, and SIL-20ACHT injector. All
chromatographic experiments were carried out in
the isocratic mode. The Thermo C18 (250 x 4.6
mm i.d. 5) column was used for the analysis. The
version was used 1.25 with applied for data
collecting and processing (Shimadzu, Japan).
Methanol and Buffer (30:70). Buffer:About 0.92
g/L of octane sulfonic acid sodium salt and 0.77
g/L of ammonium acetate in water. Add 1 mL of
trimethylamine per L of mixture, and adjust with
phosphoric acid to a pH of 4.0. Pass through a
suitable filter in Diluent of 0.45-m pore
size.Detection wavelength: 240 nm.Flow rate: 1.0
ml/min.
Pharmacokinetics parameters:
Based on the drug concentration in the plasma, the
pharmacokinetic parameters like AUC, AUMC,
Cmax, Tmax, t1/2, MRT & clearances were also
evaluated by using PK Solver Version 4.0
software.
RESULT AND DISCUSSION
Design of experiments (DOE) has been used as a
powerful approach to reduce the variation in a
process and, ultimately, to produce high product
yield with good sustained release of drug from the
formulation. Among various design approaches,
the Box-Behnken design was used to optimize and
evaluate main effects, interaction effects and
quadratic effects of the process variables on the
various dissolution time parameters like D1, D6,
D12, T50. This design is suitable for exploring
quadratic response surfaces and constructing
second order polynomial models. The design
consists of replicated centre points and the set of
points lying at the midpoint of each edge of the
multidimensional cube. These designs are
rotatable (or near rotatable) and require 3 levels of
each factor. Seventeen experiments were required
for the response surface methodology based on the
233
F1
Bulk
Density
(gm/mL)
SD*
0.821.1
Tapped
Density
(gm/mL)
SD*
0.9410.2
F2
0.801.4
F3
Compressibility
Index (%)
SD*
Hausner s Angle
of
Ratio
Repose ()
SD*
SD*
13.050.2
1.130.9
25.510.35
0.9360.8
14.5250.4
1.160.4
25.830.78
0.781
0.9350.3
15.9360.8
1.140.3
26.120.91
F4
0.810.7
0.9230.1
12.240.3
1.131.9
26.960.78
F5
0.800.2
0.9250.5
13.400.7
1.150.7
25.250.23
F6
0.810.7
0.9280.9
12.600.4
1.140.5
26.220.59
F7
0.810.9
0.9320.1
13.190.6
1.150.3
26.550.99
1.130.9
25.230.43
Code
F8
0.810.3
0.9290.2
13.240.8
*represents mean + standard deviation (n = 3)
F9
F10
F11
F12
F13
F14
F15
F16
F17
Bulk
Density
(gm/mL)
SD*
0.821.2
0.800.8
0.821.2
0.810.2
0.810.8
0.810.2
0.810.5
0.820.4
0.810.7
Tapped
Density
(gm/mL)
SD*
0.9210.2
0.9260.2
0.9500.1
0.9200.1
0.9250.2
0.9480.5
0.9200.1
0.9340.2
0.9550.3
Compressibility
Index (%)
SD*
Hausner s Angle
of
Ratio
Repose ()
SD*
SD*
14.100.2
14.1420.4
14.9060.8
12.040.3
12.100.4
12.820.2
14.240.2
12.140.4
13.400.7
1.150.4
1.140.2
1.140.4
1.131.2
1.100.5
1.100.5
1.180.3
1.120.5
1.131.9
25.300.15
26.130.48
26.440.40
26.040.70
25.450.43
26.100.41
25.510.79
25.400.13
26.960.78
250.340.0025
8.140.054
4.2460.011
0.0480.008
234
F9
F10
F11
F12
F13
F14
F15
F16
F17
F1
100
F2
F3
80
F4
60
F5
40
F6
F7
20
F8
0
0
10
15
Time in hours
Friability (%)
SD***
0.4100.441
0.500.420
0.120.014
0.1100.023
0.1240.021
0.1420.024
0.4510.424
0.1020.020
0.2010.024
120
F9
Formulation
Code
100
F10
80
F11
60
F12
F13
40
F14
20
F15
0
0
10
Time in hours
15
F16
F17
235
Design-Expert Software
D1
6.00
30
4.00
2.00
0.00
-2.00
-4.00
-6.00
30
32
34
36
38
40
Predicted
Design-Expert Software
D1
6.00
30
Externally Studentized Residuals
4.00
2.00
0.00
-2.00
-4.00
-6.00
11
13
15
17
Run Number
236
Design-Expert Software
Factor Coding: Actual
D1 (%)
Design Points
40
D1 (%)
Design-Expert Software
Factor Coding: Actual
D1 (%)
Design points above predicted value
Design points below predicted value
40
62.5
31
30
30
Actual Factor
C: HPMC = 44.5
40
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
38
Actual Factor
C: HPMC = 44.5
36
34
52.5
34
D1 (%)
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
57.5
32
33
32
30
28
47.5
62.5
35
62.5
57.5
57.5
52.5
52.5
47.5
42.5
47.5
42.5
42.5
37.5 37.5
37.5
37.5
42.5
47.5
52.5
57.5
62.5
Design-Expert Software
D1
40
30
Predicted
38
36
34
32
30
30
32
34
36
38
40
Actual
Sum of
D1=33.176470588235-1.875
*A
Table 7 : Results of Regression Analysis D1
Mean
F
p-value
Source
Squares
df
Square
Value
Prob > F
Model
42.75
14.25
3.73
0.0393
A-Eudragit RSPO
28.12
28.12
7.35
0.0178
B-Eudragit RLPO
4.50
4.50
1.18
0.0978
C-HPMC
10.13
10.13
2.65
0.0277
Residual
49.72
13
3.82
Lack of Fit
46.92
5.21
7.45
0.0344
Pure Error
2.80
0.70
Source
Model
A-Eudragit RSPO
B-Eudragit RLPO
C-HPMC
AB
AC
BC
A2
B2
C2
Residual
Lack of Fit
Pure Error
Source
Model
A-Eudragit RSPO
B-Eudragit RLPO
C-HPMC
AB
AC
BC
A2
B2
C2
Residual
Lack of Fit
Pure Error
significant
significant
significant
significant
significant
significant
238
Research article
Design-Expert Software
D6
D6 (%)
70
68
66
62.5
62.5
57.5
57.5
52.5
52.5
47.5
47.5
42.5
Design-Expert Software
D6
37.5
6.00
69
76
42.5
37.5
78
Predicted
74
72
80
69
76
Actual Factor
C: HPMC = 44.5
78
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
74
4.00
2.00
0.00
-2.00
-4.00
-6.00
68
70
72
74
76
78
80
72
Predicted
70
68
68
70
72
74
76
78
80
Actual
Design-Expert Software
D6
Design-Expert Software
Factor Coding: Actual
D6 (%)
Design Points
78
6.00
69
D6 (%)
62.5
69
4.00
57.5
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
2.00
Actual Factor
C: HPMC = 44.5
0.00
-2.00
52.5
70
72
74
42.5
47.5
74
72
47.5
-4.00
42.5
-6.00
37.5
11
13
15
17
Run Number
37.5
52.5
57.5
62.5
Design-Expert Software
D12
94
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
92
90
Actual Factor
C: HPMC = 44.5
88
D12 (%)
86
84
82
80
78
62.5
62.5
57.5
57.5
52.5
52.5
47.5
47.5
42.5
Design-Expert Software
D12
42.5
37.5
37.5
6.00
81
4.00
2.00
0.00
-2.00
-4.00
-6.00
80
82
84
86
88
90
92
94
Predicted
94
92
81
Design-Expert Software
Factor Coding: Actual
D12 (%)
Design Points
93
Predicted
90
88
86
D12 (%)
62.5
88
81
84
57.5
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
80
80
82
84
86
88
90
92
94
Actual Factor
C: HPMC = 44.5
Actual
Design-Expert Software
D12
6.00
81
4.00
82
52.5
86
82
84
86
47.5
88
2.00
42.5
0.00
90
-2.00
-4.00
37.5
37.5
42.5
47.5
52.5
57.5
62.5
-6.00
11
13
15
17
Source
Model
A-Eudragit RSPO
B-Eudragit RLPO
C-HPMC
AB
AC
BC
A2
B2
C2
Residual
Lack of Fit
Pure Error
Factor
A
B
C
Response
D1
D6
D12
T50
Observed
32.21
78.43
90.64
2.884
RLPO is the hydrophobic nature, hence reduces
surface area and decrease solubilization time. The
effect of Eudragit RLPO on 50% drug leached
depends on its swelling property. The C2
concentration insignificantly affecting rate of
retardation of dissolution rate of sustained release
tablets. The magnitude of coefficient showed that
R2 has more effect than R1 & R3 on dissolution
rate. The response surface plot and contour plot of
effect of Eudragit concentration on T50.
This is a plot of the residuals versus the
experimental run order. A random scatter data
shows no lurking variability during experiment
(Fig 12).
241
Design-Expert Software
Factor Coding: Actual
D6 (%)
Design Points
78
3.2
1.909
D6 (%)
62.5
69
57.5
Predicted
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
2.6
Actual Factor
C: HPMC = 44.5
2.4
2.2
2.8
52.5
70
72
74
42.5
47.5
74
72
47.5
1.8
42.5
1.8
2.2
2.4
2.6
2.8
3.2
Actual
37.5
37.5
Design-Expert Software
T50
52.5
57.5
62.5
6.00
2.14
4.00
2.00
0.00
-2.00
-4.00
-6.00
11
13
15
17
Run Number
78
X1 = A: Eudragit RSPO
X2 = B: Eudragit RLPO
76
Actual Factor
C: HPMC = 44.5
74
D6 (%)
72
70
68
62.5
62.5
57.5
57.5
52.5
52.5
47.5
47.5
42.5
Design-Expert Software
T50
42.5
37.5
37.5
6.00
1.909
4.00
2.00
0.00
-2.00
-4.00
-6.00
2.2
2.4
2.6
2.8
3.2
Predicted
243